Interim Analysis of Overall Survival in ICARIA-MM: Addition of Isatuximab to Pomalidomide/Dexamethasone in Relapsed or Refractory Multiple Myeloma

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As reported in The Lancet Oncology by Paul G. Richardson, MD, and colleagues, a prespecified interim overall survival analysis of the phase III ICARIA-MM trial showed that the addition of isatuximab to pomalidomide and dexamethasone in patients with relapsed or refractory multiple myeloma produced a numeric benefit that did not meet the prespecified stopping boundary.

The primary analysis of the trial supported the March 2020 approval of isatuximab in combination with pomalidomide and dexamethasone in this setting on the basis of improved progression-free survival and overall response rate. At the primary analysis, with a median follow-up of 11.6 months, median progression-free survival was significantly improved in the isatuximab group vs the control group (11.5 vs 6.5 months, hazard ratio [HR] = 0.60, 95% confidence interval [CI] = 0.44–0.81, P = .001).

Paul G. Richardson, MD

Paul G. Richardson, MD

Study Details

The current analysis is a prespecified second interim analysis of overall survival at 24 months after the primary analysis. In the open-label trial, 307 patients from sites in 24 countries were randomly assigned between January 2017 and February 2018 to receive pomalidomide plus low-dose dexamethasone with (n = 154) or without (n = 153) isatuximab. Patients had received two or more previous lines of therapy, including lenalidomide and a proteasome inhibitor; no prior pomalidomide treatment was permitted. Isatuximab was given at 10 mg/kg on days 1, 8, 15, and 22 of the first 4-week cycle and then on days 1 and 15 of subsequent cycles; both groups received pomalidomide at 4 mg on days 1 to 21 of each cycle and weekly oral or intravenous dexamethasone at 40 mg (20 mg if aged ≥ 75 years) on days 1, 8, 15, and 22 of each cycle. Treatment was continued until disease progression or unacceptable toxicity. The prespecified stopping boundary for the current analysis was a P value of ≤ .0181.

Key Findings

Median follow-up at data cutoff for the analysis (October 2020) was 35.3 months (interquartile range = 33.5–37.4 months). A total of 18% of patients in the isatuximab group and 8% of the control group remained on study treatment. Death had occurred in 60% vs 69% of patients.

Median overall survival was 24.6 months (95% CI = 20.3–31.3 months) in the isatuximