Top Banner

Click here to load reader

of 72

Relapse Myeloma

Jun 01, 2015

ReportDownload

spa718

  • 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). http://www.nccn.org/. 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 4.79.64.714.5* 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