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Slide 1 - Special Thanks to… For sponsorship of LMEF programs: Supported by an educational grant from Lilly USA, LLC Did you know that you could be receiving credit for attending today? For membership information, please visit our website: www.Lafmeded.org.
Slide 2 - Special Thanks to… For sponsorship of LMEF programs: Supported by an educational grant from Lilly USA, LLC Did you know that you could be receiving credit for attending today? For membership information, please visit our website: www.Lafmeded.org. Multiple Myeloma 2010 Wael Harb MD Horizon Oncology Center
Slide 3 - Special Thanks to… For sponsorship of LMEF programs: Supported by an educational grant from Lilly USA, LLC Did you know that you could be receiving credit for attending today? For membership information, please visit our website: www.Lafmeded.org. Multiple Myeloma 2010 Wael Harb MD Horizon Oncology Center Overview Introduction: epidemiology, clinical presentation, diagnosis, staging Autologous stem cell transplantation Initial approaches to treatment Current options Novel agents and combinations Considerations in non-transplantation-eligible patients Prevention of skeletal complications
Slide 4 - Special Thanks to… For sponsorship of LMEF programs: Supported by an educational grant from Lilly USA, LLC Did you know that you could be receiving credit for attending today? For membership information, please visit our website: www.Lafmeded.org. Multiple Myeloma 2010 Wael Harb MD Horizon Oncology Center Overview Introduction: epidemiology, clinical presentation, diagnosis, staging Autologous stem cell transplantation Initial approaches to treatment Current options Novel agents and combinations Considerations in non-transplantation-eligible patients Prevention of skeletal complications What is MM? Multiple myeloma (MM) is characterized by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin.
Slide 5 - Special Thanks to… For sponsorship of LMEF programs: Supported by an educational grant from Lilly USA, LLC Did you know that you could be receiving credit for attending today? For membership information, please visit our website: www.Lafmeded.org. Multiple Myeloma 2010 Wael Harb MD Horizon Oncology Center Overview Introduction: epidemiology, clinical presentation, diagnosis, staging Autologous stem cell transplantation Initial approaches to treatment Current options Novel agents and combinations Considerations in non-transplantation-eligible patients Prevention of skeletal complications What is MM? Multiple myeloma (MM) is characterized by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. Plasma Cell
Slide 6 - Special Thanks to… For sponsorship of LMEF programs: Supported by an educational grant from Lilly USA, LLC Did you know that you could be receiving credit for attending today? For membership information, please visit our website: www.Lafmeded.org. Multiple Myeloma 2010 Wael Harb MD Horizon Oncology Center Overview Introduction: epidemiology, clinical presentation, diagnosis, staging Autologous stem cell transplantation Initial approaches to treatment Current options Novel agents and combinations Considerations in non-transplantation-eligible patients Prevention of skeletal complications What is MM? Multiple myeloma (MM) is characterized by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. Plasma Cell Multiple Myeloma: Incidence The lifetime risk of getting MM is 1 in 159 (0.63%). 20,180 new cases will be diagnosed in 2010 (11,170 in men and 9,010 in women) 10,650 deaths are expected to occur in 2010 (5,760 in men and 4,890 in women) The 5-year relative survival rate for MM is around 35%
Slide 7 - Special Thanks to… For sponsorship of LMEF programs: Supported by an educational grant from Lilly USA, LLC Did you know that you could be receiving credit for attending today? For membership information, please visit our website: www.Lafmeded.org. Multiple Myeloma 2010 Wael Harb MD Horizon Oncology Center Overview Introduction: epidemiology, clinical presentation, diagnosis, staging Autologous stem cell transplantation Initial approaches to treatment Current options Novel agents and combinations Considerations in non-transplantation-eligible patients Prevention of skeletal complications What is MM? Multiple myeloma (MM) is characterized by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. Plasma Cell Multiple Myeloma: Incidence The lifetime risk of getting MM is 1 in 159 (0.63%). 20,180 new cases will be diagnosed in 2010 (11,170 in men and 9,010 in women) 10,650 deaths are expected to occur in 2010 (5,760 in men and 4,890 in women) The 5-year relative survival rate for MM is around 35% Incidence MM occurs in all races and all geographic locations African Americans and blacks from Africa is two to three times the risk in whites Risk is lower in Asians from Japan and in Mexicans Slightly more frequent in men than in women (1.4:1)
Slide 8 - Special Thanks to… For sponsorship of LMEF programs: Supported by an educational grant from Lilly USA, LLC Did you know that you could be receiving credit for attending today? For membership information, please visit our website: www.Lafmeded.org. Multiple Myeloma 2010 Wael Harb MD Horizon Oncology Center Overview Introduction: epidemiology, clinical presentation, diagnosis, staging Autologous stem cell transplantation Initial approaches to treatment Current options Novel agents and combinations Considerations in non-transplantation-eligible patients Prevention of skeletal complications What is MM? Multiple myeloma (MM) is characterized by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. Plasma Cell Multiple Myeloma: Incidence The lifetime risk of getting MM is 1 in 159 (0.63%). 20,180 new cases will be diagnosed in 2010 (11,170 in men and 9,010 in women) 10,650 deaths are expected to occur in 2010 (5,760 in men and 4,890 in women) The 5-year relative survival rate for MM is around 35% Incidence MM occurs in all races and all geographic locations African Americans and blacks from Africa is two to three times the risk in whites Risk is lower in Asians from Japan and in Mexicans Slightly more frequent in men than in women (1.4:1) Age MM is a disease of older adults The median age at diagnosis is 66 years Only 10 percent of patients are younger than 50 years Only 2 percent of patients are younger than 40 years
Slide 9 - Special Thanks to… For sponsorship of LMEF programs: Supported by an educational grant from Lilly USA, LLC Did you know that you could be receiving credit for attending today? For membership information, please visit our website: www.Lafmeded.org. Multiple Myeloma 2010 Wael Harb MD Horizon Oncology Center Overview Introduction: epidemiology, clinical presentation, diagnosis, staging Autologous stem cell transplantation Initial approaches to treatment Current options Novel agents and combinations Considerations in non-transplantation-eligible patients Prevention of skeletal complications What is MM? Multiple myeloma (MM) is characterized by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. Plasma Cell Multiple Myeloma: Incidence The lifetime risk of getting MM is 1 in 159 (0.63%). 20,180 new cases will be diagnosed in 2010 (11,170 in men and 9,010 in women) 10,650 deaths are expected to occur in 2010 (5,760 in men and 4,890 in women) The 5-year relative survival rate for MM is around 35% Incidence MM occurs in all races and all geographic locations African Americans and blacks from Africa is two to three times the risk in whites Risk is lower in Asians from Japan and in Mexicans Slightly more frequent in men than in women (1.4:1) Age MM is a disease of older adults The median age at diagnosis is 66 years Only 10 percent of patients are younger than 50 years Only 2 percent of patients are younger than 40 years
Slide 10 - Special Thanks to… For sponsorship of LMEF programs: Supported by an educational grant from Lilly USA, LLC Did you know that you could be receiving credit for attending today? For membership information, please visit our website: www.Lafmeded.org. Multiple Myeloma 2010 Wael Harb MD Horizon Oncology Center Overview Introduction: epidemiology, clinical presentation, diagnosis, staging Autologous stem cell transplantation Initial approaches to treatment Current options Novel agents and combinations Considerations in non-transplantation-eligible patients Prevention of skeletal complications What is MM? Multiple myeloma (MM) is characterized by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. Plasma Cell Multiple Myeloma: Incidence The lifetime risk of getting MM is 1 in 159 (0.63%). 20,180 new cases will be diagnosed in 2010 (11,170 in men and 9,010 in women) 10,650 deaths are expected to occur in 2010 (5,760 in men and 4,890 in women) The 5-year relative survival rate for MM is around 35% Incidence MM occurs in all races and all geographic locations African Americans and blacks from Africa is two to three times the risk in whites Risk is lower in Asians from Japan and in Mexicans Slightly more frequent in men than in women (1.4:1) Age MM is a disease of older adults The median age at diagnosis is 66 years Only 10 percent of patients are younger than 50 years Only 2 percent of patients are younger than 40 years MM: Clinical Presentations Anemia - 73 percent Bone pain - 58 percent Elevated creatinine - 48 percent Fatigue/generalized weakness - 32 percent Hypercalcemia- 28 percent Weight loss - 24 percent, one-half of whom had lost ≥ 9 kg
Slide 11 - Special Thanks to… For sponsorship of LMEF programs: Supported by an educational grant from Lilly USA, LLC Did you know that you could be receiving credit for attending today? For membership information, please visit our website: www.Lafmeded.org. Multiple Myeloma 2010 Wael Harb MD Horizon Oncology Center Overview Introduction: epidemiology, clinical presentation, diagnosis, staging Autologous stem cell transplantation Initial approaches to treatment Current options Novel agents and combinations Considerations in non-transplantation-eligible patients Prevention of skeletal complications What is MM? Multiple myeloma (MM) is characterized by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. Plasma Cell Multiple Myeloma: Incidence The lifetime risk of getting MM is 1 in 159 (0.63%). 20,180 new cases will be diagnosed in 2010 (11,170 in men and 9,010 in women) 10,650 deaths are expected to occur in 2010 (5,760 in men and 4,890 in women) The 5-year relative survival rate for MM is around 35% Incidence MM occurs in all races and all geographic locations African Americans and blacks from Africa is two to three times the risk in whites Risk is lower in Asians from Japan and in Mexicans Slightly more frequent in men than in women (1.4:1) Age MM is a disease of older adults The median age at diagnosis is 66 years Only 10 percent of patients are younger than 50 years Only 2 percent of patients are younger than 40 years MM: Clinical Presentations Anemia - 73 percent Bone pain - 58 percent Elevated creatinine - 48 percent Fatigue/generalized weakness - 32 percent Hypercalcemia- 28 percent Weight loss - 24 percent, one-half of whom had lost ≥ 9 kg Multiple Myeloma = M-CRAB Monoclonal protein Calcium Renal failure Anemia Bone pain with lytic lesions
Slide 12 - Special Thanks to… For sponsorship of LMEF programs: Supported by an educational grant from Lilly USA, LLC Did you know that you could be receiving credit for attending today? For membership information, please visit our website: www.Lafmeded.org. Multiple Myeloma 2010 Wael Harb MD Horizon Oncology Center Overview Introduction: epidemiology, clinical presentation, diagnosis, staging Autologous stem cell transplantation Initial approaches to treatment Current options Novel agents and combinations Considerations in non-transplantation-eligible patients Prevention of skeletal complications What is MM? Multiple myeloma (MM) is characterized by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. Plasma Cell Multiple Myeloma: Incidence The lifetime risk of getting MM is 1 in 159 (0.63%). 20,180 new cases will be diagnosed in 2010 (11,170 in men and 9,010 in women) 10,650 deaths are expected to occur in 2010 (5,760 in men and 4,890 in women) The 5-year relative survival rate for MM is around 35% Incidence MM occurs in all races and all geographic locations African Americans and blacks from Africa is two to three times the risk in whites Risk is lower in Asians from Japan and in Mexicans Slightly more frequent in men than in women (1.4:1) Age MM is a disease of older adults The median age at diagnosis is 66 years Only 10 percent of patients are younger than 50 years Only 2 percent of patients are younger than 40 years MM: Clinical Presentations Anemia - 73 percent Bone pain - 58 percent Elevated creatinine - 48 percent Fatigue/generalized weakness - 32 percent Hypercalcemia- 28 percent Weight loss - 24 percent, one-half of whom had lost ≥ 9 kg Multiple Myeloma = M-CRAB Monoclonal protein Calcium Renal failure Anemia Bone pain with lytic lesions Immunoglobulin
Slide 13 - Special Thanks to… For sponsorship of LMEF programs: Supported by an educational grant from Lilly USA, LLC Did you know that you could be receiving credit for attending today? For membership information, please visit our website: www.Lafmeded.org. Multiple Myeloma 2010 Wael Harb MD Horizon Oncology Center Overview Introduction: epidemiology, clinical presentation, diagnosis, staging Autologous stem cell transplantation Initial approaches to treatment Current options Novel agents and combinations Considerations in non-transplantation-eligible patients Prevention of skeletal complications What is MM? Multiple myeloma (MM) is characterized by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. Plasma Cell Multiple Myeloma: Incidence The lifetime risk of getting MM is 1 in 159 (0.63%). 20,180 new cases will be diagnosed in 2010 (11,170 in men and 9,010 in women) 10,650 deaths are expected to occur in 2010 (5,760 in men and 4,890 in women) The 5-year relative survival rate for MM is around 35% Incidence MM occurs in all races and all geographic locations African Americans and blacks from Africa is two to three times the risk in whites Risk is lower in Asians from Japan and in Mexicans Slightly more frequent in men than in women (1.4:1) Age MM is a disease of older adults The median age at diagnosis is 66 years Only 10 percent of patients are younger than 50 years Only 2 percent of patients are younger than 40 years MM: Clinical Presentations Anemia - 73 percent Bone pain - 58 percent Elevated creatinine - 48 percent Fatigue/generalized weakness - 32 percent Hypercalcemia- 28 percent Weight loss - 24 percent, one-half of whom had lost ≥ 9 kg Multiple Myeloma = M-CRAB Monoclonal protein Calcium Renal failure Anemia Bone pain with lytic lesions Immunoglobulin Immunoglobulins
Slide 14 - Special Thanks to… For sponsorship of LMEF programs: Supported by an educational grant from Lilly USA, LLC Did you know that you could be receiving credit for attending today? For membership information, please visit our website: www.Lafmeded.org. Multiple Myeloma 2010 Wael Harb MD Horizon Oncology Center Overview Introduction: epidemiology, clinical presentation, diagnosis, staging Autologous stem cell transplantation Initial approaches to treatment Current options Novel agents and combinations Considerations in non-transplantation-eligible patients Prevention of skeletal complications What is MM? Multiple myeloma (MM) is characterized by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. Plasma Cell Multiple Myeloma: Incidence The lifetime risk of getting MM is 1 in 159 (0.63%). 20,180 new cases will be diagnosed in 2010 (11,170 in men and 9,010 in women) 10,650 deaths are expected to occur in 2010 (5,760 in men and 4,890 in women) The 5-year relative survival rate for MM is around 35% Incidence MM occurs in all races and all geographic locations African Americans and blacks from Africa is two to three times the risk in whites Risk is lower in Asians from Japan and in Mexicans Slightly more frequent in men than in women (1.4:1) Age MM is a disease of older adults The median age at diagnosis is 66 years Only 10 percent of patients are younger than 50 years Only 2 percent of patients are younger than 40 years MM: Clinical Presentations Anemia - 73 percent Bone pain - 58 percent Elevated creatinine - 48 percent Fatigue/generalized weakness - 32 percent Hypercalcemia- 28 percent Weight loss - 24 percent, one-half of whom had lost ≥ 9 kg Multiple Myeloma = M-CRAB Monoclonal protein Calcium Renal failure Anemia Bone pain with lytic lesions Immunoglobulin Immunoglobulins SPEP: Normal
Slide 15 - Special Thanks to… For sponsorship of LMEF programs: Supported by an educational grant from Lilly USA, LLC Did you know that you could be receiving credit for attending today? For membership information, please visit our website: www.Lafmeded.org. Multiple Myeloma 2010 Wael Harb MD Horizon Oncology Center Overview Introduction: epidemiology, clinical presentation, diagnosis, staging Autologous stem cell transplantation Initial approaches to treatment Current options Novel agents and combinations Considerations in non-transplantation-eligible patients Prevention of skeletal complications What is MM? Multiple myeloma (MM) is characterized by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. Plasma Cell Multiple Myeloma: Incidence The lifetime risk of getting MM is 1 in 159 (0.63%). 20,180 new cases will be diagnosed in 2010 (11,170 in men and 9,010 in women) 10,650 deaths are expected to occur in 2010 (5,760 in men and 4,890 in women) The 5-year relative survival rate for MM is around 35% Incidence MM occurs in all races and all geographic locations African Americans and blacks from Africa is two to three times the risk in whites Risk is lower in Asians from Japan and in Mexicans Slightly more frequent in men than in women (1.4:1) Age MM is a disease of older adults The median age at diagnosis is 66 years Only 10 percent of patients are younger than 50 years Only 2 percent of patients are younger than 40 years MM: Clinical Presentations Anemia - 73 percent Bone pain - 58 percent Elevated creatinine - 48 percent Fatigue/generalized weakness - 32 percent Hypercalcemia- 28 percent Weight loss - 24 percent, one-half of whom had lost ≥ 9 kg Multiple Myeloma = M-CRAB Monoclonal protein Calcium Renal failure Anemia Bone pain with lytic lesions Immunoglobulin Immunoglobulins SPEP: Normal SPEP: M-protein, M-spike
Slide 16 - Special Thanks to… For sponsorship of LMEF programs: Supported by an educational grant from Lilly USA, LLC Did you know that you could be receiving credit for attending today? For membership information, please visit our website: www.Lafmeded.org. Multiple Myeloma 2010 Wael Harb MD Horizon Oncology Center Overview Introduction: epidemiology, clinical presentation, diagnosis, staging Autologous stem cell transplantation Initial approaches to treatment Current options Novel agents and combinations Considerations in non-transplantation-eligible patients Prevention of skeletal complications What is MM? Multiple myeloma (MM) is characterized by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. Plasma Cell Multiple Myeloma: Incidence The lifetime risk of getting MM is 1 in 159 (0.63%). 20,180 new cases will be diagnosed in 2010 (11,170 in men and 9,010 in women) 10,650 deaths are expected to occur in 2010 (5,760 in men and 4,890 in women) The 5-year relative survival rate for MM is around 35% Incidence MM occurs in all races and all geographic locations African Americans and blacks from Africa is two to three times the risk in whites Risk is lower in Asians from Japan and in Mexicans Slightly more frequent in men than in women (1.4:1) Age MM is a disease of older adults The median age at diagnosis is 66 years Only 10 percent of patients are younger than 50 years Only 2 percent of patients are younger than 40 years MM: Clinical Presentations Anemia - 73 percent Bone pain - 58 percent Elevated creatinine - 48 percent Fatigue/generalized weakness - 32 percent Hypercalcemia- 28 percent Weight loss - 24 percent, one-half of whom had lost ≥ 9 kg Multiple Myeloma = M-CRAB Monoclonal protein Calcium Renal failure Anemia Bone pain with lytic lesions Immunoglobulin Immunoglobulins SPEP: Normal SPEP: M-protein, M-spike Renal Failure Cast nephropathy (also called myeloma kidney) from light chains Hypercalcemia Light chain amyloidosis Drug-induced renal damage
Slide 17 - Special Thanks to… For sponsorship of LMEF programs: Supported by an educational grant from Lilly USA, LLC Did you know that you could be receiving credit for attending today? For membership information, please visit our website: www.Lafmeded.org. Multiple Myeloma 2010 Wael Harb MD Horizon Oncology Center Overview Introduction: epidemiology, clinical presentation, diagnosis, staging Autologous stem cell transplantation Initial approaches to treatment Current options Novel agents and combinations Considerations in non-transplantation-eligible patients Prevention of skeletal complications What is MM? Multiple myeloma (MM) is characterized by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. Plasma Cell Multiple Myeloma: Incidence The lifetime risk of getting MM is 1 in 159 (0.63%). 20,180 new cases will be diagnosed in 2010 (11,170 in men and 9,010 in women) 10,650 deaths are expected to occur in 2010 (5,760 in men and 4,890 in women) The 5-year relative survival rate for MM is around 35% Incidence MM occurs in all races and all geographic locations African Americans and blacks from Africa is two to three times the risk in whites Risk is lower in Asians from Japan and in Mexicans Slightly more frequent in men than in women (1.4:1) Age MM is a disease of older adults The median age at diagnosis is 66 years Only 10 percent of patients are younger than 50 years Only 2 percent of patients are younger than 40 years MM: Clinical Presentations Anemia - 73 percent Bone pain - 58 percent Elevated creatinine - 48 percent Fatigue/generalized weakness - 32 percent Hypercalcemia- 28 percent Weight loss - 24 percent, one-half of whom had lost ≥ 9 kg Multiple Myeloma = M-CRAB Monoclonal protein Calcium Renal failure Anemia Bone pain with lytic lesions Immunoglobulin Immunoglobulins SPEP: Normal SPEP: M-protein, M-spike Renal Failure Cast nephropathy (also called myeloma kidney) from light chains Hypercalcemia Light chain amyloidosis Drug-induced renal damage Anemia Normocytic, normochromic anemiais present in 73% at diagnosis and in 97%at some time during the course of the disease This anemia can be related to: Bone marrow replacement Kidney damage Dilution in the case of a large M-protein B12 deficiency in 14%
Slide 18 - Special Thanks to… For sponsorship of LMEF programs: Supported by an educational grant from Lilly USA, LLC Did you know that you could be receiving credit for attending today? For membership information, please visit our website: www.Lafmeded.org. Multiple Myeloma 2010 Wael Harb MD Horizon Oncology Center Overview Introduction: epidemiology, clinical presentation, diagnosis, staging Autologous stem cell transplantation Initial approaches to treatment Current options Novel agents and combinations Considerations in non-transplantation-eligible patients Prevention of skeletal complications What is MM? Multiple myeloma (MM) is characterized by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. Plasma Cell Multiple Myeloma: Incidence The lifetime risk of getting MM is 1 in 159 (0.63%). 20,180 new cases will be diagnosed in 2010 (11,170 in men and 9,010 in women) 10,650 deaths are expected to occur in 2010 (5,760 in men and 4,890 in women) The 5-year relative survival rate for MM is around 35% Incidence MM occurs in all races and all geographic locations African Americans and blacks from Africa is two to three times the risk in whites Risk is lower in Asians from Japan and in Mexicans Slightly more frequent in men than in women (1.4:1) Age MM is a disease of older adults The median age at diagnosis is 66 years Only 10 percent of patients are younger than 50 years Only 2 percent of patients are younger than 40 years MM: Clinical Presentations Anemia - 73 percent Bone pain - 58 percent Elevated creatinine - 48 percent Fatigue/generalized weakness - 32 percent Hypercalcemia- 28 percent Weight loss - 24 percent, one-half of whom had lost ≥ 9 kg Multiple Myeloma = M-CRAB Monoclonal protein Calcium Renal failure Anemia Bone pain with lytic lesions Immunoglobulin Immunoglobulins SPEP: Normal SPEP: M-protein, M-spike Renal Failure Cast nephropathy (also called myeloma kidney) from light chains Hypercalcemia Light chain amyloidosis Drug-induced renal damage Anemia Normocytic, normochromic anemiais present in 73% at diagnosis and in 97%at some time during the course of the disease This anemia can be related to: Bone marrow replacement Kidney damage Dilution in the case of a large M-protein B12 deficiency in 14% Rouleaux Formation
Slide 19 - Special Thanks to… For sponsorship of LMEF programs: Supported by an educational grant from Lilly USA, LLC Did you know that you could be receiving credit for attending today? For membership information, please visit our website: www.Lafmeded.org. Multiple Myeloma 2010 Wael Harb MD Horizon Oncology Center Overview Introduction: epidemiology, clinical presentation, diagnosis, staging Autologous stem cell transplantation Initial approaches to treatment Current options Novel agents and combinations Considerations in non-transplantation-eligible patients Prevention of skeletal complications What is MM? Multiple myeloma (MM) is characterized by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. Plasma Cell Multiple Myeloma: Incidence The lifetime risk of getting MM is 1 in 159 (0.63%). 20,180 new cases will be diagnosed in 2010 (11,170 in men and 9,010 in women) 10,650 deaths are expected to occur in 2010 (5,760 in men and 4,890 in women) The 5-year relative survival rate for MM is around 35% Incidence MM occurs in all races and all geographic locations African Americans and blacks from Africa is two to three times the risk in whites Risk is lower in Asians from Japan and in Mexicans Slightly more frequent in men than in women (1.4:1) Age MM is a disease of older adults The median age at diagnosis is 66 years Only 10 percent of patients are younger than 50 years Only 2 percent of patients are younger than 40 years MM: Clinical Presentations Anemia - 73 percent Bone pain - 58 percent Elevated creatinine - 48 percent Fatigue/generalized weakness - 32 percent Hypercalcemia- 28 percent Weight loss - 24 percent, one-half of whom had lost ≥ 9 kg Multiple Myeloma = M-CRAB Monoclonal protein Calcium Renal failure Anemia Bone pain with lytic lesions Immunoglobulin Immunoglobulins SPEP: Normal SPEP: M-protein, M-spike Renal Failure Cast nephropathy (also called myeloma kidney) from light chains Hypercalcemia Light chain amyloidosis Drug-induced renal damage Anemia Normocytic, normochromic anemiais present in 73% at diagnosis and in 97%at some time during the course of the disease This anemia can be related to: Bone marrow replacement Kidney damage Dilution in the case of a large M-protein B12 deficiency in 14% Rouleaux Formation Lytic Bone Lesion
Slide 20 - Special Thanks to… For sponsorship of LMEF programs: Supported by an educational grant from Lilly USA, LLC Did you know that you could be receiving credit for attending today? For membership information, please visit our website: www.Lafmeded.org. Multiple Myeloma 2010 Wael Harb MD Horizon Oncology Center Overview Introduction: epidemiology, clinical presentation, diagnosis, staging Autologous stem cell transplantation Initial approaches to treatment Current options Novel agents and combinations Considerations in non-transplantation-eligible patients Prevention of skeletal complications What is MM? Multiple myeloma (MM) is characterized by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. Plasma Cell Multiple Myeloma: Incidence The lifetime risk of getting MM is 1 in 159 (0.63%). 20,180 new cases will be diagnosed in 2010 (11,170 in men and 9,010 in women) 10,650 deaths are expected to occur in 2010 (5,760 in men and 4,890 in women) The 5-year relative survival rate for MM is around 35% Incidence MM occurs in all races and all geographic locations African Americans and blacks from Africa is two to three times the risk in whites Risk is lower in Asians from Japan and in Mexicans Slightly more frequent in men than in women (1.4:1) Age MM is a disease of older adults The median age at diagnosis is 66 years Only 10 percent of patients are younger than 50 years Only 2 percent of patients are younger than 40 years MM: Clinical Presentations Anemia - 73 percent Bone pain - 58 percent Elevated creatinine - 48 percent Fatigue/generalized weakness - 32 percent Hypercalcemia- 28 percent Weight loss - 24 percent, one-half of whom had lost ≥ 9 kg Multiple Myeloma = M-CRAB Monoclonal protein Calcium Renal failure Anemia Bone pain with lytic lesions Immunoglobulin Immunoglobulins SPEP: Normal SPEP: M-protein, M-spike Renal Failure Cast nephropathy (also called myeloma kidney) from light chains Hypercalcemia Light chain amyloidosis Drug-induced renal damage Anemia Normocytic, normochromic anemiais present in 73% at diagnosis and in 97%at some time during the course of the disease This anemia can be related to: Bone marrow replacement Kidney damage Dilution in the case of a large M-protein B12 deficiency in 14% Rouleaux Formation Lytic Bone Lesion MM: PET Scan
Slide 21 - Special Thanks to… For sponsorship of LMEF programs: Supported by an educational grant from Lilly USA, LLC Did you know that you could be receiving credit for attending today? For membership information, please visit our website: www.Lafmeded.org. Multiple Myeloma 2010 Wael Harb MD Horizon Oncology Center Overview Introduction: epidemiology, clinical presentation, diagnosis, staging Autologous stem cell transplantation Initial approaches to treatment Current options Novel agents and combinations Considerations in non-transplantation-eligible patients Prevention of skeletal complications What is MM? Multiple myeloma (MM) is characterized by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. Plasma Cell Multiple Myeloma: Incidence The lifetime risk of getting MM is 1 in 159 (0.63%). 20,180 new cases will be diagnosed in 2010 (11,170 in men and 9,010 in women) 10,650 deaths are expected to occur in 2010 (5,760 in men and 4,890 in women) The 5-year relative survival rate for MM is around 35% Incidence MM occurs in all races and all geographic locations African Americans and blacks from Africa is two to three times the risk in whites Risk is lower in Asians from Japan and in Mexicans Slightly more frequent in men than in women (1.4:1) Age MM is a disease of older adults The median age at diagnosis is 66 years Only 10 percent of patients are younger than 50 years Only 2 percent of patients are younger than 40 years MM: Clinical Presentations Anemia - 73 percent Bone pain - 58 percent Elevated creatinine - 48 percent Fatigue/generalized weakness - 32 percent Hypercalcemia- 28 percent Weight loss - 24 percent, one-half of whom had lost ≥ 9 kg Multiple Myeloma = M-CRAB Monoclonal protein Calcium Renal failure Anemia Bone pain with lytic lesions Immunoglobulin Immunoglobulins SPEP: Normal SPEP: M-protein, M-spike Renal Failure Cast nephropathy (also called myeloma kidney) from light chains Hypercalcemia Light chain amyloidosis Drug-induced renal damage Anemia Normocytic, normochromic anemiais present in 73% at diagnosis and in 97%at some time during the course of the disease This anemia can be related to: Bone marrow replacement Kidney damage Dilution in the case of a large M-protein B12 deficiency in 14% Rouleaux Formation Lytic Bone Lesion MM: PET Scan Extramedullary Plasmacytoma
Slide 22 - Special Thanks to… For sponsorship of LMEF programs: Supported by an educational grant from Lilly USA, LLC Did you know that you could be receiving credit for attending today? For membership information, please visit our website: www.Lafmeded.org. Multiple Myeloma 2010 Wael Harb MD Horizon Oncology Center Overview Introduction: epidemiology, clinical presentation, diagnosis, staging Autologous stem cell transplantation Initial approaches to treatment Current options Novel agents and combinations Considerations in non-transplantation-eligible patients Prevention of skeletal complications What is MM? Multiple myeloma (MM) is characterized by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. Plasma Cell Multiple Myeloma: Incidence The lifetime risk of getting MM is 1 in 159 (0.63%). 20,180 new cases will be diagnosed in 2010 (11,170 in men and 9,010 in women) 10,650 deaths are expected to occur in 2010 (5,760 in men and 4,890 in women) The 5-year relative survival rate for MM is around 35% Incidence MM occurs in all races and all geographic locations African Americans and blacks from Africa is two to three times the risk in whites Risk is lower in Asians from Japan and in Mexicans Slightly more frequent in men than in women (1.4:1) Age MM is a disease of older adults The median age at diagnosis is 66 years Only 10 percent of patients are younger than 50 years Only 2 percent of patients are younger than 40 years MM: Clinical Presentations Anemia - 73 percent Bone pain - 58 percent Elevated creatinine - 48 percent Fatigue/generalized weakness - 32 percent Hypercalcemia- 28 percent Weight loss - 24 percent, one-half of whom had lost ≥ 9 kg Multiple Myeloma = M-CRAB Monoclonal protein Calcium Renal failure Anemia Bone pain with lytic lesions Immunoglobulin Immunoglobulins SPEP: Normal SPEP: M-protein, M-spike Renal Failure Cast nephropathy (also called myeloma kidney) from light chains Hypercalcemia Light chain amyloidosis Drug-induced renal damage Anemia Normocytic, normochromic anemiais present in 73% at diagnosis and in 97%at some time during the course of the disease This anemia can be related to: Bone marrow replacement Kidney damage Dilution in the case of a large M-protein B12 deficiency in 14% Rouleaux Formation Lytic Bone Lesion MM: PET Scan Extramedullary Plasmacytoma Differential Diagnosis of MM Monoclonal gammopathy of undetermined significance (MGUS) Smoldering multiple myeloma (SMM) Waldenstrom macroglobulinemia Solitary plasmacytoma Primary amyloidosis (AL) POEMS syndrome Metastatic carcinoma
Slide 23 - Special Thanks to… For sponsorship of LMEF programs: Supported by an educational grant from Lilly USA, LLC Did you know that you could be receiving credit for attending today? For membership information, please visit our website: www.Lafmeded.org. Multiple Myeloma 2010 Wael Harb MD Horizon Oncology Center Overview Introduction: epidemiology, clinical presentation, diagnosis, staging Autologous stem cell transplantation Initial approaches to treatment Current options Novel agents and combinations Considerations in non-transplantation-eligible patients Prevention of skeletal complications What is MM? Multiple myeloma (MM) is characterized by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. Plasma Cell Multiple Myeloma: Incidence The lifetime risk of getting MM is 1 in 159 (0.63%). 20,180 new cases will be diagnosed in 2010 (11,170 in men and 9,010 in women) 10,650 deaths are expected to occur in 2010 (5,760 in men and 4,890 in women) The 5-year relative survival rate for MM is around 35% Incidence MM occurs in all races and all geographic locations African Americans and blacks from Africa is two to three times the risk in whites Risk is lower in Asians from Japan and in Mexicans Slightly more frequent in men than in women (1.4:1) Age MM is a disease of older adults The median age at diagnosis is 66 years Only 10 percent of patients are younger than 50 years Only 2 percent of patients are younger than 40 years MM: Clinical Presentations Anemia - 73 percent Bone pain - 58 percent Elevated creatinine - 48 percent Fatigue/generalized weakness - 32 percent Hypercalcemia- 28 percent Weight loss - 24 percent, one-half of whom had lost ≥ 9 kg Multiple Myeloma = M-CRAB Monoclonal protein Calcium Renal failure Anemia Bone pain with lytic lesions Immunoglobulin Immunoglobulins SPEP: Normal SPEP: M-protein, M-spike Renal Failure Cast nephropathy (also called myeloma kidney) from light chains Hypercalcemia Light chain amyloidosis Drug-induced renal damage Anemia Normocytic, normochromic anemiais present in 73% at diagnosis and in 97%at some time during the course of the disease This anemia can be related to: Bone marrow replacement Kidney damage Dilution in the case of a large M-protein B12 deficiency in 14% Rouleaux Formation Lytic Bone Lesion MM: PET Scan Extramedullary Plasmacytoma Differential Diagnosis of MM Monoclonal gammopathy of undetermined significance (MGUS) Smoldering multiple myeloma (SMM) Waldenstrom macroglobulinemia Solitary plasmacytoma Primary amyloidosis (AL) POEMS syndrome Metastatic carcinoma Multiple Myeloma All 3 criteria must be met: Presence of a serum or urinary monoclonal protein Presence of clonal plasma cells in the bone marrow or a plasmacytoma Presence of end organ damage felt related to the plasma cell dyscrasia, such as: Increased calcium concentration Lytic bone lesions Anemia Renal failure
Slide 24 - Special Thanks to… For sponsorship of LMEF programs: Supported by an educational grant from Lilly USA, LLC Did you know that you could be receiving credit for attending today? For membership information, please visit our website: www.Lafmeded.org. Multiple Myeloma 2010 Wael Harb MD Horizon Oncology Center Overview Introduction: epidemiology, clinical presentation, diagnosis, staging Autologous stem cell transplantation Initial approaches to treatment Current options Novel agents and combinations Considerations in non-transplantation-eligible patients Prevention of skeletal complications What is MM? Multiple myeloma (MM) is characterized by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. Plasma Cell Multiple Myeloma: Incidence The lifetime risk of getting MM is 1 in 159 (0.63%). 20,180 new cases will be diagnosed in 2010 (11,170 in men and 9,010 in women) 10,650 deaths are expected to occur in 2010 (5,760 in men and 4,890 in women) The 5-year relative survival rate for MM is around 35% Incidence MM occurs in all races and all geographic locations African Americans and blacks from Africa is two to three times the risk in whites Risk is lower in Asians from Japan and in Mexicans Slightly more frequent in men than in women (1.4:1) Age MM is a disease of older adults The median age at diagnosis is 66 years Only 10 percent of patients are younger than 50 years Only 2 percent of patients are younger than 40 years MM: Clinical Presentations Anemia - 73 percent Bone pain - 58 percent Elevated creatinine - 48 percent Fatigue/generalized weakness - 32 percent Hypercalcemia- 28 percent Weight loss - 24 percent, one-half of whom had lost ≥ 9 kg Multiple Myeloma = M-CRAB Monoclonal protein Calcium Renal failure Anemia Bone pain with lytic lesions Immunoglobulin Immunoglobulins SPEP: Normal SPEP: M-protein, M-spike Renal Failure Cast nephropathy (also called myeloma kidney) from light chains Hypercalcemia Light chain amyloidosis Drug-induced renal damage Anemia Normocytic, normochromic anemiais present in 73% at diagnosis and in 97%at some time during the course of the disease This anemia can be related to: Bone marrow replacement Kidney damage Dilution in the case of a large M-protein B12 deficiency in 14% Rouleaux Formation Lytic Bone Lesion MM: PET Scan Extramedullary Plasmacytoma Differential Diagnosis of MM Monoclonal gammopathy of undetermined significance (MGUS) Smoldering multiple myeloma (SMM) Waldenstrom macroglobulinemia Solitary plasmacytoma Primary amyloidosis (AL) POEMS syndrome Metastatic carcinoma Multiple Myeloma All 3 criteria must be met: Presence of a serum or urinary monoclonal protein Presence of clonal plasma cells in the bone marrow or a plasmacytoma Presence of end organ damage felt related to the plasma cell dyscrasia, such as: Increased calcium concentration Lytic bone lesions Anemia Renal failure Smoldering Multiple Myeloma SMM, Asymptomatic Both criteria must be met: Serum monoclonal protein ≥3 g/dL and/or bone marrow plasma cells ≥10 percent No end organ damage related to plasma cell dyscrasia
Slide 25 - Special Thanks to… For sponsorship of LMEF programs: Supported by an educational grant from Lilly USA, LLC Did you know that you could be receiving credit for attending today? For membership information, please visit our website: www.Lafmeded.org. Multiple Myeloma 2010 Wael Harb MD Horizon Oncology Center Overview Introduction: epidemiology, clinical presentation, diagnosis, staging Autologous stem cell transplantation Initial approaches to treatment Current options Novel agents and combinations Considerations in non-transplantation-eligible patients Prevention of skeletal complications What is MM? Multiple myeloma (MM) is characterized by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. Plasma Cell Multiple Myeloma: Incidence The lifetime risk of getting MM is 1 in 159 (0.63%). 20,180 new cases will be diagnosed in 2010 (11,170 in men and 9,010 in women) 10,650 deaths are expected to occur in 2010 (5,760 in men and 4,890 in women) The 5-year relative survival rate for MM is around 35% Incidence MM occurs in all races and all geographic locations African Americans and blacks from Africa is two to three times the risk in whites Risk is lower in Asians from Japan and in Mexicans Slightly more frequent in men than in women (1.4:1) Age MM is a disease of older adults The median age at diagnosis is 66 years Only 10 percent of patients are younger than 50 years Only 2 percent of patients are younger than 40 years MM: Clinical Presentations Anemia - 73 percent Bone pain - 58 percent Elevated creatinine - 48 percent Fatigue/generalized weakness - 32 percent Hypercalcemia- 28 percent Weight loss - 24 percent, one-half of whom had lost ≥ 9 kg Multiple Myeloma = M-CRAB Monoclonal protein Calcium Renal failure Anemia Bone pain with lytic lesions Immunoglobulin Immunoglobulins SPEP: Normal SPEP: M-protein, M-spike Renal Failure Cast nephropathy (also called myeloma kidney) from light chains Hypercalcemia Light chain amyloidosis Drug-induced renal damage Anemia Normocytic, normochromic anemiais present in 73% at diagnosis and in 97%at some time during the course of the disease This anemia can be related to: Bone marrow replacement Kidney damage Dilution in the case of a large M-protein B12 deficiency in 14% Rouleaux Formation Lytic Bone Lesion MM: PET Scan Extramedullary Plasmacytoma Differential Diagnosis of MM Monoclonal gammopathy of undetermined significance (MGUS) Smoldering multiple myeloma (SMM) Waldenstrom macroglobulinemia Solitary plasmacytoma Primary amyloidosis (AL) POEMS syndrome Metastatic carcinoma Multiple Myeloma All 3 criteria must be met: Presence of a serum or urinary monoclonal protein Presence of clonal plasma cells in the bone marrow or a plasmacytoma Presence of end organ damage felt related to the plasma cell dyscrasia, such as: Increased calcium concentration Lytic bone lesions Anemia Renal failure Smoldering Multiple Myeloma SMM, Asymptomatic Both criteria must be met: Serum monoclonal protein ≥3 g/dL and/or bone marrow plasma cells ≥10 percent No end organ damage related to plasma cell dyscrasia Monoclonal Gammopathy of Undetermined Significance (MGUS) All 3 criteria must be met: Serum monoclonal protein <3 g/dL Bone marrow plasma cells <10 percent No end organ damage related to plasma cell dyscrasia or a related B cell lymphoproliferative disorder
Slide 26 - Special Thanks to… For sponsorship of LMEF programs: Supported by an educational grant from Lilly USA, LLC Did you know that you could be receiving credit for attending today? For membership information, please visit our website: www.Lafmeded.org. Multiple Myeloma 2010 Wael Harb MD Horizon Oncology Center Overview Introduction: epidemiology, clinical presentation, diagnosis, staging Autologous stem cell transplantation Initial approaches to treatment Current options Novel agents and combinations Considerations in non-transplantation-eligible patients Prevention of skeletal complications What is MM? Multiple myeloma (MM) is characterized by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. Plasma Cell Multiple Myeloma: Incidence The lifetime risk of getting MM is 1 in 159 (0.63%). 20,180 new cases will be diagnosed in 2010 (11,170 in men and 9,010 in women) 10,650 deaths are expected to occur in 2010 (5,760 in men and 4,890 in women) The 5-year relative survival rate for MM is around 35% Incidence MM occurs in all races and all geographic locations African Americans and blacks from Africa is two to three times the risk in whites Risk is lower in Asians from Japan and in Mexicans Slightly more frequent in men than in women (1.4:1) Age MM is a disease of older adults The median age at diagnosis is 66 years Only 10 percent of patients are younger than 50 years Only 2 percent of patients are younger than 40 years MM: Clinical Presentations Anemia - 73 percent Bone pain - 58 percent Elevated creatinine - 48 percent Fatigue/generalized weakness - 32 percent Hypercalcemia- 28 percent Weight loss - 24 percent, one-half of whom had lost ≥ 9 kg Multiple Myeloma = M-CRAB Monoclonal protein Calcium Renal failure Anemia Bone pain with lytic lesions Immunoglobulin Immunoglobulins SPEP: Normal SPEP: M-protein, M-spike Renal Failure Cast nephropathy (also called myeloma kidney) from light chains Hypercalcemia Light chain amyloidosis Drug-induced renal damage Anemia Normocytic, normochromic anemiais present in 73% at diagnosis and in 97%at some time during the course of the disease This anemia can be related to: Bone marrow replacement Kidney damage Dilution in the case of a large M-protein B12 deficiency in 14% Rouleaux Formation Lytic Bone Lesion MM: PET Scan Extramedullary Plasmacytoma Differential Diagnosis of MM Monoclonal gammopathy of undetermined significance (MGUS) Smoldering multiple myeloma (SMM) Waldenstrom macroglobulinemia Solitary plasmacytoma Primary amyloidosis (AL) POEMS syndrome Metastatic carcinoma Multiple Myeloma All 3 criteria must be met: Presence of a serum or urinary monoclonal protein Presence of clonal plasma cells in the bone marrow or a plasmacytoma Presence of end organ damage felt related to the plasma cell dyscrasia, such as: Increased calcium concentration Lytic bone lesions Anemia Renal failure Smoldering Multiple Myeloma SMM, Asymptomatic Both criteria must be met: Serum monoclonal protein ≥3 g/dL and/or bone marrow plasma cells ≥10 percent No end organ damage related to plasma cell dyscrasia Monoclonal Gammopathy of Undetermined Significance (MGUS) All 3 criteria must be met: Serum monoclonal protein <3 g/dL Bone marrow plasma cells <10 percent No end organ damage related to plasma cell dyscrasia or a related B cell lymphoproliferative disorder POEMS Syndrome Osteosclerotic myeloma Polyneuropathy Organomegaly Endocrinopathy Monoclonal protein Skin changes
