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Relapsed Myeloma
 

Relapsed Myeloma

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  • Curatio Fact Check : NCCN Abbrevs Bor/Dex = bortezomib, dexamethasone Bor/Dex/Dox = bortezomib, dexamethasone, doxorubicin Bor/Thal/Dex = bortezomib, thalidomide, dexamethasone Len/Dex = lenalidomide, dexamethasone SCT = stem-cell transplant Thal/pred = thalidomide, prednsione Bor/Liposomal/Dox = bortezomib, liposomal doxorubicin
  • Experimental design: A total of 120 relapsed/refractory patients to one (52%), or two or more (48%) lines of chemotherapy were treated with THAL 100 mg/day (continuous) and DEX 40 mg (days 1–4 of each month). Their clinical outcome was compared to a control group of 120 patients frequency matched for serum b2-microglobulin levels and Durie and Salmon clinical stage. Results: In patients treated after one line of chemotherapy, THAL–DEX significantly improved outcome.Median progression-free survival (PFS) was superior in THAL–DEX group versus CC group (17 months versus 11 months, P¼0.0024). The median survival for THAL–DEX patients has not to been reached, but the probabilities of survival at 3years were 60% after THAL–DEX and 26% after CC (P¼0.0016). The clinical outcome of patients receiving THAL–DEX or CC after two or more lines of chemotherapy, was similar. In the THAL–DEX group, the median PFS was 11 months compared to 9 months in the CC group (P¼NS). No differences in overall survival (OS) were observed (median OS 19 months for both THAL–DEX and CC). Conclusions: As first salvage regimen, THAL–DEX was superior to CC, as second or third salvage regimen, it was equivalent to CC. THAL–DEX is not myelotoxic. It postpones the delivery of effective salvage chemotherapy. This might explain the survival benefit. CC: MP, VAD, intermed dose Cytoxan, VMCP-VBAP
  • Pooled Analysis of MM-009 and MM-010 Data: Response, TTP and OS According to Number of Prior Therapies TTP was longer when lenalidomide/dexamethasone was used at first relapse (median, 14.5 months) than when used later as salvage therapy (median, 9.6 months) These results indicate that lenalidomide/dexamethasone can be used effectively as second-line therapy in patients with relapsed MM Weber DM et al. Presented at: 49th ASH Annual Meeting; December 8–11, 2007; Atlanta, GA
  • Curatio PowerPoint Template 08/22/13 04:23 Curatio Fact Check Graph not provided in abstract; assuming presented at oral session
  • Impact of Prior Thalidomide Therapy: Pooled Analysis of MM-009 and MM-010 Data Pooled data from MM-009 and MM-010 showed that lenalidomide in combination with dexamethasone was more effective than dexamethasone alone in patients with relapsed or refractory MM despite prior thalidomide exposure Results with lenalidomide/dexamethasone were superior for those not exposed to thalidomide, suggesting some (but not complete) cross resistance between lenalidomide and thalidomide Patients who received prior thalidomide had a longer time for diagnosis and more lines of therapy than those who did not receive prior thalidomide Median time from diagnosis (4 yrs. vs. 3 year) Median lines of therapy (3 lines vs. 2 lines) Weber DM et al. Presented at: 49th ASH Annual Meeting; December 8–11, 2007; Atlanta, GA
  • Updated CR + PR: data on file, Millennium Pharmaceuticals, Inc. February 2006. Reference: Sonneveld P, Richardson PG, Schuster MW, et al. Bortezomib at first relapse is superior to high-dose dexamethasone and more effective than when given later in relapsed multiple myeloma. Presented at the 10 th International Myeloma Workshop, April 10-14, 2005, Sydney, Australia. Abstract 721.
  • Curatio PowerPoint Template 08/22/13 04:23 Curatio Fact Check Taken from Richardson et al, pg 3558, figure 1A Median OS values from pg 3558, col 2
  • Comparison of the triple (bortezomib-thalidomide-dexamethasone) and dual (thalidomide-dexamethasone) treatment groups. (A) Cumulative incidence for time to progression; (B and C) Kaplan-Meier plots for progression-free survival and overall survival. HR, hazard ratio (from the stratified Cox model); TD, thalidomide-dexamethasone; VTD, bortezomib-thalidomide-dexamethasone.
