December 7-10, 2013 New Orleans, Louisiana

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December 7-10, 2013 New Orleans, Louisiana Updates in Multiple Myeloma CCO Independent Conference Coverage of the 2013 Annual Meeting of the American Society of Hematology* December 7-10, 2013 New Orleans, Louisiana *CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs. Jointly sponsored by the Annenberg Center for Health Sciences at Eisenhower and Clinical Care Options, LLC This program is supported by educational grants from This program is supported by an educational grant from

Active treatment + PFS follow-up phase PD or unacceptable toxicity FIRST: Lenalidomide/Dexamethasone vs MPT in NDMM SCT-Ineligible Patients[1] Active treatment + PFS follow-up phase Phase III N = 1623 Randomization 1:1:1 Arm A Continuous Rd Len + LoDex Continuously Lenalidomide 25 mg Days 1-21/28 LoDex 40 mg Days 1, 8, 15, 22/28 PD or unacceptable toxicity subsequent anti-MM Tx PD, OS, and Len + LoDex 18 cycles (72 wks) Lenalidomide 25 mg Days 1-21/28 LoDex 40 mg Days 1, 8, 15, 22/28 Arm B Rd18 ISS, International Staging System; Len, lenalidomide; LoDex, low-dose dexamethasone; Mel, melphalan; MM, multiple myeloma; MPT, melphalan/prednisone/thalidomide; NDMM, newly diagnosed multiple myeloma; OS, overall survival; PD, progressive disease; PFS, progression-free survival; Pred, prednisone; Rd, lenalidomide/low-dose dexamethasone; SCT, stem-cell transplantation; Thal, thalidomide; Tx, treatment. Mel + Pred + Thal 12 cycles[2] (72 wks) Melphalan 0.25 mg/kg Days 1-4/42 Prednisone 2 mg/kg Days 1-4/42 Thalidomide 200 mg Days 1-42/42 Arm C MPT Pts > 75 yrs: LoDex 20 mg Days 1, 8, 15, 22/28; Thal[3] 100 mg Days 1-42/42; Mel[3] 0.2 mg/kg Days 1-4. Stratification: age, country, and ISS stage. 1. Facon T, et al. ASH 2013. Abstract 2. 2. Facon T, et al. Lancet. 2007;370:1209-1218. 3. Hulin C, et al. J Clin Oncol. 2009;27:3664-3670.

FIRST Trial: Progression-Free Survival 100 80 60 40 20 Median PFS Rd (n = 535) 25.5 mos Rd18 (n = 541) 20.7 mos MPT (n = 547) 21.2 mos HR: Rd vs MPT: 0.72 (P = .00006) Rd vs Rd18: 0.70 (P = .00001) Rd18 vs MPT: 1.03 (P = .70349) Patients (%) MPT, melphalan/prednisone/thalidomide; PFS, progression-free survival; Rd, lenalidomide/low-dose dexamethasone. 72 wks 6 12 18 24 30 36 42 48 54 60 Mos 1. Facon T, et al. ASH 2013. Abstract 2. Reproduced with permission.

MPR or CPR vs Lenalidomide/LoDex in Elderly Patients With NDMM 1st randomization 2nd randomization Rd (n = 220), 9 28-day courses R: 25 mg Days 1-21 d: 40 mg Days 1,8,15,22 R maintenance 28-day cycle until relapse R: 10 mg/day Days 1-21 Phase II trial: transplant- ineligible pts with NDMM (N = 660) MPR (n = 217), 9 28-day courses M: 0.18 mg/kg Days 1-4 P: 1.5 mg/kg Days 1-4 R: 10 mg Days 1-21 PR maintenance 28-day cycle until relapse P: 25 mg 3 x wk R: 10 mg/day Days 1-21 C, cyclophosphamide; CPR, cyclophosphamide/prednisone/lenalidomide; d, low-dose dexamethasone; LoDex, low-dose dexamethasone; M, melphalan; MPR, melphalan/prednisone/lenalidomide; NDMM, newly diagnosed multiple myeloma; P, prednisone; QOD, every other day; R, lenalidomide; Rd, lenalidomide/low-dose dexamethasone. CPR (n = 222), 9 28-day courses C: 50 mg Days 1-21 P: 25 mg 3 x wk R: 25 mg Days 1-21 Dose adjustments for patients > 75 yrs of age: dexamethasone 20 mg/wk; melphalan 0.13 mg/kg; cyclophosphamide 50 mg QOD on days 1-21. 12. Palumbo A, et al. ASH 2013. Abstract 536.