Slide 27 - Special Thanks to… For sponsorship of LMEF programs: Supported by an educational grant from Lilly USA, LLC Did you know that you could be receiving credit for attending today? For membership information, please visit our website: www.Lafmeded.org. Multiple Myeloma 2010 Wael Harb MD Horizon Oncology Center Overview Introduction: epidemiology, clinical presentation, diagnosis, staging Autologous stem cell transplantation Initial approaches to treatment Current options Novel agents and combinations Considerations in non-transplantation-eligible patients Prevention of skeletal complications What is MM? Multiple myeloma (MM) is characterized by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. Plasma Cell Multiple Myeloma: Incidence The lifetime risk of getting MM is 1 in 159 (0.63%). 20,180 new cases will be diagnosed in 2010 (11,170 in men and 9,010 in women) 10,650 deaths are expected to occur in 2010 (5,760 in men and 4,890 in women) The 5-year relative survival rate for MM is around 35% Incidence MM occurs in all races and all geographic locations African Americans and blacks from Africa is two to three times the risk in whites Risk is lower in Asians from Japan and in Mexicans Slightly more frequent in men than in women (1.4:1) Age MM is a disease of older adults The median age at diagnosis is 66 years Only 10 percent of patients are younger than 50 years Only 2 percent of patients are younger than 40 years MM: Clinical Presentations Anemia - 73 percent Bone pain - 58 percent Elevated creatinine - 48 percent Fatigue/generalized weakness - 32 percent Hypercalcemia- 28 percent Weight loss - 24 percent, one-half of whom had lost ≥ 9 kg Multiple Myeloma = M-CRAB Monoclonal protein Calcium Renal failure Anemia Bone pain with lytic lesions Immunoglobulin Immunoglobulins SPEP: Normal SPEP: M-protein, M-spike Renal Failure Cast nephropathy (also called myeloma kidney) from light chains Hypercalcemia Light chain amyloidosis Drug-induced renal damage Anemia Normocytic, normochromic anemiais present in 73% at diagnosis and in 97%at some time during the course of the disease This anemia can be related to: Bone marrow replacement Kidney damage Dilution in the case of a large M-protein B12 deficiency in 14% Rouleaux Formation Lytic Bone Lesion MM: PET Scan Extramedullary Plasmacytoma Differential Diagnosis of MM Monoclonal gammopathy of undetermined significance (MGUS) Smoldering multiple myeloma (SMM) Waldenstrom macroglobulinemia Solitary plasmacytoma Primary amyloidosis (AL) POEMS syndrome Metastatic carcinoma Multiple Myeloma All 3 criteria must be met: Presence of a serum or urinary monoclonal protein Presence of clonal plasma cells in the bone marrow or a plasmacytoma Presence of end organ damage felt related to the plasma cell dyscrasia, such as: Increased calcium concentration Lytic bone lesions Anemia Renal failure Smoldering Multiple Myeloma SMM, Asymptomatic Both criteria must be met: Serum monoclonal protein ≥3 g/dL and/or bone marrow plasma cells ≥10 percent No end organ damage related to plasma cell dyscrasia Monoclonal Gammopathy of Undetermined Significance (MGUS) All 3 criteria must be met: Serum monoclonal protein <3 g/dL Bone marrow plasma cells <10 percent No end organ damage related to plasma cell dyscrasia or a related B cell lymphoproliferative disorder POEMS Syndrome Osteosclerotic myeloma Polyneuropathy Organomegaly Endocrinopathy Monoclonal protein Skin changes MM: Evaluation CBC and differential,peripheral blood smear Chemistry:serum calcium, creatinine, albumin, LDH , beta-2 microglobulin, and C-reactive protein Serum protein electrophoresis (SPEP) + IF Quantification of immunoglobulins Urinalysis and a 24-hour urine collection for electrophoresis (UPEP) + IF Serum free monoclonal light chain (FLC)
Slide 28 - Special Thanks to… For sponsorship of LMEF programs: Supported by an educational grant from Lilly USA, LLC Did you know that you could be receiving credit for attending today? For membership information, please visit our website: www.Lafmeded.org. Multiple Myeloma 2010 Wael Harb MD Horizon Oncology Center Overview Introduction: epidemiology, clinical presentation, diagnosis, staging Autologous stem cell transplantation Initial approaches to treatment Current options Novel agents and combinations Considerations in non-transplantation-eligible patients Prevention of skeletal complications What is MM? Multiple myeloma (MM) is characterized by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. Plasma Cell Multiple Myeloma: Incidence The lifetime risk of getting MM is 1 in 159 (0.63%). 20,180 new cases will be diagnosed in 2010 (11,170 in men and 9,010 in women) 10,650 deaths are expected to occur in 2010 (5,760 in men and 4,890 in women) The 5-year relative survival rate for MM is around 35% Incidence MM occurs in all races and all geographic locations African Americans and blacks from Africa is two to three times the risk in whites Risk is lower in Asians from Japan and in Mexicans Slightly more frequent in men than in women (1.4:1) Age MM is a disease of older adults The median age at diagnosis is 66 years Only 10 percent of patients are younger than 50 years Only 2 percent of patients are younger than 40 years MM: Clinical Presentations Anemia - 73 percent Bone pain - 58 percent Elevated creatinine - 48 percent Fatigue/generalized weakness - 32 percent Hypercalcemia- 28 percent Weight loss - 24 percent, one-half of whom had lost ≥ 9 kg Multiple Myeloma = M-CRAB Monoclonal protein Calcium Renal failure Anemia Bone pain with lytic lesions Immunoglobulin Immunoglobulins SPEP: Normal SPEP: M-protein, M-spike Renal Failure Cast nephropathy (also called myeloma kidney) from light chains Hypercalcemia Light chain amyloidosis Drug-induced renal damage Anemia Normocytic, normochromic anemiais present in 73% at diagnosis and in 97%at some time during the course of the disease This anemia can be related to: Bone marrow replacement Kidney damage Dilution in the case of a large M-protein B12 deficiency in 14% Rouleaux Formation Lytic Bone Lesion MM: PET Scan Extramedullary Plasmacytoma Differential Diagnosis of MM Monoclonal gammopathy of undetermined significance (MGUS) Smoldering multiple myeloma (SMM) Waldenstrom macroglobulinemia Solitary plasmacytoma Primary amyloidosis (AL) POEMS syndrome Metastatic carcinoma Multiple Myeloma All 3 criteria must be met: Presence of a serum or urinary monoclonal protein Presence of clonal plasma cells in the bone marrow or a plasmacytoma Presence of end organ damage felt related to the plasma cell dyscrasia, such as: Increased calcium concentration Lytic bone lesions Anemia Renal failure Smoldering Multiple Myeloma SMM, Asymptomatic Both criteria must be met: Serum monoclonal protein ≥3 g/dL and/or bone marrow plasma cells ≥10 percent No end organ damage related to plasma cell dyscrasia Monoclonal Gammopathy of Undetermined Significance (MGUS) All 3 criteria must be met: Serum monoclonal protein <3 g/dL Bone marrow plasma cells <10 percent No end organ damage related to plasma cell dyscrasia or a related B cell lymphoproliferative disorder POEMS Syndrome Osteosclerotic myeloma Polyneuropathy Organomegaly Endocrinopathy Monoclonal protein Skin changes MM: Evaluation CBC and differential,peripheral blood smear Chemistry:serum calcium, creatinine, albumin, LDH , beta-2 microglobulin, and C-reactive protein Serum protein electrophoresis (SPEP) + IF Quantification of immunoglobulins Urinalysis and a 24-hour urine collection for electrophoresis (UPEP) + IF Serum free monoclonal light chain (FLC) MM Evaluation Serum viscosity should be measured if the M-protein concentration is high Bone marrow aspiration and biopsy with immunophenotyping, conventional cytogenetics, and fluorescence in situ hybridization (FISH) Metastatic bone survey with plain radiographs including the humeri and femoral bones should be performed in all patients. MRI, CT, or PET/CT
Slide 29 - Special Thanks to… For sponsorship of LMEF programs: Supported by an educational grant from Lilly USA, LLC Did you know that you could be receiving credit for attending today? For membership information, please visit our website: www.Lafmeded.org. Multiple Myeloma 2010 Wael Harb MD Horizon Oncology Center Overview Introduction: epidemiology, clinical presentation, diagnosis, staging Autologous stem cell transplantation Initial approaches to treatment Current options Novel agents and combinations Considerations in non-transplantation-eligible patients Prevention of skeletal complications What is MM? Multiple myeloma (MM) is characterized by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. Plasma Cell Multiple Myeloma: Incidence The lifetime risk of getting MM is 1 in 159 (0.63%). 20,180 new cases will be diagnosed in 2010 (11,170 in men and 9,010 in women) 10,650 deaths are expected to occur in 2010 (5,760 in men and 4,890 in women) The 5-year relative survival rate for MM is around 35% Incidence MM occurs in all races and all geographic locations African Americans and blacks from Africa is two to three times the risk in whites Risk is lower in Asians from Japan and in Mexicans Slightly more frequent in men than in women (1.4:1) Age MM is a disease of older adults The median age at diagnosis is 66 years Only 10 percent of patients are younger than 50 years Only 2 percent of patients are younger than 40 years MM: Clinical Presentations Anemia - 73 percent Bone pain - 58 percent Elevated creatinine - 48 percent Fatigue/generalized weakness - 32 percent Hypercalcemia- 28 percent Weight loss - 24 percent, one-half of whom had lost ≥ 9 kg Multiple Myeloma = M-CRAB Monoclonal protein Calcium Renal failure Anemia Bone pain with lytic lesions Immunoglobulin Immunoglobulins SPEP: Normal SPEP: M-protein, M-spike Renal Failure Cast nephropathy (also called myeloma kidney) from light chains Hypercalcemia Light chain amyloidosis Drug-induced renal damage Anemia Normocytic, normochromic anemiais present in 73% at diagnosis and in 97%at some time during the course of the disease This anemia can be related to: Bone marrow replacement Kidney damage Dilution in the case of a large M-protein B12 deficiency in 14% Rouleaux Formation Lytic Bone Lesion MM: PET Scan Extramedullary Plasmacytoma Differential Diagnosis of MM Monoclonal gammopathy of undetermined significance (MGUS) Smoldering multiple myeloma (SMM) Waldenstrom macroglobulinemia Solitary plasmacytoma Primary amyloidosis (AL) POEMS syndrome Metastatic carcinoma Multiple Myeloma All 3 criteria must be met: Presence of a serum or urinary monoclonal protein Presence of clonal plasma cells in the bone marrow or a plasmacytoma Presence of end organ damage felt related to the plasma cell dyscrasia, such as: Increased calcium concentration Lytic bone lesions Anemia Renal failure Smoldering Multiple Myeloma SMM, Asymptomatic Both criteria must be met: Serum monoclonal protein ≥3 g/dL and/or bone marrow plasma cells ≥10 percent No end organ damage related to plasma cell dyscrasia Monoclonal Gammopathy of Undetermined Significance (MGUS) All 3 criteria must be met: Serum monoclonal protein <3 g/dL Bone marrow plasma cells <10 percent No end organ damage related to plasma cell dyscrasia or a related B cell lymphoproliferative disorder POEMS Syndrome Osteosclerotic myeloma Polyneuropathy Organomegaly Endocrinopathy Monoclonal protein Skin changes MM: Evaluation CBC and differential,peripheral blood smear Chemistry:serum calcium, creatinine, albumin, LDH , beta-2 microglobulin, and C-reactive protein Serum protein electrophoresis (SPEP) + IF Quantification of immunoglobulins Urinalysis and a 24-hour urine collection for electrophoresis (UPEP) + IF Serum free monoclonal light chain (FLC) MM Evaluation Serum viscosity should be measured if the M-protein concentration is high Bone marrow aspiration and biopsy with immunophenotyping, conventional cytogenetics, and fluorescence in situ hybridization (FISH) Metastatic bone survey with plain radiographs including the humeri and femoral bones should be performed in all patients. MRI, CT, or PET/CT Bone Marrow
Slide 30 - Special Thanks to… For sponsorship of LMEF programs: Supported by an educational grant from Lilly USA, LLC Did you know that you could be receiving credit for attending today? For membership information, please visit our website: www.Lafmeded.org. Multiple Myeloma 2010 Wael Harb MD Horizon Oncology Center Overview Introduction: epidemiology, clinical presentation, diagnosis, staging Autologous stem cell transplantation Initial approaches to treatment Current options Novel agents and combinations Considerations in non-transplantation-eligible patients Prevention of skeletal complications What is MM? Multiple myeloma (MM) is characterized by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. Plasma Cell Multiple Myeloma: Incidence The lifetime risk of getting MM is 1 in 159 (0.63%). 20,180 new cases will be diagnosed in 2010 (11,170 in men and 9,010 in women) 10,650 deaths are expected to occur in 2010 (5,760 in men and 4,890 in women) The 5-year relative survival rate for MM is around 35% Incidence MM occurs in all races and all geographic locations African Americans and blacks from Africa is two to three times the risk in whites Risk is lower in Asians from Japan and in Mexicans Slightly more frequent in men than in women (1.4:1) Age MM is a disease of older adults The median age at diagnosis is 66 years Only 10 percent of patients are younger than 50 years Only 2 percent of patients are younger than 40 years MM: Clinical Presentations Anemia - 73 percent Bone pain - 58 percent Elevated creatinine - 48 percent Fatigue/generalized weakness - 32 percent Hypercalcemia- 28 percent Weight loss - 24 percent, one-half of whom had lost ≥ 9 kg Multiple Myeloma = M-CRAB Monoclonal protein Calcium Renal failure Anemia Bone pain with lytic lesions Immunoglobulin Immunoglobulins SPEP: Normal SPEP: M-protein, M-spike Renal Failure Cast nephropathy (also called myeloma kidney) from light chains Hypercalcemia Light chain amyloidosis Drug-induced renal damage Anemia Normocytic, normochromic anemiais present in 73% at diagnosis and in 97%at some time during the course of the disease This anemia can be related to: Bone marrow replacement Kidney damage Dilution in the case of a large M-protein B12 deficiency in 14% Rouleaux Formation Lytic Bone Lesion MM: PET Scan Extramedullary Plasmacytoma Differential Diagnosis of MM Monoclonal gammopathy of undetermined significance (MGUS) Smoldering multiple myeloma (SMM) Waldenstrom macroglobulinemia Solitary plasmacytoma Primary amyloidosis (AL) POEMS syndrome Metastatic carcinoma Multiple Myeloma All 3 criteria must be met: Presence of a serum or urinary monoclonal protein Presence of clonal plasma cells in the bone marrow or a plasmacytoma Presence of end organ damage felt related to the plasma cell dyscrasia, such as: Increased calcium concentration Lytic bone lesions Anemia Renal failure Smoldering Multiple Myeloma SMM, Asymptomatic Both criteria must be met: Serum monoclonal protein ≥3 g/dL and/or bone marrow plasma cells ≥10 percent No end organ damage related to plasma cell dyscrasia Monoclonal Gammopathy of Undetermined Significance (MGUS) All 3 criteria must be met: Serum monoclonal protein <3 g/dL Bone marrow plasma cells <10 percent No end organ damage related to plasma cell dyscrasia or a related B cell lymphoproliferative disorder POEMS Syndrome Osteosclerotic myeloma Polyneuropathy Organomegaly Endocrinopathy Monoclonal protein Skin changes MM: Evaluation CBC and differential,peripheral blood smear Chemistry:serum calcium, creatinine, albumin, LDH , beta-2 microglobulin, and C-reactive protein Serum protein electrophoresis (SPEP) + IF Quantification of immunoglobulins Urinalysis and a 24-hour urine collection for electrophoresis (UPEP) + IF Serum free monoclonal light chain (FLC) MM Evaluation Serum viscosity should be measured if the M-protein concentration is high Bone marrow aspiration and biopsy with immunophenotyping, conventional cytogenetics, and fluorescence in situ hybridization (FISH) Metastatic bone survey with plain radiographs including the humeri and femoral bones should be performed in all patients. MRI, CT, or PET/CT Bone Marrow Cytogenenetics, Interphase FISH Poor prognosis (median survival 25 months): t(4;14)(p16;q32), t(14;16)(q32;q23), and -17p13 Intermediate prognosis (median survival 42 months): -13q14 Good prognosis (median survival 50 months): all others
Slide 31 - Special Thanks to… For sponsorship of LMEF programs: Supported by an educational grant from Lilly USA, LLC Did you know that you could be receiving credit for attending today? For membership information, please visit our website: www.Lafmeded.org. Multiple Myeloma 2010 Wael Harb MD Horizon Oncology Center Overview Introduction: epidemiology, clinical presentation, diagnosis, staging Autologous stem cell transplantation Initial approaches to treatment Current options Novel agents and combinations Considerations in non-transplantation-eligible patients Prevention of skeletal complications What is MM? Multiple myeloma (MM) is characterized by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. Plasma Cell Multiple Myeloma: Incidence The lifetime risk of getting MM is 1 in 159 (0.63%). 20,180 new cases will be diagnosed in 2010 (11,170 in men and 9,010 in women) 10,650 deaths are expected to occur in 2010 (5,760 in men and 4,890 in women) The 5-year relative survival rate for MM is around 35% Incidence MM occurs in all races and all geographic locations African Americans and blacks from Africa is two to three times the risk in whites Risk is lower in Asians from Japan and in Mexicans Slightly more frequent in men than in women (1.4:1) Age MM is a disease of older adults The median age at diagnosis is 66 years Only 10 percent of patients are younger than 50 years Only 2 percent of patients are younger than 40 years MM: Clinical Presentations Anemia - 73 percent Bone pain - 58 percent Elevated creatinine - 48 percent Fatigue/generalized weakness - 32 percent Hypercalcemia- 28 percent Weight loss - 24 percent, one-half of whom had lost ≥ 9 kg Multiple Myeloma = M-CRAB Monoclonal protein Calcium Renal failure Anemia Bone pain with lytic lesions Immunoglobulin Immunoglobulins SPEP: Normal SPEP: M-protein, M-spike Renal Failure Cast nephropathy (also called myeloma kidney) from light chains Hypercalcemia Light chain amyloidosis Drug-induced renal damage Anemia Normocytic, normochromic anemiais present in 73% at diagnosis and in 97%at some time during the course of the disease This anemia can be related to: Bone marrow replacement Kidney damage Dilution in the case of a large M-protein B12 deficiency in 14% Rouleaux Formation Lytic Bone Lesion MM: PET Scan Extramedullary Plasmacytoma Differential Diagnosis of MM Monoclonal gammopathy of undetermined significance (MGUS) Smoldering multiple myeloma (SMM) Waldenstrom macroglobulinemia Solitary plasmacytoma Primary amyloidosis (AL) POEMS syndrome Metastatic carcinoma Multiple Myeloma All 3 criteria must be met: Presence of a serum or urinary monoclonal protein Presence of clonal plasma cells in the bone marrow or a plasmacytoma Presence of end organ damage felt related to the plasma cell dyscrasia, such as: Increased calcium concentration Lytic bone lesions Anemia Renal failure Smoldering Multiple Myeloma SMM, Asymptomatic Both criteria must be met: Serum monoclonal protein ≥3 g/dL and/or bone marrow plasma cells ≥10 percent No end organ damage related to plasma cell dyscrasia Monoclonal Gammopathy of Undetermined Significance (MGUS) All 3 criteria must be met: Serum monoclonal protein <3 g/dL Bone marrow plasma cells <10 percent No end organ damage related to plasma cell dyscrasia or a related B cell lymphoproliferative disorder POEMS Syndrome Osteosclerotic myeloma Polyneuropathy Organomegaly Endocrinopathy Monoclonal protein Skin changes MM: Evaluation CBC and differential,peripheral blood smear Chemistry:serum calcium, creatinine, albumin, LDH , beta-2 microglobulin, and C-reactive protein Serum protein electrophoresis (SPEP) + IF Quantification of immunoglobulins Urinalysis and a 24-hour urine collection for electrophoresis (UPEP) + IF Serum free monoclonal light chain (FLC) MM Evaluation Serum viscosity should be measured if the M-protein concentration is high Bone marrow aspiration and biopsy with immunophenotyping, conventional cytogenetics, and fluorescence in situ hybridization (FISH) Metastatic bone survey with plain radiographs including the humeri and femoral bones should be performed in all patients. MRI, CT, or PET/CT Bone Marrow Cytogenenetics, Interphase FISH Poor prognosis (median survival 25 months): t(4;14)(p16;q32), t(14;16)(q32;q23), and -17p13 Intermediate prognosis (median survival 42 months): -13q14 Good prognosis (median survival 50 months): all others Staging for MM International staging system (ISS)  Stage I — B2M <3.5 mg/L and serum albumin ≥3.5 g/dL Stage II — neither stage I nor stage III Stage III — B2M ≥5.5 mg/L Median overall survival for patients with ISS stages I, II, and III are 62, 44, and 29 months
Slide 32 - Special Thanks to… For sponsorship of LMEF programs: Supported by an educational grant from Lilly USA, LLC Did you know that you could be receiving credit for attending today? For membership information, please visit our website: www.Lafmeded.org. Multiple Myeloma 2010 Wael Harb MD Horizon Oncology Center Overview Introduction: epidemiology, clinical presentation, diagnosis, staging Autologous stem cell transplantation Initial approaches to treatment Current options Novel agents and combinations Considerations in non-transplantation-eligible patients Prevention of skeletal complications What is MM? Multiple myeloma (MM) is characterized by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. Plasma Cell Multiple Myeloma: Incidence The lifetime risk of getting MM is 1 in 159 (0.63%). 20,180 new cases will be diagnosed in 2010 (11,170 in men and 9,010 in women) 10,650 deaths are expected to occur in 2010 (5,760 in men and 4,890 in women) The 5-year relative survival rate for MM is around 35% Incidence MM occurs in all races and all geographic locations African Americans and blacks from Africa is two to three times the risk in whites Risk is lower in Asians from Japan and in Mexicans Slightly more frequent in men than in women (1.4:1) Age MM is a disease of older adults The median age at diagnosis is 66 years Only 10 percent of patients are younger than 50 years Only 2 percent of patients are younger than 40 years MM: Clinical Presentations Anemia - 73 percent Bone pain - 58 percent Elevated creatinine - 48 percent Fatigue/generalized weakness - 32 percent Hypercalcemia- 28 percent Weight loss - 24 percent, one-half of whom had lost ≥ 9 kg Multiple Myeloma = M-CRAB Monoclonal protein Calcium Renal failure Anemia Bone pain with lytic lesions Immunoglobulin Immunoglobulins SPEP: Normal SPEP: M-protein, M-spike Renal Failure Cast nephropathy (also called myeloma kidney) from light chains Hypercalcemia Light chain amyloidosis Drug-induced renal damage Anemia Normocytic, normochromic anemiais present in 73% at diagnosis and in 97%at some time during the course of the disease This anemia can be related to: Bone marrow replacement Kidney damage Dilution in the case of a large M-protein B12 deficiency in 14% Rouleaux Formation Lytic Bone Lesion MM: PET Scan Extramedullary Plasmacytoma Differential Diagnosis of MM Monoclonal gammopathy of undetermined significance (MGUS) Smoldering multiple myeloma (SMM) Waldenstrom macroglobulinemia Solitary plasmacytoma Primary amyloidosis (AL) POEMS syndrome Metastatic carcinoma Multiple Myeloma All 3 criteria must be met: Presence of a serum or urinary monoclonal protein Presence of clonal plasma cells in the bone marrow or a plasmacytoma Presence of end organ damage felt related to the plasma cell dyscrasia, such as: Increased calcium concentration Lytic bone lesions Anemia Renal failure Smoldering Multiple Myeloma SMM, Asymptomatic Both criteria must be met: Serum monoclonal protein ≥3 g/dL and/or bone marrow plasma cells ≥10 percent No end organ damage related to plasma cell dyscrasia Monoclonal Gammopathy of Undetermined Significance (MGUS) All 3 criteria must be met: Serum monoclonal protein <3 g/dL Bone marrow plasma cells <10 percent No end organ damage related to plasma cell dyscrasia or a related B cell lymphoproliferative disorder POEMS Syndrome Osteosclerotic myeloma Polyneuropathy Organomegaly Endocrinopathy Monoclonal protein Skin changes MM: Evaluation CBC and differential,peripheral blood smear Chemistry:serum calcium, creatinine, albumin, LDH , beta-2 microglobulin, and C-reactive protein Serum protein electrophoresis (SPEP) + IF Quantification of immunoglobulins Urinalysis and a 24-hour urine collection for electrophoresis (UPEP) + IF Serum free monoclonal light chain (FLC) MM Evaluation Serum viscosity should be measured if the M-protein concentration is high Bone marrow aspiration and biopsy with immunophenotyping, conventional cytogenetics, and fluorescence in situ hybridization (FISH) Metastatic bone survey with plain radiographs including the humeri and femoral bones should be performed in all patients. MRI, CT, or PET/CT Bone Marrow Cytogenenetics, Interphase FISH Poor prognosis (median survival 25 months): t(4;14)(p16;q32), t(14;16)(q32;q23), and -17p13 Intermediate prognosis (median survival 42 months): -13q14 Good prognosis (median survival 50 months): all others Staging for MM International staging system (ISS)  Stage I — B2M <3.5 mg/L and serum albumin ≥3.5 g/dL Stage II — neither stage I nor stage III Stage III — B2M ≥5.5 mg/L Median overall survival for patients with ISS stages I, II, and III are 62, 44, and 29 months MM: Treatment Decisions Indications for treatment Risk stratification Eligibility for stem cell transplantation
Slide 33 - Special Thanks to… For sponsorship of LMEF programs: Supported by an educational grant from Lilly USA, LLC Did you know that you could be receiving credit for attending today? For membership information, please visit our website: www.Lafmeded.org. Multiple Myeloma 2010 Wael Harb MD Horizon Oncology Center Overview Introduction: epidemiology, clinical presentation, diagnosis, staging Autologous stem cell transplantation Initial approaches to treatment Current options Novel agents and combinations Considerations in non-transplantation-eligible patients Prevention of skeletal complications What is MM? Multiple myeloma (MM) is characterized by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. Plasma Cell Multiple Myeloma: Incidence The lifetime risk of getting MM is 1 in 159 (0.63%). 20,180 new cases will be diagnosed in 2010 (11,170 in men and 9,010 in women) 10,650 deaths are expected to occur in 2010 (5,760 in men and 4,890 in women) The 5-year relative survival rate for MM is around 35% Incidence MM occurs in all races and all geographic locations African Americans and blacks from Africa is two to three times the risk in whites Risk is lower in Asians from Japan and in Mexicans Slightly more frequent in men than in women (1.4:1) Age MM is a disease of older adults The median age at diagnosis is 66 years Only 10 percent of patients are younger than 50 years Only 2 percent of patients are younger than 40 years MM: Clinical Presentations Anemia - 73 percent Bone pain - 58 percent Elevated creatinine - 48 percent Fatigue/generalized weakness - 32 percent Hypercalcemia- 28 percent Weight loss - 24 percent, one-half of whom had lost ≥ 9 kg Multiple Myeloma = M-CRAB Monoclonal protein Calcium Renal failure Anemia Bone pain with lytic lesions Immunoglobulin Immunoglobulins SPEP: Normal SPEP: M-protein, M-spike Renal Failure Cast nephropathy (also called myeloma kidney) from light chains Hypercalcemia Light chain amyloidosis Drug-induced renal damage Anemia Normocytic, normochromic anemiais present in 73% at diagnosis and in 97%at some time during the course of the disease This anemia can be related to: Bone marrow replacement Kidney damage Dilution in the case of a large M-protein B12 deficiency in 14% Rouleaux Formation Lytic Bone Lesion MM: PET Scan Extramedullary Plasmacytoma Differential Diagnosis of MM Monoclonal gammopathy of undetermined significance (MGUS) Smoldering multiple myeloma (SMM) Waldenstrom macroglobulinemia Solitary plasmacytoma Primary amyloidosis (AL) POEMS syndrome Metastatic carcinoma Multiple Myeloma All 3 criteria must be met: Presence of a serum or urinary monoclonal protein Presence of clonal plasma cells in the bone marrow or a plasmacytoma Presence of end organ damage felt related to the plasma cell dyscrasia, such as: Increased calcium concentration Lytic bone lesions Anemia Renal failure Smoldering Multiple Myeloma SMM, Asymptomatic Both criteria must be met: Serum monoclonal protein ≥3 g/dL and/or bone marrow plasma cells ≥10 percent No end organ damage related to plasma cell dyscrasia Monoclonal Gammopathy of Undetermined Significance (MGUS) All 3 criteria must be met: Serum monoclonal protein <3 g/dL Bone marrow plasma cells <10 percent No end organ damage related to plasma cell dyscrasia or a related B cell lymphoproliferative disorder POEMS Syndrome Osteosclerotic myeloma Polyneuropathy Organomegaly Endocrinopathy Monoclonal protein Skin changes MM: Evaluation CBC and differential,peripheral blood smear Chemistry:serum calcium, creatinine, albumin, LDH , beta-2 microglobulin, and C-reactive protein Serum protein electrophoresis (SPEP) + IF Quantification of immunoglobulins Urinalysis and a 24-hour urine collection for electrophoresis (UPEP) + IF Serum free monoclonal light chain (FLC) MM Evaluation Serum viscosity should be measured if the M-protein concentration is high Bone marrow aspiration and biopsy with immunophenotyping, conventional cytogenetics, and fluorescence in situ hybridization (FISH) Metastatic bone survey with plain radiographs including the humeri and femoral bones should be performed in all patients. MRI, CT, or PET/CT Bone Marrow Cytogenenetics, Interphase FISH Poor prognosis (median survival 25 months): t(4;14)(p16;q32), t(14;16)(q32;q23), and -17p13 Intermediate prognosis (median survival 42 months): -13q14 Good prognosis (median survival 50 months): all others Staging for MM International staging system (ISS)  Stage I — B2M <3.5 mg/L and serum albumin ≥3.5 g/dL Stage II — neither stage I nor stage III Stage III — B2M ≥5.5 mg/L Median overall survival for patients with ISS stages I, II, and III are 62, 44, and 29 months MM: Treatment Decisions Indications for treatment Risk stratification Eligibility for stem cell transplantation Smoldering (asymptomatic) myeloma Deferral of chemotherapy until progression to symptomatic disease Follow these patients closely, every 3 to 4 months, with serum protein electrophoresis, complete blood count, serum creatinine, and serum calcium Metastatic bone survey should be considered annually because asymptomatic bone lesions may develop
Slide 34 - Special Thanks to… For sponsorship of LMEF programs: Supported by an educational grant from Lilly USA, LLC Did you know that you could be receiving credit for attending today? For membership information, please visit our website: www.Lafmeded.org. Multiple Myeloma 2010 Wael Harb MD Horizon Oncology Center Overview Introduction: epidemiology, clinical presentation, diagnosis, staging Autologous stem cell transplantation Initial approaches to treatment Current options Novel agents and combinations Considerations in non-transplantation-eligible patients Prevention of skeletal complications What is MM? Multiple myeloma (MM) is characterized by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. Plasma Cell Multiple Myeloma: Incidence The lifetime risk of getting MM is 1 in 159 (0.63%). 20,180 new cases will be diagnosed in 2010 (11,170 in men and 9,010 in women) 10,650 deaths are expected to occur in 2010 (5,760 in men and 4,890 in women) The 5-year relative survival rate for MM is around 35% Incidence MM occurs in all races and all geographic locations African Americans and blacks from Africa is two to three times the risk in whites Risk is lower in Asians from Japan and in Mexicans Slightly more frequent in men than in women (1.4:1) Age MM is a disease of older adults The median age at diagnosis is 66 years Only 10 percent of patients are younger than 50 years Only 2 percent of patients are younger than 40 years MM: Clinical Presentations Anemia - 73 percent Bone pain - 58 percent Elevated creatinine - 48 percent Fatigue/generalized weakness - 32 percent Hypercalcemia- 28 percent Weight loss - 24 percent, one-half of whom had lost ≥ 9 kg Multiple Myeloma = M-CRAB Monoclonal protein Calcium Renal failure Anemia Bone pain with lytic lesions Immunoglobulin Immunoglobulins SPEP: Normal SPEP: M-protein, M-spike Renal Failure Cast nephropathy (also called myeloma kidney) from light chains Hypercalcemia Light chain amyloidosis Drug-induced renal damage Anemia Normocytic, normochromic anemiais present in 73% at diagnosis and in 97%at some time during the course of the disease This anemia can be related to: Bone marrow replacement Kidney damage Dilution in the case of a large M-protein B12 deficiency in 14% Rouleaux Formation Lytic Bone Lesion MM: PET Scan Extramedullary Plasmacytoma Differential Diagnosis of MM Monoclonal gammopathy of undetermined significance (MGUS) Smoldering multiple myeloma (SMM) Waldenstrom macroglobulinemia Solitary plasmacytoma Primary amyloidosis (AL) POEMS syndrome Metastatic carcinoma Multiple Myeloma All 3 criteria must be met: Presence of a serum or urinary monoclonal protein Presence of clonal plasma cells in the bone marrow or a plasmacytoma Presence of end organ damage felt related to the plasma cell dyscrasia, such as: Increased calcium concentration Lytic bone lesions Anemia Renal failure Smoldering Multiple Myeloma SMM, Asymptomatic Both criteria must be met: Serum monoclonal protein ≥3 g/dL and/or bone marrow plasma cells ≥10 percent No end organ damage related to plasma cell dyscrasia Monoclonal Gammopathy of Undetermined Significance (MGUS) All 3 criteria must be met: Serum monoclonal protein <3 g/dL Bone marrow plasma cells <10 percent No end organ damage related to plasma cell dyscrasia or a related B cell lymphoproliferative disorder POEMS Syndrome Osteosclerotic myeloma Polyneuropathy Organomegaly Endocrinopathy Monoclonal protein Skin changes MM: Evaluation CBC and differential,peripheral blood smear Chemistry:serum calcium, creatinine, albumin, LDH , beta-2 microglobulin, and C-reactive protein Serum protein electrophoresis (SPEP) + IF Quantification of immunoglobulins Urinalysis and a 24-hour urine collection for electrophoresis (UPEP) + IF Serum free monoclonal light chain (FLC) MM Evaluation Serum viscosity should be measured if the M-protein concentration is high Bone marrow aspiration and biopsy with immunophenotyping, conventional cytogenetics, and fluorescence in situ hybridization (FISH) Metastatic bone survey with plain radiographs including the humeri and femoral bones should be performed in all patients. MRI, CT, or PET/CT Bone Marrow Cytogenenetics, Interphase FISH Poor prognosis (median survival 25 months): t(4;14)(p16;q32), t(14;16)(q32;q23), and -17p13 Intermediate prognosis (median survival 42 months): -13q14 Good prognosis (median survival 50 months): all others Staging for MM International staging system (ISS)  Stage I — B2M <3.5 mg/L and serum albumin ≥3.5 g/dL Stage II — neither stage I nor stage III Stage III — B2M ≥5.5 mg/L Median overall survival for patients with ISS stages I, II, and III are 62, 44, and 29 months MM: Treatment Decisions Indications for treatment Risk stratification Eligibility for stem cell transplantation Smoldering (asymptomatic) myeloma Deferral of chemotherapy until progression to symptomatic disease Follow these patients closely, every 3 to 4 months, with serum protein electrophoresis, complete blood count, serum creatinine, and serum calcium Metastatic bone survey should be considered annually because asymptomatic bone lesions may develop MM: Indications for Treatment Anemia (hemoglobin <10 g/dL or 2 g/dL below normal) Hypercalcemia (serum calcium >11.5 mg/dL) Renal insufficiency (serum creatinine>2 mg/dL) Lytic bone lesions or severe osteopenia Extramedullary plasmacytoma
Slide 35 - Special Thanks to… For sponsorship of LMEF programs: Supported by an educational grant from Lilly USA, LLC Did you know that you could be receiving credit for attending today? For membership information, please visit our website: www.Lafmeded.org. Multiple Myeloma 2010 Wael Harb MD Horizon Oncology Center Overview Introduction: epidemiology, clinical presentation, diagnosis, staging Autologous stem cell transplantation Initial approaches to treatment Current options Novel agents and combinations Considerations in non-transplantation-eligible patients Prevention of skeletal complications What is MM? Multiple myeloma (MM) is characterized by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. Plasma Cell Multiple Myeloma: Incidence The lifetime risk of getting MM is 1 in 159 (0.63%). 20,180 new cases will be diagnosed in 2010 (11,170 in men and 9,010 in women) 10,650 deaths are expected to occur in 2010 (5,760 in men and 4,890 in women) The 5-year relative survival rate for MM is around 35% Incidence MM occurs in all races and all geographic locations African Americans and blacks from Africa is two to three times the risk in whites Risk is lower in Asians from Japan and in Mexicans Slightly more frequent in men than in women (1.4:1) Age MM is a disease of older adults The median age at diagnosis is 66 years Only 10 percent of patients are younger than 50 years Only 2 percent of patients are younger than 40 years MM: Clinical Presentations Anemia - 73 percent Bone pain - 58 percent Elevated creatinine - 48 percent Fatigue/generalized weakness - 32 percent Hypercalcemia- 28 percent Weight loss - 24 percent, one-half of whom had lost ≥ 9 kg Multiple Myeloma = M-CRAB Monoclonal protein Calcium Renal failure Anemia Bone pain with lytic lesions Immunoglobulin Immunoglobulins SPEP: Normal SPEP: M-protein, M-spike Renal Failure Cast nephropathy (also called myeloma kidney) from light chains Hypercalcemia Light chain amyloidosis Drug-induced renal damage Anemia Normocytic, normochromic anemiais present in 73% at diagnosis and in 97%at some time during the course of the disease This anemia can be related to: Bone marrow replacement Kidney damage Dilution in the case of a large M-protein B12 deficiency in 14% Rouleaux Formation Lytic Bone Lesion MM: PET Scan Extramedullary Plasmacytoma Differential Diagnosis of MM Monoclonal gammopathy of undetermined significance (MGUS) Smoldering multiple myeloma (SMM) Waldenstrom macroglobulinemia Solitary plasmacytoma Primary amyloidosis (AL) POEMS syndrome Metastatic carcinoma Multiple Myeloma All 3 criteria must be met: Presence of a serum or urinary monoclonal protein Presence of clonal plasma cells in the bone marrow or a plasmacytoma Presence of end organ damage felt related to the plasma cell dyscrasia, such as: Increased calcium concentration Lytic bone lesions Anemia Renal failure Smoldering Multiple Myeloma SMM, Asymptomatic Both criteria must be met: Serum monoclonal protein ≥3 g/dL and/or bone marrow plasma cells ≥10 percent No end organ damage related to plasma cell dyscrasia Monoclonal Gammopathy of Undetermined Significance (MGUS) All 3 criteria must be met: Serum monoclonal protein <3 g/dL Bone marrow plasma cells <10 percent No end organ damage related to plasma cell dyscrasia or a related B cell lymphoproliferative disorder POEMS Syndrome Osteosclerotic myeloma Polyneuropathy Organomegaly Endocrinopathy Monoclonal protein Skin changes MM: Evaluation CBC and differential,peripheral blood smear Chemistry:serum calcium, creatinine, albumin, LDH , beta-2 microglobulin, and C-reactive protein Serum protein electrophoresis (SPEP) + IF Quantification of immunoglobulins Urinalysis and a 24-hour urine collection for electrophoresis (UPEP) + IF Serum free monoclonal light chain (FLC) MM Evaluation Serum viscosity should be measured if the M-protein concentration is high Bone marrow aspiration and biopsy with immunophenotyping, conventional cytogenetics, and fluorescence in situ hybridization (FISH) Metastatic bone survey with plain radiographs including the humeri and femoral bones should be performed in all patients. MRI, CT, or PET/CT Bone Marrow Cytogenenetics, Interphase FISH Poor prognosis (median survival 25 months): t(4;14)(p16;q32), t(14;16)(q32;q23), and -17p13 Intermediate prognosis (median survival 42 months): -13q14 Good prognosis (median survival 50 months): all others Staging for MM International staging system (ISS)  Stage I — B2M <3.5 mg/L and serum albumin ≥3.5 g/dL Stage II — neither stage I nor stage III Stage III — B2M ≥5.5 mg/L Median overall survival for patients with ISS stages I, II, and III are 62, 44, and 29 months MM: Treatment Decisions Indications for treatment Risk stratification Eligibility for stem cell transplantation Smoldering (asymptomatic) myeloma Deferral of chemotherapy until progression to symptomatic disease Follow these patients closely, every 3 to 4 months, with serum protein electrophoresis, complete blood count, serum creatinine, and serum calcium Metastatic bone survey should be considered annually because asymptomatic bone lesions may develop MM: Indications for Treatment Anemia (hemoglobin <10 g/dL or 2 g/dL below normal) Hypercalcemia (serum calcium >11.5 mg/dL) Renal insufficiency (serum creatinine>2 mg/dL) Lytic bone lesions or severe osteopenia Extramedullary plasmacytoma MM: RISK STRATIFICATION FISH for detection of t(4;14), t(14;16), and del17p13 Conventional cytogenetics (karyotyping) for detection of del 13 or hypodiploidy The presence of any of the above markers defines high risk myeloma, which encompasses the 25 percent of MM patients who have a median survival of approximately two years or less despite standard treatment
Slide 36 - Special Thanks to… For sponsorship of LMEF programs: Supported by an educational grant from Lilly USA, LLC Did you know that you could be receiving credit for attending today? For membership information, please visit our website: www.Lafmeded.org. Multiple Myeloma 2010 Wael Harb MD Horizon Oncology Center Overview Introduction: epidemiology, clinical presentation, diagnosis, staging Autologous stem cell transplantation Initial approaches to treatment Current options Novel agents and combinations Considerations in non-transplantation-eligible patients Prevention of skeletal complications What is MM? Multiple myeloma (MM) is characterized by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. Plasma Cell Multiple Myeloma: Incidence The lifetime risk of getting MM is 1 in 159 (0.63%). 20,180 new cases will be diagnosed in 2010 (11,170 in men and 9,010 in women) 10,650 deaths are expected to occur in 2010 (5,760 in men and 4,890 in women) The 5-year relative survival rate for MM is around 35% Incidence MM occurs in all races and all geographic locations African Americans and blacks from Africa is two to three times the risk in whites Risk is lower in Asians from Japan and in Mexicans Slightly more frequent in men than in women (1.4:1) Age MM is a disease of older adults The median age at diagnosis is 66 years Only 10 percent of patients are younger than 50 years Only 2 percent of patients are younger than 40 years MM: Clinical Presentations Anemia - 73 percent Bone pain - 58 percent Elevated creatinine - 48 percent Fatigue/generalized weakness - 32 percent Hypercalcemia- 28 percent Weight loss - 24 percent, one-half of whom had lost ≥ 9 kg Multiple Myeloma = M-CRAB Monoclonal protein Calcium Renal failure Anemia Bone pain with lytic lesions Immunoglobulin Immunoglobulins SPEP: Normal SPEP: M-protein, M-spike Renal Failure Cast nephropathy (also called myeloma kidney) from light chains Hypercalcemia Light chain amyloidosis Drug-induced renal damage Anemia Normocytic, normochromic anemiais present in 73% at diagnosis and in 97%at some time during the course of the disease This anemia can be related to: Bone marrow replacement Kidney damage Dilution in the case of a large M-protein B12 deficiency in 14% Rouleaux Formation Lytic Bone Lesion MM: PET Scan Extramedullary Plasmacytoma Differential Diagnosis of MM Monoclonal gammopathy of undetermined significance (MGUS) Smoldering multiple myeloma (SMM) Waldenstrom macroglobulinemia Solitary plasmacytoma Primary amyloidosis (AL) POEMS syndrome Metastatic carcinoma Multiple Myeloma All 3 criteria must be met: Presence of a serum or urinary monoclonal protein Presence of clonal plasma cells in the bone marrow or a plasmacytoma Presence of end organ damage felt related to the plasma cell dyscrasia, such as: Increased calcium concentration Lytic bone lesions Anemia Renal failure Smoldering Multiple Myeloma SMM, Asymptomatic Both criteria must be met: Serum monoclonal protein ≥3 g/dL and/or bone marrow plasma cells ≥10 percent No end organ damage related to plasma cell dyscrasia Monoclonal Gammopathy of Undetermined Significance (MGUS) All 3 criteria must be met: Serum monoclonal protein <3 g/dL Bone marrow plasma cells <10 percent No end organ damage related to plasma cell dyscrasia or a related B cell lymphoproliferative disorder POEMS Syndrome Osteosclerotic myeloma Polyneuropathy Organomegaly Endocrinopathy Monoclonal protein Skin changes MM: Evaluation CBC and differential,peripheral blood smear Chemistry:serum calcium, creatinine, albumin, LDH , beta-2 microglobulin, and C-reactive protein Serum protein electrophoresis (SPEP) + IF Quantification of immunoglobulins Urinalysis and a 24-hour urine collection for electrophoresis (UPEP) + IF Serum free monoclonal light chain (FLC) MM Evaluation Serum viscosity should be measured if the M-protein concentration is high Bone marrow aspiration and biopsy with immunophenotyping, conventional cytogenetics, and fluorescence in situ hybridization (FISH) Metastatic bone survey with plain radiographs including the humeri and femoral bones should be performed in all patients. MRI, CT, or PET/CT Bone Marrow Cytogenenetics, Interphase FISH Poor prognosis (median survival 25 months): t(4;14)(p16;q32), t(14;16)(q32;q23), and -17p13 Intermediate prognosis (median survival 42 months): -13q14 Good prognosis (median survival 50 months): all others Staging for MM International staging system (ISS)  Stage I — B2M <3.5 mg/L and serum albumin ≥3.5 g/dL Stage II — neither stage I nor stage III Stage III — B2M ≥5.5 mg/L Median overall survival for patients with ISS stages I, II, and III are 62, 44, and 29 months MM: Treatment Decisions Indications for treatment Risk stratification Eligibility for stem cell transplantation Smoldering (asymptomatic) myeloma Deferral of chemotherapy until progression to symptomatic disease Follow these patients closely, every 3 to 4 months, with serum protein electrophoresis, complete blood count, serum creatinine, and serum calcium Metastatic bone survey should be considered annually because asymptomatic bone lesions may develop MM: Indications for Treatment Anemia (hemoglobin <10 g/dL or 2 g/dL below normal) Hypercalcemia (serum calcium >11.5 mg/dL) Renal insufficiency (serum creatinine>2 mg/dL) Lytic bone lesions or severe osteopenia Extramedullary plasmacytoma MM: RISK STRATIFICATION FISH for detection of t(4;14), t(14;16), and del17p13 Conventional cytogenetics (karyotyping) for detection of del 13 or hypodiploidy The presence of any of the above markers defines high risk myeloma, which encompasses the 25 percent of MM patients who have a median survival of approximately two years or less despite standard treatment Current Frontline Options Conventional chemotherapy Survival ≤ 3 yrs Transplantation Prolongs survival 4-5 yrs Novel agents targeting stromal interactions and associated signaling pathways have shown promise Chng WJ, et al. Cancer Control. 2005;12:91-104.
