A phase 1b study of isatuximab plus pomalidomide/dexamethasone in relapsed/refractory multiple myeloma

Abstract

This phase 1b dose-escalation study evaluated isatuximab plus pomalidomide/dexamethasone in patients with relapsed/refractory multiple myeloma (RRMM). Patients who had received ≥2 prior MM therapies, including lenalidomide and a proteasome inhibitor (PI), were enrolled and received isatuximab at 5, 10, or 20 mg/kg (weekly for 4 weeks, followed by every 2 weeks), pomalidomide 4 mg (days 1-21), and dexamethasone 40 mg (weekly) in 28-day cycles until progression/intolerable toxicity. The primary objective was to determine the safety and recommended dose of isatuximab with this combination. Secondary objectives included evaluation of pharmacokinetics, immunogenicity, and efficacy. Forty-five patients received isatuximab (5 [n = 8], 10 [n = 31], or 20 [n = 6] mg/kg). Patients received a median of 3 (range, 1-10) prior lines; most were refractory to their last regimen (91%), with 82% lenalidomide-refractory and 84% PI-refractory. Median treatment duration was 9.6 months; 19 patients (42%) remain on treatment. Most common adverse events included fatigue (62%), and upper respiratory tract infection (42%), infusion reactions (42%), and dyspnea (40%). The most common grade ≥3 treatment-emergent adverse event was pneumonia, which occurred in 8 patients (17.8%). Hematologic laboratory abnormalities were common (lymphopenia, leukopenia, anemia, 98% each; neutropenia, 93%; and thrombocytopenia, 84%). Overall response rate was 62%; median duration of response was 18.7 months; median progression-free survival was 17.6 months. These results demonstrate potential meaningful clinical activity and a manageable safety profile of isatuximab plus pomalidomide/dexamethasone in heavily pretreated patients with RRMM. The 10 mg/kg weekly/every 2 weeks isatuximab dose was selected for future studies. This trial was registered at www.clinicaltrials.gov as #NCT02283775.

Conflict of interest statement

Conflict-of-interest disclosure: J.M. received institutional research funding from AbbVie, Celgene, Onyx, and Sanofi. P.R. has a consulting or advisory role with Genmab, and has received research funding from Celgene and Millennium. S.Z.U. has received honoraria from Celgene, Skyline, Onyx, Millennium, Sanofi, and Janssen; has a consulting or advisory role with Amgen, Bristol-Myers Squibb, Celgene, Janssen, Merck, SkylineDx, and Takeda; has been on speakers’ bureaus for Amgen, Celgene, Janssen, Sanofi, and Takeda; and has received research funding from Amgen, Array Biopharma, Bristol-Myers Squibb, Celgene, Janssen, Merck, Pharmacyclics, Sanofi, and Takeda. N.R. has a consulting or advisory role with Amgen, Novartis, Takeda, and Celgene, and has received research funding from AstraZeneca. W.B. has received honoraria from Amgen, Celgene, and Acetylon; has a consulting or advisory role with Amgen, Celgene, Sanofi, Merck, and Bristol-Myers Squibb; has been on speakers’ bureaus for Celgene, Amgen, and Takeda; has received research funding from Acetylon, Bristol-Myers Squibb, Celgene, Karyopharm Therapeutics, Merck, Amgen, and Sanofi; and has given expert testimony on behalf of Takeda and Celgene. C.K. is an employee of City of Hope, and has received research funding from Sanofi, Pharmacyclics, and Celgene. F.C., D.K., F.D., Q.L., and D.S. are employees of, and hold stock or other ownership interests in, Sanofi. K.A. holds stock or other ownership interests in, and is scientific founder of, Oncopep C4 Therapeutics, and has a consulting or advisory role with Millennium, Takeda, Gilead, Bristol-Myers Squibb, Celgene, and Janssen.

© 2019 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Infusion reactions by infusion and dose.aIndicates data representing dose-escalation cohort (n = 9) and expansion cohort (n = 22) combined. Gr, grade; QW/Q2W, weekly administration in cycle 1 followed by every other week for subsequent cycles.

Figure 2.

Confirmed clinical response. (A) ORR for all patients and by dose. (B) ORR for subgroups. aIndicates data representing dose-escalation cohort (n = 9) and expansion cohort (n = 22) combined. Bor, bortezomib; Car, carfilzomib; Len, lenalidomide; sCR, stringent complete response; VGPR, very good partial response.

Figure 3.

Time on treatment by best confirmed response (at least PR).aIndicates data representing dose-escalation cohort (n = 9) and expansion cohort (n = 22) combined. bOther reasons for discontinuation were unconfirmed disease progression (n = 3) and withdrawal of consent (n = 1). cPatient had progressive disease and withdrew consent.

Figure 4.

Kaplan-Meier analysis of PFS.aIndicates data representing dose-escalation cohort (n = 9) and expansion cohort (n = 22) combined. Median PFS (95% CI) is reported for each dose cohort.