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Slide 1 - Multiple Myeloma Case studiesUKMF Education Day November 2011 Kwee Yong Cancer Institute University College London
Slide 2 - Case 1 : Lynne 36 year old business manager June 2010: fatigue & nosebleeds Hb 8.8g/dL, WBC 2.8 x 109/L, Neuts 0.9, plts 198 IgG 79g/L, pp = 61 Creatinine 109umol/L, normal Ca++ Albumin 33g/L, b2m 3.7mg/L (ISS Stage 2) BMT: 80% plasma cells, CD56+, cyclin D1+ FISH: t(11;14) SS: no lytic lesions, MRI spine: no focal lesions
Slide 3 - Several karytopic abnormalities Case 1: Lynne
Slide 4 - July 2010: CTD & zometa (sibling match) Neutropenia after one dose Cyclo Thal/Dex Poor tolerance: dizziness, bradycardia (45-50/min) Pp 46, then 53 Case 1: Lynne What would you do now?
Slide 5 - Case 1: Decision point 1 Continue with Dexamethasone alone Switch to Velcade and Dexamethasone Continue with Cyclophosphamide and dexamethasone with growth factor support Stop treatment to allow bone marrow recovery
Slide 6 - July 2010: CTD & zometa (sibling match) Neutropenia after one dose Cyclo Thal/Dex Poor tolerance: dizziness, bradycardia (45-50/min) Pp 46, then 53 Case 1: Lynne August 2010: Velcade/Dex 3 cycles Stable disease Grade 1 PN What would you do now?
Slide 7 - Case 1: Decision point 2 Continue with Velcade and Dexamethasone for further 2-3 cycles as tolerated Switch to Revlimid and Dexamethasone Add Revlimid to Velcade and Dexamethasone Arrange mobilisation and PBSCH
Slide 8 - Revlimid 10mg od days 1-14, with velcade 1.3g/m2 and dex After 14 days, neutrophils 0.6 Prolonged neutropenia Transfusions Case 1 : Lynne What would you do now?
Slide 9 - Case 1: Decision point 3 Wait for bone marrow recovery and try again with RVD Switch to Revlimid and Dexamethasone ESHAP with PBSCH Proceed to allogeneic transplant
Slide 10 - Case 1: Lynne What would you do now?
Slide 11 - Case 1: Decision point 4 Salvage regimen prior to ASCT Proceed to allogeneic transplant Proceed to ASCT Clinical trial of new agent
Slide 12 - ASCT Jan 2011 (27 weeks after diagnosis): pp 42 ASCT 14.01.2011 5 week admission Fever day -1 Grade 3/4 mucositis: diarrhoea++, nausea, dehydrated Hypokalaemia induced DI: polyuria, polydipsia Neut engraftment day +12 Discharged day +33 Case 1: Lynne
Slide 13 - Case 1: Lynne BM 3% PC VGPR What would you do now?
