Multiple Myeloma: Treatment Updates

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1 Faculty Disclosures Multiple Myeloma: Treatment Updates No conflicts of interest to disclose Andy Kurtzweil, PharmD, BCOP Pharmacy Clinical Team Leader, Hem/Onc/BMT University of Minnesota Medical Center, Fairview Los Angeles, CA/ March 23, 2013 Heimberg J, et al. N Engl J Med.1999;102: Objectives Choose appropriate initial and salvage therapies for multiple myeloma (MM) based on patient characteristics. Examine the role of transplantation in the treatment of patients with MM. Analyze the use of maintenance therapy posttransplant in MM. Describe the pharmacology, efficacy (place in therapy), and safety of newer agents used to treat MM. Treatment Options Palliation Steroids Radiation Melphalan 1950s- 1960s 5-year Survival Treatment Evolution Auto SCT Chemo VAD 1970s- 1980s : 25% Improved OS Thalidomide Tandem SCT AlloSCT Laubach JP, et al. Med Oncol. 2010; 27:S1-S6 Siegel R, et al. CA Cancer J Clin. 2012;62: Lenalidomide Bortezomib Combo Txs Thal Maint Cure?? Combos & Sequencing Risk Stratify Maintenance Carfilzomib New IMiDs New PIs Elotuzumab New Combos & Sequencing Role of Transplant New Targets? 1990s 2000s 2010s : 28% PI: Proteosome Inhibitors IMiDs: Immunomodulatory Drugs SCT: Stem Cell Transplant, Thal: Thalidomide VAD: Vincristine, Doxorubicin, Dexamethasone : 41%* 2010+:??% *P<0.05 vs Initial Treatment Goals of treatment Control disease & related complications Minimize side effects Minimize early mortality rate Allow for collection of stem cells Cure versus Control Considerations Eligible for transplant Stage of disease Risk Stratification Genetic risk factors Kumar SK, et al. Mayo Clin Proc. 2009;84: Rajkumar SV, et al. Am J Hematol. 2012; 87:79-88 Staging Stage I Kumar SK, et al. Mayo Clin Proc. 2009;84: Durie BGM, et al. Cancer. 1975;36: Identifying Risk Durie-Salmon (DS) Hgb > 10 g/dl Normal serum calcium Normal bone x-ray or solitary bone plasmacytoma only Low M-protein production International Staging System (ISS) B 2 M <3.5 mg/l Albumin 3.5 g/dl -Median OS: 62 months Stage II Not stage I or III Not stage I or III -Median OS: 45 months Stage III Hgb <8.5 g/dl Serum calcium > 12 mg/dl Bone lesions present High M-protein production Genetics & cell proliferation Hyper- or Hypodiploid Chromosome abnormalities B 2 M 5.5 mg/l -Median OS: 29 months B 2M = Beta-2 Microglobin Greipp P, et al. J Clin Oncol; 2005;23:

2 Chromosomal Abnormalities Patients enrolled in ECOG E9486 & E9487 Treatment with conventional chemo Outcomes vs cytogenetic abnormalities Genetic Abnormality N % with Fonseca R, et al. Blood. 2003;101: Median OS (Months) P- Median PFS (Months) With Without value With Without P- value t(4;14) % < <0.001 t(14;16) % t(11;14) % Del 17p % Δ % ECOG=Eastern Cooperative Oncology Group Risk Group High Risk -Deletion 17p (p53) -t(14;16) -t(14;20) -GEP High Risk signature Intermediate Risk -Chromosome 13 or 13q deletion -t(4;14)* -PCLI > 3% Standard Risk -t(11;14) -t(6;14) -Hyperdiploid -All Others Risk Stratification Comments GEP not yet standardized *Worse prognosis with high B 2 M & anemia Prognosis worsens if LDH >ULN & β-2 >5.5 for all standard risk patients Hyperdiploid = trisomy of chromosomes 3, 5, 7, 9, 11, 15, 19, or 21 GEP = gene expression profiling PCLI = plasma cell labeling index Kumar SK, et al. Mayo Clin Proc. 2009;84: ULN = upper limit of normal Munshi NC, et al. Blood. 2011;117: Adopted from: msmart 2.0: Classification of Active MM. Retreived 9/30/12 from Transplant Eligible - Induction Regimen Treatment Schedule Cycle Length Rd R= Lenalidomide 25 mg PO days 1-21 d= Dexamethasone 40 mg PO days 1, 8, 15, 22 RD R= Lenalidomide 25 mg PO days 1-21 D= Dexamethasone 40 mg PO days 1-4, 9-12, TD T = Thalidomide mg PO days 1-28 D= Dexamethasone 40 mg PO days 1-4, 9-12, BD B= Bortezomib 1.3 mg/m 2 IV days 1, 4, 8, 11 D= Dexamethasone 40 mg PO days 1-4 (all cycles) & 9-12 (cycles 1 & 2 only) PAD P= Bortezomib 1.3 mg/m 2 IV days 1, 4, 8, & 11 A= Doxorubicin 9 mg/m 2 IV days 1-4 D= Dexamethasone 40 mg PO days 1-4, 9-12, & VAD V= Vincristine 0.4 mg IV days 1-4 A= Doxorubicin 9 mg/m 2 IV days 1-4 D= Dexamethasone 40 mg PO days 1-4, 9-12, & Rajkumar SV, et al. Am J Hematol. 