  • The outcome was examined over 2-year intervals according to the date of relapse Figure A A progressive improvement in the overall survival from the time of relapse was observed during the past decade Among this patient group, 161 (41%) had at some point after their relapse received bortezomib, thalidomide, or lenalidomide Included 69, 111, and 36 patients, each who had treatment with bortezomib, thalidomide, or lenalidomide, respectively As expected, more patients in the latter years had been exposed to the new drugs as part of salvage treatment regimens This difference remained significant even when the patients were stratified by the time period of relapse. Figure B Exposed to new drugs vrs no exposure The median overall survival for the 161 patients was 30.9 months (95% CI; 23.6, 38.2) The median overall survival was 14.8 months (95% CI; 11.3, 18.4; P < .001) for patients not treated with the novel agents
  • The ORR for patients refractory to their last treatment was 73%
  • The ORR for patients refractory to their last treatment was 73%
  • Investigator-designated infusion reactions: Periorbital edema: 1 (1.4%) Nausea: 2 (2.7%) Abdominal pain: 1 (1.4%) Pyrexia: 3 (4.1%) Chest discomfort: 1 (1.4%) Chills: 1 (1.4%) Pain: 1 (1.4%) Lung disorder: 1 (1.4%) Hyperhidrosis: 1 (1.4%) Rash: 1 (1.4%) Rash maculo-papular: 1 (1.4%) Flushing: 1 (1.4%) Hot flush: 1 (1.4%)

Relapsed Myeloma Relapsed Myeloma Presentation Transcript

  • Optimizing treatment for relapsed myeloma July 2004 Myeloma “101” M.L.Gray
  • July 2004 Myeloma “101” M.L.Gray Current Treatment Goals  Cures are possible but should not be the overarching goal  30% of CR’s 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
  • 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.
  • 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 • β2-microglobulin = 3.9, albumin = 3.7 UPEP, urine protein electrophoresis.
  • 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.
  • Natural History of Relapse
  • Types of Relapse Alegre A et al. Haematologica 2002;87(6):609-614.
  • 88 Multiple Myeloma Expectations for Survival After Relapse Survival as a Function of Era-SCT Patients
  • Which of the following should NOT be considered when developing a re-treatment plan? • Age • Prior Therapy • Type of relapse • Duration of remission • Comorbidities
  • 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.
  • 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. Don’t wait for symptomatic relapse.
  • 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.
  • 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)
  • How do we treat a patient in first relapse? Sequencing of therapy is important Issues Treat or Not to Treat Single Agent vs Combinations
  • 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
  • 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
  • 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 1–4 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
  • 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* P<0.05 27.333.333.639.1 Median TTP (months) Median OS (months) Weber DM, et al. Presented at: 49th ASH Annual Meeting; December 8–11, 2007; Atlanta, GA.
  • Pooled Analysis of MM-009 and MM-010 Data: Updated OS 0 10 20 30 40 50 0 20 40 60 80 100 Overall Survival (Months) Patients(%) *P value from log-rank test (patients analyzed for extended follow-up remained in original groups despite crossover) Weber D, et al. Blood (ASH Annual Meeting Abstracts) 2007;110:412. Survival Benefit Retained Despite 47% Crossover P=0.015* Plac/Dex Median, 31 months Len/Dex Median, 35 months (58% remain alive)
  • Impact of Prior Thalidomide Therapy: Pooled Analysis of MM-009 and MM-010 Data 7.15020Refractory (PD) 7.04531SD 7.04354Progressed (CR/PR) 8.354127Prior Thal 13.865226Thal Naïve Median TTP, months ORR (≥PR), % n Thal Naïve vs. Thal Exposed Median Time from Diagnosis: 2.8 years vs. 4.0 years (P<.05) Median Lines of Prior Therapy: 2 vs. 3 (P<.05) Weber DM, et al. Presented at 49th ASH Annual Meeting; December 8-11, 2007; Atlanta, GA.; Weber DM, et al. N Engl J Med. 2007;357:2133-2142.; Dimopoulos M, et al. N Engl J Med. 2007;357:2123-2132.
  • APEX: Bortezomib Early vs. Late Relapse Bortezomib 1 prior therapy n = 132 > 1 prior therapy n = 200 Median TTP (months) 7.0 4.9 CR (%) 10%* 7%† CR + PR (%) 51%* 37%† Median Duration of Response (months) 8.1 7.8 1-year Survival 89% 73% * Evaluable patients, response to bortezomib after 1 prior therapy: n = 128 † Evaluable patients, response to bortezomib after >1 prior therapy: n = 187 Sonneveld P, et al. Haematologica. 2005;90:146-147. Abstract P140.721.; Data on file; Millennium Pharmaceuticals, Inc.
