A dose-finding Phase 2 study of single agent isatuximab (anti-CD38 mAb) in relapsed/refractory multiple myeloma

Abstract

A Phase 2 dose-finding study evaluated isatuximab, an anti-CD38 monoclonal antibody, in relapsed/refractory multiple myeloma (RRMM; NCT01084252). Patients with ≥3 prior lines or refractory to both immunomodulatory drugs and proteasome inhibitors (dual refractory) were randomized to isatuximab 3 mg/kg every 2 weeks (Q2W), 10 mg/kg Q2W(2 cycles)/Q4W, or 10 mg/kg Q2W. A fourth arm evaluated 20 mg/kg QW(1 cycle)/Q2W. Patients (N = 97) had a median (range) age of 62 years (38-85), 5 (2-14) prior therapy lines, and 85% were double refractory. The overall response rate (ORR) was 4.3, 20.0, 29.2, and 24.0% with isatuximab 3 mg/kg Q2W, 10 mg/kg Q2W/Q4W, 10 mg/kg Q2W, and 20 mg/kg QW/Q2W, respectively. At doses ≥10 mg/kg, median progression-free survival and overall survival were 4.6 and 18.7 months, respectively, and the ORR was 40.9% (9/22) in patients with high-risk cytogenetics. CD38 receptor density was similar in responders and non-responders. The most common non-hematologic adverse events (typically grade ≤2) were nausea (34.0%), fatigue (32.0%), and upper respiratory tract infections (28.9%). Infusion reactions (typically with first infusion and grade ≤2) occurred in 51.5% of patients. In conclusion, isatuximab is active and generally well tolerated in heavily pretreated RRMM, with greatest efficacy at doses ≥10 mg/kg.

Conflict of interest statement

JM has received honoraria from Amgen, Celgene, Janssen, Sanofi and Takeda. JR has received honoraria and participated in speakers bureau for Amgen, Takeda, Janssen, Celgene and Novartis, and acted in a consultancy/advisory role for Amgen and Takeda. RV has received honoraria and travel expenses from Celgene, Onyx, Takeda, Novartis, Merck, Bristol-Myers Squibb and Janssen, and research funding from Takeda and Onyx. CC has received travel/accommodation expenses from Amgen. JZ has acted in a consultancy/advisory role for Array BioPharma, Celgene, Bristol-Myers Squibb, Janssen, Intellia, Takeda, Alnylam, Caelum, and Amgen; and has received research funding from Prothena and Celgene. JLK has acted in a consultancy/advisory role for Millennium, Celgene, Novartis, Onyx, Spectrum Pharmaceuticals and Incyte, has received honoraria from Janssen, and has received research funding from Novartis, Merck and Celgene. WB has received honoraria and participated in speakers bureau for Celgene and Amgen, has acted in a consultancy/advisory role for Celgene, Bristol-Myers Squibb, Amgen and Sanofi, and received research funding from Celgene, Takeda, Amgen, Sanofi, Acetylon and Bristol-Myers Squibb. MD has received honoraria from Celgene, Takeda, BMS, Janssen and Amgen. NL is an employee of Janssen. PH discloses honoraria, travel/accommodation expenses/consultancy for Celgene, Takeda, Sanofi, Amgen, Bristol-Myers Squibb, honoraria and acted as a consultant for Janssen, honoraria from Spectrum Pharmaceuticals, and research funding from Celgene and Takeda. EMO discloses honoraria, consultancy/advisory role, research funding, travel/accommodation expenses from Celgene, honoraria, research funding from and consultancy/advisory role for Mundipharma and Amgen, honoraria from and consultancy/advisory role for Novartis, honoraria from Bristol-Myers Squibb, consultancy/advisory role for and research funding from Array Pharmaceuticals, and honoraria and travel expenses from Janssen. CG has received consultancy fees from Celgene, Millennium and Onyx, honoraria from Celgene, Millennium, Bristol-Myers Squibb and Amgen, participated in speakers bureau and received travel/accommodation expenses from Celgene and Millennium, and received research funding from Celgene. SK has acted in a consultancy/advisory role for Skyline diagnostics, Noxxon Pharma and Kesios Pharma, and has received research funding from Millenium, Onyx, Takeda, Janssen, Sanofi, Novartis and AbbVie. JSM has acted in a consultancy/advisory role for Celgene, Novartis, Millenium, Onyx, Janssen, Bristol-Myers Squibb and Merck, Sharp & Dohme. TM has received research funding from Sanofi. CO, MC, CB, and EC are employees of Sanofi.

Figures

Fig. 1. Study design and treatment disposition.

QnW every n week. *Randomization to Arms 1–3 was stratified according to whether or not patients had received prior treatment with pomalidomide and/or carfilzomib. †Analysis of the pharmacokinetic parameters of patients treated at 10 mg/kg Q2W in the expansion cohort of the Phase 1 study demonstrated a high level of variability in exposure and non-linear clearance, suggesting that a higher dose and more intense “loading” schedule may be required to reach the desired therapeutic concentration faster. Therefore, Arm 4 was included, which evaluated a dose and schedule of 20 mg/kg QW for 1 cycle followed by 20 mg/kg Q2W. ‡At study cut-off, December 9, 2016.

Fig. 2. Survival (all treated population; N = 97).

a Progression-free survival. b Overall survival.