Final results of a phase 1b study of isatuximab short-duration fixed-volume infusion combination therapy for relapsed/refractory multiple myeloma

Saad Z Usmani,Franck Dubin,William I Bensinger,Sascha A Tuchman,Anita D’Souza,Jacob P Laubach,Douglas Sborov,Paul G Richardson,Rao Saleem,Giada Bianchi,Chatchada Karanes,Noopur Raje,Dheepak Kanagavel,Frank Campana

doi:10.1038/s41375-021-01262-w

Abstract

Part B of this phase 1b study (ClinicalTrials.gov number, NCT02283775) evaluated safety and efficacy of a fixed-volume infusion of isatuximab, an anti-CD38 monoclonal antibody, in combination with pomalidomide and dexamethasone (Pd) in relapsed/refractory multiple myeloma patients. Isatuximab (10 mg/kg weekly for 4 weeks, then every other week) was administered as a fixed-volume infusion of 250 mL (mL/h infusion rate) with standard doses of Pd on 28-day cycles. Patients (N = 47) had a median of three prior treatment lines (range, 1–8). Median duration of exposure was 36.9 weeks and median duration of first, second, and 3+ infusions were 3.7, 1.8, and 1.2 h, respectively. The most common non-hematologic treatment-emergent adverse events were fatigue (63.8%), infusion reactions (IRs), cough, and upper respiratory tract infection (40.4% each). IRs were all grade 2 and occurred only during the first infusion. The overall response rate was 53.2% in all patients (55.5% in response-evaluable population, 60.0% in daratumumab-naïve patients). Efficacy and safety findings were consistent with data from the isatuximab plus Pd infusion schedule in Part A of this study and also from the phase 3 ICARIA-MM study, and these new data confirm the safety, efficacy, and feasibility of fixed-volume infusion of isatuximab.

Highlights

Seattle, WA, USA 4 Medical College of Wisconsin, Milwaukee, WI, USA 5 Massachusetts General Hospital, Boston, MA, USA 6 Division of Hematology, University of North Carolina at ChapelHill, Chapel Hill, NC, USA 7 Division of Hematology & Hematologic Malignancies, University of Utah, Salt Lake City, UT, USA 8 Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA 9 Sanofi R&D, Vitry-Alfortville, France Sanofi, Cambridge, MA, USA Present address: Takeda Pharmaceuticals, Cambridge, MA, USAMultiple myeloma (MM) is a plasma cell disorder characterized by the excess production of a monoclonal immunoglobulin protein causing end-organ damage [1, 2]
Prior daratumumab exposure was reported for 14.9% of patients; prior elotuzumab exposure was reported for 19.1% of patients
This was a phase 1b study comprising two parts, of which the objective of Part B was to evaluate the feasibility, safety, and efficacy of isatuximab 10 mg/kg administered with a 250 mL fixed-volume infusion in combination with pomalidomide and dexamethasone (Pd) in refractory MM (RRMM), with the aim of reducing the infusion time starting with the second infusion

Summary

Introduction

Proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and autologous stem cell transplantation have extended overall survival [3,4,5], the majority of patients will develop disease that is refractory to these treatments and the prognosis of relapsed/refractory MM (RRMM) patients remains poor [6, 7]. Isatuximab, a monoclonal, anti-CD38 antibody that targets a unique CD38 epitope, has antitumor activity through multiple mechanisms of action, including antibody-dependent cellular-mediated cytotoxicity, complement-dependent cytotoxicity, antibody-dependent cellular phagocytosis, and direct induction of apoptosis [9, 11, 12]. Isatuximab induces indirect antitumor activity through the elimination of CD38+ immunosuppressive Treg cells [9] and an “in vivo vaccination” effect against CD38 as well as other MM-associated antigens [14]

Methods

Results

Conclusion