Slide 37 - Special Thanks to… For sponsorship of LMEF programs: Supported by an educational grant from Lilly USA, LLC Did you know that you could be receiving credit for attending today? For membership information, please visit our website: www.Lafmeded.org. Multiple Myeloma 2010 Wael Harb MD Horizon Oncology Center Overview Introduction: epidemiology, clinical presentation, diagnosis, staging Autologous stem cell transplantation Initial approaches to treatment Current options Novel agents and combinations Considerations in non-transplantation-eligible patients Prevention of skeletal complications What is MM? Multiple myeloma (MM) is characterized by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. Plasma Cell Multiple Myeloma: Incidence The lifetime risk of getting MM is 1 in 159 (0.63%). 20,180 new cases will be diagnosed in 2010 (11,170 in men and 9,010 in women) 10,650 deaths are expected to occur in 2010 (5,760 in men and 4,890 in women) The 5-year relative survival rate for MM is around 35% Incidence MM occurs in all races and all geographic locations African Americans and blacks from Africa is two to three times the risk in whites Risk is lower in Asians from Japan and in Mexicans Slightly more frequent in men than in women (1.4:1) Age MM is a disease of older adults The median age at diagnosis is 66 years Only 10 percent of patients are younger than 50 years Only 2 percent of patients are younger than 40 years MM: Clinical Presentations Anemia - 73 percent Bone pain - 58 percent Elevated creatinine - 48 percent Fatigue/generalized weakness - 32 percent Hypercalcemia- 28 percent Weight loss - 24 percent, one-half of whom had lost ≥ 9 kg Multiple Myeloma = M-CRAB Monoclonal protein Calcium Renal failure Anemia Bone pain with lytic lesions Immunoglobulin Immunoglobulins SPEP: Normal SPEP: M-protein, M-spike Renal Failure Cast nephropathy (also called myeloma kidney) from light chains Hypercalcemia Light chain amyloidosis Drug-induced renal damage Anemia Normocytic, normochromic anemiais present in 73% at diagnosis and in 97%at some time during the course of the disease This anemia can be related to: Bone marrow replacement Kidney damage Dilution in the case of a large M-protein B12 deficiency in 14% Rouleaux Formation Lytic Bone Lesion MM: PET Scan Extramedullary Plasmacytoma Differential Diagnosis of MM Monoclonal gammopathy of undetermined significance (MGUS) Smoldering multiple myeloma (SMM) Waldenstrom macroglobulinemia Solitary plasmacytoma Primary amyloidosis (AL) POEMS syndrome Metastatic carcinoma Multiple Myeloma All 3 criteria must be met: Presence of a serum or urinary monoclonal protein Presence of clonal plasma cells in the bone marrow or a plasmacytoma Presence of end organ damage felt related to the plasma cell dyscrasia, such as: Increased calcium concentration Lytic bone lesions Anemia Renal failure Smoldering Multiple Myeloma SMM, Asymptomatic Both criteria must be met: Serum monoclonal protein ≥3 g/dL and/or bone marrow plasma cells ≥10 percent No end organ damage related to plasma cell dyscrasia Monoclonal Gammopathy of Undetermined Significance (MGUS) All 3 criteria must be met: Serum monoclonal protein <3 g/dL Bone marrow plasma cells <10 percent No end organ damage related to plasma cell dyscrasia or a related B cell lymphoproliferative disorder POEMS Syndrome Osteosclerotic myeloma Polyneuropathy Organomegaly Endocrinopathy Monoclonal protein Skin changes MM: Evaluation CBC and differential,peripheral blood smear Chemistry:serum calcium, creatinine, albumin, LDH , beta-2 microglobulin, and C-reactive protein Serum protein electrophoresis (SPEP) + IF Quantification of immunoglobulins Urinalysis and a 24-hour urine collection for electrophoresis (UPEP) + IF Serum free monoclonal light chain (FLC) MM Evaluation Serum viscosity should be measured if the M-protein concentration is high Bone marrow aspiration and biopsy with immunophenotyping, conventional cytogenetics, and fluorescence in situ hybridization (FISH) Metastatic bone survey with plain radiographs including the humeri and femoral bones should be performed in all patients. MRI, CT, or PET/CT Bone Marrow Cytogenenetics, Interphase FISH Poor prognosis (median survival 25 months): t(4;14)(p16;q32), t(14;16)(q32;q23), and -17p13 Intermediate prognosis (median survival 42 months): -13q14 Good prognosis (median survival 50 months): all others Staging for MM International staging system (ISS)  Stage I — B2M <3.5 mg/L and serum albumin ≥3.5 g/dL Stage II — neither stage I nor stage III Stage III — B2M ≥5.5 mg/L Median overall survival for patients with ISS stages I, II, and III are 62, 44, and 29 months MM: Treatment Decisions Indications for treatment Risk stratification Eligibility for stem cell transplantation Smoldering (asymptomatic) myeloma Deferral of chemotherapy until progression to symptomatic disease Follow these patients closely, every 3 to 4 months, with serum protein electrophoresis, complete blood count, serum creatinine, and serum calcium Metastatic bone survey should be considered annually because asymptomatic bone lesions may develop MM: Indications for Treatment Anemia (hemoglobin <10 g/dL or 2 g/dL below normal) Hypercalcemia (serum calcium >11.5 mg/dL) Renal insufficiency (serum creatinine>2 mg/dL) Lytic bone lesions or severe osteopenia Extramedullary plasmacytoma MM: RISK STRATIFICATION FISH for detection of t(4;14), t(14;16), and del17p13 Conventional cytogenetics (karyotyping) for detection of del 13 or hypodiploidy The presence of any of the above markers defines high risk myeloma, which encompasses the 25 percent of MM patients who have a median survival of approximately two years or less despite standard treatment Current Frontline Options Conventional chemotherapy Survival ≤ 3 yrs Transplantation Prolongs survival 4-5 yrs Novel agents targeting stromal interactions and associated signaling pathways have shown promise Chng WJ, et al. Cancer Control. 2005;12:91-104. MM: INITIAL THERAPY The initial therapy of patients with symptomatic myeloma varies depending on whether patients are eligible or not to pursue autologous hematopoietic cell transplantation
Slide 38 - Special Thanks to… For sponsorship of LMEF programs: Supported by an educational grant from Lilly USA, LLC Did you know that you could be receiving credit for attending today? For membership information, please visit our website: www.Lafmeded.org. Multiple Myeloma 2010 Wael Harb MD Horizon Oncology Center Overview Introduction: epidemiology, clinical presentation, diagnosis, staging Autologous stem cell transplantation Initial approaches to treatment Current options Novel agents and combinations Considerations in non-transplantation-eligible patients Prevention of skeletal complications What is MM? Multiple myeloma (MM) is characterized by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. Plasma Cell Multiple Myeloma: Incidence The lifetime risk of getting MM is 1 in 159 (0.63%). 20,180 new cases will be diagnosed in 2010 (11,170 in men and 9,010 in women) 10,650 deaths are expected to occur in 2010 (5,760 in men and 4,890 in women) The 5-year relative survival rate for MM is around 35% Incidence MM occurs in all races and all geographic locations African Americans and blacks from Africa is two to three times the risk in whites Risk is lower in Asians from Japan and in Mexicans Slightly more frequent in men than in women (1.4:1) Age MM is a disease of older adults The median age at diagnosis is 66 years Only 10 percent of patients are younger than 50 years Only 2 percent of patients are younger than 40 years MM: Clinical Presentations Anemia - 73 percent Bone pain - 58 percent Elevated creatinine - 48 percent Fatigue/generalized weakness - 32 percent Hypercalcemia- 28 percent Weight loss - 24 percent, one-half of whom had lost ≥ 9 kg Multiple Myeloma = M-CRAB Monoclonal protein Calcium Renal failure Anemia Bone pain with lytic lesions Immunoglobulin Immunoglobulins SPEP: Normal SPEP: M-protein, M-spike Renal Failure Cast nephropathy (also called myeloma kidney) from light chains Hypercalcemia Light chain amyloidosis Drug-induced renal damage Anemia Normocytic, normochromic anemiais present in 73% at diagnosis and in 97%at some time during the course of the disease This anemia can be related to: Bone marrow replacement Kidney damage Dilution in the case of a large M-protein B12 deficiency in 14% Rouleaux Formation Lytic Bone Lesion MM: PET Scan Extramedullary Plasmacytoma Differential Diagnosis of MM Monoclonal gammopathy of undetermined significance (MGUS) Smoldering multiple myeloma (SMM) Waldenstrom macroglobulinemia Solitary plasmacytoma Primary amyloidosis (AL) POEMS syndrome Metastatic carcinoma Multiple Myeloma All 3 criteria must be met: Presence of a serum or urinary monoclonal protein Presence of clonal plasma cells in the bone marrow or a plasmacytoma Presence of end organ damage felt related to the plasma cell dyscrasia, such as: Increased calcium concentration Lytic bone lesions Anemia Renal failure Smoldering Multiple Myeloma SMM, Asymptomatic Both criteria must be met: Serum monoclonal protein ≥3 g/dL and/or bone marrow plasma cells ≥10 percent No end organ damage related to plasma cell dyscrasia Monoclonal Gammopathy of Undetermined Significance (MGUS) All 3 criteria must be met: Serum monoclonal protein <3 g/dL Bone marrow plasma cells <10 percent No end organ damage related to plasma cell dyscrasia or a related B cell lymphoproliferative disorder POEMS Syndrome Osteosclerotic myeloma Polyneuropathy Organomegaly Endocrinopathy Monoclonal protein Skin changes MM: Evaluation CBC and differential,peripheral blood smear Chemistry:serum calcium, creatinine, albumin, LDH , beta-2 microglobulin, and C-reactive protein Serum protein electrophoresis (SPEP) + IF Quantification of immunoglobulins Urinalysis and a 24-hour urine collection for electrophoresis (UPEP) + IF Serum free monoclonal light chain (FLC) MM Evaluation Serum viscosity should be measured if the M-protein concentration is high Bone marrow aspiration and biopsy with immunophenotyping, conventional cytogenetics, and fluorescence in situ hybridization (FISH) Metastatic bone survey with plain radiographs including the humeri and femoral bones should be performed in all patients. MRI, CT, or PET/CT Bone Marrow Cytogenenetics, Interphase FISH Poor prognosis (median survival 25 months): t(4;14)(p16;q32), t(14;16)(q32;q23), and -17p13 Intermediate prognosis (median survival 42 months): -13q14 Good prognosis (median survival 50 months): all others Staging for MM International staging system (ISS)  Stage I — B2M <3.5 mg/L and serum albumin ≥3.5 g/dL Stage II — neither stage I nor stage III Stage III — B2M ≥5.5 mg/L Median overall survival for patients with ISS stages I, II, and III are 62, 44, and 29 months MM: Treatment Decisions Indications for treatment Risk stratification Eligibility for stem cell transplantation Smoldering (asymptomatic) myeloma Deferral of chemotherapy until progression to symptomatic disease Follow these patients closely, every 3 to 4 months, with serum protein electrophoresis, complete blood count, serum creatinine, and serum calcium Metastatic bone survey should be considered annually because asymptomatic bone lesions may develop MM: Indications for Treatment Anemia (hemoglobin <10 g/dL or 2 g/dL below normal) Hypercalcemia (serum calcium >11.5 mg/dL) Renal insufficiency (serum creatinine>2 mg/dL) Lytic bone lesions or severe osteopenia Extramedullary plasmacytoma MM: RISK STRATIFICATION FISH for detection of t(4;14), t(14;16), and del17p13 Conventional cytogenetics (karyotyping) for detection of del 13 or hypodiploidy The presence of any of the above markers defines high risk myeloma, which encompasses the 25 percent of MM patients who have a median survival of approximately two years or less despite standard treatment Current Frontline Options Conventional chemotherapy Survival ≤ 3 yrs Transplantation Prolongs survival 4-5 yrs Novel agents targeting stromal interactions and associated signaling pathways have shown promise Chng WJ, et al. Cancer Control. 2005;12:91-104. MM: INITIAL THERAPY The initial therapy of patients with symptomatic myeloma varies depending on whether patients are eligible or not to pursue autologous hematopoietic cell transplantation *Thal/dex or dex are additional options especially if immediate response is needed. Clearly not transplantation candidate based on age, performance score, and comorbidity MPT, MPV, Len/dex or clinical trial* Potential transplantation candidate Nonalkylator-based induction x 4 cycles Stem cell harvest Initial Approach to Treatment of MM
Slide 39 - Special Thanks to… For sponsorship of LMEF programs: Supported by an educational grant from Lilly USA, LLC Did you know that you could be receiving credit for attending today? For membership information, please visit our website: www.Lafmeded.org. Multiple Myeloma 2010 Wael Harb MD Horizon Oncology Center Overview Introduction: epidemiology, clinical presentation, diagnosis, staging Autologous stem cell transplantation Initial approaches to treatment Current options Novel agents and combinations Considerations in non-transplantation-eligible patients Prevention of skeletal complications What is MM? Multiple myeloma (MM) is characterized by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. Plasma Cell Multiple Myeloma: Incidence The lifetime risk of getting MM is 1 in 159 (0.63%). 20,180 new cases will be diagnosed in 2010 (11,170 in men and 9,010 in women) 10,650 deaths are expected to occur in 2010 (5,760 in men and 4,890 in women) The 5-year relative survival rate for MM is around 35% Incidence MM occurs in all races and all geographic locations African Americans and blacks from Africa is two to three times the risk in whites Risk is lower in Asians from Japan and in Mexicans Slightly more frequent in men than in women (1.4:1) Age MM is a disease of older adults The median age at diagnosis is 66 years Only 10 percent of patients are younger than 50 years Only 2 percent of patients are younger than 40 years MM: Clinical Presentations Anemia - 73 percent Bone pain - 58 percent Elevated creatinine - 48 percent Fatigue/generalized weakness - 32 percent Hypercalcemia- 28 percent Weight loss - 24 percent, one-half of whom had lost ≥ 9 kg Multiple Myeloma = M-CRAB Monoclonal protein Calcium Renal failure Anemia Bone pain with lytic lesions Immunoglobulin Immunoglobulins SPEP: Normal SPEP: M-protein, M-spike Renal Failure Cast nephropathy (also called myeloma kidney) from light chains Hypercalcemia Light chain amyloidosis Drug-induced renal damage Anemia Normocytic, normochromic anemiais present in 73% at diagnosis and in 97%at some time during the course of the disease This anemia can be related to: Bone marrow replacement Kidney damage Dilution in the case of a large M-protein B12 deficiency in 14% Rouleaux Formation Lytic Bone Lesion MM: PET Scan Extramedullary Plasmacytoma Differential Diagnosis of MM Monoclonal gammopathy of undetermined significance (MGUS) Smoldering multiple myeloma (SMM) Waldenstrom macroglobulinemia Solitary plasmacytoma Primary amyloidosis (AL) POEMS syndrome Metastatic carcinoma Multiple Myeloma All 3 criteria must be met: Presence of a serum or urinary monoclonal protein Presence of clonal plasma cells in the bone marrow or a plasmacytoma Presence of end organ damage felt related to the plasma cell dyscrasia, such as: Increased calcium concentration Lytic bone lesions Anemia Renal failure Smoldering Multiple Myeloma SMM, Asymptomatic Both criteria must be met: Serum monoclonal protein ≥3 g/dL and/or bone marrow plasma cells ≥10 percent No end organ damage related to plasma cell dyscrasia Monoclonal Gammopathy of Undetermined Significance (MGUS) All 3 criteria must be met: Serum monoclonal protein <3 g/dL Bone marrow plasma cells <10 percent No end organ damage related to plasma cell dyscrasia or a related B cell lymphoproliferative disorder POEMS Syndrome Osteosclerotic myeloma Polyneuropathy Organomegaly Endocrinopathy Monoclonal protein Skin changes MM: Evaluation CBC and differential,peripheral blood smear Chemistry:serum calcium, creatinine, albumin, LDH , beta-2 microglobulin, and C-reactive protein Serum protein electrophoresis (SPEP) + IF Quantification of immunoglobulins Urinalysis and a 24-hour urine collection for electrophoresis (UPEP) + IF Serum free monoclonal light chain (FLC) MM Evaluation Serum viscosity should be measured if the M-protein concentration is high Bone marrow aspiration and biopsy with immunophenotyping, conventional cytogenetics, and fluorescence in situ hybridization (FISH) Metastatic bone survey with plain radiographs including the humeri and femoral bones should be performed in all patients. MRI, CT, or PET/CT Bone Marrow Cytogenenetics, Interphase FISH Poor prognosis (median survival 25 months): t(4;14)(p16;q32), t(14;16)(q32;q23), and -17p13 Intermediate prognosis (median survival 42 months): -13q14 Good prognosis (median survival 50 months): all others Staging for MM International staging system (ISS)  Stage I — B2M <3.5 mg/L and serum albumin ≥3.5 g/dL Stage II — neither stage I nor stage III Stage III — B2M ≥5.5 mg/L Median overall survival for patients with ISS stages I, II, and III are 62, 44, and 29 months MM: Treatment Decisions Indications for treatment Risk stratification Eligibility for stem cell transplantation Smoldering (asymptomatic) myeloma Deferral of chemotherapy until progression to symptomatic disease Follow these patients closely, every 3 to 4 months, with serum protein electrophoresis, complete blood count, serum creatinine, and serum calcium Metastatic bone survey should be considered annually because asymptomatic bone lesions may develop MM: Indications for Treatment Anemia (hemoglobin <10 g/dL or 2 g/dL below normal) Hypercalcemia (serum calcium >11.5 mg/dL) Renal insufficiency (serum creatinine>2 mg/dL) Lytic bone lesions or severe osteopenia Extramedullary plasmacytoma MM: RISK STRATIFICATION FISH for detection of t(4;14), t(14;16), and del17p13 Conventional cytogenetics (karyotyping) for detection of del 13 or hypodiploidy The presence of any of the above markers defines high risk myeloma, which encompasses the 25 percent of MM patients who have a median survival of approximately two years or less despite standard treatment Current Frontline Options Conventional chemotherapy Survival ≤ 3 yrs Transplantation Prolongs survival 4-5 yrs Novel agents targeting stromal interactions and associated signaling pathways have shown promise Chng WJ, et al. Cancer Control. 2005;12:91-104. MM: INITIAL THERAPY The initial therapy of patients with symptomatic myeloma varies depending on whether patients are eligible or not to pursue autologous hematopoietic cell transplantation *Thal/dex or dex are additional options especially if immediate response is needed. Clearly not transplantation candidate based on age, performance score, and comorbidity MPT, MPV, Len/dex or clinical trial* Potential transplantation candidate Nonalkylator-based induction x 4 cycles Stem cell harvest Initial Approach to Treatment of MM DETERMINING TRANSPLANT ELIGIBILITY Autologous hematopoietic cell transplantation (HCT) results in superior event-free and overall survival rates when compared with combination chemotherapy All patients should be evaluated at diagnosis for transplant eligibility so that the risks and benefits of autologous HCT can be reviewed with those eligible A minority of patients will be eligible for allogeneic HCT, but the value of allogeneic approaches in myeloma remain investigational
Slide 40 - Special Thanks to… For sponsorship of LMEF programs: Supported by an educational grant from Lilly USA, LLC Did you know that you could be receiving credit for attending today? For membership information, please visit our website: www.Lafmeded.org. Multiple Myeloma 2010 Wael Harb MD Horizon Oncology Center Overview Introduction: epidemiology, clinical presentation, diagnosis, staging Autologous stem cell transplantation Initial approaches to treatment Current options Novel agents and combinations Considerations in non-transplantation-eligible patients Prevention of skeletal complications What is MM? Multiple myeloma (MM) is characterized by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. Plasma Cell Multiple Myeloma: Incidence The lifetime risk of getting MM is 1 in 159 (0.63%). 20,180 new cases will be diagnosed in 2010 (11,170 in men and 9,010 in women) 10,650 deaths are expected to occur in 2010 (5,760 in men and 4,890 in women) The 5-year relative survival rate for MM is around 35% Incidence MM occurs in all races and all geographic locations African Americans and blacks from Africa is two to three times the risk in whites Risk is lower in Asians from Japan and in Mexicans Slightly more frequent in men than in women (1.4:1) Age MM is a disease of older adults The median age at diagnosis is 66 years Only 10 percent of patients are younger than 50 years Only 2 percent of patients are younger than 40 years MM: Clinical Presentations Anemia - 73 percent Bone pain - 58 percent Elevated creatinine - 48 percent Fatigue/generalized weakness - 32 percent Hypercalcemia- 28 percent Weight loss - 24 percent, one-half of whom had lost ≥ 9 kg Multiple Myeloma = M-CRAB Monoclonal protein Calcium Renal failure Anemia Bone pain with lytic lesions Immunoglobulin Immunoglobulins SPEP: Normal SPEP: M-protein, M-spike Renal Failure Cast nephropathy (also called myeloma kidney) from light chains Hypercalcemia Light chain amyloidosis Drug-induced renal damage Anemia Normocytic, normochromic anemiais present in 73% at diagnosis and in 97%at some time during the course of the disease This anemia can be related to: Bone marrow replacement Kidney damage Dilution in the case of a large M-protein B12 deficiency in 14% Rouleaux Formation Lytic Bone Lesion MM: PET Scan Extramedullary Plasmacytoma Differential Diagnosis of MM Monoclonal gammopathy of undetermined significance (MGUS) Smoldering multiple myeloma (SMM) Waldenstrom macroglobulinemia Solitary plasmacytoma Primary amyloidosis (AL) POEMS syndrome Metastatic carcinoma Multiple Myeloma All 3 criteria must be met: Presence of a serum or urinary monoclonal protein Presence of clonal plasma cells in the bone marrow or a plasmacytoma Presence of end organ damage felt related to the plasma cell dyscrasia, such as: Increased calcium concentration Lytic bone lesions Anemia Renal failure Smoldering Multiple Myeloma SMM, Asymptomatic Both criteria must be met: Serum monoclonal protein ≥3 g/dL and/or bone marrow plasma cells ≥10 percent No end organ damage related to plasma cell dyscrasia Monoclonal Gammopathy of Undetermined Significance (MGUS) All 3 criteria must be met: Serum monoclonal protein <3 g/dL Bone marrow plasma cells <10 percent No end organ damage related to plasma cell dyscrasia or a related B cell lymphoproliferative disorder POEMS Syndrome Osteosclerotic myeloma Polyneuropathy Organomegaly Endocrinopathy Monoclonal protein Skin changes MM: Evaluation CBC and differential,peripheral blood smear Chemistry:serum calcium, creatinine, albumin, LDH , beta-2 microglobulin, and C-reactive protein Serum protein electrophoresis (SPEP) + IF Quantification of immunoglobulins Urinalysis and a 24-hour urine collection for electrophoresis (UPEP) + IF Serum free monoclonal light chain (FLC) MM Evaluation Serum viscosity should be measured if the M-protein concentration is high Bone marrow aspiration and biopsy with immunophenotyping, conventional cytogenetics, and fluorescence in situ hybridization (FISH) Metastatic bone survey with plain radiographs including the humeri and femoral bones should be performed in all patients. MRI, CT, or PET/CT Bone Marrow Cytogenenetics, Interphase FISH Poor prognosis (median survival 25 months): t(4;14)(p16;q32), t(14;16)(q32;q23), and -17p13 Intermediate prognosis (median survival 42 months): -13q14 Good prognosis (median survival 50 months): all others Staging for MM International staging system (ISS)  Stage I — B2M <3.5 mg/L and serum albumin ≥3.5 g/dL Stage II — neither stage I nor stage III Stage III — B2M ≥5.5 mg/L Median overall survival for patients with ISS stages I, II, and III are 62, 44, and 29 months MM: Treatment Decisions Indications for treatment Risk stratification Eligibility for stem cell transplantation Smoldering (asymptomatic) myeloma Deferral of chemotherapy until progression to symptomatic disease Follow these patients closely, every 3 to 4 months, with serum protein electrophoresis, complete blood count, serum creatinine, and serum calcium Metastatic bone survey should be considered annually because asymptomatic bone lesions may develop MM: Indications for Treatment Anemia (hemoglobin <10 g/dL or 2 g/dL below normal) Hypercalcemia (serum calcium >11.5 mg/dL) Renal insufficiency (serum creatinine>2 mg/dL) Lytic bone lesions or severe osteopenia Extramedullary plasmacytoma MM: RISK STRATIFICATION FISH for detection of t(4;14), t(14;16), and del17p13 Conventional cytogenetics (karyotyping) for detection of del 13 or hypodiploidy The presence of any of the above markers defines high risk myeloma, which encompasses the 25 percent of MM patients who have a median survival of approximately two years or less despite standard treatment Current Frontline Options Conventional chemotherapy Survival ≤ 3 yrs Transplantation Prolongs survival 4-5 yrs Novel agents targeting stromal interactions and associated signaling pathways have shown promise Chng WJ, et al. Cancer Control. 2005;12:91-104. MM: INITIAL THERAPY The initial therapy of patients with symptomatic myeloma varies depending on whether patients are eligible or not to pursue autologous hematopoietic cell transplantation *Thal/dex or dex are additional options especially if immediate response is needed. Clearly not transplantation candidate based on age, performance score, and comorbidity MPT, MPV, Len/dex or clinical trial* Potential transplantation candidate Nonalkylator-based induction x 4 cycles Stem cell harvest Initial Approach to Treatment of MM DETERMINING TRANSPLANT ELIGIBILITY Autologous hematopoietic cell transplantation (HCT) results in superior event-free and overall survival rates when compared with combination chemotherapy All patients should be evaluated at diagnosis for transplant eligibility so that the risks and benefits of autologous HCT can be reviewed with those eligible A minority of patients will be eligible for allogeneic HCT, but the value of allogeneic approaches in myeloma remain investigational NOT Eligible for Autologous HCT Age >77 years Direct bilirubin>2.0 mg/dL (34.2 µmol/liter) Serum creatinine>2.5 mg/dL (221 µmol/liter) unless on chronic stable dialysis Eastern Cooperative Oncology Group (ECOG) performance status 3 or 4 unless due to bone pain New York Heart Association functional status Class III or IV
Slide 41 - Special Thanks to… For sponsorship of LMEF programs: Supported by an educational grant from Lilly USA, LLC Did you know that you could be receiving credit for attending today? For membership information, please visit our website: www.Lafmeded.org. Multiple Myeloma 2010 Wael Harb MD Horizon Oncology Center Overview Introduction: epidemiology, clinical presentation, diagnosis, staging Autologous stem cell transplantation Initial approaches to treatment Current options Novel agents and combinations Considerations in non-transplantation-eligible patients Prevention of skeletal complications What is MM? Multiple myeloma (MM) is characterized by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. Plasma Cell Multiple Myeloma: Incidence The lifetime risk of getting MM is 1 in 159 (0.63%). 20,180 new cases will be diagnosed in 2010 (11,170 in men and 9,010 in women) 10,650 deaths are expected to occur in 2010 (5,760 in men and 4,890 in women) The 5-year relative survival rate for MM is around 35% Incidence MM occurs in all races and all geographic locations African Americans and blacks from Africa is two to three times the risk in whites Risk is lower in Asians from Japan and in Mexicans Slightly more frequent in men than in women (1.4:1) Age MM is a disease of older adults The median age at diagnosis is 66 years Only 10 percent of patients are younger than 50 years Only 2 percent of patients are younger than 40 years MM: Clinical Presentations Anemia - 73 percent Bone pain - 58 percent Elevated creatinine - 48 percent Fatigue/generalized weakness - 32 percent Hypercalcemia- 28 percent Weight loss - 24 percent, one-half of whom had lost ≥ 9 kg Multiple Myeloma = M-CRAB Monoclonal protein Calcium Renal failure Anemia Bone pain with lytic lesions Immunoglobulin Immunoglobulins SPEP: Normal SPEP: M-protein, M-spike Renal Failure Cast nephropathy (also called myeloma kidney) from light chains Hypercalcemia Light chain amyloidosis Drug-induced renal damage Anemia Normocytic, normochromic anemiais present in 73% at diagnosis and in 97%at some time during the course of the disease This anemia can be related to: Bone marrow replacement Kidney damage Dilution in the case of a large M-protein B12 deficiency in 14% Rouleaux Formation Lytic Bone Lesion MM: PET Scan Extramedullary Plasmacytoma Differential Diagnosis of MM Monoclonal gammopathy of undetermined significance (MGUS) Smoldering multiple myeloma (SMM) Waldenstrom macroglobulinemia Solitary plasmacytoma Primary amyloidosis (AL) POEMS syndrome Metastatic carcinoma Multiple Myeloma All 3 criteria must be met: Presence of a serum or urinary monoclonal protein Presence of clonal plasma cells in the bone marrow or a plasmacytoma Presence of end organ damage felt related to the plasma cell dyscrasia, such as: Increased calcium concentration Lytic bone lesions Anemia Renal failure Smoldering Multiple Myeloma SMM, Asymptomatic Both criteria must be met: Serum monoclonal protein ≥3 g/dL and/or bone marrow plasma cells ≥10 percent No end organ damage related to plasma cell dyscrasia Monoclonal Gammopathy of Undetermined Significance (MGUS) All 3 criteria must be met: Serum monoclonal protein <3 g/dL Bone marrow plasma cells <10 percent No end organ damage related to plasma cell dyscrasia or a related B cell lymphoproliferative disorder POEMS Syndrome Osteosclerotic myeloma Polyneuropathy Organomegaly Endocrinopathy Monoclonal protein Skin changes MM: Evaluation CBC and differential,peripheral blood smear Chemistry:serum calcium, creatinine, albumin, LDH , beta-2 microglobulin, and C-reactive protein Serum protein electrophoresis (SPEP) + IF Quantification of immunoglobulins Urinalysis and a 24-hour urine collection for electrophoresis (UPEP) + IF Serum free monoclonal light chain (FLC) MM Evaluation Serum viscosity should be measured if the M-protein concentration is high Bone marrow aspiration and biopsy with immunophenotyping, conventional cytogenetics, and fluorescence in situ hybridization (FISH) Metastatic bone survey with plain radiographs including the humeri and femoral bones should be performed in all patients. MRI, CT, or PET/CT Bone Marrow Cytogenenetics, Interphase FISH Poor prognosis (median survival 25 months): t(4;14)(p16;q32), t(14;16)(q32;q23), and -17p13 Intermediate prognosis (median survival 42 months): -13q14 Good prognosis (median survival 50 months): all others Staging for MM International staging system (ISS)  Stage I — B2M <3.5 mg/L and serum albumin ≥3.5 g/dL Stage II — neither stage I nor stage III Stage III — B2M ≥5.5 mg/L Median overall survival for patients with ISS stages I, II, and III are 62, 44, and 29 months MM: Treatment Decisions Indications for treatment Risk stratification Eligibility for stem cell transplantation Smoldering (asymptomatic) myeloma Deferral of chemotherapy until progression to symptomatic disease Follow these patients closely, every 3 to 4 months, with serum protein electrophoresis, complete blood count, serum creatinine, and serum calcium Metastatic bone survey should be considered annually because asymptomatic bone lesions may develop MM: Indications for Treatment Anemia (hemoglobin <10 g/dL or 2 g/dL below normal) Hypercalcemia (serum calcium >11.5 mg/dL) Renal insufficiency (serum creatinine>2 mg/dL) Lytic bone lesions or severe osteopenia Extramedullary plasmacytoma MM: RISK STRATIFICATION FISH for detection of t(4;14), t(14;16), and del17p13 Conventional cytogenetics (karyotyping) for detection of del 13 or hypodiploidy The presence of any of the above markers defines high risk myeloma, which encompasses the 25 percent of MM patients who have a median survival of approximately two years or less despite standard treatment Current Frontline Options Conventional chemotherapy Survival ≤ 3 yrs Transplantation Prolongs survival 4-5 yrs Novel agents targeting stromal interactions and associated signaling pathways have shown promise Chng WJ, et al. Cancer Control. 2005;12:91-104. MM: INITIAL THERAPY The initial therapy of patients with symptomatic myeloma varies depending on whether patients are eligible or not to pursue autologous hematopoietic cell transplantation *Thal/dex or dex are additional options especially if immediate response is needed. Clearly not transplantation candidate based on age, performance score, and comorbidity MPT, MPV, Len/dex or clinical trial* Potential transplantation candidate Nonalkylator-based induction x 4 cycles Stem cell harvest Initial Approach to Treatment of MM DETERMINING TRANSPLANT ELIGIBILITY Autologous hematopoietic cell transplantation (HCT) results in superior event-free and overall survival rates when compared with combination chemotherapy All patients should be evaluated at diagnosis for transplant eligibility so that the risks and benefits of autologous HCT can be reviewed with those eligible A minority of patients will be eligible for allogeneic HCT, but the value of allogeneic approaches in myeloma remain investigational NOT Eligible for Autologous HCT Age >77 years Direct bilirubin>2.0 mg/dL (34.2 µmol/liter) Serum creatinine>2.5 mg/dL (221 µmol/liter) unless on chronic stable dialysis Eastern Cooperative Oncology Group (ECOG) performance status 3 or 4 unless due to bone pain New York Heart Association functional status Class III or IV 54 42 Attal M, et al. N Engl J Med. 1996;335:91-97. Child JA, et al. N Engl J Med. 2003;348:1875-1883. 15 30 45 60 25 50 75 100 OS (%) 0 0 High dose Conventional dose Mos 20 40 60 80 25 50 75 100 Survival (%) 0 0 Intensive therapy Standard therapy Mos P = .03 by Wilcoxon test P = .04 by log-rank test Transplantation vs Conventional Chemotherapy
Slide 42 - Special Thanks to… For sponsorship of LMEF programs: Supported by an educational grant from Lilly USA, LLC Did you know that you could be receiving credit for attending today? For membership information, please visit our website: www.Lafmeded.org. Multiple Myeloma 2010 Wael Harb MD Horizon Oncology Center Overview Introduction: epidemiology, clinical presentation, diagnosis, staging Autologous stem cell transplantation Initial approaches to treatment Current options Novel agents and combinations Considerations in non-transplantation-eligible patients Prevention of skeletal complications What is MM? Multiple myeloma (MM) is characterized by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. Plasma Cell Multiple Myeloma: Incidence The lifetime risk of getting MM is 1 in 159 (0.63%). 20,180 new cases will be diagnosed in 2010 (11,170 in men and 9,010 in women) 10,650 deaths are expected to occur in 2010 (5,760 in men and 4,890 in women) The 5-year relative survival rate for MM is around 35% Incidence MM occurs in all races and all geographic locations African Americans and blacks from Africa is two to three times the risk in whites Risk is lower in Asians from Japan and in Mexicans Slightly more frequent in men than in women (1.4:1) Age MM is a disease of older adults The median age at diagnosis is 66 years Only 10 percent of patients are younger than 50 years Only 2 percent of patients are younger than 40 years MM: Clinical Presentations Anemia - 73 percent Bone pain - 58 percent Elevated creatinine - 48 percent Fatigue/generalized weakness - 32 percent Hypercalcemia- 28 percent Weight loss - 24 percent, one-half of whom had lost ≥ 9 kg Multiple Myeloma = M-CRAB Monoclonal protein Calcium Renal failure Anemia Bone pain with lytic lesions Immunoglobulin Immunoglobulins SPEP: Normal SPEP: M-protein, M-spike Renal Failure Cast nephropathy (also called myeloma kidney) from light chains Hypercalcemia Light chain amyloidosis Drug-induced renal damage Anemia Normocytic, normochromic anemiais present in 73% at diagnosis and in 97%at some time during the course of the disease This anemia can be related to: Bone marrow replacement Kidney damage Dilution in the case of a large M-protein B12 deficiency in 14% Rouleaux Formation Lytic Bone Lesion MM: PET Scan Extramedullary Plasmacytoma Differential Diagnosis of MM Monoclonal gammopathy of undetermined significance (MGUS) Smoldering multiple myeloma (SMM) Waldenstrom macroglobulinemia Solitary plasmacytoma Primary amyloidosis (AL) POEMS syndrome Metastatic carcinoma Multiple Myeloma All 3 criteria must be met: Presence of a serum or urinary monoclonal protein Presence of clonal plasma cells in the bone marrow or a plasmacytoma Presence of end organ damage felt related to the plasma cell dyscrasia, such as: Increased calcium concentration Lytic bone lesions Anemia Renal failure Smoldering Multiple Myeloma SMM, Asymptomatic Both criteria must be met: Serum monoclonal protein ≥3 g/dL and/or bone marrow plasma cells ≥10 percent No end organ damage related to plasma cell dyscrasia Monoclonal Gammopathy of Undetermined Significance (MGUS) All 3 criteria must be met: Serum monoclonal protein <3 g/dL Bone marrow plasma cells <10 percent No end organ damage related to plasma cell dyscrasia or a related B cell lymphoproliferative disorder POEMS Syndrome Osteosclerotic myeloma Polyneuropathy Organomegaly Endocrinopathy Monoclonal protein Skin changes MM: Evaluation CBC and differential,peripheral blood smear Chemistry:serum calcium, creatinine, albumin, LDH , beta-2 microglobulin, and C-reactive protein Serum protein electrophoresis (SPEP) + IF Quantification of immunoglobulins Urinalysis and a 24-hour urine collection for electrophoresis (UPEP) + IF Serum free monoclonal light chain (FLC) MM Evaluation Serum viscosity should be measured if the M-protein concentration is high Bone marrow aspiration and biopsy with immunophenotyping, conventional cytogenetics, and fluorescence in situ hybridization (FISH) Metastatic bone survey with plain radiographs including the humeri and femoral bones should be performed in all patients. MRI, CT, or PET/CT Bone Marrow Cytogenenetics, Interphase FISH Poor prognosis (median survival 25 months): t(4;14)(p16;q32), t(14;16)(q32;q23), and -17p13 Intermediate prognosis (median survival 42 months): -13q14 Good prognosis (median survival 50 months): all others Staging for MM International staging system (ISS)  Stage I — B2M <3.5 mg/L and serum albumin ≥3.5 g/dL Stage II — neither stage I nor stage III Stage III — B2M ≥5.5 mg/L Median overall survival for patients with ISS stages I, II, and III are 62, 44, and 29 months MM: Treatment Decisions Indications for treatment Risk stratification Eligibility for stem cell transplantation Smoldering (asymptomatic) myeloma Deferral of chemotherapy until progression to symptomatic disease Follow these patients closely, every 3 to 4 months, with serum protein electrophoresis, complete blood count, serum creatinine, and serum calcium Metastatic bone survey should be considered annually because asymptomatic bone lesions may develop MM: Indications for Treatment Anemia (hemoglobin <10 g/dL or 2 g/dL below normal) Hypercalcemia (serum calcium >11.5 mg/dL) Renal insufficiency (serum creatinine>2 mg/dL) Lytic bone lesions or severe osteopenia Extramedullary plasmacytoma MM: RISK STRATIFICATION FISH for detection of t(4;14), t(14;16), and del17p13 Conventional cytogenetics (karyotyping) for detection of del 13 or hypodiploidy The presence of any of the above markers defines high risk myeloma, which encompasses the 25 percent of MM patients who have a median survival of approximately two years or less despite standard treatment Current Frontline Options Conventional chemotherapy Survival ≤ 3 yrs Transplantation Prolongs survival 4-5 yrs Novel agents targeting stromal interactions and associated signaling pathways have shown promise Chng WJ, et al. Cancer Control. 2005;12:91-104. MM: INITIAL THERAPY The initial therapy of patients with symptomatic myeloma varies depending on whether patients are eligible or not to pursue autologous hematopoietic cell transplantation *Thal/dex or dex are additional options especially if immediate response is needed. Clearly not transplantation candidate based on age, performance score, and comorbidity MPT, MPV, Len/dex or clinical trial* Potential transplantation candidate Nonalkylator-based induction x 4 cycles Stem cell harvest Initial Approach to Treatment of MM DETERMINING TRANSPLANT ELIGIBILITY Autologous hematopoietic cell transplantation (HCT) results in superior event-free and overall survival rates when compared with combination chemotherapy All patients should be evaluated at diagnosis for transplant eligibility so that the risks and benefits of autologous HCT can be reviewed with those eligible A minority of patients will be eligible for allogeneic HCT, but the value of allogeneic approaches in myeloma remain investigational NOT Eligible for Autologous HCT Age >77 years Direct bilirubin>2.0 mg/dL (34.2 µmol/liter) Serum creatinine>2.5 mg/dL (221 µmol/liter) unless on chronic stable dialysis Eastern Cooperative Oncology Group (ECOG) performance status 3 or 4 unless due to bone pain New York Heart Association functional status Class III or IV 54 42 Attal M, et al. N Engl J Med. 1996;335:91-97. Child JA, et al. N Engl J Med. 2003;348:1875-1883. 15 30 45 60 25 50 75 100 OS (%) 0 0 High dose Conventional dose Mos 20 40 60 80 25 50 75 100 Survival (%) 0 0 Intensive therapy Standard therapy Mos P = .03 by Wilcoxon test P = .04 by log-rank test Transplantation vs Conventional Chemotherapy Autologous Stem Cell Transplantation Mel 200 mg/m2 standard conditioning regimen Sufficient performance score, and adequate liver, pulmonary, cardiac function needed Higher PR and CR rates than conventional chemotherapy Higher OS and EFS than conventional Rx Advanced age and impaired renal function are, by themselves, not contraindications Attal M, et al. N Engl J Med. 1996;335:91-97. NCCN Practice Guidelines. Myeloma. V.3.2010.
Slide 43 - Special Thanks to… For sponsorship of LMEF programs: Supported by an educational grant from Lilly USA, LLC Did you know that you could be receiving credit for attending today? For membership information, please visit our website: www.Lafmeded.org. Multiple Myeloma 2010 Wael Harb MD Horizon Oncology Center Overview Introduction: epidemiology, clinical presentation, diagnosis, staging Autologous stem cell transplantation Initial approaches to treatment Current options Novel agents and combinations Considerations in non-transplantation-eligible patients Prevention of skeletal complications What is MM? Multiple myeloma (MM) is characterized by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. Plasma Cell Multiple Myeloma: Incidence The lifetime risk of getting MM is 1 in 159 (0.63%). 20,180 new cases will be diagnosed in 2010 (11,170 in men and 9,010 in women) 10,650 deaths are expected to occur in 2010 (5,760 in men and 4,890 in women) The 5-year relative survival rate for MM is around 35% Incidence MM occurs in all races and all geographic locations African Americans and blacks from Africa is two to three times the risk in whites Risk is lower in Asians from Japan and in Mexicans Slightly more frequent in men than in women (1.4:1) Age MM is a disease of older adults The median age at diagnosis is 66 years Only 10 percent of patients are younger than 50 years Only 2 percent of patients are younger than 40 years MM: Clinical Presentations Anemia - 73 percent Bone pain - 58 percent Elevated creatinine - 48 percent Fatigue/generalized weakness - 32 percent Hypercalcemia- 28 percent Weight loss - 24 percent, one-half of whom had lost ≥ 9 kg Multiple Myeloma = M-CRAB Monoclonal protein Calcium Renal failure Anemia Bone pain with lytic lesions Immunoglobulin Immunoglobulins SPEP: Normal SPEP: M-protein, M-spike Renal Failure Cast nephropathy (also called myeloma kidney) from light chains Hypercalcemia Light chain amyloidosis Drug-induced renal damage Anemia Normocytic, normochromic anemiais present in 73% at diagnosis and in 97%at some time during the course of the disease This anemia can be related to: Bone marrow replacement Kidney damage Dilution in the case of a large M-protein B12 deficiency in 14% Rouleaux Formation Lytic Bone Lesion MM: PET Scan Extramedullary Plasmacytoma Differential Diagnosis of MM Monoclonal gammopathy of undetermined significance (MGUS) Smoldering multiple myeloma (SMM) Waldenstrom macroglobulinemia Solitary plasmacytoma Primary amyloidosis (AL) POEMS syndrome Metastatic carcinoma Multiple Myeloma All 3 criteria must be met: Presence of a serum or urinary monoclonal protein Presence of clonal plasma cells in the bone marrow or a plasmacytoma Presence of end organ damage felt related to the plasma cell dyscrasia, such as: Increased calcium concentration Lytic bone lesions Anemia Renal failure Smoldering Multiple Myeloma SMM, Asymptomatic Both criteria must be met: Serum monoclonal protein ≥3 g/dL and/or bone marrow plasma cells ≥10 percent No end organ damage related to plasma cell dyscrasia Monoclonal Gammopathy of Undetermined Significance (MGUS) All 3 criteria must be met: Serum monoclonal protein <3 g/dL Bone marrow plasma cells <10 percent No end organ damage related to plasma cell dyscrasia or a related B cell lymphoproliferative disorder POEMS Syndrome Osteosclerotic myeloma Polyneuropathy Organomegaly Endocrinopathy Monoclonal protein Skin changes MM: Evaluation CBC and differential,peripheral blood smear Chemistry:serum calcium, creatinine, albumin, LDH , beta-2 microglobulin, and C-reactive protein Serum protein electrophoresis (SPEP) + IF Quantification of immunoglobulins Urinalysis and a 24-hour urine collection for electrophoresis (UPEP) + IF Serum free monoclonal light chain (FLC) MM Evaluation Serum viscosity should be measured if the M-protein concentration is high Bone marrow aspiration and biopsy with immunophenotyping, conventional cytogenetics, and fluorescence in situ hybridization (FISH) Metastatic bone survey with plain radiographs including the humeri and femoral bones should be performed in all patients. MRI, CT, or PET/CT Bone Marrow Cytogenenetics, Interphase FISH Poor prognosis (median survival 25 months): t(4;14)(p16;q32), t(14;16)(q32;q23), and -17p13 Intermediate prognosis (median survival 42 months): -13q14 Good prognosis (median survival 50 months): all others Staging for MM International staging system (ISS)  Stage I — B2M <3.5 mg/L and serum albumin ≥3.5 g/dL Stage II — neither stage I nor stage III Stage III — B2M ≥5.5 mg/L Median overall survival for patients with ISS stages I, II, and III are 62, 44, and 29 months MM: Treatment Decisions Indications for treatment Risk stratification Eligibility for stem cell transplantation Smoldering (asymptomatic) myeloma Deferral of chemotherapy until progression to symptomatic disease Follow these patients closely, every 3 to 4 months, with serum protein electrophoresis, complete blood count, serum creatinine, and serum calcium Metastatic bone survey should be considered annually because asymptomatic bone lesions may develop MM: Indications for Treatment Anemia (hemoglobin <10 g/dL or 2 g/dL below normal) Hypercalcemia (serum calcium >11.5 mg/dL) Renal insufficiency (serum creatinine>2 mg/dL) Lytic bone lesions or severe osteopenia Extramedullary plasmacytoma MM: RISK STRATIFICATION FISH for detection of t(4;14), t(14;16), and del17p13 Conventional cytogenetics (karyotyping) for detection of del 13 or hypodiploidy The presence of any of the above markers defines high risk myeloma, which encompasses the 25 percent of MM patients who have a median survival of approximately two years or less despite standard treatment Current Frontline Options Conventional chemotherapy Survival ≤ 3 yrs Transplantation Prolongs survival 4-5 yrs Novel agents targeting stromal interactions and associated signaling pathways have shown promise Chng WJ, et al. Cancer Control. 2005;12:91-104. MM: INITIAL THERAPY The initial therapy of patients with symptomatic myeloma varies depending on whether patients are eligible or not to pursue autologous hematopoietic cell transplantation *Thal/dex or dex are additional options especially if immediate response is needed. Clearly not transplantation candidate based on age, performance score, and comorbidity MPT, MPV, Len/dex or clinical trial* Potential transplantation candidate Nonalkylator-based induction x 4 cycles Stem cell harvest Initial Approach to Treatment of MM DETERMINING TRANSPLANT ELIGIBILITY Autologous hematopoietic cell transplantation (HCT) results in superior event-free and overall survival rates when compared with combination chemotherapy All patients should be evaluated at diagnosis for transplant eligibility so that the risks and benefits of autologous HCT can be reviewed with those eligible A minority of patients will be eligible for allogeneic HCT, but the value of allogeneic approaches in myeloma remain investigational NOT Eligible for Autologous HCT Age >77 years Direct bilirubin>2.0 mg/dL (34.2 µmol/liter) Serum creatinine>2.5 mg/dL (221 µmol/liter) unless on chronic stable dialysis Eastern Cooperative Oncology Group (ECOG) performance status 3 or 4 unless due to bone pain New York Heart Association functional status Class III or IV 54 42 Attal M, et al. N Engl J Med. 1996;335:91-97. Child JA, et al. N Engl J Med. 2003;348:1875-1883. 15 30 45 60 25 50 75 100 OS (%) 0 0 High dose Conventional dose Mos 20 40 60 80 25 50 75 100 Survival (%) 0 0 Intensive therapy Standard therapy Mos P = .03 by Wilcoxon test P = .04 by log-rank test Transplantation vs Conventional Chemotherapy Autologous Stem Cell Transplantation Mel 200 mg/m2 standard conditioning regimen Sufficient performance score, and adequate liver, pulmonary, cardiac function needed Higher PR and CR rates than conventional chemotherapy Higher OS and EFS than conventional Rx Advanced age and impaired renal function are, by themselves, not contraindications Attal M, et al. N Engl J Med. 1996;335:91-97. NCCN Practice Guidelines. Myeloma. V.3.2010. Stem Cell Transplantation Key issues Efficacy compared with conventional chemotherapy Timing: early vs delayed Single vs tandem Role of allogeneic and miniallogeneic transplantations Maintenance post-SCT
Slide 44 - Special Thanks to… For sponsorship of LMEF programs: Supported by an educational grant from Lilly USA, LLC Did you know that you could be receiving credit for attending today? For membership information, please visit our website: www.Lafmeded.org. Multiple Myeloma 2010 Wael Harb MD Horizon Oncology Center Overview Introduction: epidemiology, clinical presentation, diagnosis, staging Autologous stem cell transplantation Initial approaches to treatment Current options Novel agents and combinations Considerations in non-transplantation-eligible patients Prevention of skeletal complications What is MM? Multiple myeloma (MM) is characterized by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. Plasma Cell Multiple Myeloma: Incidence The lifetime risk of getting MM is 1 in 159 (0.63%). 20,180 new cases will be diagnosed in 2010 (11,170 in men and 9,010 in women) 10,650 deaths are expected to occur in 2010 (5,760 in men and 4,890 in women) The 5-year relative survival rate for MM is around 35% Incidence MM occurs in all races and all geographic locations African Americans and blacks from Africa is two to three times the risk in whites Risk is lower in Asians from Japan and in Mexicans Slightly more frequent in men than in women (1.4:1) Age MM is a disease of older adults The median age at diagnosis is 66 years Only 10 percent of patients are younger than 50 years Only 2 percent of patients are younger than 40 years MM: Clinical Presentations Anemia - 73 percent Bone pain - 58 percent Elevated creatinine - 48 percent Fatigue/generalized weakness - 32 percent Hypercalcemia- 28 percent Weight loss - 24 percent, one-half of whom had lost ≥ 9 kg Multiple Myeloma = M-CRAB Monoclonal protein Calcium Renal failure Anemia Bone pain with lytic lesions Immunoglobulin Immunoglobulins SPEP: Normal SPEP: M-protein, M-spike Renal Failure Cast nephropathy (also called myeloma kidney) from light chains Hypercalcemia Light chain amyloidosis Drug-induced renal damage Anemia Normocytic, normochromic anemiais present in 73% at diagnosis and in 97%at some time during the course of the disease This anemia can be related to: Bone marrow replacement Kidney damage Dilution in the case of a large M-protein B12 deficiency in 14% Rouleaux Formation Lytic Bone Lesion MM: PET Scan Extramedullary Plasmacytoma Differential Diagnosis of MM Monoclonal gammopathy of undetermined significance (MGUS) Smoldering multiple myeloma (SMM) Waldenstrom macroglobulinemia Solitary plasmacytoma Primary amyloidosis (AL) POEMS syndrome Metastatic carcinoma Multiple Myeloma All 3 criteria must be met: Presence of a serum or urinary monoclonal protein Presence of clonal plasma cells in the bone marrow or a plasmacytoma Presence of end organ damage felt related to the plasma cell dyscrasia, such as: Increased calcium concentration Lytic bone lesions Anemia Renal failure Smoldering Multiple Myeloma SMM, Asymptomatic Both criteria must be met: Serum monoclonal protein ≥3 g/dL and/or bone marrow plasma cells ≥10 percent No end organ damage related to plasma cell dyscrasia Monoclonal Gammopathy of Undetermined Significance (MGUS) All 3 criteria must be met: Serum monoclonal protein <3 g/dL Bone marrow plasma cells <10 percent No end organ damage related to plasma cell dyscrasia or a related B cell lymphoproliferative disorder POEMS Syndrome Osteosclerotic myeloma Polyneuropathy Organomegaly Endocrinopathy Monoclonal protein Skin changes MM: Evaluation CBC and differential,peripheral blood smear Chemistry:serum calcium, creatinine, albumin, LDH , beta-2 microglobulin, and C-reactive protein Serum protein electrophoresis (SPEP) + IF Quantification of immunoglobulins Urinalysis and a 24-hour urine collection for electrophoresis (UPEP) + IF Serum free monoclonal light chain (FLC) MM Evaluation Serum viscosity should be measured if the M-protein concentration is high Bone marrow aspiration and biopsy with immunophenotyping, conventional cytogenetics, and fluorescence in situ hybridization (FISH) Metastatic bone survey with plain radiographs including the humeri and femoral bones should be performed in all patients. MRI, CT, or PET/CT Bone Marrow Cytogenenetics, Interphase FISH Poor prognosis (median survival 25 months): t(4;14)(p16;q32), t(14;16)(q32;q23), and -17p13 Intermediate prognosis (median survival 42 months): -13q14 Good prognosis (median survival 50 months): all others Staging for MM International staging system (ISS)  Stage I — B2M <3.5 mg/L and serum albumin ≥3.5 g/dL Stage II — neither stage I nor stage III Stage III — B2M ≥5.5 mg/L Median overall survival for patients with ISS stages I, II, and III are 62, 44, and 29 months MM: Treatment Decisions Indications for treatment Risk stratification Eligibility for stem cell transplantation Smoldering (asymptomatic) myeloma Deferral of chemotherapy until progression to symptomatic disease Follow these patients closely, every 3 to 4 months, with serum protein electrophoresis, complete blood count, serum creatinine, and serum calcium Metastatic bone survey should be considered annually because asymptomatic bone lesions may develop MM: Indications for Treatment Anemia (hemoglobin <10 g/dL or 2 g/dL below normal) Hypercalcemia (serum calcium >11.5 mg/dL) Renal insufficiency (serum creatinine>2 mg/dL) Lytic bone lesions or severe osteopenia Extramedullary plasmacytoma MM: RISK STRATIFICATION FISH for detection of t(4;14), t(14;16), and del17p13 Conventional cytogenetics (karyotyping) for detection of del 13 or hypodiploidy The presence of any of the above markers defines high risk myeloma, which encompasses the 25 percent of MM patients who have a median survival of approximately two years or less despite standard treatment Current Frontline Options Conventional chemotherapy Survival ≤ 3 yrs Transplantation Prolongs survival 4-5 yrs Novel agents targeting stromal interactions and associated signaling pathways have shown promise Chng WJ, et al. Cancer Control. 2005;12:91-104. MM: INITIAL THERAPY The initial therapy of patients with symptomatic myeloma varies depending on whether patients are eligible or not to pursue autologous hematopoietic cell transplantation *Thal/dex or dex are additional options especially if immediate response is needed. Clearly not transplantation candidate based on age, performance score, and comorbidity MPT, MPV, Len/dex or clinical trial* Potential transplantation candidate Nonalkylator-based induction x 4 cycles Stem cell harvest Initial Approach to Treatment of MM DETERMINING TRANSPLANT ELIGIBILITY Autologous hematopoietic cell transplantation (HCT) results in superior event-free and overall survival rates when compared with combination chemotherapy All patients should be evaluated at diagnosis for transplant eligibility so that the risks and benefits of autologous HCT can be reviewed with those eligible A minority of patients will be eligible for allogeneic HCT, but the value of allogeneic approaches in myeloma remain investigational NOT Eligible for Autologous HCT Age >77 years Direct bilirubin>2.0 mg/dL (34.2 µmol/liter) Serum creatinine>2.5 mg/dL (221 µmol/liter) unless on chronic stable dialysis Eastern Cooperative Oncology Group (ECOG) performance status 3 or 4 unless due to bone pain New York Heart Association functional status Class III or IV 54 42 Attal M, et al. N Engl J Med. 1996;335:91-97. Child JA, et al. N Engl J Med. 2003;348:1875-1883. 15 30 45 60 25 50 75 100 OS (%) 0 0 High dose Conventional dose Mos 20 40 60 80 25 50 75 100 Survival (%) 0 0 Intensive therapy Standard therapy Mos P = .03 by Wilcoxon test P = .04 by log-rank test Transplantation vs Conventional Chemotherapy Autologous Stem Cell Transplantation Mel 200 mg/m2 standard conditioning regimen Sufficient performance score, and adequate liver, pulmonary, cardiac function needed Higher PR and CR rates than conventional chemotherapy Higher OS and EFS than conventional Rx Advanced age and impaired renal function are, by themselves, not contraindications Attal M, et al. N Engl J Med. 1996;335:91-97. NCCN Practice Guidelines. Myeloma. V.3.2010. Stem Cell Transplantation Key issues Efficacy compared with conventional chemotherapy Timing: early vs delayed Single vs tandem Role of allogeneic and miniallogeneic transplantations Maintenance post-SCT Novel Frontline Options Immunomodulatory drugs (IMiDs) Thalidomide Lenalidomide Proteasome inhibitors Bortezomib Carfilzomib
Slide 45 - Special Thanks to… For sponsorship of LMEF programs: Supported by an educational grant from Lilly USA, LLC Did you know that you could be receiving credit for attending today? For membership information, please visit our website: www.Lafmeded.org. Multiple Myeloma 2010 Wael Harb MD Horizon Oncology Center Overview Introduction: epidemiology, clinical presentation, diagnosis, staging Autologous stem cell transplantation Initial approaches to treatment Current options Novel agents and combinations Considerations in non-transplantation-eligible patients Prevention of skeletal complications What is MM? Multiple myeloma (MM) is characterized by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. Plasma Cell Multiple Myeloma: Incidence The lifetime risk of getting MM is 1 in 159 (0.63%). 20,180 new cases will be diagnosed in 2010 (11,170 in men and 9,010 in women) 10,650 deaths are expected to occur in 2010 (5,760 in men and 4,890 in women) The 5-year relative survival rate for MM is around 35% Incidence MM occurs in all races and all geographic locations African Americans and blacks from Africa is two to three times the risk in whites Risk is lower in Asians from Japan and in Mexicans Slightly more frequent in men than in women (1.4:1) Age MM is a disease of older adults The median age at diagnosis is 66 years Only 10 percent of patients are younger than 50 years Only 2 percent of patients are younger than 40 years MM: Clinical Presentations Anemia - 73 percent Bone pain - 58 percent Elevated creatinine - 48 percent Fatigue/generalized weakness - 32 percent Hypercalcemia- 28 percent Weight loss - 24 percent, one-half of whom had lost ≥ 9 kg Multiple Myeloma = M-CRAB Monoclonal protein Calcium Renal failure Anemia Bone pain with lytic lesions Immunoglobulin Immunoglobulins SPEP: Normal SPEP: M-protein, M-spike Renal Failure Cast nephropathy (also called myeloma kidney) from light chains Hypercalcemia Light chain amyloidosis Drug-induced renal damage Anemia Normocytic, normochromic anemiais present in 73% at diagnosis and in 97%at some time during the course of the disease This anemia can be related to: Bone marrow replacement Kidney damage Dilution in the case of a large M-protein B12 deficiency in 14% Rouleaux Formation Lytic Bone Lesion MM: PET Scan Extramedullary Plasmacytoma Differential Diagnosis of MM Monoclonal gammopathy of undetermined significance (MGUS) Smoldering multiple myeloma (SMM) Waldenstrom macroglobulinemia Solitary plasmacytoma Primary amyloidosis (AL) POEMS syndrome Metastatic carcinoma Multiple Myeloma All 3 criteria must be met: Presence of a serum or urinary monoclonal protein Presence of clonal plasma cells in the bone marrow or a plasmacytoma Presence of end organ damage felt related to the plasma cell dyscrasia, such as: Increased calcium concentration Lytic bone lesions Anemia Renal failure Smoldering Multiple Myeloma SMM, Asymptomatic Both criteria must be met: Serum monoclonal protein ≥3 g/dL and/or bone marrow plasma cells ≥10 percent No end organ damage related to plasma cell dyscrasia Monoclonal Gammopathy of Undetermined Significance (MGUS) All 3 criteria must be met: Serum monoclonal protein <3 g/dL Bone marrow plasma cells <10 percent No end organ damage related to plasma cell dyscrasia or a related B cell lymphoproliferative disorder POEMS Syndrome Osteosclerotic myeloma Polyneuropathy Organomegaly Endocrinopathy Monoclonal protein Skin changes MM: Evaluation CBC and differential,peripheral blood smear Chemistry:serum calcium, creatinine, albumin, LDH , beta-2 microglobulin, and C-reactive protein Serum protein electrophoresis (SPEP) + IF Quantification of immunoglobulins Urinalysis and a 24-hour urine collection for electrophoresis (UPEP) + IF Serum free monoclonal light chain (FLC) MM Evaluation Serum viscosity should be measured if the M-protein concentration is high Bone marrow aspiration and biopsy with immunophenotyping, conventional cytogenetics, and fluorescence in situ hybridization (FISH) Metastatic bone survey with plain radiographs including the humeri and femoral bones should be performed in all patients. MRI, CT, or PET/CT Bone Marrow Cytogenenetics, Interphase FISH Poor prognosis (median survival 25 months): t(4;14)(p16;q32), t(14;16)(q32;q23), and -17p13 Intermediate prognosis (median survival 42 months): -13q14 Good prognosis (median survival 50 months): all others Staging for MM International staging system (ISS)  Stage I — B2M <3.5 mg/L and serum albumin ≥3.5 g/dL Stage II — neither stage I nor stage III Stage III — B2M ≥5.5 mg/L Median overall survival for patients with ISS stages I, II, and III are 62, 44, and 29 months MM: Treatment Decisions Indications for treatment Risk stratification Eligibility for stem cell transplantation Smoldering (asymptomatic) myeloma Deferral of chemotherapy until progression to symptomatic disease Follow these patients closely, every 3 to 4 months, with serum protein electrophoresis, complete blood count, serum creatinine, and serum calcium Metastatic bone survey should be considered annually because asymptomatic bone lesions may develop MM: Indications for Treatment Anemia (hemoglobin <10 g/dL or 2 g/dL below normal) Hypercalcemia (serum calcium >11.5 mg/dL) Renal insufficiency (serum creatinine>2 mg/dL) Lytic bone lesions or severe osteopenia Extramedullary plasmacytoma MM: RISK STRATIFICATION FISH for detection of t(4;14), t(14;16), and del17p13 Conventional cytogenetics (karyotyping) for detection of del 13 or hypodiploidy The presence of any of the above markers defines high risk myeloma, which encompasses the 25 percent of MM patients who have a median survival of approximately two years or less despite standard treatment Current Frontline Options Conventional chemotherapy Survival ≤ 3 yrs Transplantation Prolongs survival 4-5 yrs Novel agents targeting stromal interactions and associated signaling pathways have shown promise Chng WJ, et al. Cancer Control. 2005;12:91-104. MM: INITIAL THERAPY The initial therapy of patients with symptomatic myeloma varies depending on whether patients are eligible or not to pursue autologous hematopoietic cell transplantation *Thal/dex or dex are additional options especially if immediate response is needed. Clearly not transplantation candidate based on age, performance score, and comorbidity MPT, MPV, Len/dex or clinical trial* Potential transplantation candidate Nonalkylator-based induction x 4 cycles Stem cell harvest Initial Approach to Treatment of MM DETERMINING TRANSPLANT ELIGIBILITY Autologous hematopoietic cell transplantation (HCT) results in superior event-free and overall survival rates when compared with combination chemotherapy All patients should be evaluated at diagnosis for transplant eligibility so that the risks and benefits of autologous HCT can be reviewed with those eligible A minority of patients will be eligible for allogeneic HCT, but the value of allogeneic approaches in myeloma remain investigational NOT Eligible for Autologous HCT Age >77 years Direct bilirubin>2.0 mg/dL (34.2 µmol/liter) Serum creatinine>2.5 mg/dL (221 µmol/liter) unless on chronic stable dialysis Eastern Cooperative Oncology Group (ECOG) performance status 3 or 4 unless due to bone pain New York Heart Association functional status Class III or IV 54 42 Attal M, et al. N Engl J Med. 1996;335:91-97. Child JA, et al. N Engl J Med. 2003;348:1875-1883. 15 30 45 60 25 50 75 100 OS (%) 0 0 High dose Conventional dose Mos 20 40 60 80 25 50 75 100 Survival (%) 0 0 Intensive therapy Standard therapy Mos P = .03 by Wilcoxon test P = .04 by log-rank test Transplantation vs Conventional Chemotherapy Autologous Stem Cell Transplantation Mel 200 mg/m2 standard conditioning regimen Sufficient performance score, and adequate liver, pulmonary, cardiac function needed Higher PR and CR rates than conventional chemotherapy Higher OS and EFS than conventional Rx Advanced age and impaired renal function are, by themselves, not contraindications Attal M, et al. N Engl J Med. 1996;335:91-97. NCCN Practice Guidelines. Myeloma. V.3.2010. Stem Cell Transplantation Key issues Efficacy compared with conventional chemotherapy Timing: early vs delayed Single vs tandem Role of allogeneic and miniallogeneic transplantations Maintenance post-SCT Novel Frontline Options Immunomodulatory drugs (IMiDs) Thalidomide Lenalidomide Proteasome inhibitors Bortezomib Carfilzomib Kyle RA, et al. N Engl J Med. 2004;351:1860-1873. Copyright ©2004. Massachusetts Medical Society. All rights reserved. Proposed Mechanism of Action for Multiple Myeloma Therapies
Slide 46 - Special Thanks to… For sponsorship of LMEF programs: Supported by an educational grant from Lilly USA, LLC Did you know that you could be receiving credit for attending today? For membership information, please visit our website: www.Lafmeded.org. Multiple Myeloma 2010 Wael Harb MD Horizon Oncology Center Overview Introduction: epidemiology, clinical presentation, diagnosis, staging Autologous stem cell transplantation Initial approaches to treatment Current options Novel agents and combinations Considerations in non-transplantation-eligible patients Prevention of skeletal complications What is MM? Multiple myeloma (MM) is characterized by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. Plasma Cell Multiple Myeloma: Incidence The lifetime risk of getting MM is 1 in 159 (0.63%). 20,180 new cases will be diagnosed in 2010 (11,170 in men and 9,010 in women) 10,650 deaths are expected to occur in 2010 (5,760 in men and 4,890 in women) The 5-year relative survival rate for MM is around 35% Incidence MM occurs in all races and all geographic locations African Americans and blacks from Africa is two to three times the risk in whites Risk is lower in Asians from Japan and in Mexicans Slightly more frequent in men than in women (1.4:1) Age MM is a disease of older adults The median age at diagnosis is 66 years Only 10 percent of patients are younger than 50 years Only 2 percent of patients are younger than 40 years MM: Clinical Presentations Anemia - 73 percent Bone pain - 58 percent Elevated creatinine - 48 percent Fatigue/generalized weakness - 32 percent Hypercalcemia- 28 percent Weight loss - 24 percent, one-half of whom had lost ≥ 9 kg Multiple Myeloma = M-CRAB Monoclonal protein Calcium Renal failure Anemia Bone pain with lytic lesions Immunoglobulin Immunoglobulins SPEP: Normal SPEP: M-protein, M-spike Renal Failure Cast nephropathy (also called myeloma kidney) from light chains Hypercalcemia Light chain amyloidosis Drug-induced renal damage Anemia Normocytic, normochromic anemiais present in 73% at diagnosis and in 97%at some time during the course of the disease This anemia can be related to: Bone marrow replacement Kidney damage Dilution in the case of a large M-protein B12 deficiency in 14% Rouleaux Formation Lytic Bone Lesion MM: PET Scan Extramedullary Plasmacytoma Differential Diagnosis of MM Monoclonal gammopathy of undetermined significance (MGUS) Smoldering multiple myeloma (SMM) Waldenstrom macroglobulinemia Solitary plasmacytoma Primary amyloidosis (AL) POEMS syndrome Metastatic carcinoma Multiple Myeloma All 3 criteria must be met: Presence of a serum or urinary monoclonal protein Presence of clonal plasma cells in the bone marrow or a plasmacytoma Presence of end organ damage felt related to the plasma cell dyscrasia, such as: Increased calcium concentration Lytic bone lesions Anemia Renal failure Smoldering Multiple Myeloma SMM, Asymptomatic Both criteria must be met: Serum monoclonal protein ≥3 g/dL and/or bone marrow plasma cells ≥10 percent No end organ damage related to plasma cell dyscrasia Monoclonal Gammopathy of Undetermined Significance (MGUS) All 3 criteria must be met: Serum monoclonal protein <3 g/dL Bone marrow plasma cells <10 percent No end organ damage related to plasma cell dyscrasia or a related B cell lymphoproliferative disorder POEMS Syndrome Osteosclerotic myeloma Polyneuropathy Organomegaly Endocrinopathy Monoclonal protein Skin changes MM: Evaluation CBC and differential,peripheral blood smear Chemistry:serum calcium, creatinine, albumin, LDH , beta-2 microglobulin, and C-reactive protein Serum protein electrophoresis (SPEP) + IF Quantification of immunoglobulins Urinalysis and a 24-hour urine collection for electrophoresis (UPEP) + IF Serum free monoclonal light chain (FLC) MM Evaluation Serum viscosity should be measured if the M-protein concentration is high Bone marrow aspiration and biopsy with immunophenotyping, conventional cytogenetics, and fluorescence in situ hybridization (FISH) Metastatic bone survey with plain radiographs including the humeri and femoral bones should be performed in all patients. MRI, CT, or PET/CT Bone Marrow Cytogenenetics, Interphase FISH Poor prognosis (median survival 25 months): t(4;14)(p16;q32), t(14;16)(q32;q23), and -17p13 Intermediate prognosis (median survival 42 months): -13q14 Good prognosis (median survival 50 months): all others Staging for MM International staging system (ISS)  Stage I — B2M <3.5 mg/L and serum albumin ≥3.5 g/dL Stage II — neither stage I nor stage III Stage III — B2M ≥5.5 mg/L Median overall survival for patients with ISS stages I, II, and III are 62, 44, and 29 months MM: Treatment Decisions Indications for treatment Risk stratification Eligibility for stem cell transplantation Smoldering (asymptomatic) myeloma Deferral of chemotherapy until progression to symptomatic disease Follow these patients closely, every 3 to 4 months, with serum protein electrophoresis, complete blood count, serum creatinine, and serum calcium Metastatic bone survey should be considered annually because asymptomatic bone lesions may develop MM: Indications for Treatment Anemia (hemoglobin <10 g/dL or 2 g/dL below normal) Hypercalcemia (serum calcium >11.5 mg/dL) Renal insufficiency (serum creatinine>2 mg/dL) Lytic bone lesions or severe osteopenia Extramedullary plasmacytoma MM: RISK STRATIFICATION FISH for detection of t(4;14), t(14;16), and del17p13 Conventional cytogenetics (karyotyping) for detection of del 13 or hypodiploidy The presence of any of the above markers defines high risk myeloma, which encompasses the 25 percent of MM patients who have a median survival of approximately two years or less despite standard treatment Current Frontline Options Conventional chemotherapy Survival ≤ 3 yrs Transplantation Prolongs survival 4-5 yrs Novel agents targeting stromal interactions and associated signaling pathways have shown promise Chng WJ, et al. Cancer Control. 2005;12:91-104. MM: INITIAL THERAPY The initial therapy of patients with symptomatic myeloma varies depending on whether patients are eligible or not to pursue autologous hematopoietic cell transplantation *Thal/dex or dex are additional options especially if immediate response is needed. Clearly not transplantation candidate based on age, performance score, and comorbidity MPT, MPV, Len/dex or clinical trial* Potential transplantation candidate Nonalkylator-based induction x 4 cycles Stem cell harvest Initial Approach to Treatment of MM DETERMINING TRANSPLANT ELIGIBILITY Autologous hematopoietic cell transplantation (HCT) results in superior event-free and overall survival rates when compared with combination chemotherapy All patients should be evaluated at diagnosis for transplant eligibility so that the risks and benefits of autologous HCT can be reviewed with those eligible A minority of patients will be eligible for allogeneic HCT, but the value of allogeneic approaches in myeloma remain investigational NOT Eligible for Autologous HCT Age >77 years Direct bilirubin>2.0 mg/dL (34.2 µmol/liter) Serum creatinine>2.5 mg/dL (221 µmol/liter) unless on chronic stable dialysis Eastern Cooperative Oncology Group (ECOG) performance status 3 or 4 unless due to bone pain New York Heart Association functional status Class III or IV 54 42 Attal M, et al. N Engl J Med. 1996;335:91-97. Child JA, et al. N Engl J Med. 2003;348:1875-1883. 15 30 45 60 25 50 75 100 OS (%) 0 0 High dose Conventional dose Mos 20 40 60 80 25 50 75 100 Survival (%) 0 0 Intensive therapy Standard therapy Mos P = .03 by Wilcoxon test P = .04 by log-rank test Transplantation vs Conventional Chemotherapy Autologous Stem Cell Transplantation Mel 200 mg/m2 standard conditioning regimen Sufficient performance score, and adequate liver, pulmonary, cardiac function needed Higher PR and CR rates than conventional chemotherapy Higher OS and EFS than conventional Rx Advanced age and impaired renal function are, by themselves, not contraindications Attal M, et al. N Engl J Med. 1996;335:91-97. NCCN Practice Guidelines. Myeloma. V.3.2010. Stem Cell Transplantation Key issues Efficacy compared with conventional chemotherapy Timing: early vs delayed Single vs tandem Role of allogeneic and miniallogeneic transplantations Maintenance post-SCT Novel Frontline Options Immunomodulatory drugs (IMiDs) Thalidomide Lenalidomide Proteasome inhibitors Bortezomib Carfilzomib Kyle RA, et al. N Engl J Med. 2004;351:1860-1873. Copyright ©2004. Massachusetts Medical Society. All rights reserved. Proposed Mechanism of Action for Multiple Myeloma Therapies Thalidomide: Proposed Mechanism of Action Proposed mechanisms Inhibition of TNF- Suppression of angiogenesis Increase in cell-mediated cytotoxic effects Modulation of adhesion molecule expression Kyle RA, et al. N Engl J Med. 2004;351:1860-1873. Rajkumar SV, et al. Leukemia. 2003;17:775-779. D’Amato RJ, et al.Proc Natl Acad Sci U S A. 1994;91:4082-4085.