2012;87: days Transplant Eligible - Induction Regimen Treatment Schedule Cycle Length VTD V= Bortezomib 1.3 mg/m 2 IV days 1, 4, 8, & 11 T = Thalidomide mg PO days 1-21 D= Dexamethasone 40 mg PO days 1, 2, 4, 5, 8, 9, 11, & 12 or days 1-4 and 9-12 VRd V= Bortezomib 1.3 mg/m 2 IV days 1, 4, 8, 11 R= Lenalidomide 25 mg PO days 1-14 d= Dexamethasone 20 mg PO days 1, 2, 4, 5, 8, 9, 11, & 12 or 40 mg PO days 1, 8, & 15 VDC (CyBorD) V= Bortezomib 1.3 mg/m 2 IV days 1, 4, 8, 11 D= Dexamethasone 40 mg PO days 1-4, 9-12, & or 40 mg PO days 1, 8, & 15 (every 21 days) C= Cyclophosphamide 300 mg/m 2 PO days 1, 8, 15, & 22 or 500 mg/m 2 PO days 1, 8, & 15 (every 21 days) DVd D= Liposomal Doxorubicin 40 mg/m 2 IV day 1 V= Vincristine 1.4 mg/m 2 IV day 1 d= Dexamethasone 40 mg PO days 1-4 Rajkumar SV, et al. Am J Hematol. 2012;87: days 21 days 21- IMiDs Front Line TD or RD vs Dex Alone Addition of IMiDs improve RRs Dex alone is only a short-term treatment option RD vs Rd Open label randomized trial, newly diagnosed (n=445) Results CR or PR: 79% vs 68% (p=0.008) OS at 1-year: 87% vs 96% (p=0.0002) OS at 1-year (age 65): 83% vs 94% (p=0.004) Toxicity Grade 3 DVT: 26% vs 12% (p=0.0003) Infection & fatigue increased in HD group Risk of serious AEs greatest in patient > 65 years in HD group Rd is an effective option, especially elderly patients Zonder JA, et al. Blood. 2007;110:Abstract77. Rajkumar S, et a. J Clin Oncol. 2006;24: Rajkumar SV, et al. Lancet Oncol. 2010;11: Dex =Dexamethasone HD=High dose Thalidomide vs Lenalidomide Mayo Clinic retrospective analysis: TD (n=183) vs RD (n=223) PR or better: 61.2% vs 80.3% (p<0.001) TTP: 17.2 mo vs 27.4 mo (p=0.019) OS: 57.2 mo vs not reached (P=0.018) Toxicity (grade 3) Lenalidomide neutropenia Thalidomide VTE & peripheral neuropathy Lenalidomide & stem cell collection Increased risk of inadequate stem cell collection Highest risk if given >3-6 cycles or age >65 years Gay F, et al. Blood. 2010;115: Kumar S, et al. Blood. 2009;114:

3 JB is a 60 yo male with MM that will be starting treatment with lenalidomide + dexamethasone. His physician asks you what should JB expect from treatment with Rd as compared to treatment with RD? IFM : BD vs VAD A. Higher response rate B. Improved survival C. Increase risk of thromboembolism D. More toxicity in patients >65 yo E. No difference in survival for patient >65 yo Randomization Induction Consolidation Autologous Stem Cell Transplant (ASCT) Arm A1 VAD x 4 cycles (n=121) None Arm A2 VAD x 4 cycles (n=121) DCEP x 2 cycles (n=108) Total A1+A2 (n=218) Received ASCT (n=184) Did not receive ASCT (n=34) Arm B1 BD x 4 cycles (n=121) None Arm B2 BD x 4 cycles (n=119) DCEP x 2 cycles (n=111) Total B1+B2 (n=223) Received ASCT (n=197) Did not receive ASCT (n=26) Harousseau JL, et al. J Clin Oncol. 2010;28: DCEP = Dexamethasone, Cyclophosphamide, Etoposide, & Cisplatin 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% IFM Results ORR [del (13)] del(13)] Median follow-up: 32.2 months PFS (VAD vs BD): 29.7 months vs 36 months (p=0.064) Toxicity VAD: Hematologic toxicity & deaths BD: Peripheral neuropathy BD should be considered a standard induction regimen Harousseau JL, et al. J Clin Oncol. 2010;28: Response to Induction Therapy [t(4;14) or del(17p)] [B2M >3 mg/l and VAD BD NS=not significant VGPR=very good partial response HOVON-65/GMMG-HD4 Randomized, open-label phase III trial Newly diagnosed, DS stage II-III myeloma Median PFS VAD: 28 mo P=0.002 PAD: 35 mo OS at 5-years VAD: 55% P=0.07 PAD: 61% Sonneveld P, et al. J Clin Oncol. 