Update on Novel Combinations for Relapsed/Refractory Disease: Approved Drugs James R. Berenson, MD Medical & Scientific Director Institute for Myeloma & Bone Cancer Research Los Angeles, CA

Treatment Choices + + + + + + + Anthracyclines Thal Bortezomib Doxorubicin PLD Thal Bortezomib Carfilzomib Chemotherapy IMiDs Proteasome inhibitors Pom + + + + + + Len Steroids Clarithromycin Alkylating agents Melphalan Cyclophosphamide Bendamustine Dex Methylpred + Prednisone Clinical Trials Novel Combinations Investigational Drugs

Individualize your choice for the myeloma patient based on: How active is the patient? Mobility? Is potential neuropathy an issue? (e.g.- surgeon, pianist) Responseand for how long? Side effects and tolerability Work/ Lifestyle Prior Treatments Diabetes mellitus (steroids) Cardiac (Doxorubicin, PLD) Neuropathy (Thalidomide) Renal, Bone, Marrow, Subjective, Rate of ProgressionGenetics? Disease characteristics Co-morbid conditions

Principles of Treating Relapsed/Refractory Multiple Myeloma Be sure a patient has really progressed before changing therapy REPEAT MYELOMA LABS! Try to use drugs patient has not seen before HOWEVER, progression on one drug in combination does not mean that drug will not be effective w/ another agent e.g., pts progressing from bortezomib w/ melphalan often respond to bortezomib w/ PLD Even different drugs in the same class may be active so that bortezomib+melphalan failures may respond to other alkylating agents- cyclophosphamide or bendamustine LEN failures may respond to THAL and vice versa pts progressing from a drug at one dose may respond to the same drug at a higher dose- e.g., LEN the same combination may be effective again if the patient has not seen the combination in a long time

Single Agent Bortezomib Relapsed/Refractory Multiple Myeloma Initial approval in multiple myeloma based on phase II data Only single agent to demonstrate a statistically significant survival advantage (APEX) Study Regimen Evaluable Patients (n) Overall Response* Median OS (mos) SUMMIT Bortezomib 1.3 mg/m2 202 27% 17 CREST 1.0 mg/m2 54 30% 38% 26.7 Not yet reached APEX Dex 40 mg 315 312 43% 18% 29.8 23.7 PHASE II PHASE III P = .0272 *EBMT criteria 5

Efficacy and Safety of Bendamustine plus Bortezomib in R/RMM: A Phase 1/2 trial Patients were assigned to one of 3 cohorts receiving doses of intravenous bendamustine at 50 mg/m2 (cohort 1), 70 mg/m2 (cohort 2), or 90 (cohort 3) mg/m2 in combination with a fixed dose of intravenous bortezomib (1.0 mg/m2) according to the schedule in Figure 1. Berenson et al., Brit J Haematol, in press

Bendamustine & Bortezomib: Results No DLT was observed at any dose level. 50 mg/m2 (n = 5) 70 mg/m2 (n = 4) 90 mg/m2 (n = 5) The maximum dose of bendamustine (90 mg/m2) was well tolerated in combination with bortezomib 1.0 mg/m2 and was designated as the MTD Overall response rate Overall 48% (1 CR, 2 VGPR, 9 PR, & 7 MR) At MTD (90 mg/m2) 52% Bortezomib-exposed (n=31) 42% Alkylator-exposed (n=28) 46% Berenson et al., Brit J Haematol, in press

Bendamustine (B) w/ Lenalidomide (L) and Dexamethasone (D): Phase 1/2 Trial R/R MM patients N=29 Regimen (28-day cycles) B 75-100 mg/m2 d1 & 2 L 5-10 mg qd d1-21 Dex 40 mg PO weekly MTD: B 75/ L 10/ D 40 Results (only 25 considered evaluable for response) ORR (> PR): 52% w/ 24% VGPR MR 24% PFS: 6.1 mo Lentzsch et al. Blood 2012

Bortezomib + PLD vs. Bortezomib in Previously Treated MM 1° Endpoint: TTP 2° Endpoints: OS*, ORR N=646 (n=322) RANDOMI ZE q 3 weeks up to 8 cycles Days 1 4 8 11 q 3 weeks up to 8 cycles (n=324) BORT 1.3 mg/m2 PLD 30 mg/m2 *Not enough events to determine statistical significance in overall survival. ORR=overall response rate; OS=overall survival; TTP=time to progression. Doxorubicin HCl liposome injection Prescribing Information, Rev’d May 2007 9

