Addition of Daratumumab to Carfilzomib, Lenalidomide, and Dexamethasone in Newly Diagnosed MM CCO Independent Conference Highlights* of the 2017 ASCO Annual Meeting; June 2-6, 2017; Chicago, Illinois *Clinical Care Options (CCO) is an independent medical education organization that provides conference coverage and other unique educational programs for healthcare professionals MM, multiple myeloma. This activity is supported by educational grants from AbbVie, Amgen, AstraZeneca, Celgene Corporation, Genentech, Halozyme, Incyte, and Merck & Co., Inc.

Daratumumab + KRd in Newly Diagnosed MM: Background Standard of care for newly diagnosed MM: triplet regimens including PI and immunomodulatory agent with or without ASCT[1] Carfilzomib, lenalidomide, and dexamethasone: triplet highly active in newly diagnosed MM[2,3] Addition of ASCT associated with increased response and prolonged PFS[4] Daratumumab: human anti-CD38 mAb approved as monotherapy and in combination for pts with relapsed/refractory MM[5] Current study assessed tolerability, safety, activity of daratumumab addition to KRd in pts with newly diagnosed MM[1] ASCT, autologous stem cell transplantation; KRd, carfilzomib/lenalidomide/dexamethasone; MM, multiple myeloma. 1. Jakubowiak AJ, et al. ASCO 2017. Abstract 8000. 2. Jakubowiak AJ, et al. Blood. 2012;120:1801-1809. 3. Korde N, et al. JAMA Oncol. 2015;1:746-754. 4. Jakubowiak A, et al. EHA 2016. Abstract S101. 5. Daratumumab [package insert]. 2016. Slide credit: clinicaloptions.com

Daratumumab + KRd in Newly Diagnosed MM: Study Design Multicenter, open-label phase Ib study Daratumumab: cycle 1: 8 mg/kg on Days 1-2; cycles 1-2: 16 mg/kg Q1W; cycles 3-6: 16 mg/kg Q2W; cycles > 6: 16 mg/kg Q4W Carfilzomib: cycle 1, Day 1: 20 mg/m2; cycle 1, Day 8+: escalated to 70 mg/m2 weekly (Days 1, 8, 15) Lenalidomide: 25 mg on Days 1-21 Dexamethasone: 40 mg weekly* (N = 22) Transplant-eligible and transplant-ineligible pts with newly diagnosed MM, no clinically significant cardiac disease (N = 22) Until elective discontinuation for ASCT or ≤ 13 cycles *Pre- and postinfusion: dexamethasone 20 mg, diphenhydramine 25-50 mg, paracetamol 650-1000 mg, montelukast 10 mg. DoR, duration of response; IRR, infusion-related reaction; KRd, carfilzomib/lenalidomide/dexamethasone; MM, multiple myeloma; TTR, time to response. Primary endpoints: safety, tolerability Secondary endpoints: ORR, DoR, TTR, IRR Exploratory endpoint: PFS Slide credit: clinicaloptions.com Jakubowiak AJ, et al. ASCO 2017. Abstract 8000.

Daratumumab + KRd in Newly Diagnosed MM: Baseline Characteristics Pts (N = 22) Median age, yrs (range) < 65 yrs, n (%) 65 to < 75 yrs, n (%) 59.5 (34.0-74.0) 15 (68) 7 (32) Male, n (%) 12 (55) Race, n (%) White Black American Indian/Alaska Native NR 19 (86) 1 (5) ECOG PS, n (%) 1 2 9 (41) ECOG, Eastern Cooperative Oncology Group; KRd, carfilzomib/lenalidomide/dexamethasone; MM, multiple myeloma; NR, not reported; PS, performance status. Slide credit: clinicaloptions.com Jakubowiak AJ, et al. ASCO 2017. Abstract 8000.

Daratumumab + KRd in Newly Diagnosed MM: Tolerability and Infusion-Related Reactions Median follow-up: 10.8 mos (range: 4.0-12.5) Median cycles: 11.5 (range: 1.0-13.0) 19/22 pts escalated carfilzomib to 70 mg/m2 by cycle 2, Day 1 8/22 pts (36%) discontinued tx ASCT: 6 (27%) AE: 1 (5%) PD: 1 (5%) 27% of pts experienced IRR No grade 3/4 With first infusion: 5 pts (23%) With later infusions: 1 pt (5%) Lower IRR rate with first dosing split over Days 1-2 AE, adverse events; ASCT, autologous stem cell transplantation; IRR, infusion-related reaction; KRd, carfilzomib/lenalidomide/dexamethasone; MM, multiple myeloma; PD, progressive disease; tx, treatment. Slide credit: clinicaloptions.com Jakubowiak AJ, et al. ASCO 2017. Abstract 8000.