2012;30: Arm A Induction: VAD x3 cycles n=414 Arm B Induction: PAD x3 cycles n=413 Melphalan 200 mg/m 2 + ASCT x 1 or 2 Maintenance: Thal 50 mg PO Daily x 2 years Maintenance: Bortezomib 1.3 mg/m 2 IV Q2 wks x 2 yrs 100% 80% 60% 40% 20% 0% After induction Overall ISS stage III Results [β2-m >3] [del(13)] [t(4;14)] [del(17p)] PAD improved PFS (p=0.004) & OS (p<0.001) when SCr > 2 mg/dl VAD vs PAD PN grade 2: 18% vs 40% (p<0.001) GI symptoms grade 3: 7% vs 11% (p<0.05) Thrombocytopenia grade 3: 5% vs 10% (p<0.01) Bortezomib improves RR, PFS, & OS during induction therapy (including high risk patients) Sonneveld P, et al. J Clin Oncol. 2012;30: Response Rates VAD PAD PN=Peripheral neuropathy TD vs VTD Phase III, randomized, open-label study Induction: TD (n=239) vs VTD (n=241) Plus double ASCT & consolidation x2 cycles Results after induction (TD vs VTD) Response ncr: 11% vs 31% (p<0.0001) Response PR: 79% vs 93% (p<0.0001) Toxicity Grade 3/4 AEs: 33% vs 56% (p<0.0001) Grade 3/4 PN: 2% vs 10% (p<0.0001) Discontinuation due to toxic effects: 4% vs 3% VTD should be considered a standard induction regimen Cavo M, et al. Lancet. 2010;376: ncr=near CR; AE=adverse events

4 Bortezomib/Lenalidomide/Dex Phase 1/2 study VRd, newly diagnosed Treatment Eight 3 week cycles ASCT after 4 cycles if PR 100% Results 80% Medium follow-up: 21 mo 60% PFS (18 mo): 75% 40% Gr 3 PN: 2% 20% Gr 3/4 neutropenia: 9% VRd is highly effective with 0% tolerable side effect profile Best Response to Treatment ORR [del(13)] [t(4;14) or del(17p)] EVOLUTION Phase II trial in untreated MM Primary endpoint: rate of CR+PR Treatment arms (eight 3 week cycles) VDCR (R=15 mg), n=48 VRd (R=25 mg), n=42 VDC, n=33 VDC-mod, n=17 Maintenance (four 6 week cycles) Bortezomib 1.3 mg/m 2 day 1,8,15,22 V=Bortezomib 1.3 mg/m 2, days 1,4,8,11 D or d =Dexamethasone 40mg, days 1,8,15 C=Cyclophosphamide 500mg/m 2, days 1,8 -mod= additional day 15 cyclophosphamide R=Lenalidomide day 1-14 Richardson PG, et al. Blood. 2010;116: Gr = grade Kumar S, et al. Blood. 2012;119: ORR at cycle 4 ORR (overall) at cycle 4 (overall) Treatment Response Kumar S, et al. Blood. 2012;119: EVOLUTION Results VDCR VRd VDC VDCmod 80% 73% 63% 82% 88% 85% 75% 100% 33% 32% 13% 41% 58% 51% 41% 53% Neutropenia 44% 10% 30% 24% VDCR VRd VDC VDCmod Thrombocytopenia Toxicity ( grade 3) 15% 12% 12% 0% Anemia 8% 7% 0% 12% Neuropathy 13% 17% 9% 18% Fatigue 17% 7% 3% 0% At least 1 AE 83% 76% 79% 88% High rates of neuropathy in all arms No efficacy advantage for 4 drug regimen VRd & VDC-mod have good activity, tolerable side effect profile, & both would be good treatment options AE=adverse event. Weekly Bortezomib with VDC (CyBorD) Phase II study, newly diagnosed MM Administered every x 4 cycles, followed by transplant or continuation of treatment. Reeder CB, et al. Leukemia. 2009;23: Reeder CB, et al. Blood. 2010;22: Cohort 1 Cohort 2 Cyclophosphamide 300 mg/m 2 PO Days 1, 8, 15, 22 Same as cohort 1 Dexamethasone 40 mg PO Days 1-4, 9-12, & Cycle 1 & 2: same as cohort 1 Cycles 3+: 40mg PO Days 1, 8, 15, 22 Bortezomib 1.3 mg/m 2 IV Days 1, 4, 8, mg/m 2 IV Days 1, 8, 15, 22 Response Rates Toxicity ORR: 88% vs 93% Gr 3 PN: 6% vs 0% CR/nCR: 39% vs 43% : 61% vs 60% (no statistical analysis Any Grade PN: 64% vs 57% Gr 3 Thrombocytopenia: 21% vs 0% Bortezomib dose reduced: 21% vs 13% reported) -Weekly Bortezomib maintains efficacy while reducing Gr 3 PN Liposomal Doxorubicin Non-inferiority trial comparing DVd to VAd Goal: compare pegylated liposomal doxorubicin to conventional doxorubicin Patients: previously untreated age years (n=192) Results PFS & OS: no significant difference Neutropenia (Gr 3): 10.3% vs 24.2% (p=0.02) Alopecia: 20% vs 44% (p<0.0001) Hand-foot syndrome (Gr 3): 4.1% vs 0% DVd vs VAd similar efficacy, less toxic, more convenient dosing Rifkin RM, et al. Cancer. 