1. 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:
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2. 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: Weber DM, et al. N Engl J Med. 2007;357: Reddy N, et al. Br J Haematol. 2008;140: Hernandez-Ilizaliturri FJ, et al. Clin Cancer Res. 2005;11: Rice AG, et al. ASH Abstract van Rhee F, et al. Mol Cancer Ther. 2009;8: Tai YT, et al. Blood. 2008;112:

3. 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 *
Dexamethasone*
*Lenalidomide: 25 mg/day orally on Days 1-21; dexamethasone: 40 mg weekly.
Lonial S, et al. J Clin Oncol. 2012;30:

4. 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:

5. 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:

6. 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: )
Dexamethasone: 33 (range: 4-81)
AE, adverse event; Dex, dexamethasone; MM, multiple myeloma.
Lonial S, et al. J Clin Oncol. 2012;30:

7. 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: