A Multi-Center Phase I/II Trial of Carfilzomib and Pomalidomide with Dexamethasone (Car- Pom-d) in Patients with Relapsed/Refractory Multiple Myeloma

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1 A Multi-Center Phase I/II Trial of Carfilzomib and Pomalidomide with Dexamethasone (Car- Pom-d) in Patients with Relapsed/Refractory Multiple Myeloma Jatin J. Shah, MD 1, Edward A. Stadtmauer, MD 2, Rafat Abonour, MD 3, Adam D. Cohen, MD 4, William I. Bensinger, MD 5, Cristina Gasparetto, MD 6, Jonathan L. Kaufman, MD 7, Suzanne Lentzsch, MD 8, Dan T. Vogl, MD 2, Robert Z. Orlowski, MD, PhD 1, Erica L. Kim, MPH 9, Natalia Bialas 10, David D. Smith, PhD 10, Brian G.M. Durie, MD 11 1 MD Anderson Cancer Center, Houston, TX, USA 2 University of Pennsylvania Abramson Cancer Center, Philadelphia, PA, USA 3 Indiana University Simon Cancer Center, Indianapolis, IN, USA 4 Fox Chase Cancer Center, Philadelphia, PA, USA 5 Fred Hutchinson Cancer Research Center, Seattle, WA, USA 6 Duke University Medical Center, Durham, NC, USA 7 Winship Cancer Institute of Emory University, Atlanta, GA, USA 8 Columbia University Herbert Irving Comprehensive Cancer Center, NY, NY, USA 9 Academic Myeloma Consortium, Criterium, Inc., Culver City, CA & Saratoga Springs, NY, USA 10 Cedars Sinai Samuel Oschin Cancer Center, Los Angeles, CA, USA Academic Myeloma Consortium (AMyC)

2 PI Disclosures Research Funding: Onyx, Celgene, Novartis, Array Biopharma, Millennium Speaking : None Advisory Board: Onyx, Celgene, Array

3 Background Carfilzomib, a novel irreversible proteasome inhibitor, has demonstrated single-agent activity in relapsed and refractory multiple myeloma (RRMM), and has received FDA regulatory approval for this indication 1 In the pivotal phase II study, single-agent carfilzomib resulted in an ORR of 23.7%, a median DOR of 7.8 months, a median PFS of 3.7 months, and a median OS of 15.6 months 1,2 Pomalidomide is the third drug in the immunomodulatory agent (IMiD ) class, also with single-agent activity that has recently received FDA regulatory approval for patients with RRMM 3 In the pivotal phase II study, treatment with pomalidomide/low-dose dexamethasone resulted in an ORR of 29.2%, a median DOR of 7.4 months, a median PFS of 4.6 months, and a median OS of 14.9 months 3,4 1. Kyprolis [package insert]. South San Francisco, CA: Onyx Pharmaceuticals, Inc.; Siegel, et al. Blood Oct 4;120(14): Pomylast [package insert]. Summit, NJ: Celgene Corporation; Lelev, et al. Blood :

4 Background (continued) Preclinical and clinical data demonstrate that the combination of proteasome inhibitors and IMiDs can overcome resistance and improve response rates 1 5 The hypothesis is that the combination of carfilzomib and pomalidomide with dexamethasone (Car-Pom-d) would be highly active in RRMM Phase I data presented at ASH 2012 identified the maximum tolerated dose (MTD) of carfilzomib (27 mg/m 2 ), pomalidomide (4 mg), and dexamethasone (40 mg) in heavily treated RRMM with a median of 6 lines of prior therapy 6 1. Mitsiades N, et al. Blood. 2002;99: Hideshima T, et al. Blood 2002:96: Richardson PG, et al. Blood. 2010;116: Richardson PG, et al. J Clin Oncol. 2009;27: Wang M, et al. Blood. 2013;122: Shah, J, et al ASH Annual Meeting Abstracts 120(21): 74-.

5 Phase I MTD Cohort level 1 (carfilzomib 27 mg/m 2, pomalidomide 4 mg, dexamethasone 40 mg): 1 of 6 patients experienced a dose-limiting toxicity (DLT) of febrile neutropenia Cohort level 2 (carfilzomib 36 mg/m 2, pomalidomide 4 mg, dexamethasone 40 mg): 2 of 6 patients experienced DLTs consisting of grade 4 thrombocytopenia and grade 3 rash The MTD was established as carfilzomib 27 mg/m 2, pomalidomide 4 mg, dexamethasone 40 mg

6 Phase II Study Objectives Primary Objectives: To evaluate the overall response rate (ORR) of Car-Pom-d Safety Secondary Objectives: Duration of response (DOR) Time to progression Progression-free survival (PFS) Time to next therapy Overall survival

7 Study Design Phase II portion: planned enrollment of 82 efficacyevaluable patients The study was designed to detect an improvement in response rate from 35% to 50% with 81% power and a Type I error rate of 0.05 Simon s optimal two-stage design: First stage: 27 patients enrolled (11/27 responses needed) Second stage: 55 additional patients enrolled for a total of 82 efficacy-evaluable patients

