IFM Phase II Study: KRd Induction and Consolidation Before Len Maintenance Highly Effective in Newly Diagnosed MM New Findings in Hematology: Independent Conference Coverage of ASH 2016*; December 3-6, 2016; San Diego, California *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. KRd, carfilzomib/lenalidomide/dexamethasone; Len, lenalidomide; MM, multiple myeloma. This activity is supported by educational grants from Amgen, Celgene Corporation, Incyte, Merck, and Seattle Genetics.

KRd in Newly Diagnosed MM: Background For pts with newly diagnosed MM, current standard of care includes: Induction and consolidation with IMiDs, proteasome inhibitors, and corticosteroids High-dose melphalan and ASCT followed by lenalidomide maintenance Unclear whether further additional cycles of chemotherapy may improve survival Risk of bortezomib AEs may hamper benefit of additional therapy Carfilzomib: nonneurotoxic proteasome inhibitor that has demonstrated good results in both frontline and refractory/relapse settings[1-3] Current trial evaluated prolonged use of carfilzomib as a replacement for bortezomib in initial therapy and consolidation regimens[4] AE, adverse event; ASCT, autologous stem cell transplantation; IMiD, immunomodulatory drug; KRd, carfilzomib/lenalidomide/dexamethasone; MM, multiple myeloma. 1. Chen R, et al. Discov Med. 2016;22:121:189-199. 2. Jakubowiak AJ, et al. Blood. 2012. 3. Korde N, et al. JAMA Oncol. 2015;1:746-754. 4. Roussel M, et al. ASH 2016. Abstract 1142 Slide credit: clinicaloptions.com

KRd in Newly Diagnosed MM: Phase II Study Design Open-label, single-arm, multicenter study Primary endpoint: sCR at completion of consolidation Secondary endpoints: ORR at various points, MRD for pts with ≥ VGPR , safety/tolerability, PFS Induction* Carfilzomib 20/36 mg/m² IV Days 1, 2, 8, 9, 15, 16 Lenalidomide 25 mg Days 1-21 Dexamethasone 20 mg Days 1-2, 8-9, 15-16, 22-23 (Cycles 1-4) PBSC harvest (high-dose cyclophosphamide) followed by high-dose melphalan 200 mg/m2 and ASCT Pts < 65 yrs of age with symptomatic ND MM (N = 46) Consolidation* Carfilzomib 36 mg/m² IV Days 1, 2, 8, 9, 15, 16 Lenalidomide 25 mg Days 1-21 Dexamethasone 20 mg Days 1-2, 8-9, 15-16, 22-23 (Cycles 5-8) Maintenance lenalidomide 10 mg Days 1-21 for 13 cycles* ASCT, autologous stem cell transplantation; KRd, carfilzomib/lenalidomide/dexamethasone; MM, multiple myeloma; MRD, minimal residual disease; ND, newly diagnosed; PBSC, peripheral blood stem cell; sCR, stringent CR; VGPR, very good PR. *Mandatory antithrombotic prophylaxis with low molecular weight heparin. Slide credit: clinicaloptions.com Roussel M, et al. ASH 2016. Abstract 1142.

KRd in Newly Diagnosed MM: Baseline Characteristics Pt Characteristic KRd Induction and Consolidation (N = 46) Median age, yrs (age) 56 (40-65) Male, n (%) 32 (70) ISS II + III, % 25 (54) Median β2-macroglobulin level, mg/L (range) 2.8 (1.6-8.6) Cytogenetics assessed, n 43 Standard risk, n (%) High risk, n (%) 34 (79) 9 (21) t(4;14), n (%) del(17p), n (%) 5 (12) 4 (9) ISS, International Staging System; KRd, carfilzomib/lenalidomide/dexamethasone; MM, multiple myeloma. Slide credit: clinicaloptions.com Roussel M, et al. ASH 2016. Abstract 1142

KRd in Newly Diagnosed MM: Responses at End of Consolidation Endpoint, n (%) End of Consolidation (N = 46) sCR 26 (57) MRD using flow cytometry 32 (70) MRD using next-generation sequencing 23 of 34 (68) ≥ CR 28 (61) ≥ VGPR 39 (85) ORR 41 (89) PD 1 (2) KRd, carfilzomib/lenalidomide/dexamethasone; MM, multiple myeloma; MRD, minimal residual disease; PD progressive disease; sCR, stringent CR; VGPR, very good PR. Slide credit: clinicaloptions.com Roussel M, et al. ASH 2016. Abstract 1142