Slide 47 - Special Thanks to… For sponsorship of LMEF programs: Supported by an educational grant from Lilly USA, LLC Did you know that you could be receiving credit for attending today? For membership information, please visit our website: www.Lafmeded.org. Multiple Myeloma 2010 Wael Harb MD Horizon Oncology Center Overview Introduction: epidemiology, clinical presentation, diagnosis, staging Autologous stem cell transplantation Initial approaches to treatment Current options Novel agents and combinations Considerations in non-transplantation-eligible patients Prevention of skeletal complications What is MM? Multiple myeloma (MM) is characterized by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. Plasma Cell Multiple Myeloma: Incidence The lifetime risk of getting MM is 1 in 159 (0.63%). 20,180 new cases will be diagnosed in 2010 (11,170 in men and 9,010 in women) 10,650 deaths are expected to occur in 2010 (5,760 in men and 4,890 in women) The 5-year relative survival rate for MM is around 35% Incidence MM occurs in all races and all geographic locations African Americans and blacks from Africa is two to three times the risk in whites Risk is lower in Asians from Japan and in Mexicans Slightly more frequent in men than in women (1.4:1) Age MM is a disease of older adults The median age at diagnosis is 66 years Only 10 percent of patients are younger than 50 years Only 2 percent of patients are younger than 40 years MM: Clinical Presentations Anemia - 73 percent Bone pain - 58 percent Elevated creatinine - 48 percent Fatigue/generalized weakness - 32 percent Hypercalcemia- 28 percent Weight loss - 24 percent, one-half of whom had lost ≥ 9 kg Multiple Myeloma = M-CRAB Monoclonal protein Calcium Renal failure Anemia Bone pain with lytic lesions Immunoglobulin Immunoglobulins SPEP: Normal SPEP: M-protein, M-spike Renal Failure Cast nephropathy (also called myeloma kidney) from light chains Hypercalcemia Light chain amyloidosis Drug-induced renal damage Anemia Normocytic, normochromic anemiais present in 73% at diagnosis and in 97%at some time during the course of the disease This anemia can be related to: Bone marrow replacement Kidney damage Dilution in the case of a large M-protein B12 deficiency in 14% Rouleaux Formation Lytic Bone Lesion MM: PET Scan Extramedullary Plasmacytoma Differential Diagnosis of MM Monoclonal gammopathy of undetermined significance (MGUS) Smoldering multiple myeloma (SMM) Waldenstrom macroglobulinemia Solitary plasmacytoma Primary amyloidosis (AL) POEMS syndrome Metastatic carcinoma Multiple Myeloma All 3 criteria must be met: Presence of a serum or urinary monoclonal protein Presence of clonal plasma cells in the bone marrow or a plasmacytoma Presence of end organ damage felt related to the plasma cell dyscrasia, such as: Increased calcium concentration Lytic bone lesions Anemia Renal failure Smoldering Multiple Myeloma SMM, Asymptomatic Both criteria must be met: Serum monoclonal protein ≥3 g/dL and/or bone marrow plasma cells ≥10 percent No end organ damage related to plasma cell dyscrasia Monoclonal Gammopathy of Undetermined Significance (MGUS) All 3 criteria must be met: Serum monoclonal protein <3 g/dL Bone marrow plasma cells <10 percent No end organ damage related to plasma cell dyscrasia or a related B cell lymphoproliferative disorder POEMS Syndrome Osteosclerotic myeloma Polyneuropathy Organomegaly Endocrinopathy Monoclonal protein Skin changes MM: Evaluation CBC and differential,peripheral blood smear Chemistry:serum calcium, creatinine, albumin, LDH , beta-2 microglobulin, and C-reactive protein Serum protein electrophoresis (SPEP) + IF Quantification of immunoglobulins Urinalysis and a 24-hour urine collection for electrophoresis (UPEP) + IF Serum free monoclonal light chain (FLC) MM Evaluation Serum viscosity should be measured if the M-protein concentration is high Bone marrow aspiration and biopsy with immunophenotyping, conventional cytogenetics, and fluorescence in situ hybridization (FISH) Metastatic bone survey with plain radiographs including the humeri and femoral bones should be performed in all patients. MRI, CT, or PET/CT Bone Marrow Cytogenenetics, Interphase FISH Poor prognosis (median survival 25 months): t(4;14)(p16;q32), t(14;16)(q32;q23), and -17p13 Intermediate prognosis (median survival 42 months): -13q14 Good prognosis (median survival 50 months): all others Staging for MM International staging system (ISS)  Stage I — B2M <3.5 mg/L and serum albumin ≥3.5 g/dL Stage II — neither stage I nor stage III Stage III — B2M ≥5.5 mg/L Median overall survival for patients with ISS stages I, II, and III are 62, 44, and 29 months MM: Treatment Decisions Indications for treatment Risk stratification Eligibility for stem cell transplantation Smoldering (asymptomatic) myeloma Deferral of chemotherapy until progression to symptomatic disease Follow these patients closely, every 3 to 4 months, with serum protein electrophoresis, complete blood count, serum creatinine, and serum calcium Metastatic bone survey should be considered annually because asymptomatic bone lesions may develop MM: Indications for Treatment Anemia (hemoglobin <10 g/dL or 2 g/dL below normal) Hypercalcemia (serum calcium >11.5 mg/dL) Renal insufficiency (serum creatinine>2 mg/dL) Lytic bone lesions or severe osteopenia Extramedullary plasmacytoma MM: RISK STRATIFICATION FISH for detection of t(4;14), t(14;16), and del17p13 Conventional cytogenetics (karyotyping) for detection of del 13 or hypodiploidy The presence of any of the above markers defines high risk myeloma, which encompasses the 25 percent of MM patients who have a median survival of approximately two years or less despite standard treatment Current Frontline Options Conventional chemotherapy Survival ≤ 3 yrs Transplantation Prolongs survival 4-5 yrs Novel agents targeting stromal interactions and associated signaling pathways have shown promise Chng WJ, et al. Cancer Control. 2005;12:91-104. MM: INITIAL THERAPY The initial therapy of patients with symptomatic myeloma varies depending on whether patients are eligible or not to pursue autologous hematopoietic cell transplantation *Thal/dex or dex are additional options especially if immediate response is needed. Clearly not transplantation candidate based on age, performance score, and comorbidity MPT, MPV, Len/dex or clinical trial* Potential transplantation candidate Nonalkylator-based induction x 4 cycles Stem cell harvest Initial Approach to Treatment of MM DETERMINING TRANSPLANT ELIGIBILITY Autologous hematopoietic cell transplantation (HCT) results in superior event-free and overall survival rates when compared with combination chemotherapy All patients should be evaluated at diagnosis for transplant eligibility so that the risks and benefits of autologous HCT can be reviewed with those eligible A minority of patients will be eligible for allogeneic HCT, but the value of allogeneic approaches in myeloma remain investigational NOT Eligible for Autologous HCT Age >77 years Direct bilirubin>2.0 mg/dL (34.2 µmol/liter) Serum creatinine>2.5 mg/dL (221 µmol/liter) unless on chronic stable dialysis Eastern Cooperative Oncology Group (ECOG) performance status 3 or 4 unless due to bone pain New York Heart Association functional status Class III or IV 54 42 Attal M, et al. N Engl J Med. 1996;335:91-97. Child JA, et al. N Engl J Med. 2003;348:1875-1883. 15 30 45 60 25 50 75 100 OS (%) 0 0 High dose Conventional dose Mos 20 40 60 80 25 50 75 100 Survival (%) 0 0 Intensive therapy Standard therapy Mos P = .03 by Wilcoxon test P = .04 by log-rank test Transplantation vs Conventional Chemotherapy Autologous Stem Cell Transplantation Mel 200 mg/m2 standard conditioning regimen Sufficient performance score, and adequate liver, pulmonary, cardiac function needed Higher PR and CR rates than conventional chemotherapy Higher OS and EFS than conventional Rx Advanced age and impaired renal function are, by themselves, not contraindications Attal M, et al. N Engl J Med. 1996;335:91-97. NCCN Practice Guidelines. Myeloma. V.3.2010. Stem Cell Transplantation Key issues Efficacy compared with conventional chemotherapy Timing: early vs delayed Single vs tandem Role of allogeneic and miniallogeneic transplantations Maintenance post-SCT Novel Frontline Options Immunomodulatory drugs (IMiDs) Thalidomide Lenalidomide Proteasome inhibitors Bortezomib Carfilzomib Kyle RA, et al. N Engl J Med. 2004;351:1860-1873. Copyright ©2004. Massachusetts Medical Society. All rights reserved. Proposed Mechanism of Action for Multiple Myeloma Therapies Thalidomide: Proposed Mechanism of Action Proposed mechanisms Inhibition of TNF- Suppression of angiogenesis Increase in cell-mediated cytotoxic effects Modulation of adhesion molecule expression Kyle RA, et al. N Engl J Med. 2004;351:1860-1873. Rajkumar SV, et al. Leukemia. 2003;17:775-779. D’Amato RJ, et al.Proc Natl Acad Sci U S A. 1994;91:4082-4085. Lenalidomide Immunomodulatory derivative of thalidomide More potent than thalidomide in preclinical models Dose-dependent decrease in TNF-α and interleukin-6 Directly induces apoptosis, G1 growth arrest Enhances activity of dexamethasone More favorable toxicity profile than thalidomide Richardson P, et al. Blood. 2003;100:3063. Hideshima T, et al. Blood. 2000;96:2943-2950.
Slide 48 - Special Thanks to… For sponsorship of LMEF programs: Supported by an educational grant from Lilly USA, LLC Did you know that you could be receiving credit for attending today? For membership information, please visit our website: www.Lafmeded.org. Multiple Myeloma 2010 Wael Harb MD Horizon Oncology Center Overview Introduction: epidemiology, clinical presentation, diagnosis, staging Autologous stem cell transplantation Initial approaches to treatment Current options Novel agents and combinations Considerations in non-transplantation-eligible patients Prevention of skeletal complications What is MM? Multiple myeloma (MM) is characterized by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. Plasma Cell Multiple Myeloma: Incidence The lifetime risk of getting MM is 1 in 159 (0.63%). 20,180 new cases will be diagnosed in 2010 (11,170 in men and 9,010 in women) 10,650 deaths are expected to occur in 2010 (5,760 in men and 4,890 in women) The 5-year relative survival rate for MM is around 35% Incidence MM occurs in all races and all geographic locations African Americans and blacks from Africa is two to three times the risk in whites Risk is lower in Asians from Japan and in Mexicans Slightly more frequent in men than in women (1.4:1) Age MM is a disease of older adults The median age at diagnosis is 66 years Only 10 percent of patients are younger than 50 years Only 2 percent of patients are younger than 40 years MM: Clinical Presentations Anemia - 73 percent Bone pain - 58 percent Elevated creatinine - 48 percent Fatigue/generalized weakness - 32 percent Hypercalcemia- 28 percent Weight loss - 24 percent, one-half of whom had lost ≥ 9 kg Multiple Myeloma = M-CRAB Monoclonal protein Calcium Renal failure Anemia Bone pain with lytic lesions Immunoglobulin Immunoglobulins SPEP: Normal SPEP: M-protein, M-spike Renal Failure Cast nephropathy (also called myeloma kidney) from light chains Hypercalcemia Light chain amyloidosis Drug-induced renal damage Anemia Normocytic, normochromic anemiais present in 73% at diagnosis and in 97%at some time during the course of the disease This anemia can be related to: Bone marrow replacement Kidney damage Dilution in the case of a large M-protein B12 deficiency in 14% Rouleaux Formation Lytic Bone Lesion MM: PET Scan Extramedullary Plasmacytoma Differential Diagnosis of MM Monoclonal gammopathy of undetermined significance (MGUS) Smoldering multiple myeloma (SMM) Waldenstrom macroglobulinemia Solitary plasmacytoma Primary amyloidosis (AL) POEMS syndrome Metastatic carcinoma Multiple Myeloma All 3 criteria must be met: Presence of a serum or urinary monoclonal protein Presence of clonal plasma cells in the bone marrow or a plasmacytoma Presence of end organ damage felt related to the plasma cell dyscrasia, such as: Increased calcium concentration Lytic bone lesions Anemia Renal failure Smoldering Multiple Myeloma SMM, Asymptomatic Both criteria must be met: Serum monoclonal protein ≥3 g/dL and/or bone marrow plasma cells ≥10 percent No end organ damage related to plasma cell dyscrasia Monoclonal Gammopathy of Undetermined Significance (MGUS) All 3 criteria must be met: Serum monoclonal protein <3 g/dL Bone marrow plasma cells <10 percent No end organ damage related to plasma cell dyscrasia or a related B cell lymphoproliferative disorder POEMS Syndrome Osteosclerotic myeloma Polyneuropathy Organomegaly Endocrinopathy Monoclonal protein Skin changes MM: Evaluation CBC and differential,peripheral blood smear Chemistry:serum calcium, creatinine, albumin, LDH , beta-2 microglobulin, and C-reactive protein Serum protein electrophoresis (SPEP) + IF Quantification of immunoglobulins Urinalysis and a 24-hour urine collection for electrophoresis (UPEP) + IF Serum free monoclonal light chain (FLC) MM Evaluation Serum viscosity should be measured if the M-protein concentration is high Bone marrow aspiration and biopsy with immunophenotyping, conventional cytogenetics, and fluorescence in situ hybridization (FISH) Metastatic bone survey with plain radiographs including the humeri and femoral bones should be performed in all patients. MRI, CT, or PET/CT Bone Marrow Cytogenenetics, Interphase FISH Poor prognosis (median survival 25 months): t(4;14)(p16;q32), t(14;16)(q32;q23), and -17p13 Intermediate prognosis (median survival 42 months): -13q14 Good prognosis (median survival 50 months): all others Staging for MM International staging system (ISS)  Stage I — B2M <3.5 mg/L and serum albumin ≥3.5 g/dL Stage II — neither stage I nor stage III Stage III — B2M ≥5.5 mg/L Median overall survival for patients with ISS stages I, II, and III are 62, 44, and 29 months MM: Treatment Decisions Indications for treatment Risk stratification Eligibility for stem cell transplantation Smoldering (asymptomatic) myeloma Deferral of chemotherapy until progression to symptomatic disease Follow these patients closely, every 3 to 4 months, with serum protein electrophoresis, complete blood count, serum creatinine, and serum calcium Metastatic bone survey should be considered annually because asymptomatic bone lesions may develop MM: Indications for Treatment Anemia (hemoglobin <10 g/dL or 2 g/dL below normal) Hypercalcemia (serum calcium >11.5 mg/dL) Renal insufficiency (serum creatinine>2 mg/dL) Lytic bone lesions or severe osteopenia Extramedullary plasmacytoma MM: RISK STRATIFICATION FISH for detection of t(4;14), t(14;16), and del17p13 Conventional cytogenetics (karyotyping) for detection of del 13 or hypodiploidy The presence of any of the above markers defines high risk myeloma, which encompasses the 25 percent of MM patients who have a median survival of approximately two years or less despite standard treatment Current Frontline Options Conventional chemotherapy Survival ≤ 3 yrs Transplantation Prolongs survival 4-5 yrs Novel agents targeting stromal interactions and associated signaling pathways have shown promise Chng WJ, et al. Cancer Control. 2005;12:91-104. MM: INITIAL THERAPY The initial therapy of patients with symptomatic myeloma varies depending on whether patients are eligible or not to pursue autologous hematopoietic cell transplantation *Thal/dex or dex are additional options especially if immediate response is needed. Clearly not transplantation candidate based on age, performance score, and comorbidity MPT, MPV, Len/dex or clinical trial* Potential transplantation candidate Nonalkylator-based induction x 4 cycles Stem cell harvest Initial Approach to Treatment of MM DETERMINING TRANSPLANT ELIGIBILITY Autologous hematopoietic cell transplantation (HCT) results in superior event-free and overall survival rates when compared with combination chemotherapy All patients should be evaluated at diagnosis for transplant eligibility so that the risks and benefits of autologous HCT can be reviewed with those eligible A minority of patients will be eligible for allogeneic HCT, but the value of allogeneic approaches in myeloma remain investigational NOT Eligible for Autologous HCT Age >77 years Direct bilirubin>2.0 mg/dL (34.2 µmol/liter) Serum creatinine>2.5 mg/dL (221 µmol/liter) unless on chronic stable dialysis Eastern Cooperative Oncology Group (ECOG) performance status 3 or 4 unless due to bone pain New York Heart Association functional status Class III or IV 54 42 Attal M, et al. N Engl J Med. 1996;335:91-97. Child JA, et al. N Engl J Med. 2003;348:1875-1883. 15 30 45 60 25 50 75 100 OS (%) 0 0 High dose Conventional dose Mos 20 40 60 80 25 50 75 100 Survival (%) 0 0 Intensive therapy Standard therapy Mos P = .03 by Wilcoxon test P = .04 by log-rank test Transplantation vs Conventional Chemotherapy Autologous Stem Cell Transplantation Mel 200 mg/m2 standard conditioning regimen Sufficient performance score, and adequate liver, pulmonary, cardiac function needed Higher PR and CR rates than conventional chemotherapy Higher OS and EFS than conventional Rx Advanced age and impaired renal function are, by themselves, not contraindications Attal M, et al. N Engl J Med. 1996;335:91-97. NCCN Practice Guidelines. Myeloma. V.3.2010. Stem Cell Transplantation Key issues Efficacy compared with conventional chemotherapy Timing: early vs delayed Single vs tandem Role of allogeneic and miniallogeneic transplantations Maintenance post-SCT Novel Frontline Options Immunomodulatory drugs (IMiDs) Thalidomide Lenalidomide Proteasome inhibitors Bortezomib Carfilzomib Kyle RA, et al. N Engl J Med. 2004;351:1860-1873. Copyright ©2004. Massachusetts Medical Society. All rights reserved. Proposed Mechanism of Action for Multiple Myeloma Therapies Thalidomide: Proposed Mechanism of Action Proposed mechanisms Inhibition of TNF- Suppression of angiogenesis Increase in cell-mediated cytotoxic effects Modulation of adhesion molecule expression Kyle RA, et al. N Engl J Med. 2004;351:1860-1873. Rajkumar SV, et al. Leukemia. 2003;17:775-779. D’Amato RJ, et al.Proc Natl Acad Sci U S A. 1994;91:4082-4085. Lenalidomide Immunomodulatory derivative of thalidomide More potent than thalidomide in preclinical models Dose-dependent decrease in TNF-α and interleukin-6 Directly induces apoptosis, G1 growth arrest Enhances activity of dexamethasone More favorable toxicity profile than thalidomide Richardson P, et al. Blood. 2003;100:3063. Hideshima T, et al. Blood. 2000;96:2943-2950. Bortezomib: A Reversible Proteasome Inhibitor Chymo- tryptic Site Post- Glutamyl Site Tryptic Site b1 b2 b3 b4 b5 b6 b7 Cross section of  ring Bortezomib Adams J, et al. Invest New Drugs. 2000;18:109-121. Adams J, et al. Bioorg Med Chem Lett. 1998;8:333-338. H N B N H O O OH N N OH
Slide 49 - Special Thanks to… For sponsorship of LMEF programs: Supported by an educational grant from Lilly USA, LLC Did you know that you could be receiving credit for attending today? For membership information, please visit our website: www.Lafmeded.org. Multiple Myeloma 2010 Wael Harb MD Horizon Oncology Center Overview Introduction: epidemiology, clinical presentation, diagnosis, staging Autologous stem cell transplantation Initial approaches to treatment Current options Novel agents and combinations Considerations in non-transplantation-eligible patients Prevention of skeletal complications What is MM? Multiple myeloma (MM) is characterized by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. Plasma Cell Multiple Myeloma: Incidence The lifetime risk of getting MM is 1 in 159 (0.63%). 20,180 new cases will be diagnosed in 2010 (11,170 in men and 9,010 in women) 10,650 deaths are expected to occur in 2010 (5,760 in men and 4,890 in women) The 5-year relative survival rate for MM is around 35% Incidence MM occurs in all races and all geographic locations African Americans and blacks from Africa is two to three times the risk in whites Risk is lower in Asians from Japan and in Mexicans Slightly more frequent in men than in women (1.4:1) Age MM is a disease of older adults The median age at diagnosis is 66 years Only 10 percent of patients are younger than 50 years Only 2 percent of patients are younger than 40 years MM: Clinical Presentations Anemia - 73 percent Bone pain - 58 percent Elevated creatinine - 48 percent Fatigue/generalized weakness - 32 percent Hypercalcemia- 28 percent Weight loss - 24 percent, one-half of whom had lost ≥ 9 kg Multiple Myeloma = M-CRAB Monoclonal protein Calcium Renal failure Anemia Bone pain with lytic lesions Immunoglobulin Immunoglobulins SPEP: Normal SPEP: M-protein, M-spike Renal Failure Cast nephropathy (also called myeloma kidney) from light chains Hypercalcemia Light chain amyloidosis Drug-induced renal damage Anemia Normocytic, normochromic anemiais present in 73% at diagnosis and in 97%at some time during the course of the disease This anemia can be related to: Bone marrow replacement Kidney damage Dilution in the case of a large M-protein B12 deficiency in 14% Rouleaux Formation Lytic Bone Lesion MM: PET Scan Extramedullary Plasmacytoma Differential Diagnosis of MM Monoclonal gammopathy of undetermined significance (MGUS) Smoldering multiple myeloma (SMM) Waldenstrom macroglobulinemia Solitary plasmacytoma Primary amyloidosis (AL) POEMS syndrome Metastatic carcinoma Multiple Myeloma All 3 criteria must be met: Presence of a serum or urinary monoclonal protein Presence of clonal plasma cells in the bone marrow or a plasmacytoma Presence of end organ damage felt related to the plasma cell dyscrasia, such as: Increased calcium concentration Lytic bone lesions Anemia Renal failure Smoldering Multiple Myeloma SMM, Asymptomatic Both criteria must be met: Serum monoclonal protein ≥3 g/dL and/or bone marrow plasma cells ≥10 percent No end organ damage related to plasma cell dyscrasia Monoclonal Gammopathy of Undetermined Significance (MGUS) All 3 criteria must be met: Serum monoclonal protein <3 g/dL Bone marrow plasma cells <10 percent No end organ damage related to plasma cell dyscrasia or a related B cell lymphoproliferative disorder POEMS Syndrome Osteosclerotic myeloma Polyneuropathy Organomegaly Endocrinopathy Monoclonal protein Skin changes MM: Evaluation CBC and differential,peripheral blood smear Chemistry:serum calcium, creatinine, albumin, LDH , beta-2 microglobulin, and C-reactive protein Serum protein electrophoresis (SPEP) + IF Quantification of immunoglobulins Urinalysis and a 24-hour urine collection for electrophoresis (UPEP) + IF Serum free monoclonal light chain (FLC) MM Evaluation Serum viscosity should be measured if the M-protein concentration is high Bone marrow aspiration and biopsy with immunophenotyping, conventional cytogenetics, and fluorescence in situ hybridization (FISH) Metastatic bone survey with plain radiographs including the humeri and femoral bones should be performed in all patients. MRI, CT, or PET/CT Bone Marrow Cytogenenetics, Interphase FISH Poor prognosis (median survival 25 months): t(4;14)(p16;q32), t(14;16)(q32;q23), and -17p13 Intermediate prognosis (median survival 42 months): -13q14 Good prognosis (median survival 50 months): all others Staging for MM International staging system (ISS)  Stage I — B2M <3.5 mg/L and serum albumin ≥3.5 g/dL Stage II — neither stage I nor stage III Stage III — B2M ≥5.5 mg/L Median overall survival for patients with ISS stages I, II, and III are 62, 44, and 29 months MM: Treatment Decisions Indications for treatment Risk stratification Eligibility for stem cell transplantation Smoldering (asymptomatic) myeloma Deferral of chemotherapy until progression to symptomatic disease Follow these patients closely, every 3 to 4 months, with serum protein electrophoresis, complete blood count, serum creatinine, and serum calcium Metastatic bone survey should be considered annually because asymptomatic bone lesions may develop MM: Indications for Treatment Anemia (hemoglobin <10 g/dL or 2 g/dL below normal) Hypercalcemia (serum calcium >11.5 mg/dL) Renal insufficiency (serum creatinine>2 mg/dL) Lytic bone lesions or severe osteopenia Extramedullary plasmacytoma MM: RISK STRATIFICATION FISH for detection of t(4;14), t(14;16), and del17p13 Conventional cytogenetics (karyotyping) for detection of del 13 or hypodiploidy The presence of any of the above markers defines high risk myeloma, which encompasses the 25 percent of MM patients who have a median survival of approximately two years or less despite standard treatment Current Frontline Options Conventional chemotherapy Survival ≤ 3 yrs Transplantation Prolongs survival 4-5 yrs Novel agents targeting stromal interactions and associated signaling pathways have shown promise Chng WJ, et al. Cancer Control. 2005;12:91-104. MM: INITIAL THERAPY The initial therapy of patients with symptomatic myeloma varies depending on whether patients are eligible or not to pursue autologous hematopoietic cell transplantation *Thal/dex or dex are additional options especially if immediate response is needed. Clearly not transplantation candidate based on age, performance score, and comorbidity MPT, MPV, Len/dex or clinical trial* Potential transplantation candidate Nonalkylator-based induction x 4 cycles Stem cell harvest Initial Approach to Treatment of MM DETERMINING TRANSPLANT ELIGIBILITY Autologous hematopoietic cell transplantation (HCT) results in superior event-free and overall survival rates when compared with combination chemotherapy All patients should be evaluated at diagnosis for transplant eligibility so that the risks and benefits of autologous HCT can be reviewed with those eligible A minority of patients will be eligible for allogeneic HCT, but the value of allogeneic approaches in myeloma remain investigational NOT Eligible for Autologous HCT Age >77 years Direct bilirubin>2.0 mg/dL (34.2 µmol/liter) Serum creatinine>2.5 mg/dL (221 µmol/liter) unless on chronic stable dialysis Eastern Cooperative Oncology Group (ECOG) performance status 3 or 4 unless due to bone pain New York Heart Association functional status Class III or IV 54 42 Attal M, et al. N Engl J Med. 1996;335:91-97. Child JA, et al. N Engl J Med. 2003;348:1875-1883. 15 30 45 60 25 50 75 100 OS (%) 0 0 High dose Conventional dose Mos 20 40 60 80 25 50 75 100 Survival (%) 0 0 Intensive therapy Standard therapy Mos P = .03 by Wilcoxon test P = .04 by log-rank test Transplantation vs Conventional Chemotherapy Autologous Stem Cell Transplantation Mel 200 mg/m2 standard conditioning regimen Sufficient performance score, and adequate liver, pulmonary, cardiac function needed Higher PR and CR rates than conventional chemotherapy Higher OS and EFS than conventional Rx Advanced age and impaired renal function are, by themselves, not contraindications Attal M, et al. N Engl J Med. 1996;335:91-97. NCCN Practice Guidelines. Myeloma. V.3.2010. Stem Cell Transplantation Key issues Efficacy compared with conventional chemotherapy Timing: early vs delayed Single vs tandem Role of allogeneic and miniallogeneic transplantations Maintenance post-SCT Novel Frontline Options Immunomodulatory drugs (IMiDs) Thalidomide Lenalidomide Proteasome inhibitors Bortezomib Carfilzomib Kyle RA, et al. N Engl J Med. 2004;351:1860-1873. Copyright ©2004. Massachusetts Medical Society. All rights reserved. Proposed Mechanism of Action for Multiple Myeloma Therapies Thalidomide: Proposed Mechanism of Action Proposed mechanisms Inhibition of TNF- Suppression of angiogenesis Increase in cell-mediated cytotoxic effects Modulation of adhesion molecule expression Kyle RA, et al. N Engl J Med. 2004;351:1860-1873. Rajkumar SV, et al. Leukemia. 2003;17:775-779. D’Amato RJ, et al.Proc Natl Acad Sci U S A. 1994;91:4082-4085. Lenalidomide Immunomodulatory derivative of thalidomide More potent than thalidomide in preclinical models Dose-dependent decrease in TNF-α and interleukin-6 Directly induces apoptosis, G1 growth arrest Enhances activity of dexamethasone More favorable toxicity profile than thalidomide Richardson P, et al. Blood. 2003;100:3063. Hideshima T, et al. Blood. 2000;96:2943-2950. Bortezomib: A Reversible Proteasome Inhibitor Chymo- tryptic Site Post- Glutamyl Site Tryptic Site b1 b2 b3 b4 b5 b6 b7 Cross section of  ring Bortezomib Adams J, et al. Invest New Drugs. 2000;18:109-121. Adams J, et al. Bioorg Med Chem Lett. 1998;8:333-338. H N B N H O O OH N N OH Initial Approach to Treatment of MM Clearly not a transplantation candidate MPT, MPV, Len/dex or clinical trial* Potential transplantation candidate Nonalkylator-based induction Stem cell harvest
Slide 50 - Special Thanks to… For sponsorship of LMEF programs: Supported by an educational grant from Lilly USA, LLC Did you know that you could be receiving credit for attending today? For membership information, please visit our website: www.Lafmeded.org. Multiple Myeloma 2010 Wael Harb MD Horizon Oncology Center Overview Introduction: epidemiology, clinical presentation, diagnosis, staging Autologous stem cell transplantation Initial approaches to treatment Current options Novel agents and combinations Considerations in non-transplantation-eligible patients Prevention of skeletal complications What is MM? Multiple myeloma (MM) is characterized by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. Plasma Cell Multiple Myeloma: Incidence The lifetime risk of getting MM is 1 in 159 (0.63%). 20,180 new cases will be diagnosed in 2010 (11,170 in men and 9,010 in women) 10,650 deaths are expected to occur in 2010 (5,760 in men and 4,890 in women) The 5-year relative survival rate for MM is around 35% Incidence MM occurs in all races and all geographic locations African Americans and blacks from Africa is two to three times the risk in whites Risk is lower in Asians from Japan and in Mexicans Slightly more frequent in men than in women (1.4:1) Age MM is a disease of older adults The median age at diagnosis is 66 years Only 10 percent of patients are younger than 50 years Only 2 percent of patients are younger than 40 years MM: Clinical Presentations Anemia - 73 percent Bone pain - 58 percent Elevated creatinine - 48 percent Fatigue/generalized weakness - 32 percent Hypercalcemia- 28 percent Weight loss - 24 percent, one-half of whom had lost ≥ 9 kg Multiple Myeloma = M-CRAB Monoclonal protein Calcium Renal failure Anemia Bone pain with lytic lesions Immunoglobulin Immunoglobulins SPEP: Normal SPEP: M-protein, M-spike Renal Failure Cast nephropathy (also called myeloma kidney) from light chains Hypercalcemia Light chain amyloidosis Drug-induced renal damage Anemia Normocytic, normochromic anemiais present in 73% at diagnosis and in 97%at some time during the course of the disease This anemia can be related to: Bone marrow replacement Kidney damage Dilution in the case of a large M-protein B12 deficiency in 14% Rouleaux Formation Lytic Bone Lesion MM: PET Scan Extramedullary Plasmacytoma Differential Diagnosis of MM Monoclonal gammopathy of undetermined significance (MGUS) Smoldering multiple myeloma (SMM) Waldenstrom macroglobulinemia Solitary plasmacytoma Primary amyloidosis (AL) POEMS syndrome Metastatic carcinoma Multiple Myeloma All 3 criteria must be met: Presence of a serum or urinary monoclonal protein Presence of clonal plasma cells in the bone marrow or a plasmacytoma Presence of end organ damage felt related to the plasma cell dyscrasia, such as: Increased calcium concentration Lytic bone lesions Anemia Renal failure Smoldering Multiple Myeloma SMM, Asymptomatic Both criteria must be met: Serum monoclonal protein ≥3 g/dL and/or bone marrow plasma cells ≥10 percent No end organ damage related to plasma cell dyscrasia Monoclonal Gammopathy of Undetermined Significance (MGUS) All 3 criteria must be met: Serum monoclonal protein <3 g/dL Bone marrow plasma cells <10 percent No end organ damage related to plasma cell dyscrasia or a related B cell lymphoproliferative disorder POEMS Syndrome Osteosclerotic myeloma Polyneuropathy Organomegaly Endocrinopathy Monoclonal protein Skin changes MM: Evaluation CBC and differential,peripheral blood smear Chemistry:serum calcium, creatinine, albumin, LDH , beta-2 microglobulin, and C-reactive protein Serum protein electrophoresis (SPEP) + IF Quantification of immunoglobulins Urinalysis and a 24-hour urine collection for electrophoresis (UPEP) + IF Serum free monoclonal light chain (FLC) MM Evaluation Serum viscosity should be measured if the M-protein concentration is high Bone marrow aspiration and biopsy with immunophenotyping, conventional cytogenetics, and fluorescence in situ hybridization (FISH) Metastatic bone survey with plain radiographs including the humeri and femoral bones should be performed in all patients. MRI, CT, or PET/CT Bone Marrow Cytogenenetics, Interphase FISH Poor prognosis (median survival 25 months): t(4;14)(p16;q32), t(14;16)(q32;q23), and -17p13 Intermediate prognosis (median survival 42 months): -13q14 Good prognosis (median survival 50 months): all others Staging for MM International staging system (ISS)  Stage I — B2M <3.5 mg/L and serum albumin ≥3.5 g/dL Stage II — neither stage I nor stage III Stage III — B2M ≥5.5 mg/L Median overall survival for patients with ISS stages I, II, and III are 62, 44, and 29 months MM: Treatment Decisions Indications for treatment Risk stratification Eligibility for stem cell transplantation Smoldering (asymptomatic) myeloma Deferral of chemotherapy until progression to symptomatic disease Follow these patients closely, every 3 to 4 months, with serum protein electrophoresis, complete blood count, serum creatinine, and serum calcium Metastatic bone survey should be considered annually because asymptomatic bone lesions may develop MM: Indications for Treatment Anemia (hemoglobin <10 g/dL or 2 g/dL below normal) Hypercalcemia (serum calcium >11.5 mg/dL) Renal insufficiency (serum creatinine>2 mg/dL) Lytic bone lesions or severe osteopenia Extramedullary plasmacytoma MM: RISK STRATIFICATION FISH for detection of t(4;14), t(14;16), and del17p13 Conventional cytogenetics (karyotyping) for detection of del 13 or hypodiploidy The presence of any of the above markers defines high risk myeloma, which encompasses the 25 percent of MM patients who have a median survival of approximately two years or less despite standard treatment Current Frontline Options Conventional chemotherapy Survival ≤ 3 yrs Transplantation Prolongs survival 4-5 yrs Novel agents targeting stromal interactions and associated signaling pathways have shown promise Chng WJ, et al. Cancer Control. 2005;12:91-104. MM: INITIAL THERAPY The initial therapy of patients with symptomatic myeloma varies depending on whether patients are eligible or not to pursue autologous hematopoietic cell transplantation *Thal/dex or dex are additional options especially if immediate response is needed. Clearly not transplantation candidate based on age, performance score, and comorbidity MPT, MPV, Len/dex or clinical trial* Potential transplantation candidate Nonalkylator-based induction x 4 cycles Stem cell harvest Initial Approach to Treatment of MM DETERMINING TRANSPLANT ELIGIBILITY Autologous hematopoietic cell transplantation (HCT) results in superior event-free and overall survival rates when compared with combination chemotherapy All patients should be evaluated at diagnosis for transplant eligibility so that the risks and benefits of autologous HCT can be reviewed with those eligible A minority of patients will be eligible for allogeneic HCT, but the value of allogeneic approaches in myeloma remain investigational NOT Eligible for Autologous HCT Age >77 years Direct bilirubin>2.0 mg/dL (34.2 µmol/liter) Serum creatinine>2.5 mg/dL (221 µmol/liter) unless on chronic stable dialysis Eastern Cooperative Oncology Group (ECOG) performance status 3 or 4 unless due to bone pain New York Heart Association functional status Class III or IV 54 42 Attal M, et al. N Engl J Med. 1996;335:91-97. Child JA, et al. N Engl J Med. 2003;348:1875-1883. 15 30 45 60 25 50 75 100 OS (%) 0 0 High dose Conventional dose Mos 20 40 60 80 25 50 75 100 Survival (%) 0 0 Intensive therapy Standard therapy Mos P = .03 by Wilcoxon test P = .04 by log-rank test Transplantation vs Conventional Chemotherapy Autologous Stem Cell Transplantation Mel 200 mg/m2 standard conditioning regimen Sufficient performance score, and adequate liver, pulmonary, cardiac function needed Higher PR and CR rates than conventional chemotherapy Higher OS and EFS than conventional Rx Advanced age and impaired renal function are, by themselves, not contraindications Attal M, et al. N Engl J Med. 1996;335:91-97. NCCN Practice Guidelines. Myeloma. V.3.2010. Stem Cell Transplantation Key issues Efficacy compared with conventional chemotherapy Timing: early vs delayed Single vs tandem Role of allogeneic and miniallogeneic transplantations Maintenance post-SCT Novel Frontline Options Immunomodulatory drugs (IMiDs) Thalidomide Lenalidomide Proteasome inhibitors Bortezomib Carfilzomib Kyle RA, et al. N Engl J Med. 2004;351:1860-1873. Copyright ©2004. Massachusetts Medical Society. All rights reserved. Proposed Mechanism of Action for Multiple Myeloma Therapies Thalidomide: Proposed Mechanism of Action Proposed mechanisms Inhibition of TNF- Suppression of angiogenesis Increase in cell-mediated cytotoxic effects Modulation of adhesion molecule expression Kyle RA, et al. N Engl J Med. 2004;351:1860-1873. Rajkumar SV, et al. Leukemia. 2003;17:775-779. D’Amato RJ, et al.Proc Natl Acad Sci U S A. 1994;91:4082-4085. Lenalidomide Immunomodulatory derivative of thalidomide More potent than thalidomide in preclinical models Dose-dependent decrease in TNF-α and interleukin-6 Directly induces apoptosis, G1 growth arrest Enhances activity of dexamethasone More favorable toxicity profile than thalidomide Richardson P, et al. Blood. 2003;100:3063. Hideshima T, et al. Blood. 2000;96:2943-2950. Bortezomib: A Reversible Proteasome Inhibitor Chymo- tryptic Site Post- Glutamyl Site Tryptic Site b1 b2 b3 b4 b5 b6 b7 Cross section of  ring Bortezomib Adams J, et al. Invest New Drugs. 2000;18:109-121. Adams J, et al. Bioorg Med Chem Lett. 1998;8:333-338. H N B N H O O OH N N OH Initial Approach to Treatment of MM Clearly not a transplantation candidate MPT, MPV, Len/dex or clinical trial* Potential transplantation candidate Nonalkylator-based induction Stem cell harvest Melphalan/Prednisone/Thalidomide Palumbo A, et al. Blood. 2008;112:3107-3114.
