Phase I trial of isatuximab monotherapy in the treatment of refractory multiple myeloma

Abstract

This phase I dose-escalation/expansion study evaluated isatuximab (anti-CD38 monoclonal antibody) monotherapy in patients with relapsed/refractory multiple myeloma (RRMM). Patients progressing on or after standard therapy received intravenous isatuximab (weekly [QW] or every 2 weeks [Q2W]). The primary objective was to determine the maximum tolerated dose (MTD) of isatuximab. Overall, 84 patients received ≥ 1 dose of isatuximab. The MTD was not reached; no cumulative adverse reactions were noted. The most frequent adverse events were infusion reactions (IRs), occurring in 37/73 patients (51%) following introduction of mandatory prophylaxis. IRs were mostly grade 1/2, occurred predominantly during Cycle 1, and led to treatment discontinuation in two patients. CD38 receptor occupancy reached a plateau of 80% with isatuximab 20 mg/kg (highest dose tested) and was associated with clinical response. In patients receiving isatuximab ≥ 10 mg/kg, overall response rate (ORR) was 23.8% (15/63), including one complete response. In high-risk patients treated with isatuximab 10 mg/kg (QW or Q2W), ORR was 16.7% (3/18). Median (range) duration of response at doses ≥ 10 mg/kg was 25 (8-30) weeks among high-risk patients versus 36 (6-85) weeks for other patients. In conclusion, isatuximab demonstrated a manageable safety profile and clinical activity in patients with RRMM.

Conflict of interest statement

Dr. Thomas Martin has received research funding from Sanofi. Dr. Stephen Strickland has received honoraria for an advisory role from Amgen, Alexion, Boehringer Ingelheim, Baxalta, CTI Biopharma, Sunesis, and Daiichi-Sankyo. He has also received research funding from Astellas, Boehringer Ingelheim, Celator, Celgene, Cyclacel, GlaxoSmithKline, Karyopharm Therapeutics, Novartis, Sanofi, and Sunesis. Dr. Martha Glenn declares that she has no conflict of interest. Eric Charpentier, Karl Hsu, and Hélène Guillemin are employees of Sanofi. Dr. Joseph Mikhael has received funding from Abbvie, Celgene, and Sanofi.

Figures

Fig. 1

Infusion reactions according to number of infusions and dose level

Fig. 2. Relationship between receptor occupancy (RO), isatuximab concentration, and response.

Relationship between a RO and isatuximab concentration and b RO, isatuximab concentration, and response. Emax = 81.3%, EC50 = 0.019 µg/ml, γ = 0.595. C isatuximab concentration, EC50 half maximal effective concentration, Emax maximum effect, PR partial response, QW every week, Q2W every 2 weeks, RO receptor occupancy

Fig. 3. Summary of response data in patients with relapsed/refractory multiple myeloma.

a Response histogram by isatuximab dose level, using European Group for Blood and Marrow Transplant criteria; b Waterfall plot of paraprotein change by isatuximab dose level in patients treated at isatuximab ≥ 1 mg/kg. Response not evaluable in three patients (1 at 10 mg/kg and 2 at 20 mg/kg). CBR clinical benefit rate, CR complete response, MR minimal response, ORR overall response rate, PR partial response

Fig. 4

Progression-free survival Kaplan–Meier plot