Isatuximab-pomalidomide-dexamethasone versus pomalidomide-dexamethasone in patients with relapsed and refractory multiple myeloma: final overall survival analysis

Abstract

The primary and prespecified updated analyses of ICARIA-MM (clinicaltrial gov. Identifier: NCT02990338) demonstrated improved progression-free survival (PFS) and a benefit in overall survival (OS) was reported with the addition of isatuximab, an anti-CD38 monoclonal antibody, to pomalidomide-dexamethasone (Pd) in patients with relapsed/refractory multiple myeloma. Here, we report the final OS analysis. This multicenter, randomized, open-label, phase III study included patients who had received and failed ≥2 previous therapies, including lenalidomide and a proteasome inhibitor. Between January 10, 2017, and February 2, 2018, 307 patients were randomized (1:1) to isatuximab-pomalidomide-dexamethasone (Isa-Pd; N=154) or Pd (N=153), stratified based on age (<75 vs. ≥75 years) and number of previous lines of therapy (2-3 vs. >3). At data cutoff for the final OS analysis after 220 OS events (January 27, 2022), median follow-up duration was 52.4 months. Median OS was 24.6 months (95% confidence interval [CI]: 20.3-31.3) with Isa-Pd and 17.7 months (95% CI: 14.4- 26.2) with Pd (hazard ratio=0.78; 95% CI: 0.59-1.02; 1-sided P=0.0319). Despite subsequent daratumumab use in the Pd group and its potential benefit on PFS in the first subsequent therapy line, median PFS2 was significantly longer with Isa-Pd versus Pd (17.5 vs. 12.9 months; log-rank 1-sided P=0.0091). In this analysis, Isa-Pd continued to be efficacious and well tolerated after follow-up of approximately 52 months, contributing to a clinically meaningful, 6.9-month improvement in median OS in patients with relapsed/refractory multiple myeloma.

Figure 1.

Trial profile as of data cutoff for the final overall survival analysis. ^aInvestigator decision due to free light chain increase (N=3), physician’s decision (suspected progression, N=1), unconfirmed progression (N=1), poor compliance to protocol (N=1), investigator decided to switch treatment to daratumumab-pomalidomide-dexamethasone (N=1), investigator kept the same isatuximab-pomalidomide-dexamethasone (Isa-Pd) combination off protocol, as the product is available commercially (N=1). ^bPhysician decision. OS: overall survival.

Figure 2.

Overall survival and progression-free survival on subsequent therapy or death in the intention-to-treat population. (A) Kaplan–Meier analysis of overall survival (OS) after 220 events. Patients who were alive at the cutoff date (January 27, 2022), alive at the last contact before the cutoff date, or lost to follow-up were censored. (B) Kaplan-Meier analysis of time from randomization to disease progression on subsequent therapy or death, as assessed by investigators. ^aThe 1-sided log-rank P value is provided for descriptive purposes. Patients who did not experience an event were censored (denoted by crosses). Hazard ratio (HR) and corresponding 95% confidence intervals (CI) are from a Cox proportional hazard model, stratified by age and number of previous lines of therapy. Isa-Pd: isatuximab-pomalidomide-dexamethasone; mOS: median overall survival; mPFS2: median progression-free survival on subsequent therapy or death; OS: overall survival; Pd: pomalidomide-dexamethasone; PFS: progression-free survival; PFS2: progression-free survival on subsequent therapy or death.

Figure 3.

Time to next treatment (intention-to-treat population). Kaplan-Meier analysis of time to next treatment, as reported by investigators. Patients who did not proceed to subsequent anti-myeloma treatment before the cutoff date were censored. Median follow-up was 52.4 months. Hazard ratios (HR) and corresponding 95% confidence intervals (CI) are from a Cox proportional hazard model stratified by age and number of previous lines of therapy. Isa-Pd: isatuximab-pomalidomide-dexamethasone; mTNT: median time to next treatment; Pd: pomalidomide-dexamethasone.

Figure 4.

Exploratory analysis of response rate on first subsequent therapy,^* intention-to-treat population. ^*Median washout period between therapies was 13 (range, 2-100) days for the isatuximab group and 22 (range, 1-822) days for the control group. Isa-Pd: isatuximab-pomalidomide-dexamethasone; ORR: overall response rate; Pd: pomalidomide-dexamethasone; VGPR: very good partial response or better.