Slide 51 - Special Thanks to… For sponsorship of LMEF programs: Supported by an educational grant from Lilly USA, LLC Did you know that you could be receiving credit for attending today? For membership information, please visit our website: www.Lafmeded.org. Multiple Myeloma 2010 Wael Harb MD Horizon Oncology Center Overview Introduction: epidemiology, clinical presentation, diagnosis, staging Autologous stem cell transplantation Initial approaches to treatment Current options Novel agents and combinations Considerations in non-transplantation-eligible patients Prevention of skeletal complications What is MM? Multiple myeloma (MM) is characterized by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. Plasma Cell Multiple Myeloma: Incidence The lifetime risk of getting MM is 1 in 159 (0.63%). 20,180 new cases will be diagnosed in 2010 (11,170 in men and 9,010 in women) 10,650 deaths are expected to occur in 2010 (5,760 in men and 4,890 in women) The 5-year relative survival rate for MM is around 35% Incidence MM occurs in all races and all geographic locations African Americans and blacks from Africa is two to three times the risk in whites Risk is lower in Asians from Japan and in Mexicans Slightly more frequent in men than in women (1.4:1) Age MM is a disease of older adults The median age at diagnosis is 66 years Only 10 percent of patients are younger than 50 years Only 2 percent of patients are younger than 40 years MM: Clinical Presentations Anemia - 73 percent Bone pain - 58 percent Elevated creatinine - 48 percent Fatigue/generalized weakness - 32 percent Hypercalcemia- 28 percent Weight loss - 24 percent, one-half of whom had lost ≥ 9 kg Multiple Myeloma = M-CRAB Monoclonal protein Calcium Renal failure Anemia Bone pain with lytic lesions Immunoglobulin Immunoglobulins SPEP: Normal SPEP: M-protein, M-spike Renal Failure Cast nephropathy (also called myeloma kidney) from light chains Hypercalcemia Light chain amyloidosis Drug-induced renal damage Anemia Normocytic, normochromic anemiais present in 73% at diagnosis and in 97%at some time during the course of the disease This anemia can be related to: Bone marrow replacement Kidney damage Dilution in the case of a large M-protein B12 deficiency in 14% Rouleaux Formation Lytic Bone Lesion MM: PET Scan Extramedullary Plasmacytoma Differential Diagnosis of MM Monoclonal gammopathy of undetermined significance (MGUS) Smoldering multiple myeloma (SMM) Waldenstrom macroglobulinemia Solitary plasmacytoma Primary amyloidosis (AL) POEMS syndrome Metastatic carcinoma Multiple Myeloma All 3 criteria must be met: Presence of a serum or urinary monoclonal protein Presence of clonal plasma cells in the bone marrow or a plasmacytoma Presence of end organ damage felt related to the plasma cell dyscrasia, such as: Increased calcium concentration Lytic bone lesions Anemia Renal failure Smoldering Multiple Myeloma SMM, Asymptomatic Both criteria must be met: Serum monoclonal protein ≥3 g/dL and/or bone marrow plasma cells ≥10 percent No end organ damage related to plasma cell dyscrasia Monoclonal Gammopathy of Undetermined Significance (MGUS) All 3 criteria must be met: Serum monoclonal protein <3 g/dL Bone marrow plasma cells <10 percent No end organ damage related to plasma cell dyscrasia or a related B cell lymphoproliferative disorder POEMS Syndrome Osteosclerotic myeloma Polyneuropathy Organomegaly Endocrinopathy Monoclonal protein Skin changes MM: Evaluation CBC and differential,peripheral blood smear Chemistry:serum calcium, creatinine, albumin, LDH , beta-2 microglobulin, and C-reactive protein Serum protein electrophoresis (SPEP) + IF Quantification of immunoglobulins Urinalysis and a 24-hour urine collection for electrophoresis (UPEP) + IF Serum free monoclonal light chain (FLC) MM Evaluation Serum viscosity should be measured if the M-protein concentration is high Bone marrow aspiration and biopsy with immunophenotyping, conventional cytogenetics, and fluorescence in situ hybridization (FISH) Metastatic bone survey with plain radiographs including the humeri and femoral bones should be performed in all patients. MRI, CT, or PET/CT Bone Marrow Cytogenenetics, Interphase FISH Poor prognosis (median survival 25 months): t(4;14)(p16;q32), t(14;16)(q32;q23), and -17p13 Intermediate prognosis (median survival 42 months): -13q14 Good prognosis (median survival 50 months): all others Staging for MM International staging system (ISS)  Stage I — B2M <3.5 mg/L and serum albumin ≥3.5 g/dL Stage II — neither stage I nor stage III Stage III — B2M ≥5.5 mg/L Median overall survival for patients with ISS stages I, II, and III are 62, 44, and 29 months MM: Treatment Decisions Indications for treatment Risk stratification Eligibility for stem cell transplantation Smoldering (asymptomatic) myeloma Deferral of chemotherapy until progression to symptomatic disease Follow these patients closely, every 3 to 4 months, with serum protein electrophoresis, complete blood count, serum creatinine, and serum calcium Metastatic bone survey should be considered annually because asymptomatic bone lesions may develop MM: Indications for Treatment Anemia (hemoglobin <10 g/dL or 2 g/dL below normal) Hypercalcemia (serum calcium >11.5 mg/dL) Renal insufficiency (serum creatinine>2 mg/dL) Lytic bone lesions or severe osteopenia Extramedullary plasmacytoma MM: RISK STRATIFICATION FISH for detection of t(4;14), t(14;16), and del17p13 Conventional cytogenetics (karyotyping) for detection of del 13 or hypodiploidy The presence of any of the above markers defines high risk myeloma, which encompasses the 25 percent of MM patients who have a median survival of approximately two years or less despite standard treatment Current Frontline Options Conventional chemotherapy Survival ≤ 3 yrs Transplantation Prolongs survival 4-5 yrs Novel agents targeting stromal interactions and associated signaling pathways have shown promise Chng WJ, et al. Cancer Control. 2005;12:91-104. MM: INITIAL THERAPY The initial therapy of patients with symptomatic myeloma varies depending on whether patients are eligible or not to pursue autologous hematopoietic cell transplantation *Thal/dex or dex are additional options especially if immediate response is needed. Clearly not transplantation candidate based on age, performance score, and comorbidity MPT, MPV, Len/dex or clinical trial* Potential transplantation candidate Nonalkylator-based induction x 4 cycles Stem cell harvest Initial Approach to Treatment of MM DETERMINING TRANSPLANT ELIGIBILITY Autologous hematopoietic cell transplantation (HCT) results in superior event-free and overall survival rates when compared with combination chemotherapy All patients should be evaluated at diagnosis for transplant eligibility so that the risks and benefits of autologous HCT can be reviewed with those eligible A minority of patients will be eligible for allogeneic HCT, but the value of allogeneic approaches in myeloma remain investigational NOT Eligible for Autologous HCT Age >77 years Direct bilirubin>2.0 mg/dL (34.2 µmol/liter) Serum creatinine>2.5 mg/dL (221 µmol/liter) unless on chronic stable dialysis Eastern Cooperative Oncology Group (ECOG) performance status 3 or 4 unless due to bone pain New York Heart Association functional status Class III or IV 54 42 Attal M, et al. N Engl J Med. 1996;335:91-97. Child JA, et al. N Engl J Med. 2003;348:1875-1883. 15 30 45 60 25 50 75 100 OS (%) 0 0 High dose Conventional dose Mos 20 40 60 80 25 50 75 100 Survival (%) 0 0 Intensive therapy Standard therapy Mos P = .03 by Wilcoxon test P = .04 by log-rank test Transplantation vs Conventional Chemotherapy Autologous Stem Cell Transplantation Mel 200 mg/m2 standard conditioning regimen Sufficient performance score, and adequate liver, pulmonary, cardiac function needed Higher PR and CR rates than conventional chemotherapy Higher OS and EFS than conventional Rx Advanced age and impaired renal function are, by themselves, not contraindications Attal M, et al. N Engl J Med. 1996;335:91-97. NCCN Practice Guidelines. Myeloma. V.3.2010. Stem Cell Transplantation Key issues Efficacy compared with conventional chemotherapy Timing: early vs delayed Single vs tandem Role of allogeneic and miniallogeneic transplantations Maintenance post-SCT Novel Frontline Options Immunomodulatory drugs (IMiDs) Thalidomide Lenalidomide Proteasome inhibitors Bortezomib Carfilzomib Kyle RA, et al. N Engl J Med. 2004;351:1860-1873. Copyright ©2004. Massachusetts Medical Society. All rights reserved. Proposed Mechanism of Action for Multiple Myeloma Therapies Thalidomide: Proposed Mechanism of Action Proposed mechanisms Inhibition of TNF- Suppression of angiogenesis Increase in cell-mediated cytotoxic effects Modulation of adhesion molecule expression Kyle RA, et al. N Engl J Med. 2004;351:1860-1873. Rajkumar SV, et al. Leukemia. 2003;17:775-779. D’Amato RJ, et al.Proc Natl Acad Sci U S A. 1994;91:4082-4085. Lenalidomide Immunomodulatory derivative of thalidomide More potent than thalidomide in preclinical models Dose-dependent decrease in TNF-α and interleukin-6 Directly induces apoptosis, G1 growth arrest Enhances activity of dexamethasone More favorable toxicity profile than thalidomide Richardson P, et al. Blood. 2003;100:3063. Hideshima T, et al. Blood. 2000;96:2943-2950. Bortezomib: A Reversible Proteasome Inhibitor Chymo- tryptic Site Post- Glutamyl Site Tryptic Site b1 b2 b3 b4 b5 b6 b7 Cross section of  ring Bortezomib Adams J, et al. Invest New Drugs. 2000;18:109-121. Adams J, et al. Bioorg Med Chem Lett. 1998;8:333-338. H N B N H O O OH N N OH Initial Approach to Treatment of MM Clearly not a transplantation candidate MPT, MPV, Len/dex or clinical trial* Potential transplantation candidate Nonalkylator-based induction Stem cell harvest Melphalan/Prednisone/Thalidomide Palumbo A, et al. Blood. 2008;112:3107-3114. Lenalidomide 25 mg/day PO on Days 1-21 + High-dose Dex 40 mg/day PO on Days 1-4, 9-12, 17-20 (n = 223) Lenalidomide 25 mg/day PO on Days 1-21 + Low-dose Dex 40 mg/day PO on Days 1, 8, 15, 22 (n = 222) Len + High or Low-Dose Dex in Newly Diagnosed Myeloma (E4A03) Courses repeat every 28 days ≤ 1 yr in absence of PD or unacceptable toxicity Total Dex dose per cycle: 480 mg Untreated, symptomatic myeloma, no age cutoff Total Dex dose per cycle: 160 mg Rajkumar SV, et al. ASCO 2008. Abstract 8504. Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37
Slide 52 - Special Thanks to… For sponsorship of LMEF programs: Supported by an educational grant from Lilly USA, LLC Did you know that you could be receiving credit for attending today? For membership information, please visit our website: www.Lafmeded.org. Multiple Myeloma 2010 Wael Harb MD Horizon Oncology Center Overview Introduction: epidemiology, clinical presentation, diagnosis, staging Autologous stem cell transplantation Initial approaches to treatment Current options Novel agents and combinations Considerations in non-transplantation-eligible patients Prevention of skeletal complications What is MM? Multiple myeloma (MM) is characterized by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. Plasma Cell Multiple Myeloma: Incidence The lifetime risk of getting MM is 1 in 159 (0.63%). 20,180 new cases will be diagnosed in 2010 (11,170 in men and 9,010 in women) 10,650 deaths are expected to occur in 2010 (5,760 in men and 4,890 in women) The 5-year relative survival rate for MM is around 35% Incidence MM occurs in all races and all geographic locations African Americans and blacks from Africa is two to three times the risk in whites Risk is lower in Asians from Japan and in Mexicans Slightly more frequent in men than in women (1.4:1) Age MM is a disease of older adults The median age at diagnosis is 66 years Only 10 percent of patients are younger than 50 years Only 2 percent of patients are younger than 40 years MM: Clinical Presentations Anemia - 73 percent Bone pain - 58 percent Elevated creatinine - 48 percent Fatigue/generalized weakness - 32 percent Hypercalcemia- 28 percent Weight loss - 24 percent, one-half of whom had lost ≥ 9 kg Multiple Myeloma = M-CRAB Monoclonal protein Calcium Renal failure Anemia Bone pain with lytic lesions Immunoglobulin Immunoglobulins SPEP: Normal SPEP: M-protein, M-spike Renal Failure Cast nephropathy (also called myeloma kidney) from light chains Hypercalcemia Light chain amyloidosis Drug-induced renal damage Anemia Normocytic, normochromic anemiais present in 73% at diagnosis and in 97%at some time during the course of the disease This anemia can be related to: Bone marrow replacement Kidney damage Dilution in the case of a large M-protein B12 deficiency in 14% Rouleaux Formation Lytic Bone Lesion MM: PET Scan Extramedullary Plasmacytoma Differential Diagnosis of MM Monoclonal gammopathy of undetermined significance (MGUS) Smoldering multiple myeloma (SMM) Waldenstrom macroglobulinemia Solitary plasmacytoma Primary amyloidosis (AL) POEMS syndrome Metastatic carcinoma Multiple Myeloma All 3 criteria must be met: Presence of a serum or urinary monoclonal protein Presence of clonal plasma cells in the bone marrow or a plasmacytoma Presence of end organ damage felt related to the plasma cell dyscrasia, such as: Increased calcium concentration Lytic bone lesions Anemia Renal failure Smoldering Multiple Myeloma SMM, Asymptomatic Both criteria must be met: Serum monoclonal protein ≥3 g/dL and/or bone marrow plasma cells ≥10 percent No end organ damage related to plasma cell dyscrasia Monoclonal Gammopathy of Undetermined Significance (MGUS) All 3 criteria must be met: Serum monoclonal protein <3 g/dL Bone marrow plasma cells <10 percent No end organ damage related to plasma cell dyscrasia or a related B cell lymphoproliferative disorder POEMS Syndrome Osteosclerotic myeloma Polyneuropathy Organomegaly Endocrinopathy Monoclonal protein Skin changes MM: Evaluation CBC and differential,peripheral blood smear Chemistry:serum calcium, creatinine, albumin, LDH , beta-2 microglobulin, and C-reactive protein Serum protein electrophoresis (SPEP) + IF Quantification of immunoglobulins Urinalysis and a 24-hour urine collection for electrophoresis (UPEP) + IF Serum free monoclonal light chain (FLC) MM Evaluation Serum viscosity should be measured if the M-protein concentration is high Bone marrow aspiration and biopsy with immunophenotyping, conventional cytogenetics, and fluorescence in situ hybridization (FISH) Metastatic bone survey with plain radiographs including the humeri and femoral bones should be performed in all patients. MRI, CT, or PET/CT Bone Marrow Cytogenenetics, Interphase FISH Poor prognosis (median survival 25 months): t(4;14)(p16;q32), t(14;16)(q32;q23), and -17p13 Intermediate prognosis (median survival 42 months): -13q14 Good prognosis (median survival 50 months): all others Staging for MM International staging system (ISS)  Stage I — B2M <3.5 mg/L and serum albumin ≥3.5 g/dL Stage II — neither stage I nor stage III Stage III — B2M ≥5.5 mg/L Median overall survival for patients with ISS stages I, II, and III are 62, 44, and 29 months MM: Treatment Decisions Indications for treatment Risk stratification Eligibility for stem cell transplantation Smoldering (asymptomatic) myeloma Deferral of chemotherapy until progression to symptomatic disease Follow these patients closely, every 3 to 4 months, with serum protein electrophoresis, complete blood count, serum creatinine, and serum calcium Metastatic bone survey should be considered annually because asymptomatic bone lesions may develop MM: Indications for Treatment Anemia (hemoglobin <10 g/dL or 2 g/dL below normal) Hypercalcemia (serum calcium >11.5 mg/dL) Renal insufficiency (serum creatinine>2 mg/dL) Lytic bone lesions or severe osteopenia Extramedullary plasmacytoma MM: RISK STRATIFICATION FISH for detection of t(4;14), t(14;16), and del17p13 Conventional cytogenetics (karyotyping) for detection of del 13 or hypodiploidy The presence of any of the above markers defines high risk myeloma, which encompasses the 25 percent of MM patients who have a median survival of approximately two years or less despite standard treatment Current Frontline Options Conventional chemotherapy Survival ≤ 3 yrs Transplantation Prolongs survival 4-5 yrs Novel agents targeting stromal interactions and associated signaling pathways have shown promise Chng WJ, et al. Cancer Control. 2005;12:91-104. MM: INITIAL THERAPY The initial therapy of patients with symptomatic myeloma varies depending on whether patients are eligible or not to pursue autologous hematopoietic cell transplantation *Thal/dex or dex are additional options especially if immediate response is needed. Clearly not transplantation candidate based on age, performance score, and comorbidity MPT, MPV, Len/dex or clinical trial* Potential transplantation candidate Nonalkylator-based induction x 4 cycles Stem cell harvest Initial Approach to Treatment of MM DETERMINING TRANSPLANT ELIGIBILITY Autologous hematopoietic cell transplantation (HCT) results in superior event-free and overall survival rates when compared with combination chemotherapy All patients should be evaluated at diagnosis for transplant eligibility so that the risks and benefits of autologous HCT can be reviewed with those eligible A minority of patients will be eligible for allogeneic HCT, but the value of allogeneic approaches in myeloma remain investigational NOT Eligible for Autologous HCT Age >77 years Direct bilirubin>2.0 mg/dL (34.2 µmol/liter) Serum creatinine>2.5 mg/dL (221 µmol/liter) unless on chronic stable dialysis Eastern Cooperative Oncology Group (ECOG) performance status 3 or 4 unless due to bone pain New York Heart Association functional status Class III or IV 54 42 Attal M, et al. N Engl J Med. 1996;335:91-97. Child JA, et al. N Engl J Med. 2003;348:1875-1883. 15 30 45 60 25 50 75 100 OS (%) 0 0 High dose Conventional dose Mos 20 40 60 80 25 50 75 100 Survival (%) 0 0 Intensive therapy Standard therapy Mos P = .03 by Wilcoxon test P = .04 by log-rank test Transplantation vs Conventional Chemotherapy Autologous Stem Cell Transplantation Mel 200 mg/m2 standard conditioning regimen Sufficient performance score, and adequate liver, pulmonary, cardiac function needed Higher PR and CR rates than conventional chemotherapy Higher OS and EFS than conventional Rx Advanced age and impaired renal function are, by themselves, not contraindications Attal M, et al. N Engl J Med. 1996;335:91-97. NCCN Practice Guidelines. Myeloma. V.3.2010. Stem Cell Transplantation Key issues Efficacy compared with conventional chemotherapy Timing: early vs delayed Single vs tandem Role of allogeneic and miniallogeneic transplantations Maintenance post-SCT Novel Frontline Options Immunomodulatory drugs (IMiDs) Thalidomide Lenalidomide Proteasome inhibitors Bortezomib Carfilzomib Kyle RA, et al. N Engl J Med. 2004;351:1860-1873. Copyright ©2004. Massachusetts Medical Society. All rights reserved. Proposed Mechanism of Action for Multiple Myeloma Therapies Thalidomide: Proposed Mechanism of Action Proposed mechanisms Inhibition of TNF- Suppression of angiogenesis Increase in cell-mediated cytotoxic effects Modulation of adhesion molecule expression Kyle RA, et al. N Engl J Med. 2004;351:1860-1873. Rajkumar SV, et al. Leukemia. 2003;17:775-779. D’Amato RJ, et al.Proc Natl Acad Sci U S A. 1994;91:4082-4085. Lenalidomide Immunomodulatory derivative of thalidomide More potent than thalidomide in preclinical models Dose-dependent decrease in TNF-α and interleukin-6 Directly induces apoptosis, G1 growth arrest Enhances activity of dexamethasone More favorable toxicity profile than thalidomide Richardson P, et al. Blood. 2003;100:3063. Hideshima T, et al. Blood. 2000;96:2943-2950. Bortezomib: A Reversible Proteasome Inhibitor Chymo- tryptic Site Post- Glutamyl Site Tryptic Site b1 b2 b3 b4 b5 b6 b7 Cross section of  ring Bortezomib Adams J, et al. Invest New Drugs. 2000;18:109-121. Adams J, et al. Bioorg Med Chem Lett. 1998;8:333-338. H N B N H O O OH N N OH Initial Approach to Treatment of MM Clearly not a transplantation candidate MPT, MPV, Len/dex or clinical trial* Potential transplantation candidate Nonalkylator-based induction Stem cell harvest Melphalan/Prednisone/Thalidomide Palumbo A, et al. Blood. 2008;112:3107-3114. Lenalidomide 25 mg/day PO on Days 1-21 + High-dose Dex 40 mg/day PO on Days 1-4, 9-12, 17-20 (n = 223) Lenalidomide 25 mg/day PO on Days 1-21 + Low-dose Dex 40 mg/day PO on Days 1, 8, 15, 22 (n = 222) Len + High or Low-Dose Dex in Newly Diagnosed Myeloma (E4A03) Courses repeat every 28 days ≤ 1 yr in absence of PD or unacceptable toxicity Total Dex dose per cycle: 480 mg Untreated, symptomatic myeloma, no age cutoff Total Dex dose per cycle: 160 mg Rajkumar SV, et al. ASCO 2008. Abstract 8504. Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37 Len + High or Low-Dose Dex (E4A03): Response 3-yr OS rates converged (P = .467) with all pts crossed over to low dose Successful stem cell harvesting in 97.6% (n = 167) 3-yr OS for high dose or low dose followed by SCT: 92% Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37.
Slide 53 - Special Thanks to… For sponsorship of LMEF programs: Supported by an educational grant from Lilly USA, LLC Did you know that you could be receiving credit for attending today? For membership information, please visit our website: www.Lafmeded.org. Multiple Myeloma 2010 Wael Harb MD Horizon Oncology Center Overview Introduction: epidemiology, clinical presentation, diagnosis, staging Autologous stem cell transplantation Initial approaches to treatment Current options Novel agents and combinations Considerations in non-transplantation-eligible patients Prevention of skeletal complications What is MM? Multiple myeloma (MM) is characterized by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. Plasma Cell Multiple Myeloma: Incidence The lifetime risk of getting MM is 1 in 159 (0.63%). 20,180 new cases will be diagnosed in 2010 (11,170 in men and 9,010 in women) 10,650 deaths are expected to occur in 2010 (5,760 in men and 4,890 in women) The 5-year relative survival rate for MM is around 35% Incidence MM occurs in all races and all geographic locations African Americans and blacks from Africa is two to three times the risk in whites Risk is lower in Asians from Japan and in Mexicans Slightly more frequent in men than in women (1.4:1) Age MM is a disease of older adults The median age at diagnosis is 66 years Only 10 percent of patients are younger than 50 years Only 2 percent of patients are younger than 40 years MM: Clinical Presentations Anemia - 73 percent Bone pain - 58 percent Elevated creatinine - 48 percent Fatigue/generalized weakness - 32 percent Hypercalcemia- 28 percent Weight loss - 24 percent, one-half of whom had lost ≥ 9 kg Multiple Myeloma = M-CRAB Monoclonal protein Calcium Renal failure Anemia Bone pain with lytic lesions Immunoglobulin Immunoglobulins SPEP: Normal SPEP: M-protein, M-spike Renal Failure Cast nephropathy (also called myeloma kidney) from light chains Hypercalcemia Light chain amyloidosis Drug-induced renal damage Anemia Normocytic, normochromic anemiais present in 73% at diagnosis and in 97%at some time during the course of the disease This anemia can be related to: Bone marrow replacement Kidney damage Dilution in the case of a large M-protein B12 deficiency in 14% Rouleaux Formation Lytic Bone Lesion MM: PET Scan Extramedullary Plasmacytoma Differential Diagnosis of MM Monoclonal gammopathy of undetermined significance (MGUS) Smoldering multiple myeloma (SMM) Waldenstrom macroglobulinemia Solitary plasmacytoma Primary amyloidosis (AL) POEMS syndrome Metastatic carcinoma Multiple Myeloma All 3 criteria must be met: Presence of a serum or urinary monoclonal protein Presence of clonal plasma cells in the bone marrow or a plasmacytoma Presence of end organ damage felt related to the plasma cell dyscrasia, such as: Increased calcium concentration Lytic bone lesions Anemia Renal failure Smoldering Multiple Myeloma SMM, Asymptomatic Both criteria must be met: Serum monoclonal protein ≥3 g/dL and/or bone marrow plasma cells ≥10 percent No end organ damage related to plasma cell dyscrasia Monoclonal Gammopathy of Undetermined Significance (MGUS) All 3 criteria must be met: Serum monoclonal protein <3 g/dL Bone marrow plasma cells <10 percent No end organ damage related to plasma cell dyscrasia or a related B cell lymphoproliferative disorder POEMS Syndrome Osteosclerotic myeloma Polyneuropathy Organomegaly Endocrinopathy Monoclonal protein Skin changes MM: Evaluation CBC and differential,peripheral blood smear Chemistry:serum calcium, creatinine, albumin, LDH , beta-2 microglobulin, and C-reactive protein Serum protein electrophoresis (SPEP) + IF Quantification of immunoglobulins Urinalysis and a 24-hour urine collection for electrophoresis (UPEP) + IF Serum free monoclonal light chain (FLC) MM Evaluation Serum viscosity should be measured if the M-protein concentration is high Bone marrow aspiration and biopsy with immunophenotyping, conventional cytogenetics, and fluorescence in situ hybridization (FISH) Metastatic bone survey with plain radiographs including the humeri and femoral bones should be performed in all patients. MRI, CT, or PET/CT Bone Marrow Cytogenenetics, Interphase FISH Poor prognosis (median survival 25 months): t(4;14)(p16;q32), t(14;16)(q32;q23), and -17p13 Intermediate prognosis (median survival 42 months): -13q14 Good prognosis (median survival 50 months): all others Staging for MM International staging system (ISS)  Stage I — B2M <3.5 mg/L and serum albumin ≥3.5 g/dL Stage II — neither stage I nor stage III Stage III — B2M ≥5.5 mg/L Median overall survival for patients with ISS stages I, II, and III are 62, 44, and 29 months MM: Treatment Decisions Indications for treatment Risk stratification Eligibility for stem cell transplantation Smoldering (asymptomatic) myeloma Deferral of chemotherapy until progression to symptomatic disease Follow these patients closely, every 3 to 4 months, with serum protein electrophoresis, complete blood count, serum creatinine, and serum calcium Metastatic bone survey should be considered annually because asymptomatic bone lesions may develop MM: Indications for Treatment Anemia (hemoglobin <10 g/dL or 2 g/dL below normal) Hypercalcemia (serum calcium >11.5 mg/dL) Renal insufficiency (serum creatinine>2 mg/dL) Lytic bone lesions or severe osteopenia Extramedullary plasmacytoma MM: RISK STRATIFICATION FISH for detection of t(4;14), t(14;16), and del17p13 Conventional cytogenetics (karyotyping) for detection of del 13 or hypodiploidy The presence of any of the above markers defines high risk myeloma, which encompasses the 25 percent of MM patients who have a median survival of approximately two years or less despite standard treatment Current Frontline Options Conventional chemotherapy Survival ≤ 3 yrs Transplantation Prolongs survival 4-5 yrs Novel agents targeting stromal interactions and associated signaling pathways have shown promise Chng WJ, et al. Cancer Control. 2005;12:91-104. MM: INITIAL THERAPY The initial therapy of patients with symptomatic myeloma varies depending on whether patients are eligible or not to pursue autologous hematopoietic cell transplantation *Thal/dex or dex are additional options especially if immediate response is needed. Clearly not transplantation candidate based on age, performance score, and comorbidity MPT, MPV, Len/dex or clinical trial* Potential transplantation candidate Nonalkylator-based induction x 4 cycles Stem cell harvest Initial Approach to Treatment of MM DETERMINING TRANSPLANT ELIGIBILITY Autologous hematopoietic cell transplantation (HCT) results in superior event-free and overall survival rates when compared with combination chemotherapy All patients should be evaluated at diagnosis for transplant eligibility so that the risks and benefits of autologous HCT can be reviewed with those eligible A minority of patients will be eligible for allogeneic HCT, but the value of allogeneic approaches in myeloma remain investigational NOT Eligible for Autologous HCT Age >77 years Direct bilirubin>2.0 mg/dL (34.2 µmol/liter) Serum creatinine>2.5 mg/dL (221 µmol/liter) unless on chronic stable dialysis Eastern Cooperative Oncology Group (ECOG) performance status 3 or 4 unless due to bone pain New York Heart Association functional status Class III or IV 54 42 Attal M, et al. N Engl J Med. 1996;335:91-97. Child JA, et al. N Engl J Med. 2003;348:1875-1883. 15 30 45 60 25 50 75 100 OS (%) 0 0 High dose Conventional dose Mos 20 40 60 80 25 50 75 100 Survival (%) 0 0 Intensive therapy Standard therapy Mos P = .03 by Wilcoxon test P = .04 by log-rank test Transplantation vs Conventional Chemotherapy Autologous Stem Cell Transplantation Mel 200 mg/m2 standard conditioning regimen Sufficient performance score, and adequate liver, pulmonary, cardiac function needed Higher PR and CR rates than conventional chemotherapy Higher OS and EFS than conventional Rx Advanced age and impaired renal function are, by themselves, not contraindications Attal M, et al. N Engl J Med. 1996;335:91-97. NCCN Practice Guidelines. Myeloma. V.3.2010. Stem Cell Transplantation Key issues Efficacy compared with conventional chemotherapy Timing: early vs delayed Single vs tandem Role of allogeneic and miniallogeneic transplantations Maintenance post-SCT Novel Frontline Options Immunomodulatory drugs (IMiDs) Thalidomide Lenalidomide Proteasome inhibitors Bortezomib Carfilzomib Kyle RA, et al. N Engl J Med. 2004;351:1860-1873. Copyright ©2004. Massachusetts Medical Society. All rights reserved. Proposed Mechanism of Action for Multiple Myeloma Therapies Thalidomide: Proposed Mechanism of Action Proposed mechanisms Inhibition of TNF- Suppression of angiogenesis Increase in cell-mediated cytotoxic effects Modulation of adhesion molecule expression Kyle RA, et al. N Engl J Med. 2004;351:1860-1873. Rajkumar SV, et al. Leukemia. 2003;17:775-779. D’Amato RJ, et al.Proc Natl Acad Sci U S A. 1994;91:4082-4085. Lenalidomide Immunomodulatory derivative of thalidomide More potent than thalidomide in preclinical models Dose-dependent decrease in TNF-α and interleukin-6 Directly induces apoptosis, G1 growth arrest Enhances activity of dexamethasone More favorable toxicity profile than thalidomide Richardson P, et al. Blood. 2003;100:3063. Hideshima T, et al. Blood. 2000;96:2943-2950. Bortezomib: A Reversible Proteasome Inhibitor Chymo- tryptic Site Post- Glutamyl Site Tryptic Site b1 b2 b3 b4 b5 b6 b7 Cross section of  ring Bortezomib Adams J, et al. Invest New Drugs. 2000;18:109-121. Adams J, et al. Bioorg Med Chem Lett. 1998;8:333-338. H N B N H O O OH N N OH Initial Approach to Treatment of MM Clearly not a transplantation candidate MPT, MPV, Len/dex or clinical trial* Potential transplantation candidate Nonalkylator-based induction Stem cell harvest Melphalan/Prednisone/Thalidomide Palumbo A, et al. Blood. 2008;112:3107-3114. Lenalidomide 25 mg/day PO on Days 1-21 + High-dose Dex 40 mg/day PO on Days 1-4, 9-12, 17-20 (n = 223) Lenalidomide 25 mg/day PO on Days 1-21 + Low-dose Dex 40 mg/day PO on Days 1, 8, 15, 22 (n = 222) Len + High or Low-Dose Dex in Newly Diagnosed Myeloma (E4A03) Courses repeat every 28 days ≤ 1 yr in absence of PD or unacceptable toxicity Total Dex dose per cycle: 480 mg Untreated, symptomatic myeloma, no age cutoff Total Dex dose per cycle: 160 mg Rajkumar SV, et al. ASCO 2008. Abstract 8504. Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37 Len + High or Low-Dose Dex (E4A03): Response 3-yr OS rates converged (P = .467) with all pts crossed over to low dose Successful stem cell harvesting in 97.6% (n = 167) 3-yr OS for high dose or low dose followed by SCT: 92% Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37. Len + High or Low-Dose Dex (E4A03): Adverse Events Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37.
Slide 54 - Special Thanks to… For sponsorship of LMEF programs: Supported by an educational grant from Lilly USA, LLC Did you know that you could be receiving credit for attending today? For membership information, please visit our website: www.Lafmeded.org. Multiple Myeloma 2010 Wael Harb MD Horizon Oncology Center Overview Introduction: epidemiology, clinical presentation, diagnosis, staging Autologous stem cell transplantation Initial approaches to treatment Current options Novel agents and combinations Considerations in non-transplantation-eligible patients Prevention of skeletal complications What is MM? Multiple myeloma (MM) is characterized by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. Plasma Cell Multiple Myeloma: Incidence The lifetime risk of getting MM is 1 in 159 (0.63%). 20,180 new cases will be diagnosed in 2010 (11,170 in men and 9,010 in women) 10,650 deaths are expected to occur in 2010 (5,760 in men and 4,890 in women) The 5-year relative survival rate for MM is around 35% Incidence MM occurs in all races and all geographic locations African Americans and blacks from Africa is two to three times the risk in whites Risk is lower in Asians from Japan and in Mexicans Slightly more frequent in men than in women (1.4:1) Age MM is a disease of older adults The median age at diagnosis is 66 years Only 10 percent of patients are younger than 50 years Only 2 percent of patients are younger than 40 years MM: Clinical Presentations Anemia - 73 percent Bone pain - 58 percent Elevated creatinine - 48 percent Fatigue/generalized weakness - 32 percent Hypercalcemia- 28 percent Weight loss - 24 percent, one-half of whom had lost ≥ 9 kg Multiple Myeloma = M-CRAB Monoclonal protein Calcium Renal failure Anemia Bone pain with lytic lesions Immunoglobulin Immunoglobulins SPEP: Normal SPEP: M-protein, M-spike Renal Failure Cast nephropathy (also called myeloma kidney) from light chains Hypercalcemia Light chain amyloidosis Drug-induced renal damage Anemia Normocytic, normochromic anemiais present in 73% at diagnosis and in 97%at some time during the course of the disease This anemia can be related to: Bone marrow replacement Kidney damage Dilution in the case of a large M-protein B12 deficiency in 14% Rouleaux Formation Lytic Bone Lesion MM: PET Scan Extramedullary Plasmacytoma Differential Diagnosis of MM Monoclonal gammopathy of undetermined significance (MGUS) Smoldering multiple myeloma (SMM) Waldenstrom macroglobulinemia Solitary plasmacytoma Primary amyloidosis (AL) POEMS syndrome Metastatic carcinoma Multiple Myeloma All 3 criteria must be met: Presence of a serum or urinary monoclonal protein Presence of clonal plasma cells in the bone marrow or a plasmacytoma Presence of end organ damage felt related to the plasma cell dyscrasia, such as: Increased calcium concentration Lytic bone lesions Anemia Renal failure Smoldering Multiple Myeloma SMM, Asymptomatic Both criteria must be met: Serum monoclonal protein ≥3 g/dL and/or bone marrow plasma cells ≥10 percent No end organ damage related to plasma cell dyscrasia Monoclonal Gammopathy of Undetermined Significance (MGUS) All 3 criteria must be met: Serum monoclonal protein <3 g/dL Bone marrow plasma cells <10 percent No end organ damage related to plasma cell dyscrasia or a related B cell lymphoproliferative disorder POEMS Syndrome Osteosclerotic myeloma Polyneuropathy Organomegaly Endocrinopathy Monoclonal protein Skin changes MM: Evaluation CBC and differential,peripheral blood smear Chemistry:serum calcium, creatinine, albumin, LDH , beta-2 microglobulin, and C-reactive protein Serum protein electrophoresis (SPEP) + IF Quantification of immunoglobulins Urinalysis and a 24-hour urine collection for electrophoresis (UPEP) + IF Serum free monoclonal light chain (FLC) MM Evaluation Serum viscosity should be measured if the M-protein concentration is high Bone marrow aspiration and biopsy with immunophenotyping, conventional cytogenetics, and fluorescence in situ hybridization (FISH) Metastatic bone survey with plain radiographs including the humeri and femoral bones should be performed in all patients. MRI, CT, or PET/CT Bone Marrow Cytogenenetics, Interphase FISH Poor prognosis (median survival 25 months): t(4;14)(p16;q32), t(14;16)(q32;q23), and -17p13 Intermediate prognosis (median survival 42 months): -13q14 Good prognosis (median survival 50 months): all others Staging for MM International staging system (ISS)  Stage I — B2M <3.5 mg/L and serum albumin ≥3.5 g/dL Stage II — neither stage I nor stage III Stage III — B2M ≥5.5 mg/L Median overall survival for patients with ISS stages I, II, and III are 62, 44, and 29 months MM: Treatment Decisions Indications for treatment Risk stratification Eligibility for stem cell transplantation Smoldering (asymptomatic) myeloma Deferral of chemotherapy until progression to symptomatic disease Follow these patients closely, every 3 to 4 months, with serum protein electrophoresis, complete blood count, serum creatinine, and serum calcium Metastatic bone survey should be considered annually because asymptomatic bone lesions may develop MM: Indications for Treatment Anemia (hemoglobin <10 g/dL or 2 g/dL below normal) Hypercalcemia (serum calcium >11.5 mg/dL) Renal insufficiency (serum creatinine>2 mg/dL) Lytic bone lesions or severe osteopenia Extramedullary plasmacytoma MM: RISK STRATIFICATION FISH for detection of t(4;14), t(14;16), and del17p13 Conventional cytogenetics (karyotyping) for detection of del 13 or hypodiploidy The presence of any of the above markers defines high risk myeloma, which encompasses the 25 percent of MM patients who have a median survival of approximately two years or less despite standard treatment Current Frontline Options Conventional chemotherapy Survival ≤ 3 yrs Transplantation Prolongs survival 4-5 yrs Novel agents targeting stromal interactions and associated signaling pathways have shown promise Chng WJ, et al. Cancer Control. 2005;12:91-104. MM: INITIAL THERAPY The initial therapy of patients with symptomatic myeloma varies depending on whether patients are eligible or not to pursue autologous hematopoietic cell transplantation *Thal/dex or dex are additional options especially if immediate response is needed. Clearly not transplantation candidate based on age, performance score, and comorbidity MPT, MPV, Len/dex or clinical trial* Potential transplantation candidate Nonalkylator-based induction x 4 cycles Stem cell harvest Initial Approach to Treatment of MM DETERMINING TRANSPLANT ELIGIBILITY Autologous hematopoietic cell transplantation (HCT) results in superior event-free and overall survival rates when compared with combination chemotherapy All patients should be evaluated at diagnosis for transplant eligibility so that the risks and benefits of autologous HCT can be reviewed with those eligible A minority of patients will be eligible for allogeneic HCT, but the value of allogeneic approaches in myeloma remain investigational NOT Eligible for Autologous HCT Age >77 years Direct bilirubin>2.0 mg/dL (34.2 µmol/liter) Serum creatinine>2.5 mg/dL (221 µmol/liter) unless on chronic stable dialysis Eastern Cooperative Oncology Group (ECOG) performance status 3 or 4 unless due to bone pain New York Heart Association functional status Class III or IV 54 42 Attal M, et al. N Engl J Med. 1996;335:91-97. Child JA, et al. N Engl J Med. 2003;348:1875-1883. 15 30 45 60 25 50 75 100 OS (%) 0 0 High dose Conventional dose Mos 20 40 60 80 25 50 75 100 Survival (%) 0 0 Intensive therapy Standard therapy Mos P = .03 by Wilcoxon test P = .04 by log-rank test Transplantation vs Conventional Chemotherapy Autologous Stem Cell Transplantation Mel 200 mg/m2 standard conditioning regimen Sufficient performance score, and adequate liver, pulmonary, cardiac function needed Higher PR and CR rates than conventional chemotherapy Higher OS and EFS than conventional Rx Advanced age and impaired renal function are, by themselves, not contraindications Attal M, et al. N Engl J Med. 1996;335:91-97. NCCN Practice Guidelines. Myeloma. V.3.2010. Stem Cell Transplantation Key issues Efficacy compared with conventional chemotherapy Timing: early vs delayed Single vs tandem Role of allogeneic and miniallogeneic transplantations Maintenance post-SCT Novel Frontline Options Immunomodulatory drugs (IMiDs) Thalidomide Lenalidomide Proteasome inhibitors Bortezomib Carfilzomib Kyle RA, et al. N Engl J Med. 2004;351:1860-1873. Copyright ©2004. Massachusetts Medical Society. All rights reserved. Proposed Mechanism of Action for Multiple Myeloma Therapies Thalidomide: Proposed Mechanism of Action Proposed mechanisms Inhibition of TNF- Suppression of angiogenesis Increase in cell-mediated cytotoxic effects Modulation of adhesion molecule expression Kyle RA, et al. N Engl J Med. 2004;351:1860-1873. Rajkumar SV, et al. Leukemia. 2003;17:775-779. D’Amato RJ, et al.Proc Natl Acad Sci U S A. 1994;91:4082-4085. Lenalidomide Immunomodulatory derivative of thalidomide More potent than thalidomide in preclinical models Dose-dependent decrease in TNF-α and interleukin-6 Directly induces apoptosis, G1 growth arrest Enhances activity of dexamethasone More favorable toxicity profile than thalidomide Richardson P, et al. Blood. 2003;100:3063. Hideshima T, et al. Blood. 2000;96:2943-2950. Bortezomib: A Reversible Proteasome Inhibitor Chymo- tryptic Site Post- Glutamyl Site Tryptic Site b1 b2 b3 b4 b5 b6 b7 Cross section of  ring Bortezomib Adams J, et al. Invest New Drugs. 2000;18:109-121. Adams J, et al. Bioorg Med Chem Lett. 1998;8:333-338. H N B N H O O OH N N OH Initial Approach to Treatment of MM Clearly not a transplantation candidate MPT, MPV, Len/dex or clinical trial* Potential transplantation candidate Nonalkylator-based induction Stem cell harvest Melphalan/Prednisone/Thalidomide Palumbo A, et al. Blood. 2008;112:3107-3114. Lenalidomide 25 mg/day PO on Days 1-21 + High-dose Dex 40 mg/day PO on Days 1-4, 9-12, 17-20 (n = 223) Lenalidomide 25 mg/day PO on Days 1-21 + Low-dose Dex 40 mg/day PO on Days 1, 8, 15, 22 (n = 222) Len + High or Low-Dose Dex in Newly Diagnosed Myeloma (E4A03) Courses repeat every 28 days ≤ 1 yr in absence of PD or unacceptable toxicity Total Dex dose per cycle: 480 mg Untreated, symptomatic myeloma, no age cutoff Total Dex dose per cycle: 160 mg Rajkumar SV, et al. ASCO 2008. Abstract 8504. Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37 Len + High or Low-Dose Dex (E4A03): Response 3-yr OS rates converged (P = .467) with all pts crossed over to low dose Successful stem cell harvesting in 97.6% (n = 167) 3-yr OS for high dose or low dose followed by SCT: 92% Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37. Len + High or Low-Dose Dex (E4A03): Adverse Events Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37. Lenalidomide Dosing for MM and Impaired Renal Function Lenalidomide [package insert].
Slide 55 - Special Thanks to… For sponsorship of LMEF programs: Supported by an educational grant from Lilly USA, LLC Did you know that you could be receiving credit for attending today? For membership information, please visit our website: www.Lafmeded.org. Multiple Myeloma 2010 Wael Harb MD Horizon Oncology Center Overview Introduction: epidemiology, clinical presentation, diagnosis, staging Autologous stem cell transplantation Initial approaches to treatment Current options Novel agents and combinations Considerations in non-transplantation-eligible patients Prevention of skeletal complications What is MM? Multiple myeloma (MM) is characterized by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. Plasma Cell Multiple Myeloma: Incidence The lifetime risk of getting MM is 1 in 159 (0.63%). 20,180 new cases will be diagnosed in 2010 (11,170 in men and 9,010 in women) 10,650 deaths are expected to occur in 2010 (5,760 in men and 4,890 in women) The 5-year relative survival rate for MM is around 35% Incidence MM occurs in all races and all geographic locations African Americans and blacks from Africa is two to three times the risk in whites Risk is lower in Asians from Japan and in Mexicans Slightly more frequent in men than in women (1.4:1) Age MM is a disease of older adults The median age at diagnosis is 66 years Only 10 percent of patients are younger than 50 years Only 2 percent of patients are younger than 40 years MM: Clinical Presentations Anemia - 73 percent Bone pain - 58 percent Elevated creatinine - 48 percent Fatigue/generalized weakness - 32 percent Hypercalcemia- 28 percent Weight loss - 24 percent, one-half of whom had lost ≥ 9 kg Multiple Myeloma = M-CRAB Monoclonal protein Calcium Renal failure Anemia Bone pain with lytic lesions Immunoglobulin Immunoglobulins SPEP: Normal SPEP: M-protein, M-spike Renal Failure Cast nephropathy (also called myeloma kidney) from light chains Hypercalcemia Light chain amyloidosis Drug-induced renal damage Anemia Normocytic, normochromic anemiais present in 73% at diagnosis and in 97%at some time during the course of the disease This anemia can be related to: Bone marrow replacement Kidney damage Dilution in the case of a large M-protein B12 deficiency in 14% Rouleaux Formation Lytic Bone Lesion MM: PET Scan Extramedullary Plasmacytoma Differential Diagnosis of MM Monoclonal gammopathy of undetermined significance (MGUS) Smoldering multiple myeloma (SMM) Waldenstrom macroglobulinemia Solitary plasmacytoma Primary amyloidosis (AL) POEMS syndrome Metastatic carcinoma Multiple Myeloma All 3 criteria must be met: Presence of a serum or urinary monoclonal protein Presence of clonal plasma cells in the bone marrow or a plasmacytoma Presence of end organ damage felt related to the plasma cell dyscrasia, such as: Increased calcium concentration Lytic bone lesions Anemia Renal failure Smoldering Multiple Myeloma SMM, Asymptomatic Both criteria must be met: Serum monoclonal protein ≥3 g/dL and/or bone marrow plasma cells ≥10 percent No end organ damage related to plasma cell dyscrasia Monoclonal Gammopathy of Undetermined Significance (MGUS) All 3 criteria must be met: Serum monoclonal protein <3 g/dL Bone marrow plasma cells <10 percent No end organ damage related to plasma cell dyscrasia or a related B cell lymphoproliferative disorder POEMS Syndrome Osteosclerotic myeloma Polyneuropathy Organomegaly Endocrinopathy Monoclonal protein Skin changes MM: Evaluation CBC and differential,peripheral blood smear Chemistry:serum calcium, creatinine, albumin, LDH , beta-2 microglobulin, and C-reactive protein Serum protein electrophoresis (SPEP) + IF Quantification of immunoglobulins Urinalysis and a 24-hour urine collection for electrophoresis (UPEP) + IF Serum free monoclonal light chain (FLC) MM Evaluation Serum viscosity should be measured if the M-protein concentration is high Bone marrow aspiration and biopsy with immunophenotyping, conventional cytogenetics, and fluorescence in situ hybridization (FISH) Metastatic bone survey with plain radiographs including the humeri and femoral bones should be performed in all patients. MRI, CT, or PET/CT Bone Marrow Cytogenenetics, Interphase FISH Poor prognosis (median survival 25 months): t(4;14)(p16;q32), t(14;16)(q32;q23), and -17p13 Intermediate prognosis (median survival 42 months): -13q14 Good prognosis (median survival 50 months): all others Staging for MM International staging system (ISS)  Stage I — B2M <3.5 mg/L and serum albumin ≥3.5 g/dL Stage II — neither stage I nor stage III Stage III — B2M ≥5.5 mg/L Median overall survival for patients with ISS stages I, II, and III are 62, 44, and 29 months MM: Treatment Decisions Indications for treatment Risk stratification Eligibility for stem cell transplantation Smoldering (asymptomatic) myeloma Deferral of chemotherapy until progression to symptomatic disease Follow these patients closely, every 3 to 4 months, with serum protein electrophoresis, complete blood count, serum creatinine, and serum calcium Metastatic bone survey should be considered annually because asymptomatic bone lesions may develop MM: Indications for Treatment Anemia (hemoglobin <10 g/dL or 2 g/dL below normal) Hypercalcemia (serum calcium >11.5 mg/dL) Renal insufficiency (serum creatinine>2 mg/dL) Lytic bone lesions or severe osteopenia Extramedullary plasmacytoma MM: RISK STRATIFICATION FISH for detection of t(4;14), t(14;16), and del17p13 Conventional cytogenetics (karyotyping) for detection of del 13 or hypodiploidy The presence of any of the above markers defines high risk myeloma, which encompasses the 25 percent of MM patients who have a median survival of approximately two years or less despite standard treatment Current Frontline Options Conventional chemotherapy Survival ≤ 3 yrs Transplantation Prolongs survival 4-5 yrs Novel agents targeting stromal interactions and associated signaling pathways have shown promise Chng WJ, et al. Cancer Control. 2005;12:91-104. MM: INITIAL THERAPY The initial therapy of patients with symptomatic myeloma varies depending on whether patients are eligible or not to pursue autologous hematopoietic cell transplantation *Thal/dex or dex are additional options especially if immediate response is needed. Clearly not transplantation candidate based on age, performance score, and comorbidity MPT, MPV, Len/dex or clinical trial* Potential transplantation candidate Nonalkylator-based induction x 4 cycles Stem cell harvest Initial Approach to Treatment of MM DETERMINING TRANSPLANT ELIGIBILITY Autologous hematopoietic cell transplantation (HCT) results in superior event-free and overall survival rates when compared with combination chemotherapy All patients should be evaluated at diagnosis for transplant eligibility so that the risks and benefits of autologous HCT can be reviewed with those eligible A minority of patients will be eligible for allogeneic HCT, but the value of allogeneic approaches in myeloma remain investigational NOT Eligible for Autologous HCT Age >77 years Direct bilirubin>2.0 mg/dL (34.2 µmol/liter) Serum creatinine>2.5 mg/dL (221 µmol/liter) unless on chronic stable dialysis Eastern Cooperative Oncology Group (ECOG) performance status 3 or 4 unless due to bone pain New York Heart Association functional status Class III or IV 54 42 Attal M, et al. N Engl J Med. 1996;335:91-97. Child JA, et al. N Engl J Med. 2003;348:1875-1883. 15 30 45 60 25 50 75 100 OS (%) 0 0 High dose Conventional dose Mos 20 40 60 80 25 50 75 100 Survival (%) 0 0 Intensive therapy Standard therapy Mos P = .03 by Wilcoxon test P = .04 by log-rank test Transplantation vs Conventional Chemotherapy Autologous Stem Cell Transplantation Mel 200 mg/m2 standard conditioning regimen Sufficient performance score, and adequate liver, pulmonary, cardiac function needed Higher PR and CR rates than conventional chemotherapy Higher OS and EFS than conventional Rx Advanced age and impaired renal function are, by themselves, not contraindications Attal M, et al. N Engl J Med. 1996;335:91-97. NCCN Practice Guidelines. Myeloma. V.3.2010. Stem Cell Transplantation Key issues Efficacy compared with conventional chemotherapy Timing: early vs delayed Single vs tandem Role of allogeneic and miniallogeneic transplantations Maintenance post-SCT Novel Frontline Options Immunomodulatory drugs (IMiDs) Thalidomide Lenalidomide Proteasome inhibitors Bortezomib Carfilzomib Kyle RA, et al. N Engl J Med. 2004;351:1860-1873. Copyright ©2004. Massachusetts Medical Society. All rights reserved. Proposed Mechanism of Action for Multiple Myeloma Therapies Thalidomide: Proposed Mechanism of Action Proposed mechanisms Inhibition of TNF- Suppression of angiogenesis Increase in cell-mediated cytotoxic effects Modulation of adhesion molecule expression Kyle RA, et al. N Engl J Med. 2004;351:1860-1873. Rajkumar SV, et al. Leukemia. 2003;17:775-779. D’Amato RJ, et al.Proc Natl Acad Sci U S A. 1994;91:4082-4085. Lenalidomide Immunomodulatory derivative of thalidomide More potent than thalidomide in preclinical models Dose-dependent decrease in TNF-α and interleukin-6 Directly induces apoptosis, G1 growth arrest Enhances activity of dexamethasone More favorable toxicity profile than thalidomide Richardson P, et al. Blood. 2003;100:3063. Hideshima T, et al. Blood. 2000;96:2943-2950. Bortezomib: A Reversible Proteasome Inhibitor Chymo- tryptic Site Post- Glutamyl Site Tryptic Site b1 b2 b3 b4 b5 b6 b7 Cross section of  ring Bortezomib Adams J, et al. Invest New Drugs. 2000;18:109-121. Adams J, et al. Bioorg Med Chem Lett. 1998;8:333-338. H N B N H O O OH N N OH Initial Approach to Treatment of MM Clearly not a transplantation candidate MPT, MPV, Len/dex or clinical trial* Potential transplantation candidate Nonalkylator-based induction Stem cell harvest Melphalan/Prednisone/Thalidomide Palumbo A, et al. Blood. 2008;112:3107-3114. Lenalidomide 25 mg/day PO on Days 1-21 + High-dose Dex 40 mg/day PO on Days 1-4, 9-12, 17-20 (n = 223) Lenalidomide 25 mg/day PO on Days 1-21 + Low-dose Dex 40 mg/day PO on Days 1, 8, 15, 22 (n = 222) Len + High or Low-Dose Dex in Newly Diagnosed Myeloma (E4A03) Courses repeat every 28 days ≤ 1 yr in absence of PD or unacceptable toxicity Total Dex dose per cycle: 480 mg Untreated, symptomatic myeloma, no age cutoff Total Dex dose per cycle: 160 mg Rajkumar SV, et al. ASCO 2008. Abstract 8504. Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37 Len + High or Low-Dose Dex (E4A03): Response 3-yr OS rates converged (P = .467) with all pts crossed over to low dose Successful stem cell harvesting in 97.6% (n = 167) 3-yr OS for high dose or low dose followed by SCT: 92% Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37. Len + High or Low-Dose Dex (E4A03): Adverse Events Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37. Lenalidomide Dosing for MM and Impaired Renal Function Lenalidomide [package insert]. Peripheral Neuropathy Following Bortezomib Therapy in Advanced MM Peripheral neuropathy was reported in 90/256 (35%) patients with MM treated with bortezomib in phase II trials 80% of patients entered these trials with preexisting peripheral neuropathy 3% patients without vs 16% with baseline peripheral neuropathy developed grade 3 peripheral neuropathy Richardson PG, et al. ASH 2003. Abstract 512.