CPR vs MPR vs Rd Survival Outcome: PFS and OS Median follow-up 26 mos PFS OS 0.25 0.50 0.75 1.00 0.25 0.50 0.75 1.00 Median PFS CPR 24 mos MPR 27 mos Rd 22 mos 2-Yr OS CPR 84% MPR 81% Rd 80% Patients (%) CPR, cyclophosphamide/prednisone/lenalidomide; MPR, melphalan/prednisone/lenalidomide; OS, overall survival; PFS, progression-free survival; Rd, lenalidomide, low-dose dexamethasone. Rd vs MPR: HR: 1.189; Cl: 0.911-1.551; P = .20 Rd vs CPR: HR: 1.032; Cl: 0.799-1.332; P = .81 Rd vs MPR: HR: 0.954; Cl: 0.629-1.446; P = .82 Rd vs CPR: HR: 1.033; Cl: 0.680-1.570; P = .88 10 20 30 40 50 10 20 30 40 50 Mos Mos 12. Palumbo A, et al. ASH 2013. Abstract 536. Reproduced with permission.

Carfilzomib With Thalidomide and Dexamethasone Intensification* (1 cycle) Induction (Four 28-day cycles) Consolidation (Four 28-day cycles) Carfilzomib 20/27 mg/m2 Days 1, 2, 8, 9, 15, 16 Carfilzomib 27 mg/m2 Days 1, 2, 8, 9, 15, 16 Phase II open-label dose-escalation trial (N = 70) Thalidomide 200 mg Days 1-28 Thalidomide 50 mg Days 1-28 ASCT, autologous stem cell transplantation. Dexamethasone 40 mg Days 1, 8, 15, 21 Dexamethasone 40 mg Days 1, 8, 15, 21 *High-dose melphalan 200 mg/m2 plus ASCT. Carfilzomib 27 mg/m2 dose escalation: cohort 1 treatment as above; cohort 2 to 36 mg/m2; cohort 3 to 45 mg/m2; cohort 4 to 56 mg/m2 14. Sonneveld P, et al. ASH 2013. Abstract 688.

Carfilzomib/Thalidomide/Dexamethasone: Response and AEs Patient Response, % High-Risk* Patients (n = 30) Standard-Risk Patients (n = 25) All Patients (N = 70) CR/sCR 57 48 51 ≥ VGPR 90 76 84 PR 96 *t(4;14) and/or del(17p) and/or 1q and/or ISS3. Grade 3/4 AEs ≥ 5% by carfilzomib dose: 20/27 mg/m2: GI toxicity, 16%; skin, 12%; metabolism, 10%; myelotoxicity, 8%; fatigue, 8%; cardiovascular, 6% 20/36 mg/m2: metabolism, 10%; myelotoxicity, 8%; GI toxicity, 5% Neuropathy < 5% in both cohorts AEs, adverse events; CR, complete response; GI, gastrointestinal; PR, partial response; sCR, stringent complete response; VGPR, very good partial response. 14. Sonneveld P, et al. ASH 2013. Abstract 688. Reproduced with permission.

