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Relapse Myeloma

Jun 01, 2015



  • 1. Optimizing treatment for relapsed myeloma July 2004 Myeloma 101 M.L.Gray

2. July 2004 Myeloma 101 M.L.Gray Current Treatment Goals Cures are possible but should not be the overarching goal 30% of CRs can last 10% or more Aim for long term complete remission Preserve quality of life Reduce fatigue Control pain Protect from infections Improve ADLs / Performance Status 3. Multiple Myeloma Treatment Lines in Transplant- Eligible Patients Current Paradigm Induction Consolidation Frontline treatment Risk Stratification? Maintenance Maintenance Rescue Relapsed Alkylators Steroids Thalidomide Lenalidomide Bortezomib Anthacyclines e SCT Thalidomide Steroids Bortezomib Lenalidomide Alkylators Steroids Thalidomide Bortezomib Anthacyclines Carfilzomib Pomolidomide Bendamustine National Comprehensive Cancer Network. The NCCN Clinical Practice Guidelines in Oncology Multiple Myeloma (Version 1.2011). Accessed October 13, 2010. 4. Patient Case 65-year-old male presents with anemia Initial workup: hemoglobin = 9.5, normal CBC and platelets Patient is referred to a local hematologist, an extensive workup finds IgG kappa protein (3.5 g/dL) with reciprocal depression of the other immunoglobulins, negative UPEP 40% plasma cells in the bone marrow with normal cytogenetics by standard chromosomal analysis and del13 by FISH Diffuse lytic disease 2-microglobulin = 3.9, albumin = 3.7 UPEP, urine protein electrophoresis. 5. Patient Case Continued He begins induction therapy with thalidomide / bortezomib / dex (VTD) After 2 cycles he develops paresthesia not interfering with his function After 4 cycles he achieves a PR (75% reduction) Stem cells are collected and he receives a single ASCT He achieves a CR post-ASCT and declines maintenance therapy at day 100 He continues to experience grade 1 peripheral neuropathy 15 months after his stem cell transplant, he has a clinical relapse including new lytic lesions ISS, international staging system; dex, dexamethasone; PR, partial response; ASCT, autologous stem cell transplant; CR, complete response. 6. Natural History of Relapse 7. Types of Relapse Alegre A et al. Haematologica 2002;87(6):609-614. 8. 88 Multiple Myeloma Expectations for Survival After Relapse Survival as a Function of Era-SCT Patients 9. Which of the following should NOT be considered when developing a re-treatment plan? Age Prior Therapy Type of relapse Duration of remission Comorbidities 10. Factors in Selecting Salvage Therapy DISEASE-RELATEDDISEASE-RELATED DOR to initial therapyDOR to initial therapy FISH / cytogeneticsFISH / cytogenetics REGIMEN-RELATEDREGIMEN-RELATED Prior drug exposurePrior drug exposure Toxicity of regimenToxicity of regimen Mode of administrationMode of administration Previous SCTPrevious SCT PATIENT-RELATEDPATIENT-RELATED Pre-existing toxicityPre-existing toxicity Co-morbiditiesCo-morbidities AgeAge Performance statusPerformance status DOR, duration of response; FISH, fluorescent in situ hybridization; SCT, stem cell transplant.Lonial S. ASH Education Book. 2010;303-309. Stage generally does not influence salvage therapy choice. 11. Relapse Approaches Lonial S, et al. Clin Cancer Res. 2011;17:1264-1277. Bz, bortezomib; PN, peripheral neuropathy; len, lenalidomide; thal, thalidomide; CT, chemotherapy; SCT, stem cell transplant; PS, performance status. LENALIDOMIDE-BASEDLENALIDOMIDE-BASED Initial therapy with bzInitial therapy with bz Underlying PNUnderlying PN BORTEZOMIB-BASEDBORTEZOMIB-BASED Initial therapy len / thalInitial therapy len / thal Long DOR with prior bzLong DOR with prior bz Renal dysfunctionRenal dysfunction TRANSPLANTTRANSPLANT No previous SCTNo previous SCT Long remission post-SCTLong remission post-SCT CONSIDER CLINICAL TRIAL WITH A NOVEL AGENT EARLY CT-BASEDCT-BASED DCEP vs DT-PACEDCEP vs DT-PACE Oral vs IV CTOral vs IV CT PS plays an important rolePS plays an important role CT + NOVEL AGENTCT + NOVEL AGENT Combinations of lenCombinations of len and / or bz with otherand / or bz with other agentsagents SCT-BASEDSCT-BASED Likely to be short-livedLikely to be short-lived Quick disease controlQuick disease control Reconstitute marrowReconstitute marrow ? AGGRESSIVE, RAPID, OR MULTIPLE RELAPSE Consider combination therapy. Dont wait for symptomatic relapse. 12. Patient Case Continued 15 months after his stem cell transplant, he has a clinical relapse including new lytic lesions Treat or not Yes, symptomatic relapse Single or Combo Lets look at the data Retransplant? Lets look at the data ISS, international staging system; dex, dexamethasone; PR, partial response; ASCT, autologous stem cell transplant; CR, complete response. 13. Clinical Considerations for Relapsed/Refractory Disease Disease characteristics/prior therapy Aggressiveness of relapse Relapsed or relapsed and refractory disease High risk disease Prior therapies (eg SCT, prior IMiD, bortezomib-based therapy) Toxicity considerations Peripheral neuropathy Thrombotic risk Myelosuppression Impact of prior therapies (eg, SCT, other cumulative toxicity) 14. How do we treat a patient in first relapse? Sequencing of therapy is important Issues Treat or Not to Treat Single Agent vs Combinations 15. Classes of Drugs With Anti-MM Activity Steroids Immuno- modulatory Agents Proteasome Inhibitors Cytotoxic CT HDAC inhibitors mTOR inhibitors mAbs Prednisone Thalidomide Bortezomib Melphalan Vorinostat Perifosine Elotuzumab Dexa- methasone Lenalidomide Carfilzomib Cyclophos- phamide Panobinosta t Pomalidomide MLN9708 PLD ONX 0912 DCEP Marizomib BCNU CEP-18770 Benda- mustine 16. Novel Agents as Monotherapy Without Steroids Regimen Phase n CR + PR CR + nCR Reference Bortezomib (APEX) 3 331 43% 16% Richardson, et al. Blood. 2005;106 (abstract 2547) Thalidomide 2 712 28.2% 1.6% Prince, et al. Leuk Lymphoma. 2007;48:46 1629 29.4% 1.6% Glasmacher, et al. Br J Haematol. 2006;132:584 Lenalidomide 2 102 17% 4% Richardson, et al. Blood. 2006;108:3458 Proteasome inhibitor bortezomib has the best single agent activity 17. Thal + Dex vs. Combination Chemotherapy PFS median 17 vs.11 months OS at 3 years 60% vs.26% First Relapse N PFS OS at 3 years Thalidomide + Dexamethasone 62 17 months 60% Combination Chemotherapy 82 11 months 26% Palumbo A, et al. Hematol J. 2004;5:318-324. THAL 100 mg/day and DEX 40 mg (days 14 of each month) CC: MP, VAD, intermed dose Cytoxan, VMCP-VBAP Second Relapse N PFS OS at 3 years Thalidomide + Dexamethasone 58 11 months 19 Combination Chemotherapy 38 9 months 19 18. Pooled Analysis of MM-009 and MM-010 Data: Response, TTP and OS According to Number of Prior Therapies *EBMT Criteria PR (>50%) CR (IF-) PR + CR ResponseRate(%) 0 20 40 60 65%* Len/Dex n=124 26% Dex n=124 20% Dex 58%* Len/Dex 80 n=229 n=227 1 Prior Therapy 2 Prior Therapies* P62% of HD dexamethasone patients crossing over to bortezomib 1-year survival rate: 80% vs. 67%; P=.0002 P=.0272 Time (Days) Dexamethasone Bortezomib 0 180 270 360 45090 540 720 810 900 990630 1080 1170 29.8 months Richardson PG, et al. Blood. 2007;110:3557-3560. 23. 23 Bortezomib Combination Therapies in Relapse Author/Year N Regimen Overall Response Rate (%) CR/nCR Rate (%) Median PFS (mos) Median OS (mos) Pineda-Roman/2008 85 BTD 63 22 22 Jakubowiak/2005 20 BD + PLD 56 33 Biehn/2007 22 B + PLD 63 36 9.3 (TTP) 38.3 Popat/2005 22 B + Iv Mel +/- D 43 5 6.8 (TTP) Palumbo/2007 30 V Mel PT 67 17 61% (1 yr) 84% (1 yr) Reece/2008 37 B + Cy + P 95 54 >12 >12 B = bortezomib; T = thalidomide; D = dexamethasone; PLD = pegylated liposomal doxorubicin; Mel = melphalan; P = prednisone; Cy = cyclophosphamide; PFS = progression-free survival; nCR = near complete response. Kaufman J et al. Curr Hematol Malig Rep. 2009;4:99-107. 24. 24 Lenalidomide Combination Therapies in Relapse Author/Year N Regimen Overall Response Rate (%) CR/nCR Rate (%) Median PFS Median OS Schey/2009 31 LCD 81 36 (VGPR) Knop/2009 66 LDoD 73 15 40 weeks 88% (1 year) Reece/2009 15 LCP 74 45 (VGPR) Baz/2006 52 L PLD ViD 75 29 (nCR) 1 year 84% (1 year) Richardson/2009 35 LBV+/- D 60 >MR 8 7.7 months 37 months Anderson/2009 62 LBVD 69 26 12 months 29 months L = lenalidomide; C = cyclophosphamide; D = dexamethasone; DO = doxorubicin; P = prednisone; PLD = pegylated liposomal doxorubicin; Vi = vincristine; B = bortezomib. Schey S et al. ASH 2008 Annual Meeting. Abstract 3707; Knop S et al. Blood. 2009;113:4137-4143; Reece DE et al. ASH 2009 Annual Meeting. Abstract 1874; Baz R et al. Ann Oncol. 2006;17:1766-1771; Richardson PG et al. J Clin Oncol. 2009;27:5713-5719; Anderson KC et al. 2009 ASCO Annual Meeting. Abstract 8536. 25. Main Randomized Trials of TreatmentMain Randomized Trials of Treatment of Relapsed/Refractory MMof Relapsed/Refractory MM ORR = overall response rate; CR = complete response; TTP = time to progression; NR = no response. Richardson et al, 2007; Orlowski et al, 2007; Weber et al, 2007; Dimopoulos et al, 2007. 26. Additional Bortezomib and Lenalidomide Combinations Study Regimen N Responses Frequent G3/4 AEs Kropff, et al1 VCD 50 16% CR 66% PR TCP, leukopenia, infection, PN, HZV, fatigue, anemia, hypotension Morgan, et al2 CVD 47 31% CR 75% ORR TCP, neutropenia, PN, infection Reece, et al3 VCP 37 >50% CR 95% ORR Nausea, TCP, neutropenia Baz4 Len + PLD 62 29% CR/nCR 75% ORR Myelosuppression 1 Kropff M, et al. Br J Haematol. 2007;138:330-337. Comment in: Br J Haematol. 2008;140:115-116. 2 Davies FE, et al. Haematologica. 2007;92:1149-1150. 3 Reece DE, et al. J Clin Oncol. 2008;26:4777- 4783. 4 Baz R, et al. Ann Oncol. 2006;12:1766-1771. 27. PUTTING IT ALL TOGETHERPUTTING IT ALL TOGETHER 28. 28 Indolent, Slow, First Relapse Initial Tx with Bz May consider single agent w/o Dex Underlying PN IMiD-Based Salvage Lenalidomide Thalidomide Likely Single-Agent Therapy With Bz or Len/Thal Bortezomib-Based Sa