  • Updated APEX Results OS ProportionofPatients 23.7 months 0.0 0.2 0.4 0.6 0.8 1.0 • Superior survival despite >62% 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 Bortezomib Combination Therapies in Relapse Author/Year N Regimen Overall Response Rate (%) CR/nCR Rate (%) Median PFS (mos) Median OS (mos) Pineda-Romané/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 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.
  • 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.
  • 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.
  • PUTTING IT ALL TOGETHERPUTTING IT ALL TOGETHER
  • 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 Salvage Transplant-Based Salvage • Initial Tx with IMiD • Previous Bz therapy but good or long response • Renal dysfunction • Transplant not part of initial therapy • Long remission post transplant PN = peripheral neuropathy. Lonial S et al. Clin Cancer Res. 2011;17:1264-1277. Permission requested.
  • 29 Aggressive, Rapid, Multiple Relapse • DCEP vs DT-PACE • Oral vs IV chemo • PS of patient plays important role Chemotherapy-Based Salvage Likely Combination Therapy Do Not Wait for Symptomatic Relapse Chemotherapy + Novel Agent Transplant-Based Salvage • Combinations of Len/Bz and other chemo agents • Likely to be short lived • Quick disease control • Reconstitute marrow PS = performance status. Lonial S et al. Clin Cancer Res. 2011;17:1264-1277. Permission requested.
  • Comparison of the triple (bortezomib-thalidomide-dexamethasone) and dual (thalidomide- dexamethasone) treatment groups. Garderet L et al. JCO 2012;30:2475-2482 ©2012 by American Society of Clinical Oncology
  • 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 – I would use combination • VTD • VRD • Carfilzomib based • DTPace if LDH elevated • Retransplant – Difficult question if transplant naïve definitively yes. ISS, international staging system; dex, dexamethasone; PR, partial response; ASCT, autologous stem cell transplant; CR, complete response.
  • Patient Case Continued • Receives VTD x 12 months and is placed on low dose thalidomide maintenance. Within 2 months has new lytic lesions and increasing paraprotein peak. • Treat or not? • Single or Combo? • Retransplant? ISS, international staging system; dex, dexamethasone; PR, partial response; ASCT, autologous stem cell transplant; CR, complete response.
  • Response Duration Decreases With Successive Therapies • 578 patients; median age 65 years (follow up 55 months) • Overall survival – One year 72% – Two years 55% – Three years 22% • 84% died within five years Figure 3. Duration of response to each treatment 0 2 4 6 8 10 12 1 2 3 4 5 6 Treatment number Medianresponse duration(months) Kumar SK, et al. Mayo Clin Proc. 2004;79:867-874.
  • Kumar SK, et al. Bone Marrow Transplant. 2008;42:413-420. Time to Progression After SCT Correlates With OS After Initial Relapse
  • Overall survival from time of relapse after ASCT- Impact of New Agents as Salvage Therapy Kumar SK, et al. Blood. 2008;111:2516-2520. 30.9 months (95% CI; 23.6, 38.2 14.8 months (95% CI; 11.3, 18.4
  • Recurrent Myeloma • 45-year-old woman • κ light chain multiple myeloma diagnosed January 2001 – Durie-Salmon Stage IIIA, ISS Stage 2 • Laboratory findings – Total proteinuria 5.82 g/day – Bence Jones protein (BJP) 3.6 g/day – Hypogammaglobulinemia – Albumin 3.9 g/dL – β2-microglobulin 4.7 mg/L
  • Recurrent Myeloma • Bone marrow biopsy – Cellularity 80% with 25% plasma cells – Cytogenetics 46, XX, inversion 9 (p11;q13) • FISH not done • Skeletal survey: extensive lytic bone disease with healing fractures of left 7th and the 8th ribs • MRI of the spine: diffuse hyperintense homogenous signal on STIR sequence • MRI of the pelvis: diffuse marrow infiltrative changes due to myeloma
  • Recurrent Myeloma • Treatment – Vincristine 0.4 mg, doxorubicin 9 mg/m2 Days 1-4; dexamethasone 40 mg Days 1-4, 9-12, 17-20; x 4 cycles – Followed by high-dose melphalan and stem cell transplant on July 11, 2001 • Achieved complete remission • Maintained on pamidronate and prednisone x 1 year
  • First Relapse Five Years Later • First relapse January 11, 2006 – Urine total protein 550 mg/day – Creatinine clearance 84 mL/minute – BJP 100 mg/day – Urine IFE free κ light chain – Serum free κ 750 mg/L – Free λ 15 mg/L – κ:λ ratio 50 – Multiple new lytic lesions of the skull • MRI spine and pelvis January 11, 2006 – New focal lesion at L3 vertebral body
  • Second Relapse After Failure of IMiDs • Treated with thalidomide and weekly dexamethasone for 6 months → stable disease • Switched to lenalidomide and weekly dexamethasone x 3 months → stable disease
  • Third Relapse 18 Months Later • Treated with bortezomib and dexamethasone x 4 cycles • Achieved CR • Painful peripheral neuropathy grade 2 • Discontinued treatment December 2006 • PET/CT June 2008 – 1 cm focal hypermetabolic area in the inferior aspect of the left scapula – 2.2 cm focal hypermetabolic area in the region of right posterior superior iliac spine, with associated lytic changes • Laboratory findings – Free κ 117 mg/L – Free λ 15.6 mg/L – κ:λ ratio 7.5 – Urine total protein 182 mg/day – BJP 60 mg/day – Urine immunofixation electrophoresis: free κ • Treated with VRD with progressive disease CTC=common toxicity criteria
  • Definition of Relapsed/Refractory MMDefinition of Relapsed/Refractory MM  Relapsed – Relapse off therapy  Relapsed/Refractory – Relapse while on, or within 60 days of discontinuing, therapy – Unmet medical need • Lack of drug approval for relapse/refractory to IMiD, bortezomib, alkylators, anthracyclines, and steroids IMiD = immunomodulatory drugs. Anderson et al, 2008.