Slide 56 - Special Thanks to… For sponsorship of LMEF programs: Supported by an educational grant from Lilly USA, LLC Did you know that you could be receiving credit for attending today? For membership information, please visit our website: www.Lafmeded.org. Multiple Myeloma 2010 Wael Harb MD Horizon Oncology Center Overview Introduction: epidemiology, clinical presentation, diagnosis, staging Autologous stem cell transplantation Initial approaches to treatment Current options Novel agents and combinations Considerations in non-transplantation-eligible patients Prevention of skeletal complications What is MM? Multiple myeloma (MM) is characterized by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. Plasma Cell Multiple Myeloma: Incidence The lifetime risk of getting MM is 1 in 159 (0.63%). 20,180 new cases will be diagnosed in 2010 (11,170 in men and 9,010 in women) 10,650 deaths are expected to occur in 2010 (5,760 in men and 4,890 in women) The 5-year relative survival rate for MM is around 35% Incidence MM occurs in all races and all geographic locations African Americans and blacks from Africa is two to three times the risk in whites Risk is lower in Asians from Japan and in Mexicans Slightly more frequent in men than in women (1.4:1) Age MM is a disease of older adults The median age at diagnosis is 66 years Only 10 percent of patients are younger than 50 years Only 2 percent of patients are younger than 40 years MM: Clinical Presentations Anemia - 73 percent Bone pain - 58 percent Elevated creatinine - 48 percent Fatigue/generalized weakness - 32 percent Hypercalcemia- 28 percent Weight loss - 24 percent, one-half of whom had lost ≥ 9 kg Multiple Myeloma = M-CRAB Monoclonal protein Calcium Renal failure Anemia Bone pain with lytic lesions Immunoglobulin Immunoglobulins SPEP: Normal SPEP: M-protein, M-spike Renal Failure Cast nephropathy (also called myeloma kidney) from light chains Hypercalcemia Light chain amyloidosis Drug-induced renal damage Anemia Normocytic, normochromic anemiais present in 73% at diagnosis and in 97%at some time during the course of the disease This anemia can be related to: Bone marrow replacement Kidney damage Dilution in the case of a large M-protein B12 deficiency in 14% Rouleaux Formation Lytic Bone Lesion MM: PET Scan Extramedullary Plasmacytoma Differential Diagnosis of MM Monoclonal gammopathy of undetermined significance (MGUS) Smoldering multiple myeloma (SMM) Waldenstrom macroglobulinemia Solitary plasmacytoma Primary amyloidosis (AL) POEMS syndrome Metastatic carcinoma Multiple Myeloma All 3 criteria must be met: Presence of a serum or urinary monoclonal protein Presence of clonal plasma cells in the bone marrow or a plasmacytoma Presence of end organ damage felt related to the plasma cell dyscrasia, such as: Increased calcium concentration Lytic bone lesions Anemia Renal failure Smoldering Multiple Myeloma SMM, Asymptomatic Both criteria must be met: Serum monoclonal protein ≥3 g/dL and/or bone marrow plasma cells ≥10 percent No end organ damage related to plasma cell dyscrasia Monoclonal Gammopathy of Undetermined Significance (MGUS) All 3 criteria must be met: Serum monoclonal protein <3 g/dL Bone marrow plasma cells <10 percent No end organ damage related to plasma cell dyscrasia or a related B cell lymphoproliferative disorder POEMS Syndrome Osteosclerotic myeloma Polyneuropathy Organomegaly Endocrinopathy Monoclonal protein Skin changes MM: Evaluation CBC and differential,peripheral blood smear Chemistry:serum calcium, creatinine, albumin, LDH , beta-2 microglobulin, and C-reactive protein Serum protein electrophoresis (SPEP) + IF Quantification of immunoglobulins Urinalysis and a 24-hour urine collection for electrophoresis (UPEP) + IF Serum free monoclonal light chain (FLC) MM Evaluation Serum viscosity should be measured if the M-protein concentration is high Bone marrow aspiration and biopsy with immunophenotyping, conventional cytogenetics, and fluorescence in situ hybridization (FISH) Metastatic bone survey with plain radiographs including the humeri and femoral bones should be performed in all patients. MRI, CT, or PET/CT Bone Marrow Cytogenenetics, Interphase FISH Poor prognosis (median survival 25 months): t(4;14)(p16;q32), t(14;16)(q32;q23), and -17p13 Intermediate prognosis (median survival 42 months): -13q14 Good prognosis (median survival 50 months): all others Staging for MM International staging system (ISS)  Stage I — B2M <3.5 mg/L and serum albumin ≥3.5 g/dL Stage II — neither stage I nor stage III Stage III — B2M ≥5.5 mg/L Median overall survival for patients with ISS stages I, II, and III are 62, 44, and 29 months MM: Treatment Decisions Indications for treatment Risk stratification Eligibility for stem cell transplantation Smoldering (asymptomatic) myeloma Deferral of chemotherapy until progression to symptomatic disease Follow these patients closely, every 3 to 4 months, with serum protein electrophoresis, complete blood count, serum creatinine, and serum calcium Metastatic bone survey should be considered annually because asymptomatic bone lesions may develop MM: Indications for Treatment Anemia (hemoglobin <10 g/dL or 2 g/dL below normal) Hypercalcemia (serum calcium >11.5 mg/dL) Renal insufficiency (serum creatinine>2 mg/dL) Lytic bone lesions or severe osteopenia Extramedullary plasmacytoma MM: RISK STRATIFICATION FISH for detection of t(4;14), t(14;16), and del17p13 Conventional cytogenetics (karyotyping) for detection of del 13 or hypodiploidy The presence of any of the above markers defines high risk myeloma, which encompasses the 25 percent of MM patients who have a median survival of approximately two years or less despite standard treatment Current Frontline Options Conventional chemotherapy Survival ≤ 3 yrs Transplantation Prolongs survival 4-5 yrs Novel agents targeting stromal interactions and associated signaling pathways have shown promise Chng WJ, et al. Cancer Control. 2005;12:91-104. MM: INITIAL THERAPY The initial therapy of patients with symptomatic myeloma varies depending on whether patients are eligible or not to pursue autologous hematopoietic cell transplantation *Thal/dex or dex are additional options especially if immediate response is needed. Clearly not transplantation candidate based on age, performance score, and comorbidity MPT, MPV, Len/dex or clinical trial* Potential transplantation candidate Nonalkylator-based induction x 4 cycles Stem cell harvest Initial Approach to Treatment of MM DETERMINING TRANSPLANT ELIGIBILITY Autologous hematopoietic cell transplantation (HCT) results in superior event-free and overall survival rates when compared with combination chemotherapy All patients should be evaluated at diagnosis for transplant eligibility so that the risks and benefits of autologous HCT can be reviewed with those eligible A minority of patients will be eligible for allogeneic HCT, but the value of allogeneic approaches in myeloma remain investigational NOT Eligible for Autologous HCT Age >77 years Direct bilirubin>2.0 mg/dL (34.2 µmol/liter) Serum creatinine>2.5 mg/dL (221 µmol/liter) unless on chronic stable dialysis Eastern Cooperative Oncology Group (ECOG) performance status 3 or 4 unless due to bone pain New York Heart Association functional status Class III or IV 54 42 Attal M, et al. N Engl J Med. 1996;335:91-97. Child JA, et al. N Engl J Med. 2003;348:1875-1883. 15 30 45 60 25 50 75 100 OS (%) 0 0 High dose Conventional dose Mos 20 40 60 80 25 50 75 100 Survival (%) 0 0 Intensive therapy Standard therapy Mos P = .03 by Wilcoxon test P = .04 by log-rank test Transplantation vs Conventional Chemotherapy Autologous Stem Cell Transplantation Mel 200 mg/m2 standard conditioning regimen Sufficient performance score, and adequate liver, pulmonary, cardiac function needed Higher PR and CR rates than conventional chemotherapy Higher OS and EFS than conventional Rx Advanced age and impaired renal function are, by themselves, not contraindications Attal M, et al. N Engl J Med. 1996;335:91-97. NCCN Practice Guidelines. Myeloma. V.3.2010. Stem Cell Transplantation Key issues Efficacy compared with conventional chemotherapy Timing: early vs delayed Single vs tandem Role of allogeneic and miniallogeneic transplantations Maintenance post-SCT Novel Frontline Options Immunomodulatory drugs (IMiDs) Thalidomide Lenalidomide Proteasome inhibitors Bortezomib Carfilzomib Kyle RA, et al. N Engl J Med. 2004;351:1860-1873. Copyright ©2004. Massachusetts Medical Society. All rights reserved. Proposed Mechanism of Action for Multiple Myeloma Therapies Thalidomide: Proposed Mechanism of Action Proposed mechanisms Inhibition of TNF- Suppression of angiogenesis Increase in cell-mediated cytotoxic effects Modulation of adhesion molecule expression Kyle RA, et al. N Engl J Med. 2004;351:1860-1873. Rajkumar SV, et al. Leukemia. 2003;17:775-779. D’Amato RJ, et al.Proc Natl Acad Sci U S A. 1994;91:4082-4085. Lenalidomide Immunomodulatory derivative of thalidomide More potent than thalidomide in preclinical models Dose-dependent decrease in TNF-α and interleukin-6 Directly induces apoptosis, G1 growth arrest Enhances activity of dexamethasone More favorable toxicity profile than thalidomide Richardson P, et al. Blood. 2003;100:3063. Hideshima T, et al. Blood. 2000;96:2943-2950. Bortezomib: A Reversible Proteasome Inhibitor Chymo- tryptic Site Post- Glutamyl Site Tryptic Site b1 b2 b3 b4 b5 b6 b7 Cross section of  ring Bortezomib Adams J, et al. Invest New Drugs. 2000;18:109-121. Adams J, et al. Bioorg Med Chem Lett. 1998;8:333-338. H N B N H O O OH N N OH Initial Approach to Treatment of MM Clearly not a transplantation candidate MPT, MPV, Len/dex or clinical trial* Potential transplantation candidate Nonalkylator-based induction Stem cell harvest Melphalan/Prednisone/Thalidomide Palumbo A, et al. Blood. 2008;112:3107-3114. Lenalidomide 25 mg/day PO on Days 1-21 + High-dose Dex 40 mg/day PO on Days 1-4, 9-12, 17-20 (n = 223) Lenalidomide 25 mg/day PO on Days 1-21 + Low-dose Dex 40 mg/day PO on Days 1, 8, 15, 22 (n = 222) Len + High or Low-Dose Dex in Newly Diagnosed Myeloma (E4A03) Courses repeat every 28 days ≤ 1 yr in absence of PD or unacceptable toxicity Total Dex dose per cycle: 480 mg Untreated, symptomatic myeloma, no age cutoff Total Dex dose per cycle: 160 mg Rajkumar SV, et al. ASCO 2008. Abstract 8504. Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37 Len + High or Low-Dose Dex (E4A03): Response 3-yr OS rates converged (P = .467) with all pts crossed over to low dose Successful stem cell harvesting in 97.6% (n = 167) 3-yr OS for high dose or low dose followed by SCT: 92% Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37. Len + High or Low-Dose Dex (E4A03): Adverse Events Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37. Lenalidomide Dosing for MM and Impaired Renal Function Lenalidomide [package insert]. Peripheral Neuropathy Following Bortezomib Therapy in Advanced MM Peripheral neuropathy was reported in 90/256 (35%) patients with MM treated with bortezomib in phase II trials 80% of patients entered these trials with preexisting peripheral neuropathy 3% patients without vs 16% with baseline peripheral neuropathy developed grade 3 peripheral neuropathy Richardson PG, et al. ASH 2003. Abstract 512. Frontline Therapy in Elderly MM Patients For elderly patients or those who are not suitable candidates for transplantation, MP has been a standard treatment ORR: 60% Long-term CR: < 5% Trials with MP-based combinations reported improved response rates and time to progression MPT VMP NCCN Practice Guidelines. Myeloma. V.3.2010.
Slide 57 - Special Thanks to… For sponsorship of LMEF programs: Supported by an educational grant from Lilly USA, LLC Did you know that you could be receiving credit for attending today? For membership information, please visit our website: www.Lafmeded.org. Multiple Myeloma 2010 Wael Harb MD Horizon Oncology Center Overview Introduction: epidemiology, clinical presentation, diagnosis, staging Autologous stem cell transplantation Initial approaches to treatment Current options Novel agents and combinations Considerations in non-transplantation-eligible patients Prevention of skeletal complications What is MM? Multiple myeloma (MM) is characterized by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. Plasma Cell Multiple Myeloma: Incidence The lifetime risk of getting MM is 1 in 159 (0.63%). 20,180 new cases will be diagnosed in 2010 (11,170 in men and 9,010 in women) 10,650 deaths are expected to occur in 2010 (5,760 in men and 4,890 in women) The 5-year relative survival rate for MM is around 35% Incidence MM occurs in all races and all geographic locations African Americans and blacks from Africa is two to three times the risk in whites Risk is lower in Asians from Japan and in Mexicans Slightly more frequent in men than in women (1.4:1) Age MM is a disease of older adults The median age at diagnosis is 66 years Only 10 percent of patients are younger than 50 years Only 2 percent of patients are younger than 40 years MM: Clinical Presentations Anemia - 73 percent Bone pain - 58 percent Elevated creatinine - 48 percent Fatigue/generalized weakness - 32 percent Hypercalcemia- 28 percent Weight loss - 24 percent, one-half of whom had lost ≥ 9 kg Multiple Myeloma = M-CRAB Monoclonal protein Calcium Renal failure Anemia Bone pain with lytic lesions Immunoglobulin Immunoglobulins SPEP: Normal SPEP: M-protein, M-spike Renal Failure Cast nephropathy (also called myeloma kidney) from light chains Hypercalcemia Light chain amyloidosis Drug-induced renal damage Anemia Normocytic, normochromic anemiais present in 73% at diagnosis and in 97%at some time during the course of the disease This anemia can be related to: Bone marrow replacement Kidney damage Dilution in the case of a large M-protein B12 deficiency in 14% Rouleaux Formation Lytic Bone Lesion MM: PET Scan Extramedullary Plasmacytoma Differential Diagnosis of MM Monoclonal gammopathy of undetermined significance (MGUS) Smoldering multiple myeloma (SMM) Waldenstrom macroglobulinemia Solitary plasmacytoma Primary amyloidosis (AL) POEMS syndrome Metastatic carcinoma Multiple Myeloma All 3 criteria must be met: Presence of a serum or urinary monoclonal protein Presence of clonal plasma cells in the bone marrow or a plasmacytoma Presence of end organ damage felt related to the plasma cell dyscrasia, such as: Increased calcium concentration Lytic bone lesions Anemia Renal failure Smoldering Multiple Myeloma SMM, Asymptomatic Both criteria must be met: Serum monoclonal protein ≥3 g/dL and/or bone marrow plasma cells ≥10 percent No end organ damage related to plasma cell dyscrasia Monoclonal Gammopathy of Undetermined Significance (MGUS) All 3 criteria must be met: Serum monoclonal protein <3 g/dL Bone marrow plasma cells <10 percent No end organ damage related to plasma cell dyscrasia or a related B cell lymphoproliferative disorder POEMS Syndrome Osteosclerotic myeloma Polyneuropathy Organomegaly Endocrinopathy Monoclonal protein Skin changes MM: Evaluation CBC and differential,peripheral blood smear Chemistry:serum calcium, creatinine, albumin, LDH , beta-2 microglobulin, and C-reactive protein Serum protein electrophoresis (SPEP) + IF Quantification of immunoglobulins Urinalysis and a 24-hour urine collection for electrophoresis (UPEP) + IF Serum free monoclonal light chain (FLC) MM Evaluation Serum viscosity should be measured if the M-protein concentration is high Bone marrow aspiration and biopsy with immunophenotyping, conventional cytogenetics, and fluorescence in situ hybridization (FISH) Metastatic bone survey with plain radiographs including the humeri and femoral bones should be performed in all patients. MRI, CT, or PET/CT Bone Marrow Cytogenenetics, Interphase FISH Poor prognosis (median survival 25 months): t(4;14)(p16;q32), t(14;16)(q32;q23), and -17p13 Intermediate prognosis (median survival 42 months): -13q14 Good prognosis (median survival 50 months): all others Staging for MM International staging system (ISS)  Stage I — B2M <3.5 mg/L and serum albumin ≥3.5 g/dL Stage II — neither stage I nor stage III Stage III — B2M ≥5.5 mg/L Median overall survival for patients with ISS stages I, II, and III are 62, 44, and 29 months MM: Treatment Decisions Indications for treatment Risk stratification Eligibility for stem cell transplantation Smoldering (asymptomatic) myeloma Deferral of chemotherapy until progression to symptomatic disease Follow these patients closely, every 3 to 4 months, with serum protein electrophoresis, complete blood count, serum creatinine, and serum calcium Metastatic bone survey should be considered annually because asymptomatic bone lesions may develop MM: Indications for Treatment Anemia (hemoglobin <10 g/dL or 2 g/dL below normal) Hypercalcemia (serum calcium >11.5 mg/dL) Renal insufficiency (serum creatinine>2 mg/dL) Lytic bone lesions or severe osteopenia Extramedullary plasmacytoma MM: RISK STRATIFICATION FISH for detection of t(4;14), t(14;16), and del17p13 Conventional cytogenetics (karyotyping) for detection of del 13 or hypodiploidy The presence of any of the above markers defines high risk myeloma, which encompasses the 25 percent of MM patients who have a median survival of approximately two years or less despite standard treatment Current Frontline Options Conventional chemotherapy Survival ≤ 3 yrs Transplantation Prolongs survival 4-5 yrs Novel agents targeting stromal interactions and associated signaling pathways have shown promise Chng WJ, et al. Cancer Control. 2005;12:91-104. MM: INITIAL THERAPY The initial therapy of patients with symptomatic myeloma varies depending on whether patients are eligible or not to pursue autologous hematopoietic cell transplantation *Thal/dex or dex are additional options especially if immediate response is needed. Clearly not transplantation candidate based on age, performance score, and comorbidity MPT, MPV, Len/dex or clinical trial* Potential transplantation candidate Nonalkylator-based induction x 4 cycles Stem cell harvest Initial Approach to Treatment of MM DETERMINING TRANSPLANT ELIGIBILITY Autologous hematopoietic cell transplantation (HCT) results in superior event-free and overall survival rates when compared with combination chemotherapy All patients should be evaluated at diagnosis for transplant eligibility so that the risks and benefits of autologous HCT can be reviewed with those eligible A minority of patients will be eligible for allogeneic HCT, but the value of allogeneic approaches in myeloma remain investigational NOT Eligible for Autologous HCT Age >77 years Direct bilirubin>2.0 mg/dL (34.2 µmol/liter) Serum creatinine>2.5 mg/dL (221 µmol/liter) unless on chronic stable dialysis Eastern Cooperative Oncology Group (ECOG) performance status 3 or 4 unless due to bone pain New York Heart Association functional status Class III or IV 54 42 Attal M, et al. N Engl J Med. 1996;335:91-97. Child JA, et al. N Engl J Med. 2003;348:1875-1883. 15 30 45 60 25 50 75 100 OS (%) 0 0 High dose Conventional dose Mos 20 40 60 80 25 50 75 100 Survival (%) 0 0 Intensive therapy Standard therapy Mos P = .03 by Wilcoxon test P = .04 by log-rank test Transplantation vs Conventional Chemotherapy Autologous Stem Cell Transplantation Mel 200 mg/m2 standard conditioning regimen Sufficient performance score, and adequate liver, pulmonary, cardiac function needed Higher PR and CR rates than conventional chemotherapy Higher OS and EFS than conventional Rx Advanced age and impaired renal function are, by themselves, not contraindications Attal M, et al. N Engl J Med. 1996;335:91-97. NCCN Practice Guidelines. Myeloma. V.3.2010. Stem Cell Transplantation Key issues Efficacy compared with conventional chemotherapy Timing: early vs delayed Single vs tandem Role of allogeneic and miniallogeneic transplantations Maintenance post-SCT Novel Frontline Options Immunomodulatory drugs (IMiDs) Thalidomide Lenalidomide Proteasome inhibitors Bortezomib Carfilzomib Kyle RA, et al. N Engl J Med. 2004;351:1860-1873. Copyright ©2004. Massachusetts Medical Society. All rights reserved. Proposed Mechanism of Action for Multiple Myeloma Therapies Thalidomide: Proposed Mechanism of Action Proposed mechanisms Inhibition of TNF- Suppression of angiogenesis Increase in cell-mediated cytotoxic effects Modulation of adhesion molecule expression Kyle RA, et al. N Engl J Med. 2004;351:1860-1873. Rajkumar SV, et al. Leukemia. 2003;17:775-779. D’Amato RJ, et al.Proc Natl Acad Sci U S A. 1994;91:4082-4085. Lenalidomide Immunomodulatory derivative of thalidomide More potent than thalidomide in preclinical models Dose-dependent decrease in TNF-α and interleukin-6 Directly induces apoptosis, G1 growth arrest Enhances activity of dexamethasone More favorable toxicity profile than thalidomide Richardson P, et al. Blood. 2003;100:3063. Hideshima T, et al. Blood. 2000;96:2943-2950. Bortezomib: A Reversible Proteasome Inhibitor Chymo- tryptic Site Post- Glutamyl Site Tryptic Site b1 b2 b3 b4 b5 b6 b7 Cross section of  ring Bortezomib Adams J, et al. Invest New Drugs. 2000;18:109-121. Adams J, et al. Bioorg Med Chem Lett. 1998;8:333-338. H N B N H O O OH N N OH Initial Approach to Treatment of MM Clearly not a transplantation candidate MPT, MPV, Len/dex or clinical trial* Potential transplantation candidate Nonalkylator-based induction Stem cell harvest Melphalan/Prednisone/Thalidomide Palumbo A, et al. Blood. 2008;112:3107-3114. Lenalidomide 25 mg/day PO on Days 1-21 + High-dose Dex 40 mg/day PO on Days 1-4, 9-12, 17-20 (n = 223) Lenalidomide 25 mg/day PO on Days 1-21 + Low-dose Dex 40 mg/day PO on Days 1, 8, 15, 22 (n = 222) Len + High or Low-Dose Dex in Newly Diagnosed Myeloma (E4A03) Courses repeat every 28 days ≤ 1 yr in absence of PD or unacceptable toxicity Total Dex dose per cycle: 480 mg Untreated, symptomatic myeloma, no age cutoff Total Dex dose per cycle: 160 mg Rajkumar SV, et al. ASCO 2008. Abstract 8504. Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37 Len + High or Low-Dose Dex (E4A03): Response 3-yr OS rates converged (P = .467) with all pts crossed over to low dose Successful stem cell harvesting in 97.6% (n = 167) 3-yr OS for high dose or low dose followed by SCT: 92% Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37. Len + High or Low-Dose Dex (E4A03): Adverse Events Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37. Lenalidomide Dosing for MM and Impaired Renal Function Lenalidomide [package insert]. Peripheral Neuropathy Following Bortezomib Therapy in Advanced MM Peripheral neuropathy was reported in 90/256 (35%) patients with MM treated with bortezomib in phase II trials 80% of patients entered these trials with preexisting peripheral neuropathy 3% patients without vs 16% with baseline peripheral neuropathy developed grade 3 peripheral neuropathy Richardson PG, et al. ASH 2003. Abstract 512. Frontline Therapy in Elderly MM Patients For elderly patients or those who are not suitable candidates for transplantation, MP has been a standard treatment ORR: 60% Long-term CR: < 5% Trials with MP-based combinations reported improved response rates and time to progression MPT VMP NCCN Practice Guidelines. Myeloma. V.3.2010. Conclusions In elderly patients, the addition of novel agents to standard MP has provided improved response rates MP alone (ORR: 50%; CR: 5%) MPR (50% to 95% reduction in myeloma protein in 55.6%) VMP (ORR: 86%) Care should be taken with IMiD-based therapy to include aspirin prophylaxis for DVT/PE Care should be taken with bortezomib-based regimens to include herpes zoster prophylaxis
Slide 58 - Special Thanks to… For sponsorship of LMEF programs: Supported by an educational grant from Lilly USA, LLC Did you know that you could be receiving credit for attending today? For membership information, please visit our website: www.Lafmeded.org. Multiple Myeloma 2010 Wael Harb MD Horizon Oncology Center Overview Introduction: epidemiology, clinical presentation, diagnosis, staging Autologous stem cell transplantation Initial approaches to treatment Current options Novel agents and combinations Considerations in non-transplantation-eligible patients Prevention of skeletal complications What is MM? Multiple myeloma (MM) is characterized by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. Plasma Cell Multiple Myeloma: Incidence The lifetime risk of getting MM is 1 in 159 (0.63%). 20,180 new cases will be diagnosed in 2010 (11,170 in men and 9,010 in women) 10,650 deaths are expected to occur in 2010 (5,760 in men and 4,890 in women) The 5-year relative survival rate for MM is around 35% Incidence MM occurs in all races and all geographic locations African Americans and blacks from Africa is two to three times the risk in whites Risk is lower in Asians from Japan and in Mexicans Slightly more frequent in men than in women (1.4:1) Age MM is a disease of older adults The median age at diagnosis is 66 years Only 10 percent of patients are younger than 50 years Only 2 percent of patients are younger than 40 years MM: Clinical Presentations Anemia - 73 percent Bone pain - 58 percent Elevated creatinine - 48 percent Fatigue/generalized weakness - 32 percent Hypercalcemia- 28 percent Weight loss - 24 percent, one-half of whom had lost ≥ 9 kg Multiple Myeloma = M-CRAB Monoclonal protein Calcium Renal failure Anemia Bone pain with lytic lesions Immunoglobulin Immunoglobulins SPEP: Normal SPEP: M-protein, M-spike Renal Failure Cast nephropathy (also called myeloma kidney) from light chains Hypercalcemia Light chain amyloidosis Drug-induced renal damage Anemia Normocytic, normochromic anemiais present in 73% at diagnosis and in 97%at some time during the course of the disease This anemia can be related to: Bone marrow replacement Kidney damage Dilution in the case of a large M-protein B12 deficiency in 14% Rouleaux Formation Lytic Bone Lesion MM: PET Scan Extramedullary Plasmacytoma Differential Diagnosis of MM Monoclonal gammopathy of undetermined significance (MGUS) Smoldering multiple myeloma (SMM) Waldenstrom macroglobulinemia Solitary plasmacytoma Primary amyloidosis (AL) POEMS syndrome Metastatic carcinoma Multiple Myeloma All 3 criteria must be met: Presence of a serum or urinary monoclonal protein Presence of clonal plasma cells in the bone marrow or a plasmacytoma Presence of end organ damage felt related to the plasma cell dyscrasia, such as: Increased calcium concentration Lytic bone lesions Anemia Renal failure Smoldering Multiple Myeloma SMM, Asymptomatic Both criteria must be met: Serum monoclonal protein ≥3 g/dL and/or bone marrow plasma cells ≥10 percent No end organ damage related to plasma cell dyscrasia Monoclonal Gammopathy of Undetermined Significance (MGUS) All 3 criteria must be met: Serum monoclonal protein <3 g/dL Bone marrow plasma cells <10 percent No end organ damage related to plasma cell dyscrasia or a related B cell lymphoproliferative disorder POEMS Syndrome Osteosclerotic myeloma Polyneuropathy Organomegaly Endocrinopathy Monoclonal protein Skin changes MM: Evaluation CBC and differential,peripheral blood smear Chemistry:serum calcium, creatinine, albumin, LDH , beta-2 microglobulin, and C-reactive protein Serum protein electrophoresis (SPEP) + IF Quantification of immunoglobulins Urinalysis and a 24-hour urine collection for electrophoresis (UPEP) + IF Serum free monoclonal light chain (FLC) MM Evaluation Serum viscosity should be measured if the M-protein concentration is high Bone marrow aspiration and biopsy with immunophenotyping, conventional cytogenetics, and fluorescence in situ hybridization (FISH) Metastatic bone survey with plain radiographs including the humeri and femoral bones should be performed in all patients. MRI, CT, or PET/CT Bone Marrow Cytogenenetics, Interphase FISH Poor prognosis (median survival 25 months): t(4;14)(p16;q32), t(14;16)(q32;q23), and -17p13 Intermediate prognosis (median survival 42 months): -13q14 Good prognosis (median survival 50 months): all others Staging for MM International staging system (ISS)  Stage I — B2M <3.5 mg/L and serum albumin ≥3.5 g/dL Stage II — neither stage I nor stage III Stage III — B2M ≥5.5 mg/L Median overall survival for patients with ISS stages I, II, and III are 62, 44, and 29 months MM: Treatment Decisions Indications for treatment Risk stratification Eligibility for stem cell transplantation Smoldering (asymptomatic) myeloma Deferral of chemotherapy until progression to symptomatic disease Follow these patients closely, every 3 to 4 months, with serum protein electrophoresis, complete blood count, serum creatinine, and serum calcium Metastatic bone survey should be considered annually because asymptomatic bone lesions may develop MM: Indications for Treatment Anemia (hemoglobin <10 g/dL or 2 g/dL below normal) Hypercalcemia (serum calcium >11.5 mg/dL) Renal insufficiency (serum creatinine>2 mg/dL) Lytic bone lesions or severe osteopenia Extramedullary plasmacytoma MM: RISK STRATIFICATION FISH for detection of t(4;14), t(14;16), and del17p13 Conventional cytogenetics (karyotyping) for detection of del 13 or hypodiploidy The presence of any of the above markers defines high risk myeloma, which encompasses the 25 percent of MM patients who have a median survival of approximately two years or less despite standard treatment Current Frontline Options Conventional chemotherapy Survival ≤ 3 yrs Transplantation Prolongs survival 4-5 yrs Novel agents targeting stromal interactions and associated signaling pathways have shown promise Chng WJ, et al. Cancer Control. 2005;12:91-104. MM: INITIAL THERAPY The initial therapy of patients with symptomatic myeloma varies depending on whether patients are eligible or not to pursue autologous hematopoietic cell transplantation *Thal/dex or dex are additional options especially if immediate response is needed. Clearly not transplantation candidate based on age, performance score, and comorbidity MPT, MPV, Len/dex or clinical trial* Potential transplantation candidate Nonalkylator-based induction x 4 cycles Stem cell harvest Initial Approach to Treatment of MM DETERMINING TRANSPLANT ELIGIBILITY Autologous hematopoietic cell transplantation (HCT) results in superior event-free and overall survival rates when compared with combination chemotherapy All patients should be evaluated at diagnosis for transplant eligibility so that the risks and benefits of autologous HCT can be reviewed with those eligible A minority of patients will be eligible for allogeneic HCT, but the value of allogeneic approaches in myeloma remain investigational NOT Eligible for Autologous HCT Age >77 years Direct bilirubin>2.0 mg/dL (34.2 µmol/liter) Serum creatinine>2.5 mg/dL (221 µmol/liter) unless on chronic stable dialysis Eastern Cooperative Oncology Group (ECOG) performance status 3 or 4 unless due to bone pain New York Heart Association functional status Class III or IV 54 42 Attal M, et al. N Engl J Med. 1996;335:91-97. Child JA, et al. N Engl J Med. 2003;348:1875-1883. 15 30 45 60 25 50 75 100 OS (%) 0 0 High dose Conventional dose Mos 20 40 60 80 25 50 75 100 Survival (%) 0 0 Intensive therapy Standard therapy Mos P = .03 by Wilcoxon test P = .04 by log-rank test Transplantation vs Conventional Chemotherapy Autologous Stem Cell Transplantation Mel 200 mg/m2 standard conditioning regimen Sufficient performance score, and adequate liver, pulmonary, cardiac function needed Higher PR and CR rates than conventional chemotherapy Higher OS and EFS than conventional Rx Advanced age and impaired renal function are, by themselves, not contraindications Attal M, et al. N Engl J Med. 1996;335:91-97. NCCN Practice Guidelines. Myeloma. V.3.2010. Stem Cell Transplantation Key issues Efficacy compared with conventional chemotherapy Timing: early vs delayed Single vs tandem Role of allogeneic and miniallogeneic transplantations Maintenance post-SCT Novel Frontline Options Immunomodulatory drugs (IMiDs) Thalidomide Lenalidomide Proteasome inhibitors Bortezomib Carfilzomib Kyle RA, et al. N Engl J Med. 2004;351:1860-1873. Copyright ©2004. Massachusetts Medical Society. All rights reserved. Proposed Mechanism of Action for Multiple Myeloma Therapies Thalidomide: Proposed Mechanism of Action Proposed mechanisms Inhibition of TNF- Suppression of angiogenesis Increase in cell-mediated cytotoxic effects Modulation of adhesion molecule expression Kyle RA, et al. N Engl J Med. 2004;351:1860-1873. Rajkumar SV, et al. Leukemia. 2003;17:775-779. D’Amato RJ, et al.Proc Natl Acad Sci U S A. 1994;91:4082-4085. Lenalidomide Immunomodulatory derivative of thalidomide More potent than thalidomide in preclinical models Dose-dependent decrease in TNF-α and interleukin-6 Directly induces apoptosis, G1 growth arrest Enhances activity of dexamethasone More favorable toxicity profile than thalidomide Richardson P, et al. Blood. 2003;100:3063. Hideshima T, et al. Blood. 2000;96:2943-2950. Bortezomib: A Reversible Proteasome Inhibitor Chymo- tryptic Site Post- Glutamyl Site Tryptic Site b1 b2 b3 b4 b5 b6 b7 Cross section of  ring Bortezomib Adams J, et al. Invest New Drugs. 2000;18:109-121. Adams J, et al. Bioorg Med Chem Lett. 1998;8:333-338. H N B N H O O OH N N OH Initial Approach to Treatment of MM Clearly not a transplantation candidate MPT, MPV, Len/dex or clinical trial* Potential transplantation candidate Nonalkylator-based induction Stem cell harvest Melphalan/Prednisone/Thalidomide Palumbo A, et al. Blood. 2008;112:3107-3114. Lenalidomide 25 mg/day PO on Days 1-21 + High-dose Dex 40 mg/day PO on Days 1-4, 9-12, 17-20 (n = 223) Lenalidomide 25 mg/day PO on Days 1-21 + Low-dose Dex 40 mg/day PO on Days 1, 8, 15, 22 (n = 222) Len + High or Low-Dose Dex in Newly Diagnosed Myeloma (E4A03) Courses repeat every 28 days ≤ 1 yr in absence of PD or unacceptable toxicity Total Dex dose per cycle: 480 mg Untreated, symptomatic myeloma, no age cutoff Total Dex dose per cycle: 160 mg Rajkumar SV, et al. ASCO 2008. Abstract 8504. Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37 Len + High or Low-Dose Dex (E4A03): Response 3-yr OS rates converged (P = .467) with all pts crossed over to low dose Successful stem cell harvesting in 97.6% (n = 167) 3-yr OS for high dose or low dose followed by SCT: 92% Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37. Len + High or Low-Dose Dex (E4A03): Adverse Events Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37. Lenalidomide Dosing for MM and Impaired Renal Function Lenalidomide [package insert]. Peripheral Neuropathy Following Bortezomib Therapy in Advanced MM Peripheral neuropathy was reported in 90/256 (35%) patients with MM treated with bortezomib in phase II trials 80% of patients entered these trials with preexisting peripheral neuropathy 3% patients without vs 16% with baseline peripheral neuropathy developed grade 3 peripheral neuropathy Richardson PG, et al. ASH 2003. Abstract 512. Frontline Therapy in Elderly MM Patients For elderly patients or those who are not suitable candidates for transplantation, MP has been a standard treatment ORR: 60% Long-term CR: < 5% Trials with MP-based combinations reported improved response rates and time to progression MPT VMP NCCN Practice Guidelines. Myeloma. V.3.2010. Conclusions In elderly patients, the addition of novel agents to standard MP has provided improved response rates MP alone (ORR: 50%; CR: 5%) MPR (50% to 95% reduction in myeloma protein in 55.6%) VMP (ORR: 86%) Care should be taken with IMiD-based therapy to include aspirin prophylaxis for DVT/PE Care should be taken with bortezomib-based regimens to include herpes zoster prophylaxis MM & Skeletal Complications ~ 80% of patients with multiple myeloma will have evidence of skeletal involvement on skeletal survey Vertebrae: 65% Ribs: 45% Skull: 40% Shoulders: 40% Pelvis: 30% Long bones: 25% Dimopoulos M, et al. Leukemia. 2009:1-12.
Slide 59 - Special Thanks to… For sponsorship of LMEF programs: Supported by an educational grant from Lilly USA, LLC Did you know that you could be receiving credit for attending today? For membership information, please visit our website: www.Lafmeded.org. Multiple Myeloma 2010 Wael Harb MD Horizon Oncology Center Overview Introduction: epidemiology, clinical presentation, diagnosis, staging Autologous stem cell transplantation Initial approaches to treatment Current options Novel agents and combinations Considerations in non-transplantation-eligible patients Prevention of skeletal complications What is MM? Multiple myeloma (MM) is characterized by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. Plasma Cell Multiple Myeloma: Incidence The lifetime risk of getting MM is 1 in 159 (0.63%). 20,180 new cases will be diagnosed in 2010 (11,170 in men and 9,010 in women) 10,650 deaths are expected to occur in 2010 (5,760 in men and 4,890 in women) The 5-year relative survival rate for MM is around 35% Incidence MM occurs in all races and all geographic locations African Americans and blacks from Africa is two to three times the risk in whites Risk is lower in Asians from Japan and in Mexicans Slightly more frequent in men than in women (1.4:1) Age MM is a disease of older adults The median age at diagnosis is 66 years Only 10 percent of patients are younger than 50 years Only 2 percent of patients are younger than 40 years MM: Clinical Presentations Anemia - 73 percent Bone pain - 58 percent Elevated creatinine - 48 percent Fatigue/generalized weakness - 32 percent Hypercalcemia- 28 percent Weight loss - 24 percent, one-half of whom had lost ≥ 9 kg Multiple Myeloma = M-CRAB Monoclonal protein Calcium Renal failure Anemia Bone pain with lytic lesions Immunoglobulin Immunoglobulins SPEP: Normal SPEP: M-protein, M-spike Renal Failure Cast nephropathy (also called myeloma kidney) from light chains Hypercalcemia Light chain amyloidosis Drug-induced renal damage Anemia Normocytic, normochromic anemiais present in 73% at diagnosis and in 97%at some time during the course of the disease This anemia can be related to: Bone marrow replacement Kidney damage Dilution in the case of a large M-protein B12 deficiency in 14% Rouleaux Formation Lytic Bone Lesion MM: PET Scan Extramedullary Plasmacytoma Differential Diagnosis of MM Monoclonal gammopathy of undetermined significance (MGUS) Smoldering multiple myeloma (SMM) Waldenstrom macroglobulinemia Solitary plasmacytoma Primary amyloidosis (AL) POEMS syndrome Metastatic carcinoma Multiple Myeloma All 3 criteria must be met: Presence of a serum or urinary monoclonal protein Presence of clonal plasma cells in the bone marrow or a plasmacytoma Presence of end organ damage felt related to the plasma cell dyscrasia, such as: Increased calcium concentration Lytic bone lesions Anemia Renal failure Smoldering Multiple Myeloma SMM, Asymptomatic Both criteria must be met: Serum monoclonal protein ≥3 g/dL and/or bone marrow plasma cells ≥10 percent No end organ damage related to plasma cell dyscrasia Monoclonal Gammopathy of Undetermined Significance (MGUS) All 3 criteria must be met: Serum monoclonal protein <3 g/dL Bone marrow plasma cells <10 percent No end organ damage related to plasma cell dyscrasia or a related B cell lymphoproliferative disorder POEMS Syndrome Osteosclerotic myeloma Polyneuropathy Organomegaly Endocrinopathy Monoclonal protein Skin changes MM: Evaluation CBC and differential,peripheral blood smear Chemistry:serum calcium, creatinine, albumin, LDH , beta-2 microglobulin, and C-reactive protein Serum protein electrophoresis (SPEP) + IF Quantification of immunoglobulins Urinalysis and a 24-hour urine collection for electrophoresis (UPEP) + IF Serum free monoclonal light chain (FLC) MM Evaluation Serum viscosity should be measured if the M-protein concentration is high Bone marrow aspiration and biopsy with immunophenotyping, conventional cytogenetics, and fluorescence in situ hybridization (FISH) Metastatic bone survey with plain radiographs including the humeri and femoral bones should be performed in all patients. MRI, CT, or PET/CT Bone Marrow Cytogenenetics, Interphase FISH Poor prognosis (median survival 25 months): t(4;14)(p16;q32), t(14;16)(q32;q23), and -17p13 Intermediate prognosis (median survival 42 months): -13q14 Good prognosis (median survival 50 months): all others Staging for MM International staging system (ISS)  Stage I — B2M <3.5 mg/L and serum albumin ≥3.5 g/dL Stage II — neither stage I nor stage III Stage III — B2M ≥5.5 mg/L Median overall survival for patients with ISS stages I, II, and III are 62, 44, and 29 months MM: Treatment Decisions Indications for treatment Risk stratification Eligibility for stem cell transplantation Smoldering (asymptomatic) myeloma Deferral of chemotherapy until progression to symptomatic disease Follow these patients closely, every 3 to 4 months, with serum protein electrophoresis, complete blood count, serum creatinine, and serum calcium Metastatic bone survey should be considered annually because asymptomatic bone lesions may develop MM: Indications for Treatment Anemia (hemoglobin <10 g/dL or 2 g/dL below normal) Hypercalcemia (serum calcium >11.5 mg/dL) Renal insufficiency (serum creatinine>2 mg/dL) Lytic bone lesions or severe osteopenia Extramedullary plasmacytoma MM: RISK STRATIFICATION FISH for detection of t(4;14), t(14;16), and del17p13 Conventional cytogenetics (karyotyping) for detection of del 13 or hypodiploidy The presence of any of the above markers defines high risk myeloma, which encompasses the 25 percent of MM patients who have a median survival of approximately two years or less despite standard treatment Current Frontline Options Conventional chemotherapy Survival ≤ 3 yrs Transplantation Prolongs survival 4-5 yrs Novel agents targeting stromal interactions and associated signaling pathways have shown promise Chng WJ, et al. Cancer Control. 2005;12:91-104. MM: INITIAL THERAPY The initial therapy of patients with symptomatic myeloma varies depending on whether patients are eligible or not to pursue autologous hematopoietic cell transplantation *Thal/dex or dex are additional options especially if immediate response is needed. Clearly not transplantation candidate based on age, performance score, and comorbidity MPT, MPV, Len/dex or clinical trial* Potential transplantation candidate Nonalkylator-based induction x 4 cycles Stem cell harvest Initial Approach to Treatment of MM DETERMINING TRANSPLANT ELIGIBILITY Autologous hematopoietic cell transplantation (HCT) results in superior event-free and overall survival rates when compared with combination chemotherapy All patients should be evaluated at diagnosis for transplant eligibility so that the risks and benefits of autologous HCT can be reviewed with those eligible A minority of patients will be eligible for allogeneic HCT, but the value of allogeneic approaches in myeloma remain investigational NOT Eligible for Autologous HCT Age >77 years Direct bilirubin>2.0 mg/dL (34.2 µmol/liter) Serum creatinine>2.5 mg/dL (221 µmol/liter) unless on chronic stable dialysis Eastern Cooperative Oncology Group (ECOG) performance status 3 or 4 unless due to bone pain New York Heart Association functional status Class III or IV 54 42 Attal M, et al. N Engl J Med. 1996;335:91-97. Child JA, et al. N Engl J Med. 2003;348:1875-1883. 15 30 45 60 25 50 75 100 OS (%) 0 0 High dose Conventional dose Mos 20 40 60 80 25 50 75 100 Survival (%) 0 0 Intensive therapy Standard therapy Mos P = .03 by Wilcoxon test P = .04 by log-rank test Transplantation vs Conventional Chemotherapy Autologous Stem Cell Transplantation Mel 200 mg/m2 standard conditioning regimen Sufficient performance score, and adequate liver, pulmonary, cardiac function needed Higher PR and CR rates than conventional chemotherapy Higher OS and EFS than conventional Rx Advanced age and impaired renal function are, by themselves, not contraindications Attal M, et al. N Engl J Med. 1996;335:91-97. NCCN Practice Guidelines. Myeloma. V.3.2010. Stem Cell Transplantation Key issues Efficacy compared with conventional chemotherapy Timing: early vs delayed Single vs tandem Role of allogeneic and miniallogeneic transplantations Maintenance post-SCT Novel Frontline Options Immunomodulatory drugs (IMiDs) Thalidomide Lenalidomide Proteasome inhibitors Bortezomib Carfilzomib Kyle RA, et al. N Engl J Med. 2004;351:1860-1873. Copyright ©2004. Massachusetts Medical Society. All rights reserved. Proposed Mechanism of Action for Multiple Myeloma Therapies Thalidomide: Proposed Mechanism of Action Proposed mechanisms Inhibition of TNF- Suppression of angiogenesis Increase in cell-mediated cytotoxic effects Modulation of adhesion molecule expression Kyle RA, et al. N Engl J Med. 2004;351:1860-1873. Rajkumar SV, et al. Leukemia. 2003;17:775-779. D’Amato RJ, et al.Proc Natl Acad Sci U S A. 1994;91:4082-4085. Lenalidomide Immunomodulatory derivative of thalidomide More potent than thalidomide in preclinical models Dose-dependent decrease in TNF-α and interleukin-6 Directly induces apoptosis, G1 growth arrest Enhances activity of dexamethasone More favorable toxicity profile than thalidomide Richardson P, et al. Blood. 2003;100:3063. Hideshima T, et al. Blood. 2000;96:2943-2950. Bortezomib: A Reversible Proteasome Inhibitor Chymo- tryptic Site Post- Glutamyl Site Tryptic Site b1 b2 b3 b4 b5 b6 b7 Cross section of  ring Bortezomib Adams J, et al. Invest New Drugs. 2000;18:109-121. Adams J, et al. Bioorg Med Chem Lett. 1998;8:333-338. H N B N H O O OH N N OH Initial Approach to Treatment of MM Clearly not a transplantation candidate MPT, MPV, Len/dex or clinical trial* Potential transplantation candidate Nonalkylator-based induction Stem cell harvest Melphalan/Prednisone/Thalidomide Palumbo A, et al. Blood. 2008;112:3107-3114. Lenalidomide 25 mg/day PO on Days 1-21 + High-dose Dex 40 mg/day PO on Days 1-4, 9-12, 17-20 (n = 223) Lenalidomide 25 mg/day PO on Days 1-21 + Low-dose Dex 40 mg/day PO on Days 1, 8, 15, 22 (n = 222) Len + High or Low-Dose Dex in Newly Diagnosed Myeloma (E4A03) Courses repeat every 28 days ≤ 1 yr in absence of PD or unacceptable toxicity Total Dex dose per cycle: 480 mg Untreated, symptomatic myeloma, no age cutoff Total Dex dose per cycle: 160 mg Rajkumar SV, et al. ASCO 2008. Abstract 8504. Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37 Len + High or Low-Dose Dex (E4A03): Response 3-yr OS rates converged (P = .467) with all pts crossed over to low dose Successful stem cell harvesting in 97.6% (n = 167) 3-yr OS for high dose or low dose followed by SCT: 92% Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37. Len + High or Low-Dose Dex (E4A03): Adverse Events Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37. Lenalidomide Dosing for MM and Impaired Renal Function Lenalidomide [package insert]. Peripheral Neuropathy Following Bortezomib Therapy in Advanced MM Peripheral neuropathy was reported in 90/256 (35%) patients with MM treated with bortezomib in phase II trials 80% of patients entered these trials with preexisting peripheral neuropathy 3% patients without vs 16% with baseline peripheral neuropathy developed grade 3 peripheral neuropathy Richardson PG, et al. ASH 2003. Abstract 512. Frontline Therapy in Elderly MM Patients For elderly patients or those who are not suitable candidates for transplantation, MP has been a standard treatment ORR: 60% Long-term CR: < 5% Trials with MP-based combinations reported improved response rates and time to progression MPT VMP NCCN Practice Guidelines. Myeloma. V.3.2010. Conclusions In elderly patients, the addition of novel agents to standard MP has provided improved response rates MP alone (ORR: 50%; CR: 5%) MPR (50% to 95% reduction in myeloma protein in 55.6%) VMP (ORR: 86%) Care should be taken with IMiD-based therapy to include aspirin prophylaxis for DVT/PE Care should be taken with bortezomib-based regimens to include herpes zoster prophylaxis MM & Skeletal Complications ~ 80% of patients with multiple myeloma will have evidence of skeletal involvement on skeletal survey Vertebrae: 65% Ribs: 45% Skull: 40% Shoulders: 40% Pelvis: 30% Long bones: 25% Dimopoulos M, et al. Leukemia. 2009:1-12. The Central Role of the Osteoclast in Osteolytic Bone Destruction Growth factors Osteoclast differentiation Osteolysis Direct effects on osteoclast differentiation Tumor cells Bone loss Active osteoclast Adapted from Roodman GD. N Engl J Med. 2004;350:1655-1664.
Slide 60 - Special Thanks to… For sponsorship of LMEF programs: Supported by an educational grant from Lilly USA, LLC Did you know that you could be receiving credit for attending today? For membership information, please visit our website: www.Lafmeded.org. Multiple Myeloma 2010 Wael Harb MD Horizon Oncology Center Overview Introduction: epidemiology, clinical presentation, diagnosis, staging Autologous stem cell transplantation Initial approaches to treatment Current options Novel agents and combinations Considerations in non-transplantation-eligible patients Prevention of skeletal complications What is MM? Multiple myeloma (MM) is characterized by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. Plasma Cell Multiple Myeloma: Incidence The lifetime risk of getting MM is 1 in 159 (0.63%). 20,180 new cases will be diagnosed in 2010 (11,170 in men and 9,010 in women) 10,650 deaths are expected to occur in 2010 (5,760 in men and 4,890 in women) The 5-year relative survival rate for MM is around 35% Incidence MM occurs in all races and all geographic locations African Americans and blacks from Africa is two to three times the risk in whites Risk is lower in Asians from Japan and in Mexicans Slightly more frequent in men than in women (1.4:1) Age MM is a disease of older adults The median age at diagnosis is 66 years Only 10 percent of patients are younger than 50 years Only 2 percent of patients are younger than 40 years MM: Clinical Presentations Anemia - 73 percent Bone pain - 58 percent Elevated creatinine - 48 percent Fatigue/generalized weakness - 32 percent Hypercalcemia- 28 percent Weight loss - 24 percent, one-half of whom had lost ≥ 9 kg Multiple Myeloma = M-CRAB Monoclonal protein Calcium Renal failure Anemia Bone pain with lytic lesions Immunoglobulin Immunoglobulins SPEP: Normal SPEP: M-protein, M-spike Renal Failure Cast nephropathy (also called myeloma kidney) from light chains Hypercalcemia Light chain amyloidosis Drug-induced renal damage Anemia Normocytic, normochromic anemiais present in 73% at diagnosis and in 97%at some time during the course of the disease This anemia can be related to: Bone marrow replacement Kidney damage Dilution in the case of a large M-protein B12 deficiency in 14% Rouleaux Formation Lytic Bone Lesion MM: PET Scan Extramedullary Plasmacytoma Differential Diagnosis of MM Monoclonal gammopathy of undetermined significance (MGUS) Smoldering multiple myeloma (SMM) Waldenstrom macroglobulinemia Solitary plasmacytoma Primary amyloidosis (AL) POEMS syndrome Metastatic carcinoma Multiple Myeloma All 3 criteria must be met: Presence of a serum or urinary monoclonal protein Presence of clonal plasma cells in the bone marrow or a plasmacytoma Presence of end organ damage felt related to the plasma cell dyscrasia, such as: Increased calcium concentration Lytic bone lesions Anemia Renal failure Smoldering Multiple Myeloma SMM, Asymptomatic Both criteria must be met: Serum monoclonal protein ≥3 g/dL and/or bone marrow plasma cells ≥10 percent No end organ damage related to plasma cell dyscrasia Monoclonal Gammopathy of Undetermined Significance (MGUS) All 3 criteria must be met: Serum monoclonal protein <3 g/dL Bone marrow plasma cells <10 percent No end organ damage related to plasma cell dyscrasia or a related B cell lymphoproliferative disorder POEMS Syndrome Osteosclerotic myeloma Polyneuropathy Organomegaly Endocrinopathy Monoclonal protein Skin changes MM: Evaluation CBC and differential,peripheral blood smear Chemistry:serum calcium, creatinine, albumin, LDH , beta-2 microglobulin, and C-reactive protein Serum protein electrophoresis (SPEP) + IF Quantification of immunoglobulins Urinalysis and a 24-hour urine collection for electrophoresis (UPEP) + IF Serum free monoclonal light chain (FLC) MM Evaluation Serum viscosity should be measured if the M-protein concentration is high Bone marrow aspiration and biopsy with immunophenotyping, conventional cytogenetics, and fluorescence in situ hybridization (FISH) Metastatic bone survey with plain radiographs including the humeri and femoral bones should be performed in all patients. MRI, CT, or PET/CT Bone Marrow Cytogenenetics, Interphase FISH Poor prognosis (median survival 25 months): t(4;14)(p16;q32), t(14;16)(q32;q23), and -17p13 Intermediate prognosis (median survival 42 months): -13q14 Good prognosis (median survival 50 months): all others Staging for MM International staging system (ISS)  Stage I — B2M <3.5 mg/L and serum albumin ≥3.5 g/dL Stage II — neither stage I nor stage III Stage III — B2M ≥5.5 mg/L Median overall survival for patients with ISS stages I, II, and III are 62, 44, and 29 months MM: Treatment Decisions Indications for treatment Risk stratification Eligibility for stem cell transplantation Smoldering (asymptomatic) myeloma Deferral of chemotherapy until progression to symptomatic disease Follow these patients closely, every 3 to 4 months, with serum protein electrophoresis, complete blood count, serum creatinine, and serum calcium Metastatic bone survey should be considered annually because asymptomatic bone lesions may develop MM: Indications for Treatment Anemia (hemoglobin <10 g/dL or 2 g/dL below normal) Hypercalcemia (serum calcium >11.5 mg/dL) Renal insufficiency (serum creatinine>2 mg/dL) Lytic bone lesions or severe osteopenia Extramedullary plasmacytoma MM: RISK STRATIFICATION FISH for detection of t(4;14), t(14;16), and del17p13 Conventional cytogenetics (karyotyping) for detection of del 13 or hypodiploidy The presence of any of the above markers defines high risk myeloma, which encompasses the 25 percent of MM patients who have a median survival of approximately two years or less despite standard treatment Current Frontline Options Conventional chemotherapy Survival ≤ 3 yrs Transplantation Prolongs survival 4-5 yrs Novel agents targeting stromal interactions and associated signaling pathways have shown promise Chng WJ, et al. Cancer Control. 2005;12:91-104. MM: INITIAL THERAPY The initial therapy of patients with symptomatic myeloma varies depending on whether patients are eligible or not to pursue autologous hematopoietic cell transplantation *Thal/dex or dex are additional options especially if immediate response is needed. Clearly not transplantation candidate based on age, performance score, and comorbidity MPT, MPV, Len/dex or clinical trial* Potential transplantation candidate Nonalkylator-based induction x 4 cycles Stem cell harvest Initial Approach to Treatment of MM DETERMINING TRANSPLANT ELIGIBILITY Autologous hematopoietic cell transplantation (HCT) results in superior event-free and overall survival rates when compared with combination chemotherapy All patients should be evaluated at diagnosis for transplant eligibility so that the risks and benefits of autologous HCT can be reviewed with those eligible A minority of patients will be eligible for allogeneic HCT, but the value of allogeneic approaches in myeloma remain investigational NOT Eligible for Autologous HCT Age >77 years Direct bilirubin>2.0 mg/dL (34.2 µmol/liter) Serum creatinine>2.5 mg/dL (221 µmol/liter) unless on chronic stable dialysis Eastern Cooperative Oncology Group (ECOG) performance status 3 or 4 unless due to bone pain New York Heart Association functional status Class III or IV 54 42 Attal M, et al. N Engl J Med. 1996;335:91-97. Child JA, et al. N Engl J Med. 2003;348:1875-1883. 15 30 45 60 25 50 75 100 OS (%) 0 0 High dose Conventional dose Mos 20 40 60 80 25 50 75 100 Survival (%) 0 0 Intensive therapy Standard therapy Mos P = .03 by Wilcoxon test P = .04 by log-rank test Transplantation vs Conventional Chemotherapy Autologous Stem Cell Transplantation Mel 200 mg/m2 standard conditioning regimen Sufficient performance score, and adequate liver, pulmonary, cardiac function needed Higher PR and CR rates than conventional chemotherapy Higher OS and EFS than conventional Rx Advanced age and impaired renal function are, by themselves, not contraindications Attal M, et al. N Engl J Med. 1996;335:91-97. NCCN Practice Guidelines. Myeloma. V.3.2010. Stem Cell Transplantation Key issues Efficacy compared with conventional chemotherapy Timing: early vs delayed Single vs tandem Role of allogeneic and miniallogeneic transplantations Maintenance post-SCT Novel Frontline Options Immunomodulatory drugs (IMiDs) Thalidomide Lenalidomide Proteasome inhibitors Bortezomib Carfilzomib Kyle RA, et al. N Engl J Med. 2004;351:1860-1873. Copyright ©2004. Massachusetts Medical Society. All rights reserved. Proposed Mechanism of Action for Multiple Myeloma Therapies Thalidomide: Proposed Mechanism of Action Proposed mechanisms Inhibition of TNF- Suppression of angiogenesis Increase in cell-mediated cytotoxic effects Modulation of adhesion molecule expression Kyle RA, et al. N Engl J Med. 2004;351:1860-1873. Rajkumar SV, et al. Leukemia. 2003;17:775-779. D’Amato RJ, et al.Proc Natl Acad Sci U S A. 1994;91:4082-4085. Lenalidomide Immunomodulatory derivative of thalidomide More potent than thalidomide in preclinical models Dose-dependent decrease in TNF-α and interleukin-6 Directly induces apoptosis, G1 growth arrest Enhances activity of dexamethasone More favorable toxicity profile than thalidomide Richardson P, et al. Blood. 2003;100:3063. Hideshima T, et al. Blood. 2000;96:2943-2950. Bortezomib: A Reversible Proteasome Inhibitor Chymo- tryptic Site Post- Glutamyl Site Tryptic Site b1 b2 b3 b4 b5 b6 b7 Cross section of  ring Bortezomib Adams J, et al. Invest New Drugs. 2000;18:109-121. Adams J, et al. Bioorg Med Chem Lett. 1998;8:333-338. H N B N H O O OH N N OH Initial Approach to Treatment of MM Clearly not a transplantation candidate MPT, MPV, Len/dex or clinical trial* Potential transplantation candidate Nonalkylator-based induction Stem cell harvest Melphalan/Prednisone/Thalidomide Palumbo A, et al. Blood. 2008;112:3107-3114. Lenalidomide 25 mg/day PO on Days 1-21 + High-dose Dex 40 mg/day PO on Days 1-4, 9-12, 17-20 (n = 223) Lenalidomide 25 mg/day PO on Days 1-21 + Low-dose Dex 40 mg/day PO on Days 1, 8, 15, 22 (n = 222) Len + High or Low-Dose Dex in Newly Diagnosed Myeloma (E4A03) Courses repeat every 28 days ≤ 1 yr in absence of PD or unacceptable toxicity Total Dex dose per cycle: 480 mg Untreated, symptomatic myeloma, no age cutoff Total Dex dose per cycle: 160 mg Rajkumar SV, et al. ASCO 2008. Abstract 8504. Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37 Len + High or Low-Dose Dex (E4A03): Response 3-yr OS rates converged (P = .467) with all pts crossed over to low dose Successful stem cell harvesting in 97.6% (n = 167) 3-yr OS for high dose or low dose followed by SCT: 92% Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37. Len + High or Low-Dose Dex (E4A03): Adverse Events Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37. Lenalidomide Dosing for MM and Impaired Renal Function Lenalidomide [package insert]. Peripheral Neuropathy Following Bortezomib Therapy in Advanced MM Peripheral neuropathy was reported in 90/256 (35%) patients with MM treated with bortezomib in phase II trials 80% of patients entered these trials with preexisting peripheral neuropathy 3% patients without vs 16% with baseline peripheral neuropathy developed grade 3 peripheral neuropathy Richardson PG, et al. ASH 2003. Abstract 512. Frontline Therapy in Elderly MM Patients For elderly patients or those who are not suitable candidates for transplantation, MP has been a standard treatment ORR: 60% Long-term CR: < 5% Trials with MP-based combinations reported improved response rates and time to progression MPT VMP NCCN Practice Guidelines. Myeloma. V.3.2010. Conclusions In elderly patients, the addition of novel agents to standard MP has provided improved response rates MP alone (ORR: 50%; CR: 5%) MPR (50% to 95% reduction in myeloma protein in 55.6%) VMP (ORR: 86%) Care should be taken with IMiD-based therapy to include aspirin prophylaxis for DVT/PE Care should be taken with bortezomib-based regimens to include herpes zoster prophylaxis MM & Skeletal Complications ~ 80% of patients with multiple myeloma will have evidence of skeletal involvement on skeletal survey Vertebrae: 65% Ribs: 45% Skull: 40% Shoulders: 40% Pelvis: 30% Long bones: 25% Dimopoulos M, et al. Leukemia. 2009:1-12. The Central Role of the Osteoclast in Osteolytic Bone Destruction Growth factors Osteoclast differentiation Osteolysis Direct effects on osteoclast differentiation Tumor cells Bone loss Active osteoclast Adapted from Roodman GD. N Engl J Med. 2004;350:1655-1664. Mechanism of Bisphosphonate Inhibition of Osteoclast Activity Bisphosphonates inhibit osteoclast activity, and promote osteoclast apoptosis[1] Bisphosphonates are released locally during bone resorption[1] Bisphosphonates are concentrated under osteoclasts[1] Bisphosphonates may modulate signaling from osteoblasts to osteoclasts New bone X Bone Increased OPG production[2] Decreased RANKL expression[3] 1. Reszka AA, et al. Curr Rheumatol Rep. 2003;5:65-74. 2. Viereck V, et al. Biochem Biophys Res Commun. 2002;291:680-686. 3. Pan B, et al. J Bone Miner Res. 2004;19:147-154.