2006;106: VAd= VAD with dexamethasone on days 1-4 only. Transplant Ineligible - Induction Regimen Treatment Schedule Cycle Length MPT M= Melphalan mg/kg PO x 4-5 days OR 4 mg/m 2 PO x 7 days P= Prednisone 1-2 mg/kg PO x 4-5 days OR 40 mg/m 2 x 7 days T= Thalidomide mg PO daily MPR M= Melphalan 0.18 mg/kg PO days 1-4 P= Prednisone 2 mg/kg PO days 1-4 R= Lenalidomide 10 mg PO days 1-21 MPB M= Melphalan 9 mg/m 2 PO days 1-4 P= Prednisone 60 mg/m 2 PO days 1-4 B= Bortezomib 1.3 mg/m 2 IV days 1, 4, 8, 11, 22, 25, 29, & 32 (cycles 1-4) & days 1, 8, 22, & 29 (cycles 5-9) Rd VD DVD VAD See transplant eligible induction regimen table See transplant eligible induction regimen table See transplant eligible induction regimen table See transplant eligible induction regimen table Rajkumar SV, et al. Am J Hematol. 2012;87: days 42 days

5 MP vs MPT No clear survival advantage in individual studies of MPT Meta-analysis of 5 RCTs MP (n=819) vs MPT (n=752) Accrual periods: 5/2000 7/2007 Patients Age >60-75 years or Transplant ineligible Thalidomide maintenance in 3 of the studies Results Efficacy HR for OS: 0.8 (P=0.07; 95% CI: ) HR for PFS: 0.68 (P<0.001; 95% CI: ) OR of PR: 3.39 (P<0.001; 95% CI: ) Toxicity OR of grade 3 PN: 6.61 (P<0.001) OR of grade 3 DVT: 2.43 (P=0.02) In favor of MP In favor of MPT MPT can be considered a treatment option for elderly or transplant ineligible patients Must take toxicity into consideration Kapoor P, et al. Leukemia. 2011;25: RCTs=Randomized controlled clinical trials. Kapoor P, et al. Leukemia. 2011;25: VISTA Trial Randomized phase III trial of MP vs MPB Median follow-up: 60.1 months (final analysis) Results MP (n=338) MPB (n=344) P-value OS 43.1 mo 56.4 mo year OS 34.4% 46% -- Median TNT 19.2 mo 27 mo < Median TFI 8.3 mo 16.6 mo < OS benefit retained after subsequent therapies High risk cytogenetics no difference in OS benefit Novel agents could be used successfully at relapse No increased risk of 2 nd primary malignancies San Miguel JF, et al. Blood. 2011;118:Abstract 476. San Miguel, et al. J Clin Oncol. 2013; 31(4): TNT=time to next therapy TFI=treatment-free interval MP + Lenalidomide: MM-015 Trial Randomized, double-blind, phase III study Newly diagnosed, transplant ineligible Age: 65 yo MP (n= 154) vs MPR (n=153) vs MPR+R (n=152) ORR VGPR CR PFS PFS (65-75 yo) 3-year OS MP 50% 9.1% 3.2% 13 mo 12 mo 66% MPR 68% 29.4% 3.3% 14 mo 15 mo 62% P-value NS <0.001 NS MPR is an active regimen for patients years old, but benefits are less evident if >75 years Palumbo A, et al. N Engl J Med. 2012;366: NS=not significant, yo= years old +R=lenalidomide maintenance treatment HS is a 70 yo male with newly diagnosed myeloma, ineligible for transplant. Which of the following induction regimens would be the most effective and appropriate? A. VAD (Vincristine + Doxorubicin + Dexamethasone) B. MP (Melphalan + Prednisone) plus Lenalidomide or Thalidomide or Bortezomib C. Melphalan + Prednisone D. Lenalidomide + HD Dexamethasone E. Liposomal Doxorubicin + Dexamethasone Recommendation & Risk Transplant Eligible (TE) Standard risk: lenalidomide or bortezomib based High response rates & low mortality Manageable adverse effects High risk: bortezomib (preferred) or lenalidomide Bortezomib may overcome adverse prognostic factors including high risk cytogenetics High risk disease benefits most from CR Transplant Ineligible (TI) Standard risk: MPT or Rd Oral administration & convenience High risk: similar to TE +/- melphalan Kumar SK, et al. Mayo Clin Proc. 2009;84: Rajkumar SV, et al. Am J Hematol. 2012; 87:79-88