KRd in Newly Diagnosed MM: Responses Throughout Treatment Endpoint (N = 46), n After Induction, n After ASCT, n After of Consolidation, n Best Response, n (%) sCR 9 15 26 32 (70) sCR + CR 11 19 28 35 (76) VGPR 25 18 7 (15) ≥ VGPR 36 37 39 42 (91) PR 6 3 2 -- ORR 42 40 41 46 (100) PD 1 ASCT, autologous stem cell transplantation; KRd, carfilzomib/lenalidomide/dexamethasone; MM, multiple myeloma; PD progressive disease; sCR, stringent CR; VGPR, very good PR. Slide credit: clinicaloptions.com Roussel M, et al. ASH 2016. Abstract 1142

KRd in Newly Diagnosed MM: Progression and Survival PD (n = 3): 1 before ASCT, 2 during maintenance Death (n = 2): 1 during ASCT, 1 during follow-up Median PFS: not reached (95% CI: 27.4-not reached) Estimated 2-yr PFS: 91% ASCT, autologous stem cell transplantation; KRd, carfilzomib/lenalidomide/dexamethasone; MM, multiple myeloma; PD progressive disease. Slide credit: clinicaloptions.com Roussel M, et al. ASH 2016. Abstract 1142

KRd in Newly Diagnosed MM: Grade 3/4 Adverse Events Nonhematologic AE, n KRd Induction Consolidation Infections 7 1 Musculoskeletal disorders 5 2 Cardiovascular disorders -- GI disorders Injury, poisoning, procedural complications Hepatobiliary disorders Skin/subcutaneous disorders General disorders or administration site conditions Grade 3/4 Hematologic AE, n KRd Induction KRd Consolidation Neutropenia 6 12 Lymphopenia 5 17 Thrombocytopenia 1 7 Anemia -- No incidence of peripheral neuropathy reported AE, adverse event; GI, gastrointestinal; KRd, carfilzomib/lenalidomide/dexamethasone; MM, multiple myeloma. Slide credit: clinicaloptions.com Roussel M, et al. ASH 2016. Abstract 1142

KRd Induction and Consolidation KRd Induction and Consolidation KRd in Newly Diagnosed MM: Serious AEs and Cardiovascular/Pulmonary Toxicity Serious AE, n KRd Induction and Consolidation (n = 45) Any 30 Infections/infestations 12 Musculoskeletal/connective tissue 9 Cardiac and vascular 8 Blood and lymphatic 3 Injury, poisoning, procedural complications Gastrointestinal disorders 2 General disorders Psychiatric disorders 1 Cardiovascular Toxicity, All Grades, n KRd Induction and Consolidation (n = 45) Cardiac failure 2 Pulmonary embolism Venous thrombosis Intracardiac thrombosis Superficial thrombosis 1 8 Bradycardia Arrhythmia Atrial fibrillation Tachycardia Hypertension 4 Cough Dyspnea 9 5 AE, adverse event; KRd, carfilzomib/lenalidomide/dexamethasone; MM, multiple myeloma. Slide credit: clinicaloptions.com Roussel M, et al. ASH 2016. Abstract 1142

KRd in Newly Diagnosed MM: Conclusions 8 cycles of induction and consolidation with KRd in pts with ND MM was highly effective 61% CR/sCR at end of consolidation (primary endpoint) 70% of pts with negative MRD at end of consolidation Time to response quicker than standard intensive VRd At time of transplant, 78% achieved ≥ VGPR with KRd vs ~ 50% in historical VRD studies No peripheral neuropathy but cardiovascular toxicity a concern Mechanism of cardio-vascular events needs further investigation KRd, carfilzomib/lenalidomide/dexamethasone; MM, multiple myeloma; ND, newly diagnosed;; sCR, stringent CR; VGPR, very good PR; VRD, bortezomib/lenalidomide/dexamethasone. Slide credit: clinicaloptions.com Roussel M, et al. ASH 2016. Abstract 1142

Go Online for More CCO Coverage of ASH 2016! Short slideset summaries of all the key data Additional CME-certified analyses with expert faculty commentary on all the key studies in: Leukemias Lymphomas/CLL Myeloma/plasma cell disorders MDS and myeloproliferative neoplasms clinicaloptions.com/oncology