Slide 61 - Special Thanks to… For sponsorship of LMEF programs: Supported by an educational grant from Lilly USA, LLC Did you know that you could be receiving credit for attending today? For membership information, please visit our website: www.Lafmeded.org. Multiple Myeloma 2010 Wael Harb MD Horizon Oncology Center Overview Introduction: epidemiology, clinical presentation, diagnosis, staging Autologous stem cell transplantation Initial approaches to treatment Current options Novel agents and combinations Considerations in non-transplantation-eligible patients Prevention of skeletal complications What is MM? Multiple myeloma (MM) is characterized by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. Plasma Cell Multiple Myeloma: Incidence The lifetime risk of getting MM is 1 in 159 (0.63%). 20,180 new cases will be diagnosed in 2010 (11,170 in men and 9,010 in women) 10,650 deaths are expected to occur in 2010 (5,760 in men and 4,890 in women) The 5-year relative survival rate for MM is around 35% Incidence MM occurs in all races and all geographic locations African Americans and blacks from Africa is two to three times the risk in whites Risk is lower in Asians from Japan and in Mexicans Slightly more frequent in men than in women (1.4:1) Age MM is a disease of older adults The median age at diagnosis is 66 years Only 10 percent of patients are younger than 50 years Only 2 percent of patients are younger than 40 years MM: Clinical Presentations Anemia - 73 percent Bone pain - 58 percent Elevated creatinine - 48 percent Fatigue/generalized weakness - 32 percent Hypercalcemia- 28 percent Weight loss - 24 percent, one-half of whom had lost ≥ 9 kg Multiple Myeloma = M-CRAB Monoclonal protein Calcium Renal failure Anemia Bone pain with lytic lesions Immunoglobulin Immunoglobulins SPEP: Normal SPEP: M-protein, M-spike Renal Failure Cast nephropathy (also called myeloma kidney) from light chains Hypercalcemia Light chain amyloidosis Drug-induced renal damage Anemia Normocytic, normochromic anemiais present in 73% at diagnosis and in 97%at some time during the course of the disease This anemia can be related to: Bone marrow replacement Kidney damage Dilution in the case of a large M-protein B12 deficiency in 14% Rouleaux Formation Lytic Bone Lesion MM: PET Scan Extramedullary Plasmacytoma Differential Diagnosis of MM Monoclonal gammopathy of undetermined significance (MGUS) Smoldering multiple myeloma (SMM) Waldenstrom macroglobulinemia Solitary plasmacytoma Primary amyloidosis (AL) POEMS syndrome Metastatic carcinoma Multiple Myeloma All 3 criteria must be met: Presence of a serum or urinary monoclonal protein Presence of clonal plasma cells in the bone marrow or a plasmacytoma Presence of end organ damage felt related to the plasma cell dyscrasia, such as: Increased calcium concentration Lytic bone lesions Anemia Renal failure Smoldering Multiple Myeloma SMM, Asymptomatic Both criteria must be met: Serum monoclonal protein ≥3 g/dL and/or bone marrow plasma cells ≥10 percent No end organ damage related to plasma cell dyscrasia Monoclonal Gammopathy of Undetermined Significance (MGUS) All 3 criteria must be met: Serum monoclonal protein <3 g/dL Bone marrow plasma cells <10 percent No end organ damage related to plasma cell dyscrasia or a related B cell lymphoproliferative disorder POEMS Syndrome Osteosclerotic myeloma Polyneuropathy Organomegaly Endocrinopathy Monoclonal protein Skin changes MM: Evaluation CBC and differential,peripheral blood smear Chemistry:serum calcium, creatinine, albumin, LDH , beta-2 microglobulin, and C-reactive protein Serum protein electrophoresis (SPEP) + IF Quantification of immunoglobulins Urinalysis and a 24-hour urine collection for electrophoresis (UPEP) + IF Serum free monoclonal light chain (FLC) MM Evaluation Serum viscosity should be measured if the M-protein concentration is high Bone marrow aspiration and biopsy with immunophenotyping, conventional cytogenetics, and fluorescence in situ hybridization (FISH) Metastatic bone survey with plain radiographs including the humeri and femoral bones should be performed in all patients. MRI, CT, or PET/CT Bone Marrow Cytogenenetics, Interphase FISH Poor prognosis (median survival 25 months): t(4;14)(p16;q32), t(14;16)(q32;q23), and -17p13 Intermediate prognosis (median survival 42 months): -13q14 Good prognosis (median survival 50 months): all others Staging for MM International staging system (ISS)  Stage I — B2M <3.5 mg/L and serum albumin ≥3.5 g/dL Stage II — neither stage I nor stage III Stage III — B2M ≥5.5 mg/L Median overall survival for patients with ISS stages I, II, and III are 62, 44, and 29 months MM: Treatment Decisions Indications for treatment Risk stratification Eligibility for stem cell transplantation Smoldering (asymptomatic) myeloma Deferral of chemotherapy until progression to symptomatic disease Follow these patients closely, every 3 to 4 months, with serum protein electrophoresis, complete blood count, serum creatinine, and serum calcium Metastatic bone survey should be considered annually because asymptomatic bone lesions may develop MM: Indications for Treatment Anemia (hemoglobin <10 g/dL or 2 g/dL below normal) Hypercalcemia (serum calcium >11.5 mg/dL) Renal insufficiency (serum creatinine>2 mg/dL) Lytic bone lesions or severe osteopenia Extramedullary plasmacytoma MM: RISK STRATIFICATION FISH for detection of t(4;14), t(14;16), and del17p13 Conventional cytogenetics (karyotyping) for detection of del 13 or hypodiploidy The presence of any of the above markers defines high risk myeloma, which encompasses the 25 percent of MM patients who have a median survival of approximately two years or less despite standard treatment Current Frontline Options Conventional chemotherapy Survival ≤ 3 yrs Transplantation Prolongs survival 4-5 yrs Novel agents targeting stromal interactions and associated signaling pathways have shown promise Chng WJ, et al. Cancer Control. 2005;12:91-104. MM: INITIAL THERAPY The initial therapy of patients with symptomatic myeloma varies depending on whether patients are eligible or not to pursue autologous hematopoietic cell transplantation *Thal/dex or dex are additional options especially if immediate response is needed. Clearly not transplantation candidate based on age, performance score, and comorbidity MPT, MPV, Len/dex or clinical trial* Potential transplantation candidate Nonalkylator-based induction x 4 cycles Stem cell harvest Initial Approach to Treatment of MM DETERMINING TRANSPLANT ELIGIBILITY Autologous hematopoietic cell transplantation (HCT) results in superior event-free and overall survival rates when compared with combination chemotherapy All patients should be evaluated at diagnosis for transplant eligibility so that the risks and benefits of autologous HCT can be reviewed with those eligible A minority of patients will be eligible for allogeneic HCT, but the value of allogeneic approaches in myeloma remain investigational NOT Eligible for Autologous HCT Age >77 years Direct bilirubin>2.0 mg/dL (34.2 µmol/liter) Serum creatinine>2.5 mg/dL (221 µmol/liter) unless on chronic stable dialysis Eastern Cooperative Oncology Group (ECOG) performance status 3 or 4 unless due to bone pain New York Heart Association functional status Class III or IV 54 42 Attal M, et al. N Engl J Med. 1996;335:91-97. Child JA, et al. N Engl J Med. 2003;348:1875-1883. 15 30 45 60 25 50 75 100 OS (%) 0 0 High dose Conventional dose Mos 20 40 60 80 25 50 75 100 Survival (%) 0 0 Intensive therapy Standard therapy Mos P = .03 by Wilcoxon test P = .04 by log-rank test Transplantation vs Conventional Chemotherapy Autologous Stem Cell Transplantation Mel 200 mg/m2 standard conditioning regimen Sufficient performance score, and adequate liver, pulmonary, cardiac function needed Higher PR and CR rates than conventional chemotherapy Higher OS and EFS than conventional Rx Advanced age and impaired renal function are, by themselves, not contraindications Attal M, et al. N Engl J Med. 1996;335:91-97. NCCN Practice Guidelines. Myeloma. V.3.2010. Stem Cell Transplantation Key issues Efficacy compared with conventional chemotherapy Timing: early vs delayed Single vs tandem Role of allogeneic and miniallogeneic transplantations Maintenance post-SCT Novel Frontline Options Immunomodulatory drugs (IMiDs) Thalidomide Lenalidomide Proteasome inhibitors Bortezomib Carfilzomib Kyle RA, et al. N Engl J Med. 2004;351:1860-1873. Copyright ©2004. Massachusetts Medical Society. All rights reserved. Proposed Mechanism of Action for Multiple Myeloma Therapies Thalidomide: Proposed Mechanism of Action Proposed mechanisms Inhibition of TNF- Suppression of angiogenesis Increase in cell-mediated cytotoxic effects Modulation of adhesion molecule expression Kyle RA, et al. N Engl J Med. 2004;351:1860-1873. Rajkumar SV, et al. Leukemia. 2003;17:775-779. D’Amato RJ, et al.Proc Natl Acad Sci U S A. 1994;91:4082-4085. Lenalidomide Immunomodulatory derivative of thalidomide More potent than thalidomide in preclinical models Dose-dependent decrease in TNF-α and interleukin-6 Directly induces apoptosis, G1 growth arrest Enhances activity of dexamethasone More favorable toxicity profile than thalidomide Richardson P, et al. Blood. 2003;100:3063. Hideshima T, et al. Blood. 2000;96:2943-2950. Bortezomib: A Reversible Proteasome Inhibitor Chymo- tryptic Site Post- Glutamyl Site Tryptic Site b1 b2 b3 b4 b5 b6 b7 Cross section of  ring Bortezomib Adams J, et al. Invest New Drugs. 2000;18:109-121. Adams J, et al. Bioorg Med Chem Lett. 1998;8:333-338. H N B N H O O OH N N OH Initial Approach to Treatment of MM Clearly not a transplantation candidate MPT, MPV, Len/dex or clinical trial* Potential transplantation candidate Nonalkylator-based induction Stem cell harvest Melphalan/Prednisone/Thalidomide Palumbo A, et al. Blood. 2008;112:3107-3114. Lenalidomide 25 mg/day PO on Days 1-21 + High-dose Dex 40 mg/day PO on Days 1-4, 9-12, 17-20 (n = 223) Lenalidomide 25 mg/day PO on Days 1-21 + Low-dose Dex 40 mg/day PO on Days 1, 8, 15, 22 (n = 222) Len + High or Low-Dose Dex in Newly Diagnosed Myeloma (E4A03) Courses repeat every 28 days ≤ 1 yr in absence of PD or unacceptable toxicity Total Dex dose per cycle: 480 mg Untreated, symptomatic myeloma, no age cutoff Total Dex dose per cycle: 160 mg Rajkumar SV, et al. ASCO 2008. Abstract 8504. Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37 Len + High or Low-Dose Dex (E4A03): Response 3-yr OS rates converged (P = .467) with all pts crossed over to low dose Successful stem cell harvesting in 97.6% (n = 167) 3-yr OS for high dose or low dose followed by SCT: 92% Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37. Len + High or Low-Dose Dex (E4A03): Adverse Events Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37. Lenalidomide Dosing for MM and Impaired Renal Function Lenalidomide [package insert]. Peripheral Neuropathy Following Bortezomib Therapy in Advanced MM Peripheral neuropathy was reported in 90/256 (35%) patients with MM treated with bortezomib in phase II trials 80% of patients entered these trials with preexisting peripheral neuropathy 3% patients without vs 16% with baseline peripheral neuropathy developed grade 3 peripheral neuropathy Richardson PG, et al. ASH 2003. Abstract 512. Frontline Therapy in Elderly MM Patients For elderly patients or those who are not suitable candidates for transplantation, MP has been a standard treatment ORR: 60% Long-term CR: < 5% Trials with MP-based combinations reported improved response rates and time to progression MPT VMP NCCN Practice Guidelines. Myeloma. V.3.2010. Conclusions In elderly patients, the addition of novel agents to standard MP has provided improved response rates MP alone (ORR: 50%; CR: 5%) MPR (50% to 95% reduction in myeloma protein in 55.6%) VMP (ORR: 86%) Care should be taken with IMiD-based therapy to include aspirin prophylaxis for DVT/PE Care should be taken with bortezomib-based regimens to include herpes zoster prophylaxis MM & Skeletal Complications ~ 80% of patients with multiple myeloma will have evidence of skeletal involvement on skeletal survey Vertebrae: 65% Ribs: 45% Skull: 40% Shoulders: 40% Pelvis: 30% Long bones: 25% Dimopoulos M, et al. Leukemia. 2009:1-12. The Central Role of the Osteoclast in Osteolytic Bone Destruction Growth factors Osteoclast differentiation Osteolysis Direct effects on osteoclast differentiation Tumor cells Bone loss Active osteoclast Adapted from Roodman GD. N Engl J Med. 2004;350:1655-1664. Mechanism of Bisphosphonate Inhibition of Osteoclast Activity Bisphosphonates inhibit osteoclast activity, and promote osteoclast apoptosis[1] Bisphosphonates are released locally during bone resorption[1] Bisphosphonates are concentrated under osteoclasts[1] Bisphosphonates may modulate signaling from osteoblasts to osteoclasts New bone X Bone Increased OPG production[2] Decreased RANKL expression[3] 1. Reszka AA, et al. Curr Rheumatol Rep. 2003;5:65-74. 2. Viereck V, et al. Biochem Biophys Res Commun. 2002;291:680-686. 3. Pan B, et al. J Bone Miner Res. 2004;19:147-154. Recommended Doses and Infusion Times *Consider dose reduction . †3.5mg (CrCl 50-60 mL/min); 3.3 mg (CrCl 40-49 mL/min); 3.0 mg (CrCl 30-39 mL/min). Kyle R, et al. J Clin Oncol. 2007;25:2464-2472.
Slide 62 - Special Thanks to… For sponsorship of LMEF programs: Supported by an educational grant from Lilly USA, LLC Did you know that you could be receiving credit for attending today? For membership information, please visit our website: www.Lafmeded.org. Multiple Myeloma 2010 Wael Harb MD Horizon Oncology Center Overview Introduction: epidemiology, clinical presentation, diagnosis, staging Autologous stem cell transplantation Initial approaches to treatment Current options Novel agents and combinations Considerations in non-transplantation-eligible patients Prevention of skeletal complications What is MM? Multiple myeloma (MM) is characterized by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. Plasma Cell Multiple Myeloma: Incidence The lifetime risk of getting MM is 1 in 159 (0.63%). 20,180 new cases will be diagnosed in 2010 (11,170 in men and 9,010 in women) 10,650 deaths are expected to occur in 2010 (5,760 in men and 4,890 in women) The 5-year relative survival rate for MM is around 35% Incidence MM occurs in all races and all geographic locations African Americans and blacks from Africa is two to three times the risk in whites Risk is lower in Asians from Japan and in Mexicans Slightly more frequent in men than in women (1.4:1) Age MM is a disease of older adults The median age at diagnosis is 66 years Only 10 percent of patients are younger than 50 years Only 2 percent of patients are younger than 40 years MM: Clinical Presentations Anemia - 73 percent Bone pain - 58 percent Elevated creatinine - 48 percent Fatigue/generalized weakness - 32 percent Hypercalcemia- 28 percent Weight loss - 24 percent, one-half of whom had lost ≥ 9 kg Multiple Myeloma = M-CRAB Monoclonal protein Calcium Renal failure Anemia Bone pain with lytic lesions Immunoglobulin Immunoglobulins SPEP: Normal SPEP: M-protein, M-spike Renal Failure Cast nephropathy (also called myeloma kidney) from light chains Hypercalcemia Light chain amyloidosis Drug-induced renal damage Anemia Normocytic, normochromic anemiais present in 73% at diagnosis and in 97%at some time during the course of the disease This anemia can be related to: Bone marrow replacement Kidney damage Dilution in the case of a large M-protein B12 deficiency in 14% Rouleaux Formation Lytic Bone Lesion MM: PET Scan Extramedullary Plasmacytoma Differential Diagnosis of MM Monoclonal gammopathy of undetermined significance (MGUS) Smoldering multiple myeloma (SMM) Waldenstrom macroglobulinemia Solitary plasmacytoma Primary amyloidosis (AL) POEMS syndrome Metastatic carcinoma Multiple Myeloma All 3 criteria must be met: Presence of a serum or urinary monoclonal protein Presence of clonal plasma cells in the bone marrow or a plasmacytoma Presence of end organ damage felt related to the plasma cell dyscrasia, such as: Increased calcium concentration Lytic bone lesions Anemia Renal failure Smoldering Multiple Myeloma SMM, Asymptomatic Both criteria must be met: Serum monoclonal protein ≥3 g/dL and/or bone marrow plasma cells ≥10 percent No end organ damage related to plasma cell dyscrasia Monoclonal Gammopathy of Undetermined Significance (MGUS) All 3 criteria must be met: Serum monoclonal protein <3 g/dL Bone marrow plasma cells <10 percent No end organ damage related to plasma cell dyscrasia or a related B cell lymphoproliferative disorder POEMS Syndrome Osteosclerotic myeloma Polyneuropathy Organomegaly Endocrinopathy Monoclonal protein Skin changes MM: Evaluation CBC and differential,peripheral blood smear Chemistry:serum calcium, creatinine, albumin, LDH , beta-2 microglobulin, and C-reactive protein Serum protein electrophoresis (SPEP) + IF Quantification of immunoglobulins Urinalysis and a 24-hour urine collection for electrophoresis (UPEP) + IF Serum free monoclonal light chain (FLC) MM Evaluation Serum viscosity should be measured if the M-protein concentration is high Bone marrow aspiration and biopsy with immunophenotyping, conventional cytogenetics, and fluorescence in situ hybridization (FISH) Metastatic bone survey with plain radiographs including the humeri and femoral bones should be performed in all patients. MRI, CT, or PET/CT Bone Marrow Cytogenenetics, Interphase FISH Poor prognosis (median survival 25 months): t(4;14)(p16;q32), t(14;16)(q32;q23), and -17p13 Intermediate prognosis (median survival 42 months): -13q14 Good prognosis (median survival 50 months): all others Staging for MM International staging system (ISS)  Stage I — B2M <3.5 mg/L and serum albumin ≥3.5 g/dL Stage II — neither stage I nor stage III Stage III — B2M ≥5.5 mg/L Median overall survival for patients with ISS stages I, II, and III are 62, 44, and 29 months MM: Treatment Decisions Indications for treatment Risk stratification Eligibility for stem cell transplantation Smoldering (asymptomatic) myeloma Deferral of chemotherapy until progression to symptomatic disease Follow these patients closely, every 3 to 4 months, with serum protein electrophoresis, complete blood count, serum creatinine, and serum calcium Metastatic bone survey should be considered annually because asymptomatic bone lesions may develop MM: Indications for Treatment Anemia (hemoglobin <10 g/dL or 2 g/dL below normal) Hypercalcemia (serum calcium >11.5 mg/dL) Renal insufficiency (serum creatinine>2 mg/dL) Lytic bone lesions or severe osteopenia Extramedullary plasmacytoma MM: RISK STRATIFICATION FISH for detection of t(4;14), t(14;16), and del17p13 Conventional cytogenetics (karyotyping) for detection of del 13 or hypodiploidy The presence of any of the above markers defines high risk myeloma, which encompasses the 25 percent of MM patients who have a median survival of approximately two years or less despite standard treatment Current Frontline Options Conventional chemotherapy Survival ≤ 3 yrs Transplantation Prolongs survival 4-5 yrs Novel agents targeting stromal interactions and associated signaling pathways have shown promise Chng WJ, et al. Cancer Control. 2005;12:91-104. MM: INITIAL THERAPY The initial therapy of patients with symptomatic myeloma varies depending on whether patients are eligible or not to pursue autologous hematopoietic cell transplantation *Thal/dex or dex are additional options especially if immediate response is needed. Clearly not transplantation candidate based on age, performance score, and comorbidity MPT, MPV, Len/dex or clinical trial* Potential transplantation candidate Nonalkylator-based induction x 4 cycles Stem cell harvest Initial Approach to Treatment of MM DETERMINING TRANSPLANT ELIGIBILITY Autologous hematopoietic cell transplantation (HCT) results in superior event-free and overall survival rates when compared with combination chemotherapy All patients should be evaluated at diagnosis for transplant eligibility so that the risks and benefits of autologous HCT can be reviewed with those eligible A minority of patients will be eligible for allogeneic HCT, but the value of allogeneic approaches in myeloma remain investigational NOT Eligible for Autologous HCT Age >77 years Direct bilirubin>2.0 mg/dL (34.2 µmol/liter) Serum creatinine>2.5 mg/dL (221 µmol/liter) unless on chronic stable dialysis Eastern Cooperative Oncology Group (ECOG) performance status 3 or 4 unless due to bone pain New York Heart Association functional status Class III or IV 54 42 Attal M, et al. N Engl J Med. 1996;335:91-97. Child JA, et al. N Engl J Med. 2003;348:1875-1883. 15 30 45 60 25 50 75 100 OS (%) 0 0 High dose Conventional dose Mos 20 40 60 80 25 50 75 100 Survival (%) 0 0 Intensive therapy Standard therapy Mos P = .03 by Wilcoxon test P = .04 by log-rank test Transplantation vs Conventional Chemotherapy Autologous Stem Cell Transplantation Mel 200 mg/m2 standard conditioning regimen Sufficient performance score, and adequate liver, pulmonary, cardiac function needed Higher PR and CR rates than conventional chemotherapy Higher OS and EFS than conventional Rx Advanced age and impaired renal function are, by themselves, not contraindications Attal M, et al. N Engl J Med. 1996;335:91-97. NCCN Practice Guidelines. Myeloma. V.3.2010. Stem Cell Transplantation Key issues Efficacy compared with conventional chemotherapy Timing: early vs delayed Single vs tandem Role of allogeneic and miniallogeneic transplantations Maintenance post-SCT Novel Frontline Options Immunomodulatory drugs (IMiDs) Thalidomide Lenalidomide Proteasome inhibitors Bortezomib Carfilzomib Kyle RA, et al. N Engl J Med. 2004;351:1860-1873. Copyright ©2004. Massachusetts Medical Society. All rights reserved. Proposed Mechanism of Action for Multiple Myeloma Therapies Thalidomide: Proposed Mechanism of Action Proposed mechanisms Inhibition of TNF- Suppression of angiogenesis Increase in cell-mediated cytotoxic effects Modulation of adhesion molecule expression Kyle RA, et al. N Engl J Med. 2004;351:1860-1873. Rajkumar SV, et al. Leukemia. 2003;17:775-779. D’Amato RJ, et al.Proc Natl Acad Sci U S A. 1994;91:4082-4085. Lenalidomide Immunomodulatory derivative of thalidomide More potent than thalidomide in preclinical models Dose-dependent decrease in TNF-α and interleukin-6 Directly induces apoptosis, G1 growth arrest Enhances activity of dexamethasone More favorable toxicity profile than thalidomide Richardson P, et al. Blood. 2003;100:3063. Hideshima T, et al. Blood. 2000;96:2943-2950. Bortezomib: A Reversible Proteasome Inhibitor Chymo- tryptic Site Post- Glutamyl Site Tryptic Site b1 b2 b3 b4 b5 b6 b7 Cross section of  ring Bortezomib Adams J, et al. Invest New Drugs. 2000;18:109-121. Adams J, et al. Bioorg Med Chem Lett. 1998;8:333-338. H N B N H O O OH N N OH Initial Approach to Treatment of MM Clearly not a transplantation candidate MPT, MPV, Len/dex or clinical trial* Potential transplantation candidate Nonalkylator-based induction Stem cell harvest Melphalan/Prednisone/Thalidomide Palumbo A, et al. Blood. 2008;112:3107-3114. Lenalidomide 25 mg/day PO on Days 1-21 + High-dose Dex 40 mg/day PO on Days 1-4, 9-12, 17-20 (n = 223) Lenalidomide 25 mg/day PO on Days 1-21 + Low-dose Dex 40 mg/day PO on Days 1, 8, 15, 22 (n = 222) Len + High or Low-Dose Dex in Newly Diagnosed Myeloma (E4A03) Courses repeat every 28 days ≤ 1 yr in absence of PD or unacceptable toxicity Total Dex dose per cycle: 480 mg Untreated, symptomatic myeloma, no age cutoff Total Dex dose per cycle: 160 mg Rajkumar SV, et al. ASCO 2008. Abstract 8504. Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37 Len + High or Low-Dose Dex (E4A03): Response 3-yr OS rates converged (P = .467) with all pts crossed over to low dose Successful stem cell harvesting in 97.6% (n = 167) 3-yr OS for high dose or low dose followed by SCT: 92% Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37. Len + High or Low-Dose Dex (E4A03): Adverse Events Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37. Lenalidomide Dosing for MM and Impaired Renal Function Lenalidomide [package insert]. Peripheral Neuropathy Following Bortezomib Therapy in Advanced MM Peripheral neuropathy was reported in 90/256 (35%) patients with MM treated with bortezomib in phase II trials 80% of patients entered these trials with preexisting peripheral neuropathy 3% patients without vs 16% with baseline peripheral neuropathy developed grade 3 peripheral neuropathy Richardson PG, et al. ASH 2003. Abstract 512. Frontline Therapy in Elderly MM Patients For elderly patients or those who are not suitable candidates for transplantation, MP has been a standard treatment ORR: 60% Long-term CR: < 5% Trials with MP-based combinations reported improved response rates and time to progression MPT VMP NCCN Practice Guidelines. Myeloma. V.3.2010. Conclusions In elderly patients, the addition of novel agents to standard MP has provided improved response rates MP alone (ORR: 50%; CR: 5%) MPR (50% to 95% reduction in myeloma protein in 55.6%) VMP (ORR: 86%) Care should be taken with IMiD-based therapy to include aspirin prophylaxis for DVT/PE Care should be taken with bortezomib-based regimens to include herpes zoster prophylaxis MM & Skeletal Complications ~ 80% of patients with multiple myeloma will have evidence of skeletal involvement on skeletal survey Vertebrae: 65% Ribs: 45% Skull: 40% Shoulders: 40% Pelvis: 30% Long bones: 25% Dimopoulos M, et al. Leukemia. 2009:1-12. The Central Role of the Osteoclast in Osteolytic Bone Destruction Growth factors Osteoclast differentiation Osteolysis Direct effects on osteoclast differentiation Tumor cells Bone loss Active osteoclast Adapted from Roodman GD. N Engl J Med. 2004;350:1655-1664. Mechanism of Bisphosphonate Inhibition of Osteoclast Activity Bisphosphonates inhibit osteoclast activity, and promote osteoclast apoptosis[1] Bisphosphonates are released locally during bone resorption[1] Bisphosphonates are concentrated under osteoclasts[1] Bisphosphonates may modulate signaling from osteoblasts to osteoclasts New bone X Bone Increased OPG production[2] Decreased RANKL expression[3] 1. Reszka AA, et al. Curr Rheumatol Rep. 2003;5:65-74. 2. Viereck V, et al. Biochem Biophys Res Commun. 2002;291:680-686. 3. Pan B, et al. J Bone Miner Res. 2004;19:147-154. Recommended Doses and Infusion Times *Consider dose reduction . †3.5mg (CrCl 50-60 mL/min); 3.3 mg (CrCl 40-49 mL/min); 3.0 mg (CrCl 30-39 mL/min). Kyle R, et al. J Clin Oncol. 2007;25:2464-2472. Bisphosphonates and Osteonecrosis Uncommon complication causing avascular necrosis of maxilla or mandible Suspect with tooth or jaw pain or exposed bone May be related to duration of therapy True incidence unknown Papapetrou PD. Hormones (Athens). 2009;8:96-110.
Slide 63 - Special Thanks to… For sponsorship of LMEF programs: Supported by an educational grant from Lilly USA, LLC Did you know that you could be receiving credit for attending today? For membership information, please visit our website: www.Lafmeded.org. Multiple Myeloma 2010 Wael Harb MD Horizon Oncology Center Overview Introduction: epidemiology, clinical presentation, diagnosis, staging Autologous stem cell transplantation Initial approaches to treatment Current options Novel agents and combinations Considerations in non-transplantation-eligible patients Prevention of skeletal complications What is MM? Multiple myeloma (MM) is characterized by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. Plasma Cell Multiple Myeloma: Incidence The lifetime risk of getting MM is 1 in 159 (0.63%). 20,180 new cases will be diagnosed in 2010 (11,170 in men and 9,010 in women) 10,650 deaths are expected to occur in 2010 (5,760 in men and 4,890 in women) The 5-year relative survival rate for MM is around 35% Incidence MM occurs in all races and all geographic locations African Americans and blacks from Africa is two to three times the risk in whites Risk is lower in Asians from Japan and in Mexicans Slightly more frequent in men than in women (1.4:1) Age MM is a disease of older adults The median age at diagnosis is 66 years Only 10 percent of patients are younger than 50 years Only 2 percent of patients are younger than 40 years MM: Clinical Presentations Anemia - 73 percent Bone pain - 58 percent Elevated creatinine - 48 percent Fatigue/generalized weakness - 32 percent Hypercalcemia- 28 percent Weight loss - 24 percent, one-half of whom had lost ≥ 9 kg Multiple Myeloma = M-CRAB Monoclonal protein Calcium Renal failure Anemia Bone pain with lytic lesions Immunoglobulin Immunoglobulins SPEP: Normal SPEP: M-protein, M-spike Renal Failure Cast nephropathy (also called myeloma kidney) from light chains Hypercalcemia Light chain amyloidosis Drug-induced renal damage Anemia Normocytic, normochromic anemiais present in 73% at diagnosis and in 97%at some time during the course of the disease This anemia can be related to: Bone marrow replacement Kidney damage Dilution in the case of a large M-protein B12 deficiency in 14% Rouleaux Formation Lytic Bone Lesion MM: PET Scan Extramedullary Plasmacytoma Differential Diagnosis of MM Monoclonal gammopathy of undetermined significance (MGUS) Smoldering multiple myeloma (SMM) Waldenstrom macroglobulinemia Solitary plasmacytoma Primary amyloidosis (AL) POEMS syndrome Metastatic carcinoma Multiple Myeloma All 3 criteria must be met: Presence of a serum or urinary monoclonal protein Presence of clonal plasma cells in the bone marrow or a plasmacytoma Presence of end organ damage felt related to the plasma cell dyscrasia, such as: Increased calcium concentration Lytic bone lesions Anemia Renal failure Smoldering Multiple Myeloma SMM, Asymptomatic Both criteria must be met: Serum monoclonal protein ≥3 g/dL and/or bone marrow plasma cells ≥10 percent No end organ damage related to plasma cell dyscrasia Monoclonal Gammopathy of Undetermined Significance (MGUS) All 3 criteria must be met: Serum monoclonal protein <3 g/dL Bone marrow plasma cells <10 percent No end organ damage related to plasma cell dyscrasia or a related B cell lymphoproliferative disorder POEMS Syndrome Osteosclerotic myeloma Polyneuropathy Organomegaly Endocrinopathy Monoclonal protein Skin changes MM: Evaluation CBC and differential,peripheral blood smear Chemistry:serum calcium, creatinine, albumin, LDH , beta-2 microglobulin, and C-reactive protein Serum protein electrophoresis (SPEP) + IF Quantification of immunoglobulins Urinalysis and a 24-hour urine collection for electrophoresis (UPEP) + IF Serum free monoclonal light chain (FLC) MM Evaluation Serum viscosity should be measured if the M-protein concentration is high Bone marrow aspiration and biopsy with immunophenotyping, conventional cytogenetics, and fluorescence in situ hybridization (FISH) Metastatic bone survey with plain radiographs including the humeri and femoral bones should be performed in all patients. MRI, CT, or PET/CT Bone Marrow Cytogenenetics, Interphase FISH Poor prognosis (median survival 25 months): t(4;14)(p16;q32), t(14;16)(q32;q23), and -17p13 Intermediate prognosis (median survival 42 months): -13q14 Good prognosis (median survival 50 months): all others Staging for MM International staging system (ISS)  Stage I — B2M <3.5 mg/L and serum albumin ≥3.5 g/dL Stage II — neither stage I nor stage III Stage III — B2M ≥5.5 mg/L Median overall survival for patients with ISS stages I, II, and III are 62, 44, and 29 months MM: Treatment Decisions Indications for treatment Risk stratification Eligibility for stem cell transplantation Smoldering (asymptomatic) myeloma Deferral of chemotherapy until progression to symptomatic disease Follow these patients closely, every 3 to 4 months, with serum protein electrophoresis, complete blood count, serum creatinine, and serum calcium Metastatic bone survey should be considered annually because asymptomatic bone lesions may develop MM: Indications for Treatment Anemia (hemoglobin <10 g/dL or 2 g/dL below normal) Hypercalcemia (serum calcium >11.5 mg/dL) Renal insufficiency (serum creatinine>2 mg/dL) Lytic bone lesions or severe osteopenia Extramedullary plasmacytoma MM: RISK STRATIFICATION FISH for detection of t(4;14), t(14;16), and del17p13 Conventional cytogenetics (karyotyping) for detection of del 13 or hypodiploidy The presence of any of the above markers defines high risk myeloma, which encompasses the 25 percent of MM patients who have a median survival of approximately two years or less despite standard treatment Current Frontline Options Conventional chemotherapy Survival ≤ 3 yrs Transplantation Prolongs survival 4-5 yrs Novel agents targeting stromal interactions and associated signaling pathways have shown promise Chng WJ, et al. Cancer Control. 2005;12:91-104. MM: INITIAL THERAPY The initial therapy of patients with symptomatic myeloma varies depending on whether patients are eligible or not to pursue autologous hematopoietic cell transplantation *Thal/dex or dex are additional options especially if immediate response is needed. Clearly not transplantation candidate based on age, performance score, and comorbidity MPT, MPV, Len/dex or clinical trial* Potential transplantation candidate Nonalkylator-based induction x 4 cycles Stem cell harvest Initial Approach to Treatment of MM DETERMINING TRANSPLANT ELIGIBILITY Autologous hematopoietic cell transplantation (HCT) results in superior event-free and overall survival rates when compared with combination chemotherapy All patients should be evaluated at diagnosis for transplant eligibility so that the risks and benefits of autologous HCT can be reviewed with those eligible A minority of patients will be eligible for allogeneic HCT, but the value of allogeneic approaches in myeloma remain investigational NOT Eligible for Autologous HCT Age >77 years Direct bilirubin>2.0 mg/dL (34.2 µmol/liter) Serum creatinine>2.5 mg/dL (221 µmol/liter) unless on chronic stable dialysis Eastern Cooperative Oncology Group (ECOG) performance status 3 or 4 unless due to bone pain New York Heart Association functional status Class III or IV 54 42 Attal M, et al. N Engl J Med. 1996;335:91-97. Child JA, et al. N Engl J Med. 2003;348:1875-1883. 15 30 45 60 25 50 75 100 OS (%) 0 0 High dose Conventional dose Mos 20 40 60 80 25 50 75 100 Survival (%) 0 0 Intensive therapy Standard therapy Mos P = .03 by Wilcoxon test P = .04 by log-rank test Transplantation vs Conventional Chemotherapy Autologous Stem Cell Transplantation Mel 200 mg/m2 standard conditioning regimen Sufficient performance score, and adequate liver, pulmonary, cardiac function needed Higher PR and CR rates than conventional chemotherapy Higher OS and EFS than conventional Rx Advanced age and impaired renal function are, by themselves, not contraindications Attal M, et al. N Engl J Med. 1996;335:91-97. NCCN Practice Guidelines. Myeloma. V.3.2010. Stem Cell Transplantation Key issues Efficacy compared with conventional chemotherapy Timing: early vs delayed Single vs tandem Role of allogeneic and miniallogeneic transplantations Maintenance post-SCT Novel Frontline Options Immunomodulatory drugs (IMiDs) Thalidomide Lenalidomide Proteasome inhibitors Bortezomib Carfilzomib Kyle RA, et al. N Engl J Med. 2004;351:1860-1873. Copyright ©2004. Massachusetts Medical Society. All rights reserved. Proposed Mechanism of Action for Multiple Myeloma Therapies Thalidomide: Proposed Mechanism of Action Proposed mechanisms Inhibition of TNF- Suppression of angiogenesis Increase in cell-mediated cytotoxic effects Modulation of adhesion molecule expression Kyle RA, et al. N Engl J Med. 2004;351:1860-1873. Rajkumar SV, et al. Leukemia. 2003;17:775-779. D’Amato RJ, et al.Proc Natl Acad Sci U S A. 1994;91:4082-4085. Lenalidomide Immunomodulatory derivative of thalidomide More potent than thalidomide in preclinical models Dose-dependent decrease in TNF-α and interleukin-6 Directly induces apoptosis, G1 growth arrest Enhances activity of dexamethasone More favorable toxicity profile than thalidomide Richardson P, et al. Blood. 2003;100:3063. Hideshima T, et al. Blood. 2000;96:2943-2950. Bortezomib: A Reversible Proteasome Inhibitor Chymo- tryptic Site Post- Glutamyl Site Tryptic Site b1 b2 b3 b4 b5 b6 b7 Cross section of  ring Bortezomib Adams J, et al. Invest New Drugs. 2000;18:109-121. Adams J, et al. Bioorg Med Chem Lett. 1998;8:333-338. H N B N H O O OH N N OH Initial Approach to Treatment of MM Clearly not a transplantation candidate MPT, MPV, Len/dex or clinical trial* Potential transplantation candidate Nonalkylator-based induction Stem cell harvest Melphalan/Prednisone/Thalidomide Palumbo A, et al. Blood. 2008;112:3107-3114. Lenalidomide 25 mg/day PO on Days 1-21 + High-dose Dex 40 mg/day PO on Days 1-4, 9-12, 17-20 (n = 223) Lenalidomide 25 mg/day PO on Days 1-21 + Low-dose Dex 40 mg/day PO on Days 1, 8, 15, 22 (n = 222) Len + High or Low-Dose Dex in Newly Diagnosed Myeloma (E4A03) Courses repeat every 28 days ≤ 1 yr in absence of PD or unacceptable toxicity Total Dex dose per cycle: 480 mg Untreated, symptomatic myeloma, no age cutoff Total Dex dose per cycle: 160 mg Rajkumar SV, et al. ASCO 2008. Abstract 8504. Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37 Len + High or Low-Dose Dex (E4A03): Response 3-yr OS rates converged (P = .467) with all pts crossed over to low dose Successful stem cell harvesting in 97.6% (n = 167) 3-yr OS for high dose or low dose followed by SCT: 92% Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37. Len + High or Low-Dose Dex (E4A03): Adverse Events Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37. Lenalidomide Dosing for MM and Impaired Renal Function Lenalidomide [package insert]. Peripheral Neuropathy Following Bortezomib Therapy in Advanced MM Peripheral neuropathy was reported in 90/256 (35%) patients with MM treated with bortezomib in phase II trials 80% of patients entered these trials with preexisting peripheral neuropathy 3% patients without vs 16% with baseline peripheral neuropathy developed grade 3 peripheral neuropathy Richardson PG, et al. ASH 2003. Abstract 512. Frontline Therapy in Elderly MM Patients For elderly patients or those who are not suitable candidates for transplantation, MP has been a standard treatment ORR: 60% Long-term CR: < 5% Trials with MP-based combinations reported improved response rates and time to progression MPT VMP NCCN Practice Guidelines. Myeloma. V.3.2010. Conclusions In elderly patients, the addition of novel agents to standard MP has provided improved response rates MP alone (ORR: 50%; CR: 5%) MPR (50% to 95% reduction in myeloma protein in 55.6%) VMP (ORR: 86%) Care should be taken with IMiD-based therapy to include aspirin prophylaxis for DVT/PE Care should be taken with bortezomib-based regimens to include herpes zoster prophylaxis MM & Skeletal Complications ~ 80% of patients with multiple myeloma will have evidence of skeletal involvement on skeletal survey Vertebrae: 65% Ribs: 45% Skull: 40% Shoulders: 40% Pelvis: 30% Long bones: 25% Dimopoulos M, et al. Leukemia. 2009:1-12. The Central Role of the Osteoclast in Osteolytic Bone Destruction Growth factors Osteoclast differentiation Osteolysis Direct effects on osteoclast differentiation Tumor cells Bone loss Active osteoclast Adapted from Roodman GD. N Engl J Med. 2004;350:1655-1664. Mechanism of Bisphosphonate Inhibition of Osteoclast Activity Bisphosphonates inhibit osteoclast activity, and promote osteoclast apoptosis[1] Bisphosphonates are released locally during bone resorption[1] Bisphosphonates are concentrated under osteoclasts[1] Bisphosphonates may modulate signaling from osteoblasts to osteoclasts New bone X Bone Increased OPG production[2] Decreased RANKL expression[3] 1. Reszka AA, et al. Curr Rheumatol Rep. 2003;5:65-74. 2. Viereck V, et al. Biochem Biophys Res Commun. 2002;291:680-686. 3. Pan B, et al. J Bone Miner Res. 2004;19:147-154. Recommended Doses and Infusion Times *Consider dose reduction . †3.5mg (CrCl 50-60 mL/min); 3.3 mg (CrCl 40-49 mL/min); 3.0 mg (CrCl 30-39 mL/min). Kyle R, et al. J Clin Oncol. 2007;25:2464-2472. Bisphosphonates and Osteonecrosis Uncommon complication causing avascular necrosis of maxilla or mandible Suspect with tooth or jaw pain or exposed bone May be related to duration of therapy True incidence unknown Papapetrou PD. Hormones (Athens). 2009;8:96-110. Normal RANKL/OPG Prevents Promotes Osteoclastic Activity RANKL OPG Hofbauer LC, et al. JAMA. 2004;292:490-495.