6 Stem Cell Transplantation Integral part of myeloma treatment Autologous, Tandem, & Allogeneic vs Eligibility Transplant vs standard treatment Conflicting results TBI inferior to HD Melphalan conditioning Longer symptom free interval Early vs Delayed ASCT Similar OS Improved QoL with early ASCT IMiDs/Bortezomib & past transplant results Giralt S. Hematology Am Soc Hematol Educ Program. 2011;2011: Attal M, et al. N Engl J Med. 1996;335: Fermand JP, et al. Blood. 1998;92: TBI=Total body irradiation Induction Response & ASCT Results Results after ASCT in IFM 2005/01 (VAD vs BD) Median PFS if vs <VGPR after induction: 41.1 vs 29 mo Median PFS if vs <VGPR after ASCT: 41.1 vs 33.5 mo BDT vs TD before ASCT : 62% vs 31% Similar responses after ASCT Suggest improved responses before ASCT result in improved responses after ASCT Kumar, et al Patients with refractory myeloma can still respond to ASCT ASCT is still an option in patient with refractory disease Harousseau JL, et al. J Clin Oncol. 2010;28: Harousseau JL, et al. Blood. 2009;114:Abstract 353. Kumar S, et al. Bone Marrow Transplant. 2004;34: Tandem ASCT Updates Updated results of 8 trials French: IFM90, IFM94, IFM9902, IFM9904, US: TT1, TT2, TT3, & SWOG S9321 Results Tandem transplants associated with better survival, HR 0.61 (P<0.001; 95% CI: 0.55,0.68) If EFS > 3.5 years, then PRS was increased Ten year OS estimates approaching >50% Tandem ASCTs should be considered in all patients Benefit most evident if achieve <VGPR after 1 st ASCT If VGPR or CR after 1 st ASCT consider clinical trial IFM: Intergroupe Francophone du Myelome SWOG: Southwest Oncology Group TT: Total Therapy (Univ of Arkansas group) EFS: Event-free Survival; PRS: Post-Relapse Survival Barlogie B, et al. J Clin Oncol. 2010;26: NCCN Guidelines & Clinical Practice. Multiple Myeloma. Accessed Oct 1 st, Role of Allogeneic Transplant Prospective analysis of allogeneic transplant based on availability of donor Patients DS stage II-III Age yo Allo-RIC TBI 2 Gy Cyclosporine & mycophenolate Lokhorst HM, et al. Blood. 2012;119: HOVON-50 Trial (n=536) Induction: VAD vs TAD ASCT: HD Melphalan (n=439) Included in DvND analysis (n=260) No Match Sib (N=138) Further Treatments: -Maintenance: n=97-2 nd ASCT: n=3 Match Sib (N=122) Further Treatments: -Maintenance: n=15 -Allo RIC: n=99 T-Thalidomide, A: doxorubicin, D:dexamethasone, V: vincristine; DvND: Donor versus no donor RIC: reduced intensity conditioning regimen Results Progression Free Survival No Donor Donor Significance PFS at 6 years 22% 28% P=0.17 (HR 0.82, 95% CI: ) OS at 6 years 55% 55% P=0.72 (HR 1.07, 95% CI: ) Cumulative Incidence of Relapse at 6 years Cumulative Incidence of NRM at 6 years 77% 55% P= % 16% P<0.001 No differences for high risk patients Rates of agvhd: 50% (9% grade 3) Conclusions No benefit to allo-sct Benefits may require longer follow-up Only conduct as part of clinical trial Lokhorst HM, et al. Blood. 2012;119: NRM = non-relapse mortality agvhd = actue graft versus host disease Republished with permission of the American Society of Hematology, from Donor Versus No-Donor Comparison of Newly Diagnosed Myeloma Patients Included in the HOVON-50 Multiple Myeloma Study, Lokhorst, H. M., et al., 119, 2012; permission conveyed through Copyright Clearance Center, Inc.

7 Post ASCT Thalidomide Studies Maintenance Treatments Author Maintenance Treatment N Results Barlogie T vs none 668 No difference in EFS or OS overall. Thal improved RR, EFS, & OS for high-risk cytogenetics Attal T+Pam vs Pam vs None 597 EFS: 52% vs 37% vs 3yr (P<0.01) OS: 87% vs 74% vs 4yr (P=0.04) Spencer T+Pred vs Pred 243 PFS: 42% vs 3yr (P<0.001) OS: 86% vs 3yr (P=0.004) Lokhorst T vs IFN 556 Median PFS: 34 mo vs 25 mo (P<0.001) Median OS: 73 mo vs 60 mo (P=0.77) Stewart T+Pred vs none 332 Median PFS: 28 mo vs 17 mo (p<0.0001) Median OS: Not reached vs5 yrs (P=0.18) Barlogie B, et al. J Clin Oncol. 2010;28: Attal M, et al. Blood. 2006;108: Spencer A, et al. J Clin Oncol. 2009;27: Pam = pamidronate, Pred = prednisone, IFN = interferon Lokhorst HM, et al. Blood. 2010;115: Stewart AK, et al. Blood. 