Slide 14 - Case 1: Decision point 5 Nothing Reduced intensity sibling allograft (LenaRIC study) Maintenance with lenalidomide Maintenance with thalidomide
Slide 15 - Case 1: issues Primary refractory MM Discordance in prognostic information between FISH and karyotype Sibling match – when to allograft? Case for tandem sib RIC allo? Poor tolerance of chemotherapy Toxicity of conditioning
Slide 16 - Case 2: Joanna 49 year old charity worker June 2010 ‘blocked ear’ for 2 mo Sudden onset diplopia and numbness R face 4 days Right 6th nerve palsy MRI head: large irregular tumour arising from clivus and R sphenoid, invading cavernous sinus CT scan: rib lesions, T5 lesion invading canal, large sacral mass, sternal mass, L iliac lesion, breast lump
Slide 17 - R L Case 2: Joanna
Slide 18 - Immune paresis Urine protein: 2g/24 hr SFLC: kappa 4720mg/L BMT: 80% plasma cells, cyclin D1+, CD56- FISH: IgH split, 17p loss in all cells CT-PET: FDG avid lesions manubrium, R iliac bone, R base of skull, T5 Case 2: Joanna Case 2: Joanna
Slide 19 - Case 2 : Decision point 1How would you manage this patient? Urgent DXT to base of skull Treat with CTD Use high grade NHL protocol with CNS treatment Velcade and dexamethasone
Slide 20 - LP: no cells, methotrexate High dose dexamethasone Velcade, Idarubicin & Ara-C (June 2010) Clinical response, MRI improvement, KLC 79mg/L July 2010: Ida-Ara-C no.2 with Velcade/dex Neutropenic fever, klebsiella septicaemia Hypoxia, severe mucositis Case 1: Joanna Case 2: Joanna Case 2: Joanna
Slide 21 - Velcade / dexamethasone no.3 Re-staging MRI: good response to treatment PET-CT scan: new FDG-avid lesions in liver and spleen, previous lesions resolved BM: CR, KLC 1.7mg/L, urine: IF neg for BJP Case 2: Joanna
Slide 22 - Biopsy liver lesions x 3!! Fibrosis with inflammatory cells Rx: posaconazole 3 mo Velcade / Dexamethasone no.4 Cyclo-G-CSF prime and PBSC harvest Repeat CT scan: lesions unchanged Case 2: Joanna What would you do now?
Slide 23 - Case 2: Decision point 2 Assume liver lesions disease and treat with Revlimid and dexamethasone Attempt further biopsy of liver Continue posaconazole and re-scan Proceed with ASCT
Slide 24 - 25 Feb 2011: Melphalan 140 / TBI 12 Gy in 6 fractions ASCT in ambulatory care Fever day +8, resistant E Coli, PICC line out Engrafted day +12, discharged day +15 May 2011: BM clear, SFLC normal, CT abdo: lesions smaller MRI head Case 2: Joanna Case 2: Joanna
Slide 25 - Case 2: repeat imaging What would you do now?
Slide 26 - Case 2: Decision point 3 Consolidation DXT to base of skull Do nothing Maintenance with thalidomide (lenalidomide) Search for donor (MUD RIC-allo, -LenaRIC?) Case 2: Joanna 30 Gy DXT to base of skull in 15 fractions Watch and wait
Slide 27 - Case 3: Lenny 45 yr old warehouse supervisor Aug 2011: Back pain since Dec 2010 Anorexia and weight loss Unsteady walking “Numb balls” Sluggish bowels, urinary hesitancy Pain radiating down legs, walking with sticks Case 3: Lenny
Slide 28 - Case 3: Lenny
Slide 29 - Case 3: Lenny MRI: extensive paravertebral mass T11-L2, extending into soft tissues, and into the spinal canal at L1 compressing the conus Biopsy at Stanmore: Plasma cell tumour
Slide 30 - Dexamethasone 4mg qds BM clear FBC normal, renal function normal SEP small IgAk pp, total IgA 9.8g/L SFLC SS, MRI spine: no other lesions Solitary plasmacytoma Case 3: Lenny Case 3: Lenny
Slide 31 - Case 3: Decision point 1How would you manage this patient? Surgery and decompression Radiotherapy Treat with CTD Treat with velcade and dexamethasone Case 3: Lenny
Slide 32 - Velcade, cyclophosphamide & dexamethasone started within 24 hours Radiotherapy review – on hold Pain decreased, improved mobility Postural drop beginning of cycle 2 Lying 130/75, standing 107/70 asymptomatic Delay 1 week Case 3: Lenny Case 3: Lenny
Slide 33 - MRI after 2 cycles CVD, marked improvement Sensation in groins now normal, perineal parasthesiae persists but better Bowels : grade 1 constipation Bladder function normal IgA reduced from 9.8 to 1.7g/L Case 3: Lenny What would you do now?