Progression-Free Survival and Overall Survival, PAD vs VAD PFS, Censored at Allo SCT OS 100 100 75 75 PAD PAD Cumulative Percentage 50 VAD 50 Cumulative Percentage VAD N F N D 25 25 VAD 414 311 VAD 414 182 Allo SCT, allogeneic stem-cell transplant; D, number of patients who died; F, number of patients who progressed; LR, log-rank; N, number of patients in study arm; OS, overall survival; PAD, bortezomib/doxorubicin/dexamethasone; PFS, progression-free survival; VAD, vincristine/doxorubicin/dexamethasone. PAD 413 284 PAD 413 155 Cox LR stratified P = .002 Cox LR stratified P = .05 12 24 36 48 60 72 84 12 24 36 48 60 72 84 Mos Mos Pts at Risk, n VAD 414 292 202 143 100 59 30 10 PAD 413 326 240 170 122 82 45 17 Pts at Risk, n VAD 414 361 327 278 249 182 79 20 PAD 413 375 343 307 271 193 101 28 HR: 0.76 (95% CI: 0.64-0.91; P = .001) HR: 0.78 (95% CI: 0.64-0.91; P = .01) 20. Sonneveld P, et al. ASH 2013. Abstract 404. Reproduced with permission.

Survival of Patients With Renal Failure, PAD vs VAD PFS OS N D VAD, BLC < 2 368 159 VAD, BLC > 2 45 35 PAD, BLC < 2 376 149 PAD, BLC > 2 36 16 N F VAD, BLC < 2 368 271 VAD, BLC > 2 45 39 PAD, BLC < 2 376 260 PAD, BLC > 2 36 23 100 100 75 75 Cumulative Percentage 50 Cumulative Percentage 50 BLC, baseline creatinine level; D, number of patients who died; F, number of patients who progressed; N, number of patients in study arm; OS, overall survival; PAD, bortezomib/doxorubicin/dexamethasone; PFS, progression-free survival; VAD, vincristine/doxorubicin/dexamethasone. 25 25 12 24 36 48 60 72 84 12 24 36 48 60 72 84 Mos Mos 20. Sonneveld P, et al. ASH 2013. Abstract 404. Reproduced with permission.

Ixazomib in Combination With Lenalidomide and Dexamethasone 1 8 15 21 Induction: up to 16 21-day treatment cycles Ixazomib* Ixazomib Dex† Dex Lenalidomide 25 mg, Days 1-14 4 11 2 5 9 12 *Dose escalation, 3.0 or 3.7 mg †20/10 mg cycles 1-8/9-16 Maintenance Ixazomib maintenance Days 1, 4, 8, 11 21-day cycles ASCT, autologous stem-cell transplantation; Dex, dexamethasone; DLT, dose-limiting toxicity; LMWH, low–molecular-weight heparin; QD, every day; Rd, lenalidomide/low-dose dexamethasone; RP2D, recommended phase II dose; VTE, venous thromboembolism. Phase I: standard 3 + 3 schema, 33% dose increments, based on cycle 1 DLTs Phase II: treatment at the RP2D established for ixazomib in phase I (3.0 mg) VTE prophylaxis with aspirin 81-325 mg QD or LMWH while receiving Rd Stem cell collection allowed after cycle 4, with ASCT deferred until after 8 cycles 27. Richardson PG, et al. ASH 2013. Abstract 535.

Ixazomib Plus RD: ORR Over Course of Treatment 100 80 60 40 20 93% 95% 95% 9 16 2 21 7 6 50 48 Patients (%) 48 CR, complete response; DOR, duration of response; ORR, overall response rate; PR, partial response; RD, lenalidomide/dexamethasone; sCR, stringent complete response; VGPR, very good partial response. 32 24 20 After 4 Cycles After 8 Cycles Overall (N = 56) Median DOR 13.8 mos, ranging up to 18.8+ mos PR VGPR CR sCR 27. Richardson PG, et al. ASH 2013. Abstract 535. Reproduced with permission.

Summary: Treatment for Patients With Newly Diagnosed Multiple Myeloma In phase 3 results from FIRST trial, Rd therapy superior to MPT for PFS and OS with similar safety profiles In elderly patients, similar efficacy seen with MPR, CPR, and Rd treatment; MPR AEs worse than CPR and Rd Bortezomib-based treatment significantly improved PFS and OS in transplant-eligible NDMM patients vs VAD Lenalidomide-based maintenance therapy showed significantly higher PFS vs no maintenance or placebo, but greater risk of grade 3/4 neutropenia, VTE, thrombocytopenia, fatigue, and secondary malignancies Twice-wkly oral ixazomib plus lenalidomide/dexamethasone active in patients with NDMM AEs, adverse events; CPR, cyclophosphamide/prednisone/lenalidomide; MPR, melphalan/prednisone/lenalidomide; MPT, melphalan/prednisone/thalidomide; NDMM, newly diagnosed multiple myeloma; OS, overall survival; PFS, progression-free survival; Rd, lenalidomide/low-dose dexamethasone; VAD, vincristine/doxorubicin/dexamethasone; VTE, venous thromboembolism.