2010;116:Abstract 39. Post ASCT Thalidomide Efficacy Most benefit if <VGPR after ASCT Similar OS if wait until relapse to start thalidomide Toxicities Neuropathy: 52-69% (grade 3: 6-10%) Fatigue up to 78% Infection 6-28% Constipation 18-44% Thrombosis 6-8% Discontinuation of drug due to toxicity Overall: 23-80% Mainly related to neuropathy Post ASCT Lenalidomide CALGB (McCarthy) IFM (Attal) Patients Age <71 years, post ASCT (n=460) Age <65 years, post ASCT (n=614) Treatment Median followup Results Side Effects (Grade 3) Len 10mg/day until disease progression vs placebo 34 months 45 months PFS: 46 mo vs 27 mo (P<0.001) OS: 88% vs 3yr (P=0.03) PD or death: 37% vs 34 mo (HR 0.48; 95% CI, 0.36 to 0.63) Hematologic: 48% vs 17% (p<0.001) Infection: 6% vs 3% (p=0.108) Febrile Neutropenia: 5% vs 1% (p=0.019) Fatigue: 6% vs 3% (p=0.253) Thrombotic events: 1.3% vs 0.4% Second primary cancers: 7.8% vs 2.6% Discontinuation 10% vs3.1% 27.1% vs 14.6% Len 10mg/day x 3 mo, then 15mg/day until relapse vs placebo PFS: 41 mo vs 23 mo (P<0.001) -Observed in high risk also OS: 70% in both 45 months Hematologic: 58% vs 23% (p<0.001) Infections: 13% vs 5% Fatigue: 5% vs 2% Thrombotic events: 6% vs 2% (p=0.01) Second primary cancers: 7.5% vs 2.9% Barlogie B, et al. J Clin Oncol. 2010;28: Attal M, et al. Blood. 2006;108: Spencer A, et al. J Clin Oncol. 2009;27: Lokhorst HM, et al. Blood. 2010;115: Stewart AK, et al. Blood. 2010;116:Abstract 39. McCarthy PL, et al. N Engl J Med. 2012;366: Attal M, et al. N Engl J Med. 2012;366: PD = progressive disease Lenalidomide Maintenance MM-015 Trial (MP vs MPR vs MPR-R) Transplant ineligible, age 65 years Maintenance: Lenalidomide 10mg days 1-21 of 28 Results Median PFS: 13 mo vs 14 mo vs 31 mo (P<0.001) OS at 3-yrs: 66% vs 62% vs 70% (P=NS) Toxicities Hematologic, infection, fatigue, GI, & rash Maintenance Discontinuation: 8% (at yo) & 17% (>75 yo) Risk of second primary malignancies (SPMs) Lenalidomide prolongs response, but OS benefit is less obvious & it has toxicity. Need to inform patients before starting. Palumbo A, et al. N Engl J Med. 2012;366: MPR-R= MPR with Lenalidomide Maintenance Study CALGB (McCarthy) IFM (Attal) MM-015 (Palumbo) Lenalidomide & SPMs Hematologic Malignancies Solid Tumors Totals (excluding non-melanomaskin cancer) Lenalidomide Placebo Lenalidomide Placebo Lenalidomide Placebo P-value 3.5% 0.4% 4.3% 2.2% 7.8% 2.6% % 1.7% 3.3% 1.3% 7.5% 2.9% % 3% Median time to diagnosis of SPM (CALGB ) Hematologic: 28 mo (12-46) vs 30 mo Solid Tumor: 15 mo (3-51) vs 21 mo (6-34) Incidence of SPM (IFM ): Lenalidomide vs placebo: 3.1/100 pt-yrs vs 1.2/100 pt-yrs (P=0.002) Risk factors identified: age 55-67, male gender, & ISS stage III McCarthy PL, et al. N Engl J Med. 2012;366: Attal M, et al. N Engl J Med. 2012;366: Palumbo A, et al. N Engl J Med. 2012;366: not reported

8 Outcomes & Risk SPMs MM-015: CALGB : From N EnglJ Med, Palumbo, A., et al., Continuous Lenalidomide Treatment for Newly Diagnosed Multiple Myeloma, 366, Copyright 2012 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. From N EnglJ Med, McCarthy, P. L., Owzar, K., Hofmeister, C. C., et al. Lenalidomide after Stem-Cell Transplantation for Multiple Myeloma, 366, Copyright 2012 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. NB is a 62 yo female post Autologous HSCT. She is starting treatment with Lenalidomide maintenance and heard about the risk of SPMs. What should you tell her? A. The incidence was not different than placebo B. Lenalidomide increases the risk of developing solid tumors only C. The decreased risk of death and disease progression with lenalidomide outweigh the risks of second malignancies D. Female gender & ISS stage I may be risk factors E. Lenalidomide should not be used in the maintenance setting due to the risk of 2 nd malignancies Maintenance Post ASCT Bortezomib Maintenance Study N & age Treatment EFS/PFS OS HOVON-65 (Sonneveld) PETHEMA/ GEM (Rosinol) yo yo Bor 1.3 mg/m 2 q2wk vs Thal 50mg daily x 2yr Bor 1.3 mg/m 2 d1,4,8,11 q3mo + Thal 100mg daily vs Thal 100mg daily vs IFN-α2b x 3yr Maintenance Post Induction (Transplant Ineligible) 48% vs 42% (@ 3 yrs)* 78% vs 63% vs 49% (@ 2 yrs)* 78% vs 71% (@ 3 yrs)* Not Significant Study N & age Treatment EFS/PFS OS GIMEMA (Palumbo) yo Sonneveld P, et al. J Clin Oncol. 2012;30: Rosinol, et al. Blood. 