Phase 1b trial of isatuximab, an anti-CD38 monoclonal antibody, in combination with carfilzomib as treatment of relapsed/refractory multiple myeloma

Abstract

Background: Isatuximab (Isa), an anti-CD38 monoclonal antibody, and carfilzomib (K), a next-generation proteasome inhibitor (PI), both have potent single-agent activity in relapsed and refractory multiple myeloma (RRMM).

Methods: This phase 1b study evaluated the combination of Isa and K in 33 patients with RRMM. Isa was administered by intravenous infusion in 3 dosing cohorts: dose level 1 (Isa at 10 mg/kg biweekly), dose level 2 (DL2; Isa at 10 mg/kg weekly for 4 doses and then biweekly), and dose level 3 (Isa at 20 mg/kg weekly for 4 doses and then biweekly) and all patients received K (20 mg/m² intravenously for cycle 1, days 1 and 2, and then 27 mg/m² for all subsequent doses). A standard 3+3 dose-escalation design was used, no dose-limiting toxicity was observed, and the maximum tolerated dose was not reached. An expansion cohort of 18 patients was enrolled at DL2 to further evaluate safety and efficacy. Responses were assessed with the International Myeloma Working Group response criteria, and patients continued treatment until disease progression or unacceptable toxicity.

Results: With a median follow-up of 26.7 months, in this heavily pretreated population with a median of 3 prior lines (refractory to PIs and immunomodulatory drugs, 76%; refractory to K, 27%), the overall response rate was 70% (stringent complete response/complete response, 4; very good partial response, 8; partial response, 11). The median progression-free survival was 10.1 months, and the 2-year survival probability was 76%. The most common treatment-related adverse events (grade 2 or higher) were anemia, leukopenia, neutropenia, thrombocytopenia, hypertension, and infection. Infusion reactions were common (55%) but did not limit dosing.

Conclusions: Treatment with Isa plus K was well tolerated with no unexpected toxicity. The combination was effective despite the enrollment of heavily pretreated patients with RRMM.

Lay summary: This phase 1b study was designed to assess the safety, pharmacokinetics, and preliminary efficacy of isatuximab and carfilzomib in patients with relapsed and refractory multiple myeloma. Thirty-three patients were treated: 15 in dose escalation and 18 in dose expansion. Patients received an average of 10 cycles. The treatment was safe and effective. No unexpected toxicity or drug-drug interactions were noted. Seventy percent of the subjects responded to therapy, and the progression-free survival was 10.1 months.

Keywords: carfilzomib; immunomodulatory; isatuximab; monoclonal antibody; pharmacokinetics; proteasome.

Figure 1

Infusion reactions in cycle 1 by drug, grade, and infusion day. No reactions were seen after cycle 1, D8. D indicates day; Gr, grade, Isa, isatuximab; K, carfilzomib.

Figure 2

ORRs by dose level and overall. CBR indicates clinical benefit rate; MR, minor response; ORR, overall response rate; PR, partial response; Q2W, every 2 weeks; QW, weekly; sCR/CR, stringent complete response/complete response; VGPR, very good partial response.

Figure 3

Kaplan‐Meier analysis of PFS. The median PFS (along with the 95% CI) is plotted for all treated patients (isatuximab plus carfilzomib). CI indicates confidence interval; PFS, progression‐free survival.

Figure 4

Kaplan‐Meier analysis of OS. OS is plotted for the total population treated with isatuximab plus carfilzomib. CI indicates confidence interval; OS, overall survival.