MM-003 Final Analysis: Pomalidomide/ LoDex vs HiDex: PFS and OS Median PFS, Mos POM + LoDex (n = 302) 4.0 HiDex† (n = 153) 1.9 Median OS, Mos POM + LoDex (n = 302) 13.1 HiDex† (n = 153) 8.1 1.0 0.8 0.6 0.4 0.2 1.0 0.8 0.6 0.4 0.2 HR: 0.72 P = .009 HR: 0.50 P < .001 Proportion of Patients Proportion of Patients HiDex, high-dose dexamethasone; LoDex, low-dose dexamethasone; OS, overall survival; PFS, progression-free survival; POM, pomalidomide. 0 4 8 12 16 20 24 PFS (Mos) 0 4 8 12 16 20 24 28 OS (Mos) *Primary endpoint. †85 pts (56%) on the HiDex arm received subsequent POM. 36. Dimopoulos MA, et al. ASH 2013. Abstract 408. Reproduced with permission.

MM-003: PFS Based on Cytogenetic Profile del(17p)/t(4;14) Standard Risk Median PFS, Mos POM + LoDex (n = 77) 3.8 HiDex (n = 35) 1.1 Median PFS, Mos POM + LoDex (n = 148) 4.2 HiDex (n = 72) 2.3 1.0 0.8 0.6 0.4 0.2 1.0 0.8 0.6 0.4 0.2 HR = 0.55 P < .001 HR = 0.44 P < .001 Proportion of Patients Proportion of Patients HiDex, high-dose dexamethasone; LoDex, low-dose dexamethasone; PFS, progression-free survival; POM, pomalidomide. 0 4 8 12 16 20 24 PFS (Mos) 0 4 8 12 16 20 24 PFS (Mos) 36. Dimopoulos MA, et al. ASH 2013. Abstract 408. Reproduced with permission.

Induction (cycles 1-6, 28-day cycle) Phase II Trial: Carfilzomib/Pomalidomide/ Dexamethasone in Patients With RRMM Induction (cycles 1-6, 28-day cycle) Carfilzomib 20 mg/m2 days 1,2 of cycle 1; 27 mg/m2 days 8,9,15,16 cycle 1, all days of following cycles Dexamethasone 40 mg Days 1, 8, 15, 22 N = 79 Pomalidomide 4 mg Days 1-21 LMWH, low–molecular-weight heparin; QD, every day; RRMM, relapsed/refractory multiple myeloma. Maintenance cycles: cycles 7+, 28-day cycle, carfilzomib 27 mg/m2 Days 1,2,15,16; dexamethasone and pomalidomide dosing remain unchanged Coagulation prophylaxis with aspirin 81 mg QD or LMWH in aspirin-intolerant patients Antiviral therapy administered with treatment All patients refractory to previous lenalidomide treatment 42. Shah JJ, et al. ASH 2013. Abstract 690.

Ixazomib in Patients With RRMM Not Refractory to Bortezomib Phase II Trial N = 32 < MR by 2 cycles or < PR by 4 cycles or PD anytime Add 40 mg/wk dexamethasone Continue treatment until progression Ixazomib 5.5 mg Days 1, 8, 15 28-day cycle 2-4 cycles ≥ MR by 2 cycles or ≥ PR by 4 cycles Continue treatment until progression MR, minimal response; PD, progressive disease; PR, partial response; RRMM, relapsed/refractory multiple myeloma. Patients receive standard supportive care, including antiemitics Key exclusions: grade ≥ 3 neuropathy (or grade 2 with pain); previous proteasome inhibitor therapy except bortezomib 44. Kumar SK, et al. ASH 2013. Abstract 1944.