Bortezomib ± PLD MMY-3001 Trial *By EBMT criteria Response* B (n = 322) B+D (n = 324) P value CR + nCR 11% 13% PR 39% 40% ORR 41% 44% 0.43 Efficacy DOR, months 7.0 10.2 0.0008 TTP, months 6.5 9.3 0.000004 An overall survival advantage was observed for the combination arm (P=0.0476) Survival rate (15 months) 65% 76% 0.03 Orlowski et al. J Clin Oncol 25:3892-901 (2007) 10

More Frequent Dosing with PLD Improves Anti-Myeloma Effect in a SCID-hu MM Model Weekly Dosing1 Daily Dosing2 1Twenty days post-implantation, mice received i.p. injection of PLD once weekly. Human IgG was measured weekly in the mouse serum by ELISA. 2Seventeen days post-implantation, mice received i.p. injection of PLD once daily for three consecutive days weekly. Human IgG was measured weekly in the mouse serum by ELISA. Campbell et al. Br J Haematol 2006

Bortezomib + PLD + Dexamethasone for Patients with Previously Untreated Myeloma: A Phase II Trial Dexamethasone 40 mg IV Bortezomib: 1.0 mg/m2 IV Cycle repeats PLD: 5 mg/m2 IV infusion Days 1 2 3 4 5 6 7 8 9 10 11 29 Berenson et al. Brit J Haematol, 2011 12

DVD: Response Rates Response Type Number of Patients (N = 35) Complete Response (CR) (no serum M-protein) 7 (20%) Very Good Partial Response (VGPR) (≥ 90% decrease in serum M-protein) 3 (8.6%) Partial Response (PR) (50-74% decrease in serum M-protein) 15 (42.9%) Minor Response (MR) (25-49% decrease in serum M-protein) 5 (14.3%) Objective Response (CR+VGPR+PR+MR) 30 (85.8%) Stable Disease (SD) Disease Control (CR+VGPR +PR+MR+SD) 33 (94.4%) Progressive Disease (PD) (>25% increase in serum M-protein) 2 (5.7%) Berenson et al. Brit J Haematol, 2011

Comparison of Adverse Events w/ Modified DVD vs Conventional Dosing Adverse Event Comparison Between DVD (Current Study) and Standard Dosing (Jakubowiak et al., Blood 2009).

Phase II Study of Bortezomib plus Lenalidomide and Dex (VRD) in Rel/Ref MM: Updated Results After >2 Years’ Follow-up1 Endpoints: Primary: PFS; Secondary: ORR (≥MR), DOR, TTP, OS, safety Patients: 64 pts with relapsed/refractory MM; median age 65 years (range 32–83); ISS stage I/II/III/unknown (%): 27/25/23/25; median 2 (range 1–3) prior therapies Study design: Anticoagulation with aspirin ± warfarin or LMWH, and antiviral prophylaxis against herpes zoster were required 15 Richardson PG et al. ASH 2010, abstract #3049 15

Phase II Study of Bortezomib plus Lenalidomide and Dex (VRD) in Rel/Ref MM: Updated Results After >2 Years’ Follow-up Results: 62 pts evaluable for response Outcomes Median, mos 1-yr, % 2-yr, % TTP 9.5 37 16 PFS 36 15 OS 26 86 55 Best response,% CR/nCR 11/14 PR/VGPR 36/3 ORR (≥MR) 78 Median duration of ≥MR: 8.3 months Median duration of ≥PR: 8.4 months Gr ≥3 AE, % VRD (n=64) Neutropenia 30 Thrombocytopenia 22 Lymphopenia 11 Leukopenia 9 Hyperglycemia Hyponatremia 8 Hypophosphatemia Fatigue 5 Diarrhea 3 Limb edema Pain in extremity 2 Safety: Median cycles received: 11 (range 1–48) Median treatment duration: 7.9 months (range 0.4–36); 66% of pts completed ≥8 cycles with all three drugs Richardson PG et al. ASH 2010, abstract #3049 16 16

DVD-R (Bortezomib + PLD + Dexamethasone + Lenalidomide) for Patients with R/R MM: A Phase II Trial Dexamethasone 40 mg IV Bortezomib: 1.0 mg/m2 IV Cycle repeats PLD: 4 mg/m2 IV infusion Days 1 2 3 4 5 6 7 8 9 10 11 12 13 14 29 Len 10 mg po qd d1-14 Berenson et al., Leukemia 2012