  • 43 Kumar SK et al. Leukemia. 2012;26:149-157. Once Treatment Fails, Trouble Begins Kumar S. Mayo Clin Proc. 2004;79:867-874. Overall Survival From Start of Therapy by Regimen Number 00.20.40.60.81.0 0 2 4 6 8 10 CumulativeProbability(%) Years From Start of Regimen Regimen 1 Regimen 2 Regimen 3 Regimen 4 Regimen 5 Regimen 6 0 20 40 60 80 100 0 12 24 36 48 60 Months From Time Zero Survival with Bz/Len Refractory Ds Overall Survival 173/231 9 (7, 11) Event-Free Survival 222/291 5 (4, 6) Events/N Median (Months) Survival(%)
  • Newer agents 44
  • 45 Bortezomib (reversible) Carfilzomib (irreversible) CEP 18770 (reversible) MLN9708 (reversible) NPI-0052 (irreversible) β1 Post- glutamyl Tryptic Chymo- tryptic NP I β2 β3 β4 β5 β6 β7 NP I NP IPost- glutamyl Tryptic Chymo- tryptic β3 β4 β5 β6 β7 Bortezomib β1 Comparison of Proteasome Inhibitors
  • 46 Study 004: Phase 2 Trial of Single-Agent Carfilzomib in Relapsed/Refractory Multiple Myeloma • Primary endpoint: ORR (CR + IVGPR + PR [IMWG criteria]) • Secondary endpoints: CBR (ORR + MR [EBMT criteria]), DOR, PFS, TTP, OS, safety – OS, TTP, response rate (EBMT criteria), safety *Results for bortezomib (BOR)-treated cohort have been reported previously (Vij R et al. J Clin Oncol. 2010. Abstract 8000). † Subjects who enrolled under amended protocol allowing dose increase to 27 mg/m2 or who re-consented before Cycle 4 start were grouped in Cohort 2. Study population (N = 165) • Measurable disease • Responsive to ≥1 prior therapy • Relapsed and/or refractory MM following 1-3 prior treatment regimens • ECOG PS 0-2 Carfilzomib IV qd x 2 for 3 weeks (28-day cycle for up to 12 cycles) Cohort 1 20 mg/m2 Cohort 2† 20 mg/m2 cycle 1 Escalation to 27 mg/m2 in all subsequent cycles BOR-treated* (n = 35) BOR-naive (n = 59) BOR-naive (n = 70) Vij R et al. ASH 2011 Annual Meeting. Abstract 813.
  • Bortezomib-naïve patients (Wang, et al) N = 59 Bortezomib-treated patients (Siegel, et al) N = 35 Evaluable patients 54 33 Complete response 1 (2%) 1 (3%) Very good partial response 5 (9%) 1 (3%) PR/MR/SD 35%/15%/22% 12%/12%/39% Duration of response (≥ PR) 8.4 months 10.6 months Treatment-emergent peripheral neuropathy Grade 1/2: 12% Grade 3: 2% Grade 1/2: n = 3 (9%) Grade 3: n = 1 (3%) Results of the PX-171-004 Phase II Trial – Carfilzomib in Relapsed and/or Refractory MM Wang L, et al. Blood (ASH Annual Meeting Abstracts). 2009;114:302. Siegel D, et al. Blood (ASH Annual Meeting Abstracts). 2009;114:303.
