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 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. 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. 30. 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 31. 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 nave definitively yes. ISS, international staging system; dex, dexamethasone; PR, partial response; ASCT, autologous stem cell transplant; CR, complete response. 32. 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. 33. 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. 34. Kumar SK, et al. Bone Marrow Transplant. 2008;42:413-420. Time to Progression After SCT Correlates With OS After Initial Relapse 35. 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 36. Recurrent Myeloma 45-year-old woman 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 2-microglobulin 4.7 mg/L 37. 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 38. 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 39. 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 light chain Serum free 750 mg/L Free 15 mg/L : ratio 50 Multiple new lytic lesions of the skull MRI spine and pelvis January 11, 2006 New focal lesion at L3 vertebral body 40. 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 41. 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 117 mg/L Free 15.6 mg/L : ratio 7.5 Urine total protein 182 mg/day BJP 60 mg/day Urine immunofixation electrophoresis: free Treated with VRD with progressive disease CTC=common toxicity criteria 42. 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. 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(%) 44. Newer agents 44 45. 45 Bortezomib (reversible) Carfilzomib (irreversible) CEP 18770 (reversible) MLN9708 (reversible) NPI-0052 (irreversible) 1 Post- glutamyl Tryptic Chymo- tryptic NP I 2 3 4 5 6 7 NP I NP IPost- glutamyl Tryptic Chymo- tryptic 3 4 5 6 7 Bortezomib 1 Comparison of Proteasome Inhibitors 46. 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. 47. Bortezomib-nave 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. 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. 49 Progression-Free Survival: Response Evaluable Population Vij R et al. ASH 2011 Annual Meeting. Abstract 813. 50. 50 Overall Survival: Response Evaluable Population Vij R et al. ASH 2011 Annual Meeting. Abstract 813. 51. 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. 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. 53 Arm A Cycle 21 days Pomalidomide 4 mg oral/d, Days 121 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 128 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. 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. 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. 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. 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. 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. 59 EBMT Response Assessment (IAC): Response-Evaluable Population ORR = 56% vs 41%, P80% 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. 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)