Percent w/o Progression DVD-R: Response Rate N=39 Complete Response (CR) 8* (21%) (no serum M-protein) Very Good Partial Responses (VGPR) 4 (10%) (> 90% decrease in serum M-protein) Partial Response (PR) 7 (18%) (50-74% decrease in serum M-protein) Minor Response (MR) 14 (36%) (25-49% decrease in serum M-protein) Objective Response (CR+VGPR+PR+MR) 30 (85%) Stable Disease (SD) (change in M-protein + 25%) Disease Control (CR+VGPR+PR+MR+SD) 37 (95%) Progressive Disease (PD) 2 (5%) (>25% increase in M-protein) *Based on the modified Blade’ criteria Percent w/o Progression *Based on the modified Blade’ criteria *Based on the modified Blade’ criteria *Based on the modified Blade’ criteria

DVD-R Study: Adverse Events Grade 3 adverse events included: 6 reversible neutropenia, 4 reversible anemia, 4 pneumonia, 1 dyspnea, 3 reversible thrombocytopenia, 1 reversible peripheral neuropathy, 1 mental confusion, 1 hypophosphatemia, 1 fall, 1 skin BCC, 1 allergic reaction to moxifloxacin, 1 dysphagia, 1 syncope, 1 respiratory distress. Grade 4 adverse events included: 1 reversible thrombocytopenia & 1 anemia No cases of stomatitis or hand-foot syndrome reported! Treatment-emergent peripheral neuropathy (25%): Grade 1: n=8 (20%) Grade 2: n=1 (2.5%) Grade 3: n=1 (2.5%) Percent w/o Progression

Retreatment w/ IMiDs for MM Patients Retrospective study in 140 pts treated firstline w/ THAL/DEX- 58% LEN/DEX- 42% Retreatment w/ a regimen containing THAL- 24% LEN- 76% # of treatments before retreatment - median of 2 (range 1-6) 89% received IMiD w/ DEX 113 considered evaluable for response 44% > PR MR not reported LEN (n=48) THAL (n=11) (n=58) THAL (n=23) > PR 54% 20% 48% 30% Madan et al. Blood 2011

PX-171-003: Study Overview Phase 2 Study Population Study expanded to registration trial Phase 2 Study Population PX-171-003-A1 (N=266) PX-171-003-A0 (N=46) Progressive disease required at study entry Relapsed from ≥2 prior lines of therapy Must include bortezomib Must include thalidomide or lenalidomide Refractory to last regimen Carfilzomib for Injection* days 1,2,8,9,15,16 (28-day cycles) Maximum 12 cycles Dosing regimen, premedication, and hydration were defined in 003-A0 *Cycle 1, 20 mg/m2 Cycle 2 and beyond, 27 mg/m2 Primary endpoint: Overall response rate Assessed by an Independent Review Committee, using International Myeloma Working Group criteria Adapted from Siegel D, et al. ASCO 2011. Abstract 8027 (poster presentation). 22

PX-171-003-A1 (N=266): Disease characteristics Median prior regimens (range) 5 (1-20) Median years since diagnosis (range) 5.35 (0.5-22.3) Prior transplant 74.4% Refractory status to most recent therapy Refractory: Progression during most recent therapy Refractory: Progression within 60 days after completion of most recent therapy Refractory: ≤25% response to treatment Relapsed: Progression after 60 days post treatment 14.3% 6.0% 5.3% Creatinine clearance <30 mL/min 2.3% Median serum b2-microglobulin (range) 4.3 (0.4-20.5) Cytogenetics Normal/Favorable Unfavorable Unknown 59.8% 28.2% 12.0% 23

PX-171-003-A1: Response N=266 Response rates* Overall response rate (ORR) Complete response Very good partial response Partial response 61 (22.9%) 1 (0.4%) 13 (4.9%) 47 (17.7%) Median duration of response (95% CI) 7.8 months (5.6-9.2) *As assessed by the Independent Response Review Committee 24