Daratumumab + KRd in Newly Diagnosed MM: Nonhematologic and Hematologic TEAEs Nonhematologic TEAE in ≥ 30% Pts,* % Daratumumab + KRd (N = 22) All Grade Grade 3/4 Diarrhea 73 14 URTI 59 Cough 55 5 Constipation 50 Fatigue Dyspnea 46 Insomnia Nausea 41 Rash Back pain Muscle spasm 36 Vomiting 32 Pain in extremity Hematologic TEAE in ≥ 30% Pts, % Daratumumab + KRd (N = 22) All Grade Grade 3/4 Lymphopenia 68 64 Thrombocytopenia 55 9 Anemia 46 Leukopenia 41 Neutropenia 32 14 ALT, alanine aminotransferase; KRd, carfilzomib/lenalidomide/dexamethasone; MM, multiple myeloma; TEAE, treatment-emergent adverse event; URTI, upper respiratory tract infection. *Also included hyperglycemia (all grade: 32%; no grade 3/4) and increased ALT (all-grade: 32%; grade 3/4: 9%). Slide credit: clinicaloptions.com Jakubowiak AJ, et al. ASCO 2017. Abstract 8000.

Daratumumab + KRd in Newly Diagnosed MM: Serious TEAEs Serious TEAE, n Pts (N = 22) Pulmonary embolism* 3 Pyrexia 2 Influenza Abdominal pain 1 Chest pain Dyspnea Allergic dermatitis Serious TEAE, n Pts (N = 22) Presyncope 1 Gastroenteritis Lobular pneumonitis Bacterial pneumonia Tachycardia Congestive heart failure Hypertension *1 pt had bilateral deep vein thrombosis and pulmonary embolism. 10/22 pts (46%) experienced serious TEAEs; all pts on aspirin prophylaxis Likely related to: daratumumab, n = 3 (14%), carfilzomib, n = 5 (23%), lenalidomide, n = 5 (23%), dexamethasone, n = 2 (9%) 1 pt (5%) d/c for pulmonary embolism considered unrelated to daratumumab or carfilzomib No change in LVEF measurements over time d/c, discontinued; KRd, carfilzomib/lenalidomide/dexamethasone; LVEF, left ventricle ejection fraction; MM, multiple myeloma; TEAE, treatment-emergent adverse event. Slide credit: clinicaloptions.com Jakubowiak AJ, et al. ASCO 2017. Abstract 8000.

Daratumumab + KRd in Newly Diagnosed MM: Response Median number of treatment cycles: 11.5 (range: 1.0-13.0) After 4 Cycles, n = 21 After 8 Cycles, n = 15* Best Response, n = 21 100 100 100 100 100 100 91 87 80 71 80 80 60 60 60 Response rate (%) Response rate (%) Response rate (%) 43 40 40 40 29 27 27 20 20 20 5 5 ≥ PR ≥ CR sCR ≥ PR ≥ CR sCR ≥ PR ≥ CR sCR ≥ VGPR ≥ VGPR ≥ VGPR ASCT, autologous stem cell transplantation; KRd, carfilzomib/lenalidomide/dexamethasone; MM, multiple myeloma; PD, progressive disease. Depth of response improved with duration of treatment *5 pts who proceeded to ASCT before cycle 8 and 1 pt who discontinued due to PD at cycle 7 were excluded. Median follow-up: 10.8 mos (range: 4.0-12.5) OS: 100% at follow-up Jakubowiak AJ, et al. ASCO 2017. Abstract 8000. Reproduced with permission.

Daratumumab + KRd in Newly Diagnosed MM: Investigator Conclusions Daratumumab + KRd was well tolerated and safe in pts with newly diagnosed MM IRR rate was low with split first dose (no grade 3/4 IRRs observed) Daratumumab + KRd had 100% ORR in this pt population ≥ CR in 43%, ≥ VGPR in 91% Responses improved with treatment duration Investigators concluded that these results support further study of daratumumab + KRd in newly diagnosed MM and that daratumumab + KRd feasible as induction therapy IRR, infusion-related reaction; KRd, carfilzomib/lenalidomide/dexamethasone; MM, multiple myeloma. Slide credit: clinicaloptions.com Jakubowiak AJ, et al. ASCO 2017. Abstract 8000. Slide credit: clinicaloptions.com

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