Slide 64 - Special Thanks to… For sponsorship of LMEF programs: Supported by an educational grant from Lilly USA, LLC Did you know that you could be receiving credit for attending today? For membership information, please visit our website: www.Lafmeded.org. Multiple Myeloma 2010 Wael Harb MD Horizon Oncology Center Overview Introduction: epidemiology, clinical presentation, diagnosis, staging Autologous stem cell transplantation Initial approaches to treatment Current options Novel agents and combinations Considerations in non-transplantation-eligible patients Prevention of skeletal complications What is MM? Multiple myeloma (MM) is characterized by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. Plasma Cell Multiple Myeloma: Incidence The lifetime risk of getting MM is 1 in 159 (0.63%). 20,180 new cases will be diagnosed in 2010 (11,170 in men and 9,010 in women) 10,650 deaths are expected to occur in 2010 (5,760 in men and 4,890 in women) The 5-year relative survival rate for MM is around 35% Incidence MM occurs in all races and all geographic locations African Americans and blacks from Africa is two to three times the risk in whites Risk is lower in Asians from Japan and in Mexicans Slightly more frequent in men than in women (1.4:1) Age MM is a disease of older adults The median age at diagnosis is 66 years Only 10 percent of patients are younger than 50 years Only 2 percent of patients are younger than 40 years MM: Clinical Presentations Anemia - 73 percent Bone pain - 58 percent Elevated creatinine - 48 percent Fatigue/generalized weakness - 32 percent Hypercalcemia- 28 percent Weight loss - 24 percent, one-half of whom had lost ≥ 9 kg Multiple Myeloma = M-CRAB Monoclonal protein Calcium Renal failure Anemia Bone pain with lytic lesions Immunoglobulin Immunoglobulins SPEP: Normal SPEP: M-protein, M-spike Renal Failure Cast nephropathy (also called myeloma kidney) from light chains Hypercalcemia Light chain amyloidosis Drug-induced renal damage Anemia Normocytic, normochromic anemiais present in 73% at diagnosis and in 97%at some time during the course of the disease This anemia can be related to: Bone marrow replacement Kidney damage Dilution in the case of a large M-protein B12 deficiency in 14% Rouleaux Formation Lytic Bone Lesion MM: PET Scan Extramedullary Plasmacytoma Differential Diagnosis of MM Monoclonal gammopathy of undetermined significance (MGUS) Smoldering multiple myeloma (SMM) Waldenstrom macroglobulinemia Solitary plasmacytoma Primary amyloidosis (AL) POEMS syndrome Metastatic carcinoma Multiple Myeloma All 3 criteria must be met: Presence of a serum or urinary monoclonal protein Presence of clonal plasma cells in the bone marrow or a plasmacytoma Presence of end organ damage felt related to the plasma cell dyscrasia, such as: Increased calcium concentration Lytic bone lesions Anemia Renal failure Smoldering Multiple Myeloma SMM, Asymptomatic Both criteria must be met: Serum monoclonal protein ≥3 g/dL and/or bone marrow plasma cells ≥10 percent No end organ damage related to plasma cell dyscrasia Monoclonal Gammopathy of Undetermined Significance (MGUS) All 3 criteria must be met: Serum monoclonal protein <3 g/dL Bone marrow plasma cells <10 percent No end organ damage related to plasma cell dyscrasia or a related B cell lymphoproliferative disorder POEMS Syndrome Osteosclerotic myeloma Polyneuropathy Organomegaly Endocrinopathy Monoclonal protein Skin changes MM: Evaluation CBC and differential,peripheral blood smear Chemistry:serum calcium, creatinine, albumin, LDH , beta-2 microglobulin, and C-reactive protein Serum protein electrophoresis (SPEP) + IF Quantification of immunoglobulins Urinalysis and a 24-hour urine collection for electrophoresis (UPEP) + IF Serum free monoclonal light chain (FLC) MM Evaluation Serum viscosity should be measured if the M-protein concentration is high Bone marrow aspiration and biopsy with immunophenotyping, conventional cytogenetics, and fluorescence in situ hybridization (FISH) Metastatic bone survey with plain radiographs including the humeri and femoral bones should be performed in all patients. MRI, CT, or PET/CT Bone Marrow Cytogenenetics, Interphase FISH Poor prognosis (median survival 25 months): t(4;14)(p16;q32), t(14;16)(q32;q23), and -17p13 Intermediate prognosis (median survival 42 months): -13q14 Good prognosis (median survival 50 months): all others Staging for MM International staging system (ISS)  Stage I — B2M <3.5 mg/L and serum albumin ≥3.5 g/dL Stage II — neither stage I nor stage III Stage III — B2M ≥5.5 mg/L Median overall survival for patients with ISS stages I, II, and III are 62, 44, and 29 months MM: Treatment Decisions Indications for treatment Risk stratification Eligibility for stem cell transplantation Smoldering (asymptomatic) myeloma Deferral of chemotherapy until progression to symptomatic disease Follow these patients closely, every 3 to 4 months, with serum protein electrophoresis, complete blood count, serum creatinine, and serum calcium Metastatic bone survey should be considered annually because asymptomatic bone lesions may develop MM: Indications for Treatment Anemia (hemoglobin <10 g/dL or 2 g/dL below normal) Hypercalcemia (serum calcium >11.5 mg/dL) Renal insufficiency (serum creatinine>2 mg/dL) Lytic bone lesions or severe osteopenia Extramedullary plasmacytoma MM: RISK STRATIFICATION FISH for detection of t(4;14), t(14;16), and del17p13 Conventional cytogenetics (karyotyping) for detection of del 13 or hypodiploidy The presence of any of the above markers defines high risk myeloma, which encompasses the 25 percent of MM patients who have a median survival of approximately two years or less despite standard treatment Current Frontline Options Conventional chemotherapy Survival ≤ 3 yrs Transplantation Prolongs survival 4-5 yrs Novel agents targeting stromal interactions and associated signaling pathways have shown promise Chng WJ, et al. Cancer Control. 2005;12:91-104. MM: INITIAL THERAPY The initial therapy of patients with symptomatic myeloma varies depending on whether patients are eligible or not to pursue autologous hematopoietic cell transplantation *Thal/dex or dex are additional options especially if immediate response is needed. Clearly not transplantation candidate based on age, performance score, and comorbidity MPT, MPV, Len/dex or clinical trial* Potential transplantation candidate Nonalkylator-based induction x 4 cycles Stem cell harvest Initial Approach to Treatment of MM DETERMINING TRANSPLANT ELIGIBILITY Autologous hematopoietic cell transplantation (HCT) results in superior event-free and overall survival rates when compared with combination chemotherapy All patients should be evaluated at diagnosis for transplant eligibility so that the risks and benefits of autologous HCT can be reviewed with those eligible A minority of patients will be eligible for allogeneic HCT, but the value of allogeneic approaches in myeloma remain investigational NOT Eligible for Autologous HCT Age >77 years Direct bilirubin>2.0 mg/dL (34.2 µmol/liter) Serum creatinine>2.5 mg/dL (221 µmol/liter) unless on chronic stable dialysis Eastern Cooperative Oncology Group (ECOG) performance status 3 or 4 unless due to bone pain New York Heart Association functional status Class III or IV 54 42 Attal M, et al. N Engl J Med. 1996;335:91-97. Child JA, et al. N Engl J Med. 2003;348:1875-1883. 15 30 45 60 25 50 75 100 OS (%) 0 0 High dose Conventional dose Mos 20 40 60 80 25 50 75 100 Survival (%) 0 0 Intensive therapy Standard therapy Mos P = .03 by Wilcoxon test P = .04 by log-rank test Transplantation vs Conventional Chemotherapy Autologous Stem Cell Transplantation Mel 200 mg/m2 standard conditioning regimen Sufficient performance score, and adequate liver, pulmonary, cardiac function needed Higher PR and CR rates than conventional chemotherapy Higher OS and EFS than conventional Rx Advanced age and impaired renal function are, by themselves, not contraindications Attal M, et al. N Engl J Med. 1996;335:91-97. NCCN Practice Guidelines. Myeloma. V.3.2010. Stem Cell Transplantation Key issues Efficacy compared with conventional chemotherapy Timing: early vs delayed Single vs tandem Role of allogeneic and miniallogeneic transplantations Maintenance post-SCT Novel Frontline Options Immunomodulatory drugs (IMiDs) Thalidomide Lenalidomide Proteasome inhibitors Bortezomib Carfilzomib Kyle RA, et al. N Engl J Med. 2004;351:1860-1873. Copyright ©2004. Massachusetts Medical Society. All rights reserved. Proposed Mechanism of Action for Multiple Myeloma Therapies Thalidomide: Proposed Mechanism of Action Proposed mechanisms Inhibition of TNF- Suppression of angiogenesis Increase in cell-mediated cytotoxic effects Modulation of adhesion molecule expression Kyle RA, et al. N Engl J Med. 2004;351:1860-1873. Rajkumar SV, et al. Leukemia. 2003;17:775-779. D’Amato RJ, et al.Proc Natl Acad Sci U S A. 1994;91:4082-4085. Lenalidomide Immunomodulatory derivative of thalidomide More potent than thalidomide in preclinical models Dose-dependent decrease in TNF-α and interleukin-6 Directly induces apoptosis, G1 growth arrest Enhances activity of dexamethasone More favorable toxicity profile than thalidomide Richardson P, et al. Blood. 2003;100:3063. Hideshima T, et al. Blood. 2000;96:2943-2950. Bortezomib: A Reversible Proteasome Inhibitor Chymo- tryptic Site Post- Glutamyl Site Tryptic Site b1 b2 b3 b4 b5 b6 b7 Cross section of  ring Bortezomib Adams J, et al. Invest New Drugs. 2000;18:109-121. Adams J, et al. Bioorg Med Chem Lett. 1998;8:333-338. H N B N H O O OH N N OH Initial Approach to Treatment of MM Clearly not a transplantation candidate MPT, MPV, Len/dex or clinical trial* Potential transplantation candidate Nonalkylator-based induction Stem cell harvest Melphalan/Prednisone/Thalidomide Palumbo A, et al. Blood. 2008;112:3107-3114. Lenalidomide 25 mg/day PO on Days 1-21 + High-dose Dex 40 mg/day PO on Days 1-4, 9-12, 17-20 (n = 223) Lenalidomide 25 mg/day PO on Days 1-21 + Low-dose Dex 40 mg/day PO on Days 1, 8, 15, 22 (n = 222) Len + High or Low-Dose Dex in Newly Diagnosed Myeloma (E4A03) Courses repeat every 28 days ≤ 1 yr in absence of PD or unacceptable toxicity Total Dex dose per cycle: 480 mg Untreated, symptomatic myeloma, no age cutoff Total Dex dose per cycle: 160 mg Rajkumar SV, et al. ASCO 2008. Abstract 8504. Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37 Len + High or Low-Dose Dex (E4A03): Response 3-yr OS rates converged (P = .467) with all pts crossed over to low dose Successful stem cell harvesting in 97.6% (n = 167) 3-yr OS for high dose or low dose followed by SCT: 92% Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37. Len + High or Low-Dose Dex (E4A03): Adverse Events Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37. Lenalidomide Dosing for MM and Impaired Renal Function Lenalidomide [package insert]. Peripheral Neuropathy Following Bortezomib Therapy in Advanced MM Peripheral neuropathy was reported in 90/256 (35%) patients with MM treated with bortezomib in phase II trials 80% of patients entered these trials with preexisting peripheral neuropathy 3% patients without vs 16% with baseline peripheral neuropathy developed grade 3 peripheral neuropathy Richardson PG, et al. ASH 2003. Abstract 512. Frontline Therapy in Elderly MM Patients For elderly patients or those who are not suitable candidates for transplantation, MP has been a standard treatment ORR: 60% Long-term CR: < 5% Trials with MP-based combinations reported improved response rates and time to progression MPT VMP NCCN Practice Guidelines. Myeloma. V.3.2010. Conclusions In elderly patients, the addition of novel agents to standard MP has provided improved response rates MP alone (ORR: 50%; CR: 5%) MPR (50% to 95% reduction in myeloma protein in 55.6%) VMP (ORR: 86%) Care should be taken with IMiD-based therapy to include aspirin prophylaxis for DVT/PE Care should be taken with bortezomib-based regimens to include herpes zoster prophylaxis MM & Skeletal Complications ~ 80% of patients with multiple myeloma will have evidence of skeletal involvement on skeletal survey Vertebrae: 65% Ribs: 45% Skull: 40% Shoulders: 40% Pelvis: 30% Long bones: 25% Dimopoulos M, et al. Leukemia. 2009:1-12. The Central Role of the Osteoclast in Osteolytic Bone Destruction Growth factors Osteoclast differentiation Osteolysis Direct effects on osteoclast differentiation Tumor cells Bone loss Active osteoclast Adapted from Roodman GD. N Engl J Med. 2004;350:1655-1664. Mechanism of Bisphosphonate Inhibition of Osteoclast Activity Bisphosphonates inhibit osteoclast activity, and promote osteoclast apoptosis[1] Bisphosphonates are released locally during bone resorption[1] Bisphosphonates are concentrated under osteoclasts[1] Bisphosphonates may modulate signaling from osteoblasts to osteoclasts New bone X Bone Increased OPG production[2] Decreased RANKL expression[3] 1. Reszka AA, et al. Curr Rheumatol Rep. 2003;5:65-74. 2. Viereck V, et al. Biochem Biophys Res Commun. 2002;291:680-686. 3. Pan B, et al. J Bone Miner Res. 2004;19:147-154. Recommended Doses and Infusion Times *Consider dose reduction . †3.5mg (CrCl 50-60 mL/min); 3.3 mg (CrCl 40-49 mL/min); 3.0 mg (CrCl 30-39 mL/min). Kyle R, et al. J Clin Oncol. 2007;25:2464-2472. Bisphosphonates and Osteonecrosis Uncommon complication causing avascular necrosis of maxilla or mandible Suspect with tooth or jaw pain or exposed bone May be related to duration of therapy True incidence unknown Papapetrou PD. Hormones (Athens). 2009;8:96-110. Normal RANKL/OPG Prevents Promotes Osteoclastic Activity RANKL OPG Hofbauer LC, et al. JAMA. 2004;292:490-495. The RANK/RANKL/OPG Pathway in Osteolytic Bone Disease Prevents Promotes Increased osteoclastic activity and decreased OPG OPG RANKL Adapted from Roodman GD. N Engl J Med. 2004;350:1655-1664.
Slide 65 - Special Thanks to… For sponsorship of LMEF programs: Supported by an educational grant from Lilly USA, LLC Did you know that you could be receiving credit for attending today? For membership information, please visit our website: www.Lafmeded.org. Multiple Myeloma 2010 Wael Harb MD Horizon Oncology Center Overview Introduction: epidemiology, clinical presentation, diagnosis, staging Autologous stem cell transplantation Initial approaches to treatment Current options Novel agents and combinations Considerations in non-transplantation-eligible patients Prevention of skeletal complications What is MM? Multiple myeloma (MM) is characterized by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. Plasma Cell Multiple Myeloma: Incidence The lifetime risk of getting MM is 1 in 159 (0.63%). 20,180 new cases will be diagnosed in 2010 (11,170 in men and 9,010 in women) 10,650 deaths are expected to occur in 2010 (5,760 in men and 4,890 in women) The 5-year relative survival rate for MM is around 35% Incidence MM occurs in all races and all geographic locations African Americans and blacks from Africa is two to three times the risk in whites Risk is lower in Asians from Japan and in Mexicans Slightly more frequent in men than in women (1.4:1) Age MM is a disease of older adults The median age at diagnosis is 66 years Only 10 percent of patients are younger than 50 years Only 2 percent of patients are younger than 40 years MM: Clinical Presentations Anemia - 73 percent Bone pain - 58 percent Elevated creatinine - 48 percent Fatigue/generalized weakness - 32 percent Hypercalcemia- 28 percent Weight loss - 24 percent, one-half of whom had lost ≥ 9 kg Multiple Myeloma = M-CRAB Monoclonal protein Calcium Renal failure Anemia Bone pain with lytic lesions Immunoglobulin Immunoglobulins SPEP: Normal SPEP: M-protein, M-spike Renal Failure Cast nephropathy (also called myeloma kidney) from light chains Hypercalcemia Light chain amyloidosis Drug-induced renal damage Anemia Normocytic, normochromic anemiais present in 73% at diagnosis and in 97%at some time during the course of the disease This anemia can be related to: Bone marrow replacement Kidney damage Dilution in the case of a large M-protein B12 deficiency in 14% Rouleaux Formation Lytic Bone Lesion MM: PET Scan Extramedullary Plasmacytoma Differential Diagnosis of MM Monoclonal gammopathy of undetermined significance (MGUS) Smoldering multiple myeloma (SMM) Waldenstrom macroglobulinemia Solitary plasmacytoma Primary amyloidosis (AL) POEMS syndrome Metastatic carcinoma Multiple Myeloma All 3 criteria must be met: Presence of a serum or urinary monoclonal protein Presence of clonal plasma cells in the bone marrow or a plasmacytoma Presence of end organ damage felt related to the plasma cell dyscrasia, such as: Increased calcium concentration Lytic bone lesions Anemia Renal failure Smoldering Multiple Myeloma SMM, Asymptomatic Both criteria must be met: Serum monoclonal protein ≥3 g/dL and/or bone marrow plasma cells ≥10 percent No end organ damage related to plasma cell dyscrasia Monoclonal Gammopathy of Undetermined Significance (MGUS) All 3 criteria must be met: Serum monoclonal protein <3 g/dL Bone marrow plasma cells <10 percent No end organ damage related to plasma cell dyscrasia or a related B cell lymphoproliferative disorder POEMS Syndrome Osteosclerotic myeloma Polyneuropathy Organomegaly Endocrinopathy Monoclonal protein Skin changes MM: Evaluation CBC and differential,peripheral blood smear Chemistry:serum calcium, creatinine, albumin, LDH , beta-2 microglobulin, and C-reactive protein Serum protein electrophoresis (SPEP) + IF Quantification of immunoglobulins Urinalysis and a 24-hour urine collection for electrophoresis (UPEP) + IF Serum free monoclonal light chain (FLC) MM Evaluation Serum viscosity should be measured if the M-protein concentration is high Bone marrow aspiration and biopsy with immunophenotyping, conventional cytogenetics, and fluorescence in situ hybridization (FISH) Metastatic bone survey with plain radiographs including the humeri and femoral bones should be performed in all patients. MRI, CT, or PET/CT Bone Marrow Cytogenenetics, Interphase FISH Poor prognosis (median survival 25 months): t(4;14)(p16;q32), t(14;16)(q32;q23), and -17p13 Intermediate prognosis (median survival 42 months): -13q14 Good prognosis (median survival 50 months): all others Staging for MM International staging system (ISS)  Stage I — B2M <3.5 mg/L and serum albumin ≥3.5 g/dL Stage II — neither stage I nor stage III Stage III — B2M ≥5.5 mg/L Median overall survival for patients with ISS stages I, II, and III are 62, 44, and 29 months MM: Treatment Decisions Indications for treatment Risk stratification Eligibility for stem cell transplantation Smoldering (asymptomatic) myeloma Deferral of chemotherapy until progression to symptomatic disease Follow these patients closely, every 3 to 4 months, with serum protein electrophoresis, complete blood count, serum creatinine, and serum calcium Metastatic bone survey should be considered annually because asymptomatic bone lesions may develop MM: Indications for Treatment Anemia (hemoglobin <10 g/dL or 2 g/dL below normal) Hypercalcemia (serum calcium >11.5 mg/dL) Renal insufficiency (serum creatinine>2 mg/dL) Lytic bone lesions or severe osteopenia Extramedullary plasmacytoma MM: RISK STRATIFICATION FISH for detection of t(4;14), t(14;16), and del17p13 Conventional cytogenetics (karyotyping) for detection of del 13 or hypodiploidy The presence of any of the above markers defines high risk myeloma, which encompasses the 25 percent of MM patients who have a median survival of approximately two years or less despite standard treatment Current Frontline Options Conventional chemotherapy Survival ≤ 3 yrs Transplantation Prolongs survival 4-5 yrs Novel agents targeting stromal interactions and associated signaling pathways have shown promise Chng WJ, et al. Cancer Control. 2005;12:91-104. MM: INITIAL THERAPY The initial therapy of patients with symptomatic myeloma varies depending on whether patients are eligible or not to pursue autologous hematopoietic cell transplantation *Thal/dex or dex are additional options especially if immediate response is needed. Clearly not transplantation candidate based on age, performance score, and comorbidity MPT, MPV, Len/dex or clinical trial* Potential transplantation candidate Nonalkylator-based induction x 4 cycles Stem cell harvest Initial Approach to Treatment of MM DETERMINING TRANSPLANT ELIGIBILITY Autologous hematopoietic cell transplantation (HCT) results in superior event-free and overall survival rates when compared with combination chemotherapy All patients should be evaluated at diagnosis for transplant eligibility so that the risks and benefits of autologous HCT can be reviewed with those eligible A minority of patients will be eligible for allogeneic HCT, but the value of allogeneic approaches in myeloma remain investigational NOT Eligible for Autologous HCT Age >77 years Direct bilirubin>2.0 mg/dL (34.2 µmol/liter) Serum creatinine>2.5 mg/dL (221 µmol/liter) unless on chronic stable dialysis Eastern Cooperative Oncology Group (ECOG) performance status 3 or 4 unless due to bone pain New York Heart Association functional status Class III or IV 54 42 Attal M, et al. N Engl J Med. 1996;335:91-97. Child JA, et al. N Engl J Med. 2003;348:1875-1883. 15 30 45 60 25 50 75 100 OS (%) 0 0 High dose Conventional dose Mos 20 40 60 80 25 50 75 100 Survival (%) 0 0 Intensive therapy Standard therapy Mos P = .03 by Wilcoxon test P = .04 by log-rank test Transplantation vs Conventional Chemotherapy Autologous Stem Cell Transplantation Mel 200 mg/m2 standard conditioning regimen Sufficient performance score, and adequate liver, pulmonary, cardiac function needed Higher PR and CR rates than conventional chemotherapy Higher OS and EFS than conventional Rx Advanced age and impaired renal function are, by themselves, not contraindications Attal M, et al. N Engl J Med. 1996;335:91-97. NCCN Practice Guidelines. Myeloma. V.3.2010. Stem Cell Transplantation Key issues Efficacy compared with conventional chemotherapy Timing: early vs delayed Single vs tandem Role of allogeneic and miniallogeneic transplantations Maintenance post-SCT Novel Frontline Options Immunomodulatory drugs (IMiDs) Thalidomide Lenalidomide Proteasome inhibitors Bortezomib Carfilzomib Kyle RA, et al. N Engl J Med. 2004;351:1860-1873. Copyright ©2004. Massachusetts Medical Society. All rights reserved. Proposed Mechanism of Action for Multiple Myeloma Therapies Thalidomide: Proposed Mechanism of Action Proposed mechanisms Inhibition of TNF- Suppression of angiogenesis Increase in cell-mediated cytotoxic effects Modulation of adhesion molecule expression Kyle RA, et al. N Engl J Med. 2004;351:1860-1873. Rajkumar SV, et al. Leukemia. 2003;17:775-779. D’Amato RJ, et al.Proc Natl Acad Sci U S A. 1994;91:4082-4085. Lenalidomide Immunomodulatory derivative of thalidomide More potent than thalidomide in preclinical models Dose-dependent decrease in TNF-α and interleukin-6 Directly induces apoptosis, G1 growth arrest Enhances activity of dexamethasone More favorable toxicity profile than thalidomide Richardson P, et al. Blood. 2003;100:3063. Hideshima T, et al. Blood. 2000;96:2943-2950. Bortezomib: A Reversible Proteasome Inhibitor Chymo- tryptic Site Post- Glutamyl Site Tryptic Site b1 b2 b3 b4 b5 b6 b7 Cross section of  ring Bortezomib Adams J, et al. Invest New Drugs. 2000;18:109-121. Adams J, et al. Bioorg Med Chem Lett. 1998;8:333-338. H N B N H O O OH N N OH Initial Approach to Treatment of MM Clearly not a transplantation candidate MPT, MPV, Len/dex or clinical trial* Potential transplantation candidate Nonalkylator-based induction Stem cell harvest Melphalan/Prednisone/Thalidomide Palumbo A, et al. Blood. 2008;112:3107-3114. Lenalidomide 25 mg/day PO on Days 1-21 + High-dose Dex 40 mg/day PO on Days 1-4, 9-12, 17-20 (n = 223) Lenalidomide 25 mg/day PO on Days 1-21 + Low-dose Dex 40 mg/day PO on Days 1, 8, 15, 22 (n = 222) Len + High or Low-Dose Dex in Newly Diagnosed Myeloma (E4A03) Courses repeat every 28 days ≤ 1 yr in absence of PD or unacceptable toxicity Total Dex dose per cycle: 480 mg Untreated, symptomatic myeloma, no age cutoff Total Dex dose per cycle: 160 mg Rajkumar SV, et al. ASCO 2008. Abstract 8504. Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37 Len + High or Low-Dose Dex (E4A03): Response 3-yr OS rates converged (P = .467) with all pts crossed over to low dose Successful stem cell harvesting in 97.6% (n = 167) 3-yr OS for high dose or low dose followed by SCT: 92% Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37. Len + High or Low-Dose Dex (E4A03): Adverse Events Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37. Lenalidomide Dosing for MM and Impaired Renal Function Lenalidomide [package insert]. Peripheral Neuropathy Following Bortezomib Therapy in Advanced MM Peripheral neuropathy was reported in 90/256 (35%) patients with MM treated with bortezomib in phase II trials 80% of patients entered these trials with preexisting peripheral neuropathy 3% patients without vs 16% with baseline peripheral neuropathy developed grade 3 peripheral neuropathy Richardson PG, et al. ASH 2003. Abstract 512. Frontline Therapy in Elderly MM Patients For elderly patients or those who are not suitable candidates for transplantation, MP has been a standard treatment ORR: 60% Long-term CR: < 5% Trials with MP-based combinations reported improved response rates and time to progression MPT VMP NCCN Practice Guidelines. Myeloma. V.3.2010. Conclusions In elderly patients, the addition of novel agents to standard MP has provided improved response rates MP alone (ORR: 50%; CR: 5%) MPR (50% to 95% reduction in myeloma protein in 55.6%) VMP (ORR: 86%) Care should be taken with IMiD-based therapy to include aspirin prophylaxis for DVT/PE Care should be taken with bortezomib-based regimens to include herpes zoster prophylaxis MM & Skeletal Complications ~ 80% of patients with multiple myeloma will have evidence of skeletal involvement on skeletal survey Vertebrae: 65% Ribs: 45% Skull: 40% Shoulders: 40% Pelvis: 30% Long bones: 25% Dimopoulos M, et al. Leukemia. 2009:1-12. The Central Role of the Osteoclast in Osteolytic Bone Destruction Growth factors Osteoclast differentiation Osteolysis Direct effects on osteoclast differentiation Tumor cells Bone loss Active osteoclast Adapted from Roodman GD. N Engl J Med. 2004;350:1655-1664. Mechanism of Bisphosphonate Inhibition of Osteoclast Activity Bisphosphonates inhibit osteoclast activity, and promote osteoclast apoptosis[1] Bisphosphonates are released locally during bone resorption[1] Bisphosphonates are concentrated under osteoclasts[1] Bisphosphonates may modulate signaling from osteoblasts to osteoclasts New bone X Bone Increased OPG production[2] Decreased RANKL expression[3] 1. Reszka AA, et al. Curr Rheumatol Rep. 2003;5:65-74. 2. Viereck V, et al. Biochem Biophys Res Commun. 2002;291:680-686. 3. Pan B, et al. J Bone Miner Res. 2004;19:147-154. Recommended Doses and Infusion Times *Consider dose reduction . †3.5mg (CrCl 50-60 mL/min); 3.3 mg (CrCl 40-49 mL/min); 3.0 mg (CrCl 30-39 mL/min). Kyle R, et al. J Clin Oncol. 2007;25:2464-2472. Bisphosphonates and Osteonecrosis Uncommon complication causing avascular necrosis of maxilla or mandible Suspect with tooth or jaw pain or exposed bone May be related to duration of therapy True incidence unknown Papapetrou PD. Hormones (Athens). 2009;8:96-110. Normal RANKL/OPG Prevents Promotes Osteoclastic Activity RANKL OPG Hofbauer LC, et al. JAMA. 2004;292:490-495. The RANK/RANKL/OPG Pathway in Osteolytic Bone Disease Prevents Promotes Increased osteoclastic activity and decreased OPG OPG RANKL Adapted from Roodman GD. N Engl J Med. 2004;350:1655-1664. Denosumab: Inhibiting RANK in Bone Disease High affinity human monoclonal antibody that binds RANKL Administered via SC injection Specific: does not bind to TNF-α, TNF-β, TRAIL, or CD40L Inhibits formation and activation of osteoclasts
Slide 66 - Special Thanks to… For sponsorship of LMEF programs: Supported by an educational grant from Lilly USA, LLC Did you know that you could be receiving credit for attending today? For membership information, please visit our website: www.Lafmeded.org. Multiple Myeloma 2010 Wael Harb MD Horizon Oncology Center Overview Introduction: epidemiology, clinical presentation, diagnosis, staging Autologous stem cell transplantation Initial approaches to treatment Current options Novel agents and combinations Considerations in non-transplantation-eligible patients Prevention of skeletal complications What is MM? Multiple myeloma (MM) is characterized by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. Plasma Cell Multiple Myeloma: Incidence The lifetime risk of getting MM is 1 in 159 (0.63%). 20,180 new cases will be diagnosed in 2010 (11,170 in men and 9,010 in women) 10,650 deaths are expected to occur in 2010 (5,760 in men and 4,890 in women) The 5-year relative survival rate for MM is around 35% Incidence MM occurs in all races and all geographic locations African Americans and blacks from Africa is two to three times the risk in whites Risk is lower in Asians from Japan and in Mexicans Slightly more frequent in men than in women (1.4:1) Age MM is a disease of older adults The median age at diagnosis is 66 years Only 10 percent of patients are younger than 50 years Only 2 percent of patients are younger than 40 years MM: Clinical Presentations Anemia - 73 percent Bone pain - 58 percent Elevated creatinine - 48 percent Fatigue/generalized weakness - 32 percent Hypercalcemia- 28 percent Weight loss - 24 percent, one-half of whom had lost ≥ 9 kg Multiple Myeloma = M-CRAB Monoclonal protein Calcium Renal failure Anemia Bone pain with lytic lesions Immunoglobulin Immunoglobulins SPEP: Normal SPEP: M-protein, M-spike Renal Failure Cast nephropathy (also called myeloma kidney) from light chains Hypercalcemia Light chain amyloidosis Drug-induced renal damage Anemia Normocytic, normochromic anemiais present in 73% at diagnosis and in 97%at some time during the course of the disease This anemia can be related to: Bone marrow replacement Kidney damage Dilution in the case of a large M-protein B12 deficiency in 14% Rouleaux Formation Lytic Bone Lesion MM: PET Scan Extramedullary Plasmacytoma Differential Diagnosis of MM Monoclonal gammopathy of undetermined significance (MGUS) Smoldering multiple myeloma (SMM) Waldenstrom macroglobulinemia Solitary plasmacytoma Primary amyloidosis (AL) POEMS syndrome Metastatic carcinoma Multiple Myeloma All 3 criteria must be met: Presence of a serum or urinary monoclonal protein Presence of clonal plasma cells in the bone marrow or a plasmacytoma Presence of end organ damage felt related to the plasma cell dyscrasia, such as: Increased calcium concentration Lytic bone lesions Anemia Renal failure Smoldering Multiple Myeloma SMM, Asymptomatic Both criteria must be met: Serum monoclonal protein ≥3 g/dL and/or bone marrow plasma cells ≥10 percent No end organ damage related to plasma cell dyscrasia Monoclonal Gammopathy of Undetermined Significance (MGUS) All 3 criteria must be met: Serum monoclonal protein <3 g/dL Bone marrow plasma cells <10 percent No end organ damage related to plasma cell dyscrasia or a related B cell lymphoproliferative disorder POEMS Syndrome Osteosclerotic myeloma Polyneuropathy Organomegaly Endocrinopathy Monoclonal protein Skin changes MM: Evaluation CBC and differential,peripheral blood smear Chemistry:serum calcium, creatinine, albumin, LDH , beta-2 microglobulin, and C-reactive protein Serum protein electrophoresis (SPEP) + IF Quantification of immunoglobulins Urinalysis and a 24-hour urine collection for electrophoresis (UPEP) + IF Serum free monoclonal light chain (FLC) MM Evaluation Serum viscosity should be measured if the M-protein concentration is high Bone marrow aspiration and biopsy with immunophenotyping, conventional cytogenetics, and fluorescence in situ hybridization (FISH) Metastatic bone survey with plain radiographs including the humeri and femoral bones should be performed in all patients. MRI, CT, or PET/CT Bone Marrow Cytogenenetics, Interphase FISH Poor prognosis (median survival 25 months): t(4;14)(p16;q32), t(14;16)(q32;q23), and -17p13 Intermediate prognosis (median survival 42 months): -13q14 Good prognosis (median survival 50 months): all others Staging for MM International staging system (ISS)  Stage I — B2M <3.5 mg/L and serum albumin ≥3.5 g/dL Stage II — neither stage I nor stage III Stage III — B2M ≥5.5 mg/L Median overall survival for patients with ISS stages I, II, and III are 62, 44, and 29 months MM: Treatment Decisions Indications for treatment Risk stratification Eligibility for stem cell transplantation Smoldering (asymptomatic) myeloma Deferral of chemotherapy until progression to symptomatic disease Follow these patients closely, every 3 to 4 months, with serum protein electrophoresis, complete blood count, serum creatinine, and serum calcium Metastatic bone survey should be considered annually because asymptomatic bone lesions may develop MM: Indications for Treatment Anemia (hemoglobin <10 g/dL or 2 g/dL below normal) Hypercalcemia (serum calcium >11.5 mg/dL) Renal insufficiency (serum creatinine>2 mg/dL) Lytic bone lesions or severe osteopenia Extramedullary plasmacytoma MM: RISK STRATIFICATION FISH for detection of t(4;14), t(14;16), and del17p13 Conventional cytogenetics (karyotyping) for detection of del 13 or hypodiploidy The presence of any of the above markers defines high risk myeloma, which encompasses the 25 percent of MM patients who have a median survival of approximately two years or less despite standard treatment Current Frontline Options Conventional chemotherapy Survival ≤ 3 yrs Transplantation Prolongs survival 4-5 yrs Novel agents targeting stromal interactions and associated signaling pathways have shown promise Chng WJ, et al. Cancer Control. 2005;12:91-104. MM: INITIAL THERAPY The initial therapy of patients with symptomatic myeloma varies depending on whether patients are eligible or not to pursue autologous hematopoietic cell transplantation *Thal/dex or dex are additional options especially if immediate response is needed. Clearly not transplantation candidate based on age, performance score, and comorbidity MPT, MPV, Len/dex or clinical trial* Potential transplantation candidate Nonalkylator-based induction x 4 cycles Stem cell harvest Initial Approach to Treatment of MM DETERMINING TRANSPLANT ELIGIBILITY Autologous hematopoietic cell transplantation (HCT) results in superior event-free and overall survival rates when compared with combination chemotherapy All patients should be evaluated at diagnosis for transplant eligibility so that the risks and benefits of autologous HCT can be reviewed with those eligible A minority of patients will be eligible for allogeneic HCT, but the value of allogeneic approaches in myeloma remain investigational NOT Eligible for Autologous HCT Age >77 years Direct bilirubin>2.0 mg/dL (34.2 µmol/liter) Serum creatinine>2.5 mg/dL (221 µmol/liter) unless on chronic stable dialysis Eastern Cooperative Oncology Group (ECOG) performance status 3 or 4 unless due to bone pain New York Heart Association functional status Class III or IV 54 42 Attal M, et al. N Engl J Med. 1996;335:91-97. Child JA, et al. N Engl J Med. 2003;348:1875-1883. 15 30 45 60 25 50 75 100 OS (%) 0 0 High dose Conventional dose Mos 20 40 60 80 25 50 75 100 Survival (%) 0 0 Intensive therapy Standard therapy Mos P = .03 by Wilcoxon test P = .04 by log-rank test Transplantation vs Conventional Chemotherapy Autologous Stem Cell Transplantation Mel 200 mg/m2 standard conditioning regimen Sufficient performance score, and adequate liver, pulmonary, cardiac function needed Higher PR and CR rates than conventional chemotherapy Higher OS and EFS than conventional Rx Advanced age and impaired renal function are, by themselves, not contraindications Attal M, et al. N Engl J Med. 1996;335:91-97. NCCN Practice Guidelines. Myeloma. V.3.2010. Stem Cell Transplantation Key issues Efficacy compared with conventional chemotherapy Timing: early vs delayed Single vs tandem Role of allogeneic and miniallogeneic transplantations Maintenance post-SCT Novel Frontline Options Immunomodulatory drugs (IMiDs) Thalidomide Lenalidomide Proteasome inhibitors Bortezomib Carfilzomib Kyle RA, et al. N Engl J Med. 2004;351:1860-1873. Copyright ©2004. Massachusetts Medical Society. All rights reserved. Proposed Mechanism of Action for Multiple Myeloma Therapies Thalidomide: Proposed Mechanism of Action Proposed mechanisms Inhibition of TNF- Suppression of angiogenesis Increase in cell-mediated cytotoxic effects Modulation of adhesion molecule expression Kyle RA, et al. N Engl J Med. 2004;351:1860-1873. Rajkumar SV, et al. Leukemia. 2003;17:775-779. D’Amato RJ, et al.Proc Natl Acad Sci U S A. 1994;91:4082-4085. Lenalidomide Immunomodulatory derivative of thalidomide More potent than thalidomide in preclinical models Dose-dependent decrease in TNF-α and interleukin-6 Directly induces apoptosis, G1 growth arrest Enhances activity of dexamethasone More favorable toxicity profile than thalidomide Richardson P, et al. Blood. 2003;100:3063. Hideshima T, et al. Blood. 2000;96:2943-2950. Bortezomib: A Reversible Proteasome Inhibitor Chymo- tryptic Site Post- Glutamyl Site Tryptic Site b1 b2 b3 b4 b5 b6 b7 Cross section of  ring Bortezomib Adams J, et al. Invest New Drugs. 2000;18:109-121. Adams J, et al. Bioorg Med Chem Lett. 1998;8:333-338. H N B N H O O OH N N OH Initial Approach to Treatment of MM Clearly not a transplantation candidate MPT, MPV, Len/dex or clinical trial* Potential transplantation candidate Nonalkylator-based induction Stem cell harvest Melphalan/Prednisone/Thalidomide Palumbo A, et al. Blood. 2008;112:3107-3114. Lenalidomide 25 mg/day PO on Days 1-21 + High-dose Dex 40 mg/day PO on Days 1-4, 9-12, 17-20 (n = 223) Lenalidomide 25 mg/day PO on Days 1-21 + Low-dose Dex 40 mg/day PO on Days 1, 8, 15, 22 (n = 222) Len + High or Low-Dose Dex in Newly Diagnosed Myeloma (E4A03) Courses repeat every 28 days ≤ 1 yr in absence of PD or unacceptable toxicity Total Dex dose per cycle: 480 mg Untreated, symptomatic myeloma, no age cutoff Total Dex dose per cycle: 160 mg Rajkumar SV, et al. ASCO 2008. Abstract 8504. Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37 Len + High or Low-Dose Dex (E4A03): Response 3-yr OS rates converged (P = .467) with all pts crossed over to low dose Successful stem cell harvesting in 97.6% (n = 167) 3-yr OS for high dose or low dose followed by SCT: 92% Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37. Len + High or Low-Dose Dex (E4A03): Adverse Events Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37. Lenalidomide Dosing for MM and Impaired Renal Function Lenalidomide [package insert]. Peripheral Neuropathy Following Bortezomib Therapy in Advanced MM Peripheral neuropathy was reported in 90/256 (35%) patients with MM treated with bortezomib in phase II trials 80% of patients entered these trials with preexisting peripheral neuropathy 3% patients without vs 16% with baseline peripheral neuropathy developed grade 3 peripheral neuropathy Richardson PG, et al. ASH 2003. Abstract 512. Frontline Therapy in Elderly MM Patients For elderly patients or those who are not suitable candidates for transplantation, MP has been a standard treatment ORR: 60% Long-term CR: < 5% Trials with MP-based combinations reported improved response rates and time to progression MPT VMP NCCN Practice Guidelines. Myeloma. V.3.2010. Conclusions In elderly patients, the addition of novel agents to standard MP has provided improved response rates MP alone (ORR: 50%; CR: 5%) MPR (50% to 95% reduction in myeloma protein in 55.6%) VMP (ORR: 86%) Care should be taken with IMiD-based therapy to include aspirin prophylaxis for DVT/PE Care should be taken with bortezomib-based regimens to include herpes zoster prophylaxis MM & Skeletal Complications ~ 80% of patients with multiple myeloma will have evidence of skeletal involvement on skeletal survey Vertebrae: 65% Ribs: 45% Skull: 40% Shoulders: 40% Pelvis: 30% Long bones: 25% Dimopoulos M, et al. Leukemia. 2009:1-12. The Central Role of the Osteoclast in Osteolytic Bone Destruction Growth factors Osteoclast differentiation Osteolysis Direct effects on osteoclast differentiation Tumor cells Bone loss Active osteoclast Adapted from Roodman GD. N Engl J Med. 2004;350:1655-1664. Mechanism of Bisphosphonate Inhibition of Osteoclast Activity Bisphosphonates inhibit osteoclast activity, and promote osteoclast apoptosis[1] Bisphosphonates are released locally during bone resorption[1] Bisphosphonates are concentrated under osteoclasts[1] Bisphosphonates may modulate signaling from osteoblasts to osteoclasts New bone X Bone Increased OPG production[2] Decreased RANKL expression[3] 1. Reszka AA, et al. Curr Rheumatol Rep. 2003;5:65-74. 2. Viereck V, et al. Biochem Biophys Res Commun. 2002;291:680-686. 3. Pan B, et al. J Bone Miner Res. 2004;19:147-154. Recommended Doses and Infusion Times *Consider dose reduction . †3.5mg (CrCl 50-60 mL/min); 3.3 mg (CrCl 40-49 mL/min); 3.0 mg (CrCl 30-39 mL/min). Kyle R, et al. J Clin Oncol. 2007;25:2464-2472. Bisphosphonates and Osteonecrosis Uncommon complication causing avascular necrosis of maxilla or mandible Suspect with tooth or jaw pain or exposed bone May be related to duration of therapy True incidence unknown Papapetrou PD. Hormones (Athens). 2009;8:96-110. Normal RANKL/OPG Prevents Promotes Osteoclastic Activity RANKL OPG Hofbauer LC, et al. JAMA. 2004;292:490-495. The RANK/RANKL/OPG Pathway in Osteolytic Bone Disease Prevents Promotes Increased osteoclastic activity and decreased OPG OPG RANKL Adapted from Roodman GD. N Engl J Med. 2004;350:1655-1664. Denosumab: Inhibiting RANK in Bone Disease High affinity human monoclonal antibody that binds RANKL Administered via SC injection Specific: does not bind to TNF-α, TNF-β, TRAIL, or CD40L Inhibits formation and activation of osteoclasts Multiple Myeloma = M-CRAB Monoclonal protein Calcium Renal failure Anemia Bone pain with lytic lesions
Slide 67 - Special Thanks to… For sponsorship of LMEF programs: Supported by an educational grant from Lilly USA, LLC Did you know that you could be receiving credit for attending today? For membership information, please visit our website: www.Lafmeded.org. Multiple Myeloma 2010 Wael Harb MD Horizon Oncology Center Overview Introduction: epidemiology, clinical presentation, diagnosis, staging Autologous stem cell transplantation Initial approaches to treatment Current options Novel agents and combinations Considerations in non-transplantation-eligible patients Prevention of skeletal complications What is MM? Multiple myeloma (MM) is characterized by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. Plasma Cell Multiple Myeloma: Incidence The lifetime risk of getting MM is 1 in 159 (0.63%). 20,180 new cases will be diagnosed in 2010 (11,170 in men and 9,010 in women) 10,650 deaths are expected to occur in 2010 (5,760 in men and 4,890 in women) The 5-year relative survival rate for MM is around 35% Incidence MM occurs in all races and all geographic locations African Americans and blacks from Africa is two to three times the risk in whites Risk is lower in Asians from Japan and in Mexicans Slightly more frequent in men than in women (1.4:1) Age MM is a disease of older adults The median age at diagnosis is 66 years Only 10 percent of patients are younger than 50 years Only 2 percent of patients are younger than 40 years MM: Clinical Presentations Anemia - 73 percent Bone pain - 58 percent Elevated creatinine - 48 percent Fatigue/generalized weakness - 32 percent Hypercalcemia- 28 percent Weight loss - 24 percent, one-half of whom had lost ≥ 9 kg Multiple Myeloma = M-CRAB Monoclonal protein Calcium Renal failure Anemia Bone pain with lytic lesions Immunoglobulin Immunoglobulins SPEP: Normal SPEP: M-protein, M-spike Renal Failure Cast nephropathy (also called myeloma kidney) from light chains Hypercalcemia Light chain amyloidosis Drug-induced renal damage Anemia Normocytic, normochromic anemiais present in 73% at diagnosis and in 97%at some time during the course of the disease This anemia can be related to: Bone marrow replacement Kidney damage Dilution in the case of a large M-protein B12 deficiency in 14% Rouleaux Formation Lytic Bone Lesion MM: PET Scan Extramedullary Plasmacytoma Differential Diagnosis of MM Monoclonal gammopathy of undetermined significance (MGUS) Smoldering multiple myeloma (SMM) Waldenstrom macroglobulinemia Solitary plasmacytoma Primary amyloidosis (AL) POEMS syndrome Metastatic carcinoma Multiple Myeloma All 3 criteria must be met: Presence of a serum or urinary monoclonal protein Presence of clonal plasma cells in the bone marrow or a plasmacytoma Presence of end organ damage felt related to the plasma cell dyscrasia, such as: Increased calcium concentration Lytic bone lesions Anemia Renal failure Smoldering Multiple Myeloma SMM, Asymptomatic Both criteria must be met: Serum monoclonal protein ≥3 g/dL and/or bone marrow plasma cells ≥10 percent No end organ damage related to plasma cell dyscrasia Monoclonal Gammopathy of Undetermined Significance (MGUS) All 3 criteria must be met: Serum monoclonal protein <3 g/dL Bone marrow plasma cells <10 percent No end organ damage related to plasma cell dyscrasia or a related B cell lymphoproliferative disorder POEMS Syndrome Osteosclerotic myeloma Polyneuropathy Organomegaly Endocrinopathy Monoclonal protein Skin changes MM: Evaluation CBC and differential,peripheral blood smear Chemistry:serum calcium, creatinine, albumin, LDH , beta-2 microglobulin, and C-reactive protein Serum protein electrophoresis (SPEP) + IF Quantification of immunoglobulins Urinalysis and a 24-hour urine collection for electrophoresis (UPEP) + IF Serum free monoclonal light chain (FLC) MM Evaluation Serum viscosity should be measured if the M-protein concentration is high Bone marrow aspiration and biopsy with immunophenotyping, conventional cytogenetics, and fluorescence in situ hybridization (FISH) Metastatic bone survey with plain radiographs including the humeri and femoral bones should be performed in all patients. MRI, CT, or PET/CT Bone Marrow Cytogenenetics, Interphase FISH Poor prognosis (median survival 25 months): t(4;14)(p16;q32), t(14;16)(q32;q23), and -17p13 Intermediate prognosis (median survival 42 months): -13q14 Good prognosis (median survival 50 months): all others Staging for MM International staging system (ISS)  Stage I — B2M <3.5 mg/L and serum albumin ≥3.5 g/dL Stage II — neither stage I nor stage III Stage III — B2M ≥5.5 mg/L Median overall survival for patients with ISS stages I, II, and III are 62, 44, and 29 months MM: Treatment Decisions Indications for treatment Risk stratification Eligibility for stem cell transplantation Smoldering (asymptomatic) myeloma Deferral of chemotherapy until progression to symptomatic disease Follow these patients closely, every 3 to 4 months, with serum protein electrophoresis, complete blood count, serum creatinine, and serum calcium Metastatic bone survey should be considered annually because asymptomatic bone lesions may develop MM: Indications for Treatment Anemia (hemoglobin <10 g/dL or 2 g/dL below normal) Hypercalcemia (serum calcium >11.5 mg/dL) Renal insufficiency (serum creatinine>2 mg/dL) Lytic bone lesions or severe osteopenia Extramedullary plasmacytoma MM: RISK STRATIFICATION FISH for detection of t(4;14), t(14;16), and del17p13 Conventional cytogenetics (karyotyping) for detection of del 13 or hypodiploidy The presence of any of the above markers defines high risk myeloma, which encompasses the 25 percent of MM patients who have a median survival of approximately two years or less despite standard treatment Current Frontline Options Conventional chemotherapy Survival ≤ 3 yrs Transplantation Prolongs survival 4-5 yrs Novel agents targeting stromal interactions and associated signaling pathways have shown promise Chng WJ, et al. Cancer Control. 2005;12:91-104. MM: INITIAL THERAPY The initial therapy of patients with symptomatic myeloma varies depending on whether patients are eligible or not to pursue autologous hematopoietic cell transplantation *Thal/dex or dex are additional options especially if immediate response is needed. Clearly not transplantation candidate based on age, performance score, and comorbidity MPT, MPV, Len/dex or clinical trial* Potential transplantation candidate Nonalkylator-based induction x 4 cycles Stem cell harvest Initial Approach to Treatment of MM DETERMINING TRANSPLANT ELIGIBILITY Autologous hematopoietic cell transplantation (HCT) results in superior event-free and overall survival rates when compared with combination chemotherapy All patients should be evaluated at diagnosis for transplant eligibility so that the risks and benefits of autologous HCT can be reviewed with those eligible A minority of patients will be eligible for allogeneic HCT, but the value of allogeneic approaches in myeloma remain investigational NOT Eligible for Autologous HCT Age >77 years Direct bilirubin>2.0 mg/dL (34.2 µmol/liter) Serum creatinine>2.5 mg/dL (221 µmol/liter) unless on chronic stable dialysis Eastern Cooperative Oncology Group (ECOG) performance status 3 or 4 unless due to bone pain New York Heart Association functional status Class III or IV 54 42 Attal M, et al. N Engl J Med. 1996;335:91-97. Child JA, et al. N Engl J Med. 2003;348:1875-1883. 15 30 45 60 25 50 75 100 OS (%) 0 0 High dose Conventional dose Mos 20 40 60 80 25 50 75 100 Survival (%) 0 0 Intensive therapy Standard therapy Mos P = .03 by Wilcoxon test P = .04 by log-rank test Transplantation vs Conventional Chemotherapy Autologous Stem Cell Transplantation Mel 200 mg/m2 standard conditioning regimen Sufficient performance score, and adequate liver, pulmonary, cardiac function needed Higher PR and CR rates than conventional chemotherapy Higher OS and EFS than conventional Rx Advanced age and impaired renal function are, by themselves, not contraindications Attal M, et al. N Engl J Med. 1996;335:91-97. NCCN Practice Guidelines. Myeloma. V.3.2010. Stem Cell Transplantation Key issues Efficacy compared with conventional chemotherapy Timing: early vs delayed Single vs tandem Role of allogeneic and miniallogeneic transplantations Maintenance post-SCT Novel Frontline Options Immunomodulatory drugs (IMiDs) Thalidomide Lenalidomide Proteasome inhibitors Bortezomib Carfilzomib Kyle RA, et al. N Engl J Med. 2004;351:1860-1873. Copyright ©2004. Massachusetts Medical Society. All rights reserved. Proposed Mechanism of Action for Multiple Myeloma Therapies Thalidomide: Proposed Mechanism of Action Proposed mechanisms Inhibition of TNF- Suppression of angiogenesis Increase in cell-mediated cytotoxic effects Modulation of adhesion molecule expression Kyle RA, et al. N Engl J Med. 2004;351:1860-1873. Rajkumar SV, et al. Leukemia. 2003;17:775-779. D’Amato RJ, et al.Proc Natl Acad Sci U S A. 1994;91:4082-4085. Lenalidomide Immunomodulatory derivative of thalidomide More potent than thalidomide in preclinical models Dose-dependent decrease in TNF-α and interleukin-6 Directly induces apoptosis, G1 growth arrest Enhances activity of dexamethasone More favorable toxicity profile than thalidomide Richardson P, et al. Blood. 2003;100:3063. Hideshima T, et al. Blood. 2000;96:2943-2950. Bortezomib: A Reversible Proteasome Inhibitor Chymo- tryptic Site Post- Glutamyl Site Tryptic Site b1 b2 b3 b4 b5 b6 b7 Cross section of  ring Bortezomib Adams J, et al. Invest New Drugs. 2000;18:109-121. Adams J, et al. Bioorg Med Chem Lett. 1998;8:333-338. H N B N H O O OH N N OH Initial Approach to Treatment of MM Clearly not a transplantation candidate MPT, MPV, Len/dex or clinical trial* Potential transplantation candidate Nonalkylator-based induction Stem cell harvest Melphalan/Prednisone/Thalidomide Palumbo A, et al. Blood. 2008;112:3107-3114. Lenalidomide 25 mg/day PO on Days 1-21 + High-dose Dex 40 mg/day PO on Days 1-4, 9-12, 17-20 (n = 223) Lenalidomide 25 mg/day PO on Days 1-21 + Low-dose Dex 40 mg/day PO on Days 1, 8, 15, 22 (n = 222) Len + High or Low-Dose Dex in Newly Diagnosed Myeloma (E4A03) Courses repeat every 28 days ≤ 1 yr in absence of PD or unacceptable toxicity Total Dex dose per cycle: 480 mg Untreated, symptomatic myeloma, no age cutoff Total Dex dose per cycle: 160 mg Rajkumar SV, et al. ASCO 2008. Abstract 8504. Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37 Len + High or Low-Dose Dex (E4A03): Response 3-yr OS rates converged (P = .467) with all pts crossed over to low dose Successful stem cell harvesting in 97.6% (n = 167) 3-yr OS for high dose or low dose followed by SCT: 92% Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37. Len + High or Low-Dose Dex (E4A03): Adverse Events Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37. Lenalidomide Dosing for MM and Impaired Renal Function Lenalidomide [package insert]. Peripheral Neuropathy Following Bortezomib Therapy in Advanced MM Peripheral neuropathy was reported in 90/256 (35%) patients with MM treated with bortezomib in phase II trials 80% of patients entered these trials with preexisting peripheral neuropathy 3% patients without vs 16% with baseline peripheral neuropathy developed grade 3 peripheral neuropathy Richardson PG, et al. ASH 2003. Abstract 512. Frontline Therapy in Elderly MM Patients For elderly patients or those who are not suitable candidates for transplantation, MP has been a standard treatment ORR: 60% Long-term CR: < 5% Trials with MP-based combinations reported improved response rates and time to progression MPT VMP NCCN Practice Guidelines. Myeloma. V.3.2010. Conclusions In elderly patients, the addition of novel agents to standard MP has provided improved response rates MP alone (ORR: 50%; CR: 5%) MPR (50% to 95% reduction in myeloma protein in 55.6%) VMP (ORR: 86%) Care should be taken with IMiD-based therapy to include aspirin prophylaxis for DVT/PE Care should be taken with bortezomib-based regimens to include herpes zoster prophylaxis MM & Skeletal Complications ~ 80% of patients with multiple myeloma will have evidence of skeletal involvement on skeletal survey Vertebrae: 65% Ribs: 45% Skull: 40% Shoulders: 40% Pelvis: 30% Long bones: 25% Dimopoulos M, et al. Leukemia. 2009:1-12. The Central Role of the Osteoclast in Osteolytic Bone Destruction Growth factors Osteoclast differentiation Osteolysis Direct effects on osteoclast differentiation Tumor cells Bone loss Active osteoclast Adapted from Roodman GD. N Engl J Med. 2004;350:1655-1664. Mechanism of Bisphosphonate Inhibition of Osteoclast Activity Bisphosphonates inhibit osteoclast activity, and promote osteoclast apoptosis[1] Bisphosphonates are released locally during bone resorption[1] Bisphosphonates are concentrated under osteoclasts[1] Bisphosphonates may modulate signaling from osteoblasts to osteoclasts New bone X Bone Increased OPG production[2] Decreased RANKL expression[3] 1. Reszka AA, et al. Curr Rheumatol Rep. 2003;5:65-74. 2. Viereck V, et al. Biochem Biophys Res Commun. 2002;291:680-686. 3. Pan B, et al. J Bone Miner Res. 2004;19:147-154. Recommended Doses and Infusion Times *Consider dose reduction . †3.5mg (CrCl 50-60 mL/min); 3.3 mg (CrCl 40-49 mL/min); 3.0 mg (CrCl 30-39 mL/min). Kyle R, et al. J Clin Oncol. 2007;25:2464-2472. Bisphosphonates and Osteonecrosis Uncommon complication causing avascular necrosis of maxilla or mandible Suspect with tooth or jaw pain or exposed bone May be related to duration of therapy True incidence unknown Papapetrou PD. Hormones (Athens). 2009;8:96-110. Normal RANKL/OPG Prevents Promotes Osteoclastic Activity RANKL OPG Hofbauer LC, et al. JAMA. 2004;292:490-495. The RANK/RANKL/OPG Pathway in Osteolytic Bone Disease Prevents Promotes Increased osteoclastic activity and decreased OPG OPG RANKL Adapted from Roodman GD. N Engl J Med. 2004;350:1655-1664. Denosumab: Inhibiting RANK in Bone Disease High affinity human monoclonal antibody that binds RANKL Administered via SC injection Specific: does not bind to TNF-α, TNF-β, TRAIL, or CD40L Inhibits formation and activation of osteoclasts Multiple Myeloma = M-CRAB Monoclonal protein Calcium Renal failure Anemia Bone pain with lytic lesions Thank you