Carfilzomib in MM Patients Following 1-3 Prior Therapies Novel Agents for Frontline Multiple Myeloma: A New Era of Efficacy Carfilzomib in MM Patients Following 1-3 Prior Therapies 004, Phase II 1:1 Carfilzomib Cohort 1 20 mg/m2 Relapsed / Refractory Multiple Myeloma 1-3 Prior Therapies N = 165 Cohort 2 20 mg/m2→27 mg/m2 Bortezomib-treated Bortezomib-naïve Carfilzomib: IV, days 1, 2, 8, 9, 15, and 16 every 28 days for up to 12 cycles Bortezomib-naïve Bortezomib-treated N 129 36 Median age 65 years 63 years Median # prior therapies 2 3 Stewart AK, et al. ASCO Meeting Abstracts. 2011;29(15 suppl):8026. Stewart K, et al. Hematologica. 2010;95(S2). Abstract 1099. Vij R, et al. ASH Annual Meeting Abstracts. 2011;118(21):813. 25

Carfilzomib Monotherapy MM Patients With 1-3 Prior Therapies Novel Agents for Frontline Multiple Myeloma: A New Era of Efficacy Carfilzomib Monotherapy MM Patients With 1-3 Prior Therapies Bortezomib-Treated Cohort 1 (20 mg/m2 Carfilzomib) n = 34 ORR 21% CBR (> MR) 33% Median TTP 8.1 months Median DOR (> PR) 11.5 months Bortezomib-naïve Cohort 1 (20 mg/m2) n = 59 Cohort 2 (20→27 mg/m2) n = 70 ORR 42% 52% CBR 59% 64% CR 3% 2% VGPR 14% 27% Median TTP 8.3 mo Not reached Median DOR 13.1 mo Median PFS 8.2 mo Stewart K, et al. Hematologica. 2010;95(S2). Abstract 1099. Vij R, et al. ASH Annual Meeting Abstracts. 2011;118(21):813. 26

Carfilzomib / Lenalidomide / Dex (CRd) in Relapsed / Refractory MM Novel Agents for Frontline Multiple Myeloma: A New Era of Efficacy Carfilzomib / Lenalidomide / Dex (CRd) in Relapsed / Refractory MM Carfilzomib Lenalidomide Low-dose dex MM: 1-3 Prior Therapies N = 52 1o Endpoint ORR 2o Endpoint DOR, TTP, OS, PFS, Safety CRd N = 51 Median age 63 years Median # of prior therapies Prior bortezomib Prior lenalidomide Prior lenalidomide and bortezomib Prior thalidomide 2 85% 73% 50% 44% Wang M, et al. ASCO Meeting Abstracts. 2011;29(15 suppl):8025. 28

Carfilzomib / Lenalidomide / Dex (CRd) in Relapsed/Refractory MM Novel Agents for Frontline Multiple Myeloma: A New Era of Efficacy Carfilzomib / Lenalidomide / Dex (CRd) in Relapsed/Refractory MM Response CRd N = 51 ORR 78% CR / nCR 24% VGPR 18% PR 37% Grade 3/4 Adverse Events CRd N = 51 Neutropenia 23% Thrombocytopenia 15% Anemia Hypophosphatemia 13% Fatigue 12% ORR, overall response rate; CR, complete response; nCR, near complete response; VGPR, very good partial response; PR, partial response. Wang M, et al. ASCO Meeting Abstracts. 2011;29(15 suppl):8025. 29

Nontraditional intrapatient Phase I/II trial A Phase I/II Study of Carfilzomib as a Replacement for Bortezomib for Multiple Myeloma Patients Failing Bortezomib-Containing Regimens Nontraditional intrapatient Phase I/II trial Eligibility: Progressive disease while on bortezomib or relapsed within 12 wks of the last dose of bortezomib in a combination regimen Carfilzomib replaces bortezomib in combination with: Alkylating agent Anthracycline Glucocorticosteroid IMiD

Study Design (cont’d) Study treatment Carfilzomib starting at 20 mg/m2 for the 1st cycle increased to 27, 36 and 45 mg/m2 during cycles 2, 3 and 4, respectively if no DLT is observed DLT considered > Grade 2 administered on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle Cycle length, schedule(s) and dose(s) of other drugs identical to that of the previous bortezomib-containing regimen A patient must complete a minimum of a full cycle without DLT before continuing onto a subsequent cycle (cycles 1-4 only) Maximum # of cycles- 8