2012;120: Palumbo A, et al. J Clin Oncol. 2010;28: Bor 1.3 mg/m 2 d1&15 q4wk + Thal 50mg daily vs Observation NR vs 27mo* 89% vs 87% (@ 3 years) Bortezomib is an effective maintenance treatment. Must consider neuropathy as a long term toxicity. NR= not reached, Bor=bortezomib, Thal=thalidomide. *Denotes statistically significant difference. Relapsed/Refractory Myeloma Combination or single agent? Available agents Bortezomib, thalidomide, lenalidomide Cyclophosphamide, doxorubicin (liposomal), cisplatin, etoposide, & dexamethasone Carfilzomib Bendamustine & vorinostat Around the corner Pomalidomide Elotuzumab New proteosome inhibitors Moreau P, et al. Sem Hematol. 2012;49:S33-S46. Lonial S, et al. Clin cancer Res. 2011;17: Subcutaneous Bortezomib Randomized, phase III, non-inferiority study Patients Age 18 years old Disease progression after 1-3 prior lines of treatment No prior bortezomib Treatment (Assigned 2:1) Bortezomib 1.3 mg/m 2 SQ or IV days 1, 4, 8, & 11 Up to 8 cycles SQ injection: 2.5 mg/ml Moreau P, et al. Lancet Oncol. 2011;12: SQ = subcutaneous Results SQ vs IV Subcutaneous (n=147) Injection site reaction: 9 of 147 (6%) No differences in PK or PD based on site of SQ inj Republished with the permission of the American Society of Hematology, from Potent Activity of Carfilzomib, a Novel, Irreversible Inhibitor of the Ubiquitin-Proteasome Pathway, Against Preclinical Models of Multiple Myeloma, Kuhn, D. J., et al., 110, 2007; permission conveyed through Copyright Clearance Center, Inc. Intravenous (n=74) ORR 61 (42%) 31 (42%) Significance P=0.002 for noninferiority 24 (17%) 12 (16%) n/a PN any grade 38% 53% P=0.044 PN grade 2 24% 41% P=0.012 PN grade 3 6% 16% P=0.026 C max (ng/ml) 20.4 (8.87) 223 (101) n/a AUC last (ngxh/ml) 155 (56.8) 151 (42.9) n/a E max (%) 63.7% (10.6) 69.3% (13.2) n/a PD: progressive disease, Cmax: max plasma conc AUClast: AUC from time 0-last timepoint Emax: max % inhibition of 20S proteasome activity

9 Carfilzomib Carfilzomib Bortezomib Novel epoxyketone proteasome inhibitor Irreversible binding More selective for chymotrypsin-like active site of the proteasome Fewer off-target effects than bortezomib Active against bortezomib resistant cell lines Kyprolis [package insert]. South San Francisco, CA: Onyx Pharmaceuticals, Inc; Velcade [package insert]. Cambridge, MA: Millennium Pharmaceuticals, Inc: Kuhn, et al. Blood. 2007;110: Phase II PX Patients Relapsed from 2 prior therapies including bortezomib & an IMiD Refractory to last therapy Carfilzomib dose Given IV on days 1, 2, 8, 9, 15, & 16 q Pilot Study (A0): 20 mg/m 2 all 12 cycles Amended (A1): 20 mg/m 2 cycle 1, then 27 mg/m 2 cycles 2-12 Jagannath S, et al. Clin Lymphoma Myeloma Leuk. 2012;12: Siegel DS, et al. Blood. 2012;120: PX Results PX A0 (95% CI) Jagannath S, et al. Clin Lymphoma Myeloma Leuk. 2012;12: Siegel DS, et al. Blood. 2012;120: PX A1 (95% CI) Number of patients n = 46 n = 266 Median number of prior therapies 5 (range of 2-15) 5 (range 1-20) ORR 16.7% (7-31.4) 23.7% ( ) CBR 23.8% ( ) 37% ( ) Median DOR (mo) 7.2 (1.9-NR) 7.8 ( ) Median PFS (mo) 3.5 ( ) 3.7 ( ) Median OS (mo) ( ) DOR = duration of response CBR=clinical benefit response ( minimal response) Carfilzomib Adverse Effects Toxicity (PX A1) All grades Grade 3 or 4 Neutropenia Thrombocytopenia Anemia 18% 39% 46% 11% 29% 24% Upper respiratory tract infection Pneumonia Dyspnea Febrile Neutropenia Nausea Vomiting Diarrhea 27% 12% 34% 0.8% 45% 22.2% 32% 4.5% 9.4% 3.4% 0.8% 1.9% 0.8% 0.8% Fatigue 46% 7.5% Pyrexia 31% 1.5% Headache 28% 1.9% Increased serum creatinine Acute renal failure 25% 4.9% 2.6% 3.4% Tumor lysis syndrome 0.4% 0% -Cardiac adverse effects CHF: 10 pts (3.8%), cardiac arrest: 4 pts (1.5%), MI: 2 pts (0.8%) -Peripheral neuropathy All grades: 33 pts (12.4%), grade 3/4: 3 pts (1.1%) Siegel DS, et al. Blood. 2012;120: Singhal S, et al. Blood. 