8 Cycles 1 6: 28-day cycle Carfilzomib Treatment Schema Carfilzomib dose on days 1 and 2 of cycle 1 was 20 mg/m 2 ; escalated to 27 mg/m 2 starting on day 8 of cycle 1 Carfilzomib was infused over 30 minutes Pomalidomide 1 21 Dexamethasone Concomitant medications: Anti-viral therapy Anticoagulation: aspirin 81 mg; LMWH in aspirin-intolerant patients Cycles 7+ : maintenance cycles Carfilzomib dosed on days 1, 2, 15, 16 Pomalidomide/dexamethasone were unchanged Patients treated until progressive disease or unacceptable toxicity

9 Key Inclusion Criteria Relapsed and/or refractory multiple myeloma All patients must have received prior lenalidomide therapy and have been determined to be refractory Refractory defined as 25% response or progression during therapy or within 60 days after completion of a regimen Patients must have had full or maximally tolerated dose of lenalidomide administered for a minimum of at least two completed cycles of therapy Measurable disease ECOG 0 2 Adequate hematologic, renal, liver, and cardiac function

10 Patient Demographics Characteristic N=79 Sex, n (%) Male 50 (63%) Female 29 (37%) ECOG performance status, n (%) 0 35 (44%) 1 39 (49%) 2 5 (6%) Median age, years (range) 64 years (41 78) Number of prior regimens, median (range) 5 (1 12) Median time since initial diagnosis, years (range) 4.9 years (1.2 23)

11 Prior Therapies Received Therapy, n (%) Prior stem cell transplant 44/74* (59%) Prior bortezomib** 66/74* (89%) Prior lenalidomide Lenalidomide-refractory 79/79 (100%) 79/79 (100%) * Five patients did not have complete prior therapy data available ** Includes multiple bortezomib combinations **29 of 32 (91%) patients in the phase I portion were bortezomib-refractory

12 Baseline FISH/Cytogenetics FISH/Cytogenetics, n (%) N=79* Del(13) by FISH 34% Hyperdiploid 32% Del(17p) / p53 22% t(11;14) 21% Hypodiploid 11% t(4;14) 10% msmart risk stratification, n (%) N=75** High risk 18 (24%) Intermediate risk 19 (25%) Low risk 38 (51%) **4 patients did not have complete FISH/cytogenetics data Del(1) 9% t(14;16) 7% Del(13) / RB locus 6% *Up to N=79, or as many cytogenetics tests that were reported

13 Treatment-Related Hematologic Adverse Events (N=79) Adverse event Grade 1, n Grade 2, n Grade 3, n Grade 4, n All grades, n (%) Neutropenia (34%) Anemia (32%) Thrombocytopenia (28%) Febrile neutropenia (4%) Toxicities were generally reversible and manageable

14 Treatment-Related Non-Hematologic Adverse Events (N=79) Grade 1, Grade 2, Grade 3, Grade 4, All grades, Adverse event, n n n n n n (%) Fatigue (42%) Dyspnea (28%) Muscle spasms (18%) Diarrhea (16%) Skin, rash, pruritis (13%) Pneumonia* (11%) Hypocalcemia (10%) Creatinine elevated (8%) Peripheral sensory neuropathy (6%) DVT/PE/VTE* (6%) Cardiac failure, congestive (3%) *1 grade 5 pneumonia event and 1 grade 5 pulmonary embolism event; both treatment-related

15 Clinical Activity: Response Rates Best overall response N=79 VGPR 21 (27%) PR 34 (43%) MR 10 (13%) SD 13 (16%) PD 1 (1%)

16 Clinical Activity: Response Rates Best overall response N=79 VGPR 21 (27%) PR 34 (43%) MR 10 (13%) SD 13 (16%) PD 1 (1%) ORR = 70%

17 Clinical Activity: Response Rates Best overall response N=79 VGPR 21 (27%) PR 34 (43%) MR 10 (13%) SD 13 (16%) PD 1 (1%) ORR = 70% CBR = 83%

18 Duration of Response Median DOR = 17.7 months

19 Progression-Free Survival Median PFS = 9.7 months Median 6 cycles of therapy (range, 1 23)

20 Median Overall Survival Not Reached at 18 Months

21 Best overall response, n Responses by Risk Status* High n=18 (24%) Intermediate n=19 (25%) Standard n=38 (51%) VGPR PR MR SD PD ORR 14/18 (78%) 10/19 (53%) 28/38 (74%) Responses are preserved in patients with high risk FISH/cytogenetics * msmart risk classification; 4 patients did not have complete FISH/cytogenetics data

22 Survival and Risk Status Progression-Free Survival Overall Survival PFS and OS are sustained independent of risk status

23 Outcomes for Patients with Deletion 17p

24 Conclusions The combination of Car-Pom-d is highly active in this heavily pretreated, lenalidomide-refractory patient population Patients had received a median of 5 prior lines of therapy; 49% of patients had high/intermediate risk cytogenetics at baseline VGPR 27% ORR 70% CBR 83% DOR (median) 17.7 months PFS (median) 9.7 months OS (median) > 18 months Response rates, PFS, and OS were preserved independent of FISH/cytogenetic risk status The regimen was well tolerated with no unexpected toxicities Enrollment is nearly complete in this phase II trial; subsequent dose escalation of carfilzomib in less heavily treated patients with 1 3 lines of prior therapy is planned

25 Acknowledgment Academic Myeloma Consortium: Dr. Brian Durie Unique collaboration of Academic Myeloma Centers of Excellence Onyx and Celgene: Collaboration between two pharmaceutical companies Patients/Caregivers/Families Research staff

26 Columbia University Department of Medicine Division of Hematology/Oncology