Impact of α-1 Acid Glycoprotein Levels on Filanesib Treatment Single-Agent Filanesib (median 6 previous therapies) Low* High All Filanesib + Dex (median 8 previous therapies) 100 75 50 25 100 75 50 25 Survival (%) Survival (%) AAG, α-1 acid glycoprotein; Dex, dexamethasone; OS, overall survival. 0 6 12 18 24 30 36 OS (Mos) 0 6 12 18 24 30 36 OS (Mos) *Low AAG is associated with longer survival. 48. Lonial S, et al. ASH 2013. Abstract 285. Reproduced with permission.

Akt Inhibitor Afuresertib in Combination With Bortezomib and Dexamethasone Phase I (n = 15), dose escalation Phase II (n = 40), safety expansion cycles 1-8, 21-day cycles Afuresertib Dose escalation, 75-175 mg Days 1-21 Dexamethasone 20, 40 mg Days 1,4,8,11 IV, intravenously; PR, partial response; SQ, subcutaneously. Bortezomib, IV or SQ 1.0, 1.3 mg/m2 Days 1,4,8,11 Phase I: modified 3 + 3 schema; < 5 PRs, stop; ≥ 5 PRs, expand Phase I and II: cycle 9 and beyond, afuresertib monotherapy daily 49. Voorhees PM, et al. ASH 2013. Abstract 283.

Summary: Treatment of Patients With Relapsed/Refractory Multiple Myeloma Pomalidomide in combination with low-dose dexamethasone with or without carfilzomib showed activity in RR patients with a good safety profile Ixazomib, an oral proteasome inhibitor, showed activity used alone as well as in combination with dexamethasone Oral HDAC-6 inhibitor ACY-1215 showed clinical benefit in patients refractory to proteasome inhibitor and/or immunomodulatory agents, including bortezomib KSP inhibitor ARRY-520 (filanesib) showed higher OS in pts with lower α-1 acid glycoprotein levels Bortezomib-refractory patients responded to novel Akt inhibitor afuresertib combination therapy HDAC, histone deacetylase; KSP, kinesin spindle protein; OS, overall survival; RR, relapsed/refractory.

Summary: Treatment of Patients With RRMM Monoclonal antibody daratumumab well tolerated in combination with lenalidomide and dexamethasone Antibody-drug conjugate indatuximab ravtansine with lenalidomide and low-dose dexamethasone achieved responses (including CR) at MTD CD38 monoclonal antibody SAR650984 showed clinical response that correlated with bone marrow plasma cell clearance CR, complete response; MTD, maximum tolerated dose; RRMM, relapsed/refractory multiple myeloma.

Treatment of Multiple Myeloma: Conclusions Lenalidomide and dexamethasone until DP is standard of care for nontransplant patients with NDMM In NDMM transplant candidates, 3-drug regimens using immunomodulatory drugs and proteasome inhibitors pre- and posttransplant can prolong PFS and OS Lenalidomide maintenance until DP prolongs PFS and OS, with increased risk of secondary cancers in patients who received MP or high-dose therapy and ASCT ASCT, autologous stem-cell transplantation; DP, disease progression; MP, melphalan/prednisone; NDMM, newly diagnosed multiple myeloma; OS, overall survival; PFS, progression-free survival.

Treatment of Multiple Myeloma: Conclusions Pomalidomide with low-dose dexamethasone is active in RRMM (including 17p deletion) Carfilzomib/pomalidomide/low-dose dexamethasone increases response and is tolerated in RRMM Novel agents, including oral proteasome inhibitors, monoclonal antibodies/immunotoxins, KSP inhibitors, Akt inhibitors, and HDAC-6 inhibitors, demonstrate promising activity in RRMM 2 vs 3 drugs in early relapse setting will be addressed in coming mos with results from ongoing phase 3 trials Incorporation of novel therapies at all stages of disease is improving patient outcome in MM HDAC, histone deacetylase; KSP, kinesin spindle protein; MM, multiple myeloma; RRMM, relapsed/refractory multiple myeloma.