2011;118:(abstract 1876). MI = myocardial infarction, pts = patients Use in Special Populations Patients with renal insufficiency Studied in a phase II study Patients divided into cohorts based on creatinine clearance (>80, 50-80, 30-49, <30, & dialysis)* No effect on peak exposure, AUC, or clearance Specific Warnings (use with caution): Cardiac arrest, CHF, MI Pulmonary complications Hepatic toxicity Thrombocytopenia treatment related Niesvizky R, et al. Haematologica. 2011;96(suppl2): Siegel DS, et al. Blood. 2012;120: Vij R, et al. Blood. 2012;119: Kyprolis [package insert]. South San Francisco, CA: Onyx Pharmaceuticals, Inc; *Displayed in ml/min. Carfilzomib Approval Indication Received at least 2 prior therapies, including bortezomib and an IMiD, & progressed within 60 days of last therapy FDA approved dosing (BSA capped at 2.2 m 2 ): Cycle 1: 20 mg/m 2 /dose Cycle 2: 27 mg/m 2 /dose (if tolerated) Increased RRs at 27 mg/m 2 /dose Administration IV over 2-10 minutes Hydration ( ml) before & after (cycle 1) To prevent TLS & associated nephrotoxicity Infusion reaction prevention Premed: dexamethasone 4 mg IV/PO (cycles 1&2) Kyprolis [package insert]. South San Francisco, CA: Onyx Pharmaceuticals, Inc; Vij R, et al. Blood. 2012;119: TLS = tumor lysis syndrome

10 Carfilzomib Combination Studies Carfilzomib/lenalidomide/dexamethasone, phase 1/2 Dosing schemes: 20/27 mg/m 2 and 20/36 mg/m 2 Response: PR 98%, CR 42% (n=53) Carfilzomib/melphalan/prednisone, phase 1/2 Dosing: up to 45 mg/m 2 Overall response rate: 92% (n=40) ENDEAVOR, phase III study Carfilzomib/Dex vs Bortezomib/Dex Dose: 20 mg/m 2 days 1 & 2, then 56 mg/m 2 /dose thereafter Planned enrollment of 888 patients ASPIRE, phase III study Lenalidomide/Dexamethasone ± Carfilzomib Enrolled 792 patients (accrual complete) UR is starting his 2 nd cycle of carfilzomib for relapsed multiple myeloma. He tolerated his 1 st cycle very well. What concominant treatment should he receive with his carfilzomib infusion? A. Ondansetron 8 mg IV before each dose B. Normal saline 250 ml IV before and after each dose C. Acetaminophen 500 mg PO before each dose D. Dexamethasone 4 mg PO before each dose E. Loperamide 2 mg PO before each dose accessed January 28 th, Thompson JL. Annals Pharmacother. 2013; 47:56-62 Pomalidomide Thalidomide Lenalidomide Pomalidomide Immunomodulatory drug (IMiD) Structurally similar to lenalidomide & thalidomide Greater activity than thalidomide (in vitro) Possible better safety profile than other IMiDs Pomalidomide MM-002 Trial Phase II trial POM 4mg PO days 1-21 q28, ±Dex 40mg/wk Refractory to lenalidomide and/or bortezomib Results (POM vs POM+Dex) Overall PR: 13% vs 34% Median DOR: 8.5 mo vs 7.9 mo Median PFS: 2.7 mo vs 4.7 mo Median OS: 14 mo vs 16.9 mo Moreau, et al. Sem Hematol. 2012;49:S33-S46. Quach H, et al. Leukemia. 2010;24: Richardson PG, et al. Proc ASH. 2011: Abstract 634. POM = pomalidomide Pomalidomide Toxicity Elotuzumab POM (n = 107) POM + DEX (n = 112) Neutropenia 45% 38% Thrombocytopenia 21% 19% Anemia 17% 21% Pneumonia 8% 19% Fatigue 8% 10% Thrombotic events, grade 3/4 3% 4% Discontinue due to AE 8% 10% -No grade 3/4 peripheral neuropathy Pomalidomide with or without dexamethasone shows good activity in patient refractory to lenalidomide and/or bortezomib. **FDA to make decision on application for pomalidomide by Feb 10 th, 2013** Humanized Mab against cell surface adhesion molecule CS1 Phase II trial with lenalidomide & dex (n=73) ORR 84% (48% ) Median PFS: 26.9 mo (10 mg/kg) & 18.6 mo (20 mg/kg) Toxicities: hematologic, hyperglycemia, pneumonia, diarrhea, fatigue, & hypokalemia ELOQUENT-1 & ELOQUENT-2 Phase III Trials Len/Dex ± Elotuzumab in previously untreated or relapsed/refractory myeloma Elotuzumab 10 mg/kg weekly Results not yet available Richardson PG, et al. Proc ASH. 2011;118: Abstract 634. Richardson PG, et al. Blood. 2012;120:abstr202. Mab = Monoclonal Antibody

11 Conclusions Expanding arsenal Newer combinations & sequences New agents Potential for cure??