Slide 34 - Case 3: Decision point 2 Stop CVD and give radical DXT Continue with CVD Switch to CTD Surgery to stabilise spine Case 3: Lenny
Slide 35 - Spinal plasmacytoma:Radiotherapy, surgical decompression/fixation or systemic treatment? Level of tumour Cervical, thoracic, T-L jn, lumbo-sacral Spinal cord issues: bony or tumour Spinal stability: (bracing?) Presence of disease elsewhere Stage of disease (diagnosis, relapse) Access (clinical oncologists, surgical colleagues)
Slide 36 - Solitary bone plasmacytoma Most (>70%) progress to MM, majority within 2-4 years Risk of progression assoc with persistence of M-band, abnormal SFLC ratio PET-CT scanning may be useful to identify occult disease Relatively indolent disease even after progression, OS 5-10 years
Slide 37 - 55 yr old schoolteacher March 2010: back pain (previous L4/5 vertebrectomy) Hb 6.6g/dl, WBC 2.4, neuts 1.2, Plats 34 SEP: pp 2 g/L, UTP 9 g/L b2microglobulin 9.3mg/L SFLC lambda 5270mg/L Calcium and Renal function normal Case 4: Michael
Slide 38 - BM 90% cyclin D1+ PC, FISH ? Partial p53 loss MRI: diffuse abn BM signal, extraosseus tumour left 6th rib, paravertebral mass at T11/12 No spinal cord issues, neurologically intact Case 4: Michael
Slide 39 - Case 4: Decision point 1How would you treat this patient? CTD Velcade and dexamethasone Urgent radiotherapy to paravertebral mass VAD/Idarubicin & Dex (Myeloma XI, PADIMAC)
Slide 40 - Case 4: Michael What would you do now? FISH: t(11;14) single fusion TP53: deleted in 88% BM
Slide 41 - Case 4: Decision point 2 Add Cyclophosphamide to Revlimid /Dex Proceed with mobilising stem cells ESHAP-type regimen Palliate
Slide 42 - Case 4: Michael What would you do now?
Slide 43 - Case 4: Decision point 3 Do nothing Search for donor for RIC allo Maintenance with thalidomide Consolidation - ? VTD consolidation
Slide 44 - VAD TD VD RD TAD PAD VTD Summary of novel agent induction trials (randomized studies) Post-induction Post-transplant ≥ VGPR rates post-induction and post-transplant Harousseau et al. ASH/ASCO symposium during ASH 2008 Rajkumar et al. ASCO 2008 (Abstract 8504); ASH/ASCO symposium during ASH 2008 Lokhorst et al. Haematologica 2008;93:124–7 Sonneveld et al. ASH 2008 (abstract 653); IMW (abstract 152) Cavo et al. ASH 2008 (abstract 158); IMW 2009 (abstract 451) *Post-transplant data not available 15-16% 30- 35% 39% 33% 45% 62% 42%
Slide 45 - 17p- disease in MM 9-10% at presentation Progression event Associated with Light chain only disease, high ISS stage Prognostic only if in ≥50% plasma cells Very poor outlook IFM study of Vel/Dex, EFS 14 mo vs 36mo
Slide 46 - (A) Event-free survival (EFS) and (B) overall survival (OS) in patients with del(17p) (n = 54) or without del(17p) (n = 453) treated with bortezomib-dexamethasone induction (EFS and OS in years; P < .001 for EFS and OS). Avet-Loiseau H et al. JCO 2010;28:4630-4634 ©2010 by American Society of Clinical Oncology
Slide 47 - Case 5: John 63 year old aircraft engineer Presented with anaemia Diagnosed with IgGk MM Initial treatment with VAMP, minor response CDT x 5 ASCT
Slide 48 - Case 5: John ?
Slide 49 - Case 5: Decision point 1 Palliate Cyclophosphamide and dexamethasone Thalidomide regimen Re-treat with velcade on NHS
Slide 50 - Case 5: John
Slide 51 - Case 5: Decision point 2 Palliate Thalidomide Cyclophosphamide and dexamethasone Clinical trial
Slide 52 - Clinical trials for relapsed MM Bortezomib trials (± HDACi, ±hsp90i, ±mAb) Usually IV velcade 1-3 prior lines Lenalidomide trials (±carfilzomib, ±CS1 mAb) Pomalidomide trials MUK Clinical Trials Network early phase studies Less restriction in no of prior lines Other, eg carfilzomib