  • 48 Median, months Cohort 1 20 mg/m2 (n = 59) Cohort 2 20/27 mg/m2 (n = 67)* Duration of response n = 25 n = 35 Median, (95% CI) 13.1 (7.2-NE) NR (NE-NE) Duration of clinical benefit response n = 35 n = 43 Median, (95% CI) 11.5 (6.2-NE) NR (NE-NE) Time to progression n = 59 n = 67 Median, (95% CI) 8.3 (6.0-12.3) NR (11.3-NE) Time to response n = 25 n = 35 Median, (min, max) 1.0 (0.5, 3.7) 1.9 (0.5, 3.7) Time to clinical benefit response n = 35 n = 43 Median, (min, max) 0.5 (0.5, 6.5) 0.5 (0.5, 5.9) Single-Agent Anti-Tumor Activity: Bortezomib-Naive Response-Evaluable Population by Cohorts *3 patients were not evaluable for response as they did not have either baseline or post-baseline assessment. NE = not estimable; NR = not reached. Vij R et al. ASH 2011 Annual Meeting. Abstract 813.
  • 49 Progression-Free Survival: Response Evaluable Population Vij R et al. ASH 2011 Annual Meeting. Abstract 813.
  • 50 Overall Survival: Response Evaluable Population Vij R et al. ASH 2011 Annual Meeting. Abstract 813.
  • 51 Pomalidomide Summary Study N Regimen Median Prior Therapies ORR (%) MR (%) Richardson et al1 38 Pom (2-5 mg daily for 21/28 days) ± dex 6 25 50 120 Pom (4 mg daily for 21/28 days) ± dex 5 25 38 Lacy et al2 35 Pom (2 mg daily) + low-dose dex 6 26 49 35 Pom (4 mg daily) + low-dose dex 6 28 43 Leleu et al3 43 Pom (4 mg 21/28 days) + low-dose dex 4 18 NR 41 Pom (4 mg 21/28 days) + low-dose dex 4 16 NR Pom = pomalidomide; dex = low-dose dexamethasone; ORR = overall response rate; MR = marginal response. 1. Richardson P et al. ASH 2010 Annual Meeting. Abstract 864. 2. Lacy MQ et al. Blood. 2011;118;2970-2975. 3. Leleu X et al. ASH 2010 Annual Meeting. Abstract 859.
  • 52 Pomalidomide: Previous Phase 2 Studies in RRMM Study Phase N Pom. schedule Treatment Population Prior Lines* ORR (≥ PR) (%) Richardson et al1 2 221 21/28 Pom: 4 mg vs Pom 4 mg + Dex Len & Bort refractory 5 13 vs 34 Lacy et al2 2 34 28/28# Pom: 2 mg Dex: 40 mg/week Len refractory 4 32 Lacy et al3 2 70 28/28* Pom: 2 and 4 mg Dex: 40 mg/week Len & Bort refractory 6 25 and 29 Len = lenalidomide; bort = bortezomib; Pom = pomalidomide; RRMM = relapsed/refractory multiple myeloma. *Median prior therapies; † continuous. 1. Richardson P et al. ASH 2011 Annual Meeting. Abstract 634. 2. Lacy MQ et al. Leukemia. 2010;24:1934-1939. 3. Lacy MQ et al. Blood. 2011;118:2970-2975.
  • 53 Arm A – Cycle 21 days • Pomalidomide 4 mg oral/d, Days 1–21 Dexamethasone 40 mg oral/Weeks 1, 8, 15, 22 • Aspirin/LMWH continue Primary objective: Response rate (PR and better) according to IMWG in either arm Arm B – Cycle 28 days • Pomalidomide 4 mg oral/d, Days 1–28 Dexamethasone 40 mg oral/Weeks 1, 8, 15, 22 • Aspirin/LMWH continue Key inclusion criteria: • Relapsed MM • Resistant or refractory to both lenalidomide and bortezomib • Measurable disease (central lab) • ANC >1 x109 /L; Platelets ≥ 75 x109 /L; Hb ≥ 8 g/dL • Creatinine clearance ≥50 mL/min N = 84 randomized Pomalidomide: IFM 2009-2012 Study Design Until progression (relapse or refractory) 17 patients per arm 40 patients per arm 6 patients per arm DMC – TOLERANCE Rule: no difference DMC – EFFICACY Rule: 4 ≥ PR /arm LMWH = low molecular weight heparin; IMWG = International Myeloma Working Group. Leleu X et al. ASH 2011 Annual Meeting. Abstract 812.
