Elotuzumab, Lenalidomide, and Low-Dose Dexamethasone in Relapsed/Refractory Myeloma Slideset on: Lonial S, Vij R, Harousseau JL, et al. Elotuzumab in combination.

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Elotuzumab, Lenalidomide, and Low-Dose Dexamethasone in Relapsed/Refractory Myeloma Slideset on: Lonial S, Vij R, Harousseau JL, et al. Elotuzumab in combination with lenalidomide and low-dose dexamethasone in relapsed or refractory multiple myeloma. J Clin Oncol. 2012;30:1953-1959. This program is supported by educational grants from

Introduction Elotuzumab: humanized monoclonal IgG1 antibody targeting CS1 (target antigen in MM) CS1 is highly expressed on primary MM cells in newly diagnosed and relapsed disease Lenalidomide with high-dose dexamethasone induced ORR of ~ 60% and improved PFS and OS vs high-dose dexamethasone alone in 2 large randomized trials in relapsed/refractory MM[1,2] Lenalidomide improves efficacy of monoclonal antibodies by enhancing ADCC and immune function[3,4] Preclinical data suggest combining elotuzumab with other agents, including lenalidomide, enhances ADCC activity against MM cells[5-7] ADCC, antibody-dependent cellular cytotoxicity; MM, multiple myeloma; ORR, overall response rate; OS, overall survival; PFS, progression-free survival. 1. Dimopoulos M, et al. N Engl J Med. 2007;357:2123-2132. 2. Weber DM, et al. N Engl J Med. 2007;357: 2133-2142. 3. Reddy N, et al. Br J Haematol. 2008;140:36-45. 4. Hernandez-Ilizaliturri FJ, et al. Clin Cancer Res. 2005;11:5984-5992. 5. Rice AG, et al. ASH 2007. Abstract 2517. 6. van Rhee F, et al. Mol Cancer Ther. 2009;8:2616-2624. 7. Tai YT, et al. Blood. 2008;112:1329-1337.

Phase I Study: Elotuzumab, Lenalidomide, Low-Dose Dex in Relapsed/Refractory MM Open-label dose-escalation study conducted at 5 centers Enrolled 3 cohorts for elotuzumab dosing: 5 mg/kg, 10 mg/kg, and 20 mg/kg (MPD) Additional pts to be enrolled at MTD or MPD in expansion phase for further safety and initial efficacy data If no DLT in cycle 1, next higher-dose cohort enrolled DLT Observation Response Assessments Dex, dexamethasone; DLT, dose-limiting toxicity; MM, multiple myeloma; MPD, maximum planned dose; MTD, maximum tolerated dose. Elotuzumab Dosing CYCLE 1 CYCLE 2 CYCLE 3 CYCLE 4 CYCLE N-1 CYCLE N * Lenalidomide* daily dose Cycle day * 1 8 15 22 1 8 15 22 1 8 15 22 1 8 15 22 1 8 15 22 1 8 15 22 28 Dexamethasone* *Lenalidomide: 25 mg/day orally on Days 1-21; dexamethasone: 40 mg weekly. Lonial S, et al. J Clin Oncol. 2012;30:1953-1959.

Refractory to Most Recent MM Therapy Elotuzumab, Lenalidomide, Low-Dose Dex in Relapsed/Refractory MM: Outcomes No DLTs observed during cycle 1 of dose-escalation phase Elotuzumab MTD not reached up to MPD of 20 mg/kg ORR: 82% (≥ VGPR: 32%) Number of previous therapies did not appear to affect response rate ORR with ≤ 3 therapies: 88% ORR with ≥ 4 therapies: 75% Best Response, n (%) All Patients (N = 28) Len Naive (n = 22) Previous Thalidomide (n = 16) Previous Bortezomib (n = 20) Refractory to Most Recent MM Therapy (n = 12) ORR 23 (82) 21 (95) 15 (94) 15 (75) 10 (83) CR 1 (4) 1 (5) VGPR 8 (29) 7 (32) 7 (44) 4 (20) 4 (33) PR 14 (50) 13 (59) 8 (50) 10 (50) 6 (50) SD 3 (11) 1 (6) 3 (15) 2 (17) PD 2 (7) 2 (10) CR, complete response; Dex, dexamethasone; DLT, dose-limiting toxicity; Len, lenalidomide; MM, multiple myeloma; MPD, maximum planned dose; MTD, maximum tolerated dose; ORR, overall response rate; PD, progressive disease; PR, partial response; SD, stable disease; VGPR, very good partial response. Lonial S, et al. J Clin Oncol. 2012;30:1953-1959.

Elotuzumab, Lenalidomide, Low-Dose Dex in Relapsed/Refractory MM: Safety Most frequent AEs: fatigue, gastrointestinal AEs, myelosuppression Serious AEs: n = 12 Treatment-Emergent AEs, n (%) All Grades ≥ 20% (n = 28) Grade 3/4 ≥ 5% Fatigue 17 (61) 3 (11) Anemia 13 (46) 2 (7) Diarrhea 14 (50) Nausea 12 (43) Constipation 11 (39) 1 (4) Neutropenia 10 (36) Muscle spasms 9 (32) Hypokalemia 8 (29) Insomnia Pyrexia Thrombocytopenia 7 (25) 6 (21) Back pain Arthralgia AE, adverse event; CR, complete response; Dex, dexamethasone; DLT, dose-limiting toxicity; Len, lenalidomide; MM, multiple myeloma; MPD, maximum planned dose; MTD, maximum tolerated dose; ORR, overall response rate; PD, progressive disease; PR, partial response; SD, stable disease; VGPR, very good partial response. Lonial S, et al. J Clin Oncol. 2012;30:1953-1959.

Elotuzumab, Lenalidomide, Low-Dose Dex in Relapsed/Refractory MM: Safety Infusion reactions (primarily related to elotuzumab) occurred in 89% of pts at least once Most common: nausea, headache, dyspnea, dizziness, hyperhidrosis, cough, rash Most resolved in ≤ 24 hrs (spontaneously or following treatment) Premedication regimen adjusted for phase II trial to mitigate transfusion reactions 13 pts discontinued treatment due to AEs (n = 5), progression (n = 4), investigator decision (n = 3), patient decision (n = 1) 4 pts discontinued treatment following completion of 6 cycles (per original protocol) Median number of doses Elotuzumab: 25 (range: 4-45) Lenalidomide: 215 (range: 19-419) Dexamethasone: 33 (range: 4-81) AE, adverse event; Dex, dexamethasone; MM, multiple myeloma. Lonial S, et al. J Clin Oncol. 2012;30:1953-1959.

Elotuzumab, Lenalidomide, Low-Dose Dex in Relapsed/Refractory MM: Summary Combination of elotuzumab, lenalidomide, and low-dose dexamethasone showed encouraging safety profile and responses in pts with relapsed/refractory MM MTD not reached No DLTs observed up to MPD of 20 mg/kg Most frequent grade 3/4 AE: neutropenia, thrombocytopenia Median TTP not reached after median follow-up of 16.4 mos for pts treated with 20-mg/kg dose until disease progression ORR 82% AE, adverse event; Dex, dexamethasone; DLTs, dose-limiting toxicities; MM, multiple myeloma; MPD, maximum proposed dose; MTD, maximum tolerated dose; ORR, overall response rate; TTP, time to progression. Lonial S, et al. J Clin Oncol. 2012;30:1953-1959.