Results Demographics Enrolled (N) 32 Efficacy (N) 24 Age (median) 67 Sex (M:F) 21:11 Prior Regimens Number of prior regimens- median (range) 6 (1-18) Number of prior bortezomib-containing regimens- median (range) 2 (1-13) Regimen Details Cycle length 8 pts- 21-day 24 pts- 28-day Cycles completed, median (range) 3 (range 0-12) Follow-up median (range) 5.9 mo (0.4-14.4 mo) Number of DLTs 8 (25%)

Regimen in addition to carfilzomib (N=32) Dexamethasone 9 (28%) Cyclophosphamide+ ascorbic acid 5 (16%) Cyclophosphamide+ascorbic acid+dexamethasone 1 (3%) Melphalan Bendamustine 3 (9%) Bendamustine+methylprednisolone PLD PLD+dexamethasone Lenalidomide 2 (6%) Lenalidomide + dexamethasone Lenalidomide + dexamethasone + PLD 1 (3% Thalidomide + dexamethasone Thalidomide + lenalidomide + bendamustine + clarithromycin + methylprednisolone

Efficacy (N=24) PD 2 8% SD 4 17% MR 5 21% PR 7 29% VGPR CR Best Response # of Patients % PD 2 8% SD 4 17% MR 5 21% PR 7 29% VGPR CR Overall Response Rate (PR+VGPR+CR) 13 54% Clinical Benefit Rate (MR+PR+VGPR+CR) 18 75%

Summary Intrapatient Phase I/II trial of MM patients refractory to bortezomib combination therapy with and without IMiDs Treatment with same regimen w/ carfilzomib (CAR) replacing bortezomib CAR escalated from 20 to 27, 36, and 45 mg/m2 during cycles 1-4; maximum of 8 cycles MTD for one regimen (CY+CAR) reached at the maximum dose of CAR (45 mg/m2) with no DLT Well tolerated Clinical benefit rate 75% including 8% CR, 17% VGPR, 29% PR, & 21% MR Responses observed with all drugs!

A Phase I/II Trial of Weekly Carfilzomib in Combination With IV Dexamethasone for R/R Multiple Myeloma Phase I/II, open-label, multi-center trial investigating weekly carfilzomib + dexamethasone in R/R MM patients Phase I: 28-day cycle Carfilzomib 45, 56 or 70 mg/m2 on days 1, 8 & 15 Dexamethasone IV at 40 mg days 1, 8, 15, & 22 Phase II: Carfilzomib at MTD on days 1, 8 & 15 Enrollment: second cohort (56 mg/m2) currently being treated!

Bortezomib + Vorinostat HDAC Inhibitor Vorinostat & Bortezomib for R/R MM: VANTAGE 088: Phase III Trial Bortezomib + Vorinostat Multiple Myeloma 1-3 Prior Therapies N = 637 R Bortezomib + Placebo Bortezomib + Vorinostat Bortezomib + Placebo P ORR 56% 41% < 0.0001 CBR 71% 54% Median PFS 7.63 mo 6.83 mo < 0.01 Median OS NR 28.1 mo 0.35 ORR, overall response rate; CBR, clinical benefit rate; PFS, progression-free survival; OS, overall survival. Dimopoulos MA, et al. ASH Annual Meeting Abstracts. 2011;118(21):811.

Vorinostat, Lenalidomide & Dexamethasone for R/R MM Vorinostat (300 or 400 mg, 1x daily) Lenalidomide (10, 20, 25 mg daily) Dexamethasone (40 mg weekly) Relapsed / Refractory MM N = 28 1:1 Response Vorinostat / Lenalidomide / Dexamethasone N = 28 ORR 46% CR 7% > SD 86% Serious AE Neutropenia, diarrhea, ↑ QTc, extrasystole, dehydration, ↑ troponin, fever Grade 3 DVT in 2 patients No treatment-related deaths Siegel D, et al. Blood. 2009;114(22). Abstract 305. Vorhees PM, et al. Blood. 2009;114(22). Abstract 306.

Novel Combinations of Approved Drugs Greatly Expand the Therapeutic Options for R/R Myeloma Patients! Approved drugs Novel combinations Modifications of dose and schedule Improve efficacy Better tolerability Many new drugs in development Similar targets Proteasome inhibitors- carfilzomib (FDA-approved!) IMiDs- pomalidomide New classes of agents HDAC inhibitors- vorinostat, panobinostat Monoclonal antibodies Anti-CS-1- elotuzumab Anti-CD40- dacetuzumab MTOR inhibitors- temsirolimus PI3K inhibitors- perifosine