  • 54 Time to Events 00.20.40.60.81.0 0 2 4 6 8 15 SurvivalDistributionFunctionEstimate Time From First Intake (months) HR = 1.18 [0.65] Log-rank P = 0.5875 KM median: A = 9.23 [5.42] KM median: B = 7.36 [4.60, 9.96] Events: A = 21, B = 23 Time to Progression Median 9.1 months (95%CI, 5.8-10.0) 121 3 5 7 1410 139 11 A B 43 32 23 20 17 0636 30 22 19 011 215 8 41 32 23 20 16 0237 27 21 18 07 214 6 No. at Risk A B Overall Survival Median 13.4 months (95%CI, 9.8-) 00.20.40.60.81.0 0 2 4 6 8 SurvivalDistributionFunctionEstimate Time From First Intake (months) HR = 0.90 [0.46, 1.73] Log-rank P = 0.7453 KM median: A = 13.44 [8.90, 13.93] KM median: B = 15.26 [9.17] Events: A = 19, B = 18 121 3 5 7 109 11 A B 43 40 36 31 29 942 38 32 30 2126 14 41 39 32 30 27 840 34 32 29 1926 15 No. at Risk A B Leleu X et al. ASH 2011 Annual Meeting. Abstract 812.
  • 55 ≥ PR 21/28 N = 43 28/28 N = 41 Total All patients % 35 34 34.5 Refractory to* % Lenalidomide 36 36 36 Bortezomib 32 26.5 29 Both lenalidomide and bortezomib 34 28 31 Last prior therapy 33 31 32 Del17p and/or t(4;14) 25 31 30 Response by Prior Therapy: ITT, IRC *Refractory to as per IMWG criteria. Leleu X et al. ASH 2011 Annual Meeting. Abstract 812.
  • 56 AEs, % 21/28 N = 43 28/28 N = 41 Total Serious AEs 33 41.5 37 Any grade 3 and 4 AEs 91 83 87 Blood and lymphatic system disorders 72 71 71 Anemia 33 32 32 Neutropenia 63 56 59.5 Thrombocytopenia 28 24 26 General disorders and administration site conditions 23 27 25 Asthenia 14 5 9.5 Discontinued due to drug-related AE, n = 2. Leleu X et al. ASH 2011 Annual Meeting. Abstract 812. Adverse Events
  • 57 Tai YT et al. Cancer Res. 2005;65:5898-5906; Hideshima T et al. Clin Cancer Res. 2005;11:8530-8533. Permission requested; Catley L et al. Blood. 2006;108:3441-3449. Blockade of Ubiquitinated Protein Catabolism HDAC6 HDAC6 HDAC6 Protein Protein aggregates (toxic) Ub 26S Proteasome Ub Ub Ub Aggresome Tubacin LBH, vorinostat Dynein Dynein Microtubule Autophagy Bortezomib Ub Ub Ub Lysosome Ub Ub Ub Ub UbUb Ub Ub Ub
  • 58 VANTAGE PN088: Phase 3 Trial Design • Primary endpoint – PFS† • Secondary endpoints – OS, TTP, response rate† (EBMT criteria), safety * Constitutes patients who received treatment after randomization. † Assessed by an Independent Adjudication Committee. EBMT = European Group for Blood and Marrow Transplantation. Dimopoulos MA et al. ASH 2011 Annual Meeting. Abstract 811. Patients enrolled (N = 637) • Progressive disease after the most recent treatment • 1 to 3 prior treatment regimens • Bortezomib-sensitive patients Dosing schedule Bortezomib 1.3 mg/m2 IV on Days 1, 4, 8, 11 in combination with Vorinostat 400 mg OR placebo Once daily on Days 1-14 (21-day treatment cycle) Analysis populations Intent-to-treat (ITT) PFS, TTP, OS Bortezomib + Vorinostat (N = 317) Bortezomib + Placebo (N = 320) Full analysis set (FAS)* ORR, safety Bortezomib + Vorinostat (N = 315) Bortezomib + Placebo (N = 320)
  • 59 EBMT Response Assessment (IAC): Response-Evaluable Population ORR = 56% vs 41%, P<0.0001 CBR = 71% vs 54%, P<0.0001 Bortezomib + vorinostat (N = 315) Bortezomib + placebo (N = 320) IAC = Independent Adjudication Committee; SD = stable disease. Dimopoulos MA et al. ASH 2011 Annual Meeting. Abstract 811.
  • 60 0 5 10 15 20 25 Time (months) 0 10 20 30 40 50 60 70 80 90 100 PFS(%) BTZ + Placebo BTZ + Vorinostat 320 157 58 12 4 0 317 196 75 14 3 0 BTZ + Placebo No. at Risk: BTZ + Vorinostat Progression-Free Survival (IAC) Events Median PFS (95% CI) HR (95% CI) P value BTZ + Vorinostat BTZ + Placebo 201/317 216/320 7.63 months (6.9-8.4) 6.83 months (5.7-7.7) 0.774 (0.64-0.94) 0.01 Dimopoulos MA et al. ASH 2011 Annual Meeting. Abstract 811.
  • 61 Overall Survival 0 5 10 15 20 25 30 Time (months) 0 10 20 30 40 50 60 70 80 90 100 OS(%) 320 286 235 124 48 16 0 317 291 238 120 43 12 1 BTZ + Placebo No. at Risk: BTZ + Vorinostat Events Median OS (95% CI) HR (95% CI) P value BTZ + Vorinostat BTZ + Placebo 71/317 80/320 NA 28.1 months (28.1 – NA) 0.86 (0.62 – 01.18) 0.35 NA = not available. Dimopoulos MA et al. ASH 2011 Annual Meeting. Abstract 811. BTZ + Placebo BTZ + Vorinostat
  • Second Salvage ASCT for Relapsed Myeloma Princess Margaret Hospital (N=79) Mikhael J, et al. Blood 2009; 114: abstract #1217 • Median 60 years (39-72) • Median TTP after 1st transplant 2.72 years (0.81-8.26) • Median interval between transplants 3.61 years (1.63-9.59) • NRM 2.5% • Response after 2nd transplant: 15% CR/nCR, 78% PR, 8% MR/SD • Results after 2nd transplant based on TTP after 1st transplant Group N Median PFS (mos) Median OS (mos) All 79 18.5 52.8 <24 mos 15 12.7 42.2 24-36 mos 30 17.0 52.7 >36 mos 34 32.6 NYR
  • Second Salvage AlloSCT for Myeloma Study N Median FU (mo) Response rate (CR) (%) Median PFS (mos) Median OS (mos) Gerull/20051 52 19 -- ~6 ~16 Quazilbash/20062 26 30 69 (31) 7.3 13 Majolino/20073 41 -- -- ~28 ~30 van Dorp/20074 23 -- --(4) 12 -- de Lavallade/20085 18 36 61 ~24 ~36 Kroger/20096 96 43 95 (46) 10.6 22.6 1 Gerull S, et al. Bone Marrow Transplant 2005; 36: 963-939; 2 Quazilbash MH, et al. Cancer 2006; 106; 1084-1089; 3 MajolinoI et al. Leuk Lymphoma 2007; 48: 759-766; 4 van Dorp S, et al. Neth J Med 2007; 65: 178-184; 5 de Lavallade H, et al. Bone Marrow Transplant 2008; 41: 953-960; 6 Kroger N, et al. Br J Haematol 2010; 148: 323-331.
  • CIBMTR Data
  • 65 Antibodies • BT-062 (CD138 + maytansinoids) • CD40 • CD200 • CD56 Bortezomib combinations have activity: Bz + CNTO 328 (anti IL6 ab)1 : ORR of 57% with TTP of 8.7 months (1-3 prior lines) Bz + Elotuzumab (anti CS1 ab)2 : ORR of 48% TTP of 9.4 months (median of 2 prior lines) 1. Rossi JF et al. ASH 2008 Annual Meeting. Abstract 1867. 2. Jakubowiak AJ et al. 2010 ASCO Annual Meeting. Abstract 8003.
  • 66 Elotuzumab Background ADCC = antibody-dependent cellular cytotoxicity; DMSO = dimethyl sulfoxide; mAb = monoclonal antibody; MED = maximum efficacious dose; MoA = mechanism of action; NK = natural killer. 1. Hsi ED et al. Clin Cancer Res. 2008;14:2775-2784. Permission requested; 2. Tai YT et al. Blood. 2008;112:1329-1337; 3. Van Rhee F et al. Mol Cancer Ther. 2009;8:2616-2624; 4. Lonial S et al. ASH 2009 Annual Meeting. Abstract 432. • Elotuzumab is a humanized IgG1 mAb targeting human CS1, a cell surface glycoprotein1,2 • CS1 is highly expressed on >95% of MM cells1-3 – Lower expression on NK cells – Little to no expression on normal tissues TumorVolume(mm3 ) Study Day 600 400 300 200 100 0 500 14 28 35 4221 Lenalidomide dosing (50 mg/kg) Elotuzumab (1 mg/kg) or control IgG1 dosing Control IgG1 + DMSO Elotuzumab + DMSO Lenalidomide + control IgG1 Elotuzumab + lenalidomide • MoA of elotuzumab is primarily through NK cell- mediated ADCC against myeloma cells1,2 • In a MM xenograft mouse model, the combination of elotuzumab + lenalidomide significantly reduced tumor volume compared with either agent alone4 Normal plasma cells Plasmacytoma Lymphoplasmacytic lymphoma Myeloma cells in bone marrow
  • 67 Elotuzumab + Lenalidomide + Low-Dose Dexamethasone: Phase 1 Results • Elotuzumab tested at 5, 10, and 20 mg/kg – Elotuzumab-related AEs were primarily infusion-related – 89% experienced at least 1 infusion reaction AE, no DLTs observed and MTD not reached VGPR = very good partial response; DLT = dose-limiting toxicity. Lonial S et al. ASCO 2010 Annual Meeting. Abstract 8020; Lonial S et al. ASH 2010 Annual Meeting. Abstract 1936. • Median TTP not reached at a median 12.7 months’ follow-up • Elotuzumab saturation of CS1 binding sites in BM MM cells >80% at both 10 (n = 1) and 20 mg/kg (n = 4) Total Lenalidomide- Naive Prior Thalidomide Refractory to Most Recent Therapy Total Patients, n 28 22 16 12 ≥ PR, n (%) 23 (82) 21 (95) 15 (94) 10 (83) CR/VGPR, n (%) 11 (39) 10 (45) 7 (44) 5 (42) PR, n (%) 12 (43) 11 (50) 8 (50) 5 (42)
  • 68 Elotuzumab 10 mg/kg Elotuzumab 20 mg/kg Total Patients, n 36 37 73 ORR (≥PR), n (%) 33 (92) 27 (73) 60 (82) CR/stringent CR, n (%) 5 (14) 4 (11) 9 (12) VGPR, n (%) 14 (39) 12 (32) 26 (36) PR, n (%) 14 (39) 11 (30) 25 (34) <PR, n (%) 3 (8) 10 (27) 13 (18) Efficacy Best Response (IMWG Criteria) • Median time to response: 1 month (range, 0.7-5.8) • Median time to best response: 2.2 months (range, 0.7-17.5) Lonial S et al. ASH 2011 Annual Meeting. Abstract 303.
  • 69 Progression-Free Survival No. at Risk: 10 mg/kg 20 mg/kg 36 32 30 29 21 37 29 26 23 19 13 4 1 0 14 4 0 0 Months 100 Proportionof Progression-FreePatients(%) 0 1 2 3 4 5 6 7 8 9 10 11 12 13 Median Time to Progression/Death: 10 mg/kg (n = 36): NA 20 mg/kg (n = 37): NA 14 15 16 17 18 19 20 21 22 90 80 70 60 50 40 30 20 10 0 Median Follow-Up: 10 mg/kg: 14.0 mo (range 2.6-21.2 mo) 20 mg/kg: 14.3 mo (range 2.1-20.5 mo) At a median follow-up of 14.1 months, the median PFS was not reached – PFS rate was 75% (10 mg/kg) and 65% (20 mg/kg) Lonial S et al. ASH 2011 Annual Meeting. Abstract 303.
  • 70 Investigator-Designated Infusion Reactions Elotuzumab Total N = 73 Parameter, n (%) 10 mg/kg n = 36 20 mg/kg n = 37 Any AE 5 (14) 4 (11) 9 (12) Grade 1 3 (8) 2 (5) 5 (7) Grade 2 1 (3) 2 (5) 3 (4) Grade 3* 1 (3) Rash 0 1(1) • Investigator-designated infusion reactions are AEs identified by the investigator as a sign or symptom of an elotuzumab-related infusion reaction • AEs that occurred in ≥ 2 subjects included nausea, pyrexia, and rash *There were no Grade 4 infusion reaction AEs. Lonial S et al. ASH 2011 Annual Meeting. Abstract 303.
  • 71 Summary • New options and combinations are active in relapsed/refractory disease • Novel targets help to improve outcomes perhaps even better than the historical use of alkylators • Proteasome inhibitors, IMiDs, HDACs, and antibodies will help to improve outcomes in relapse and induction
  • 72 Conclusion • THERE IS NO EASY ALGORITHM FOR MANAGING RELAPSED/REFRACTORY MULTIPLE MYELOMA • Patient-specific issues and prior therapy should be used to determine choice of agents • Use of FISH and cytogenetics can guide single- agent vs combo decision and prognosis • New targets and agents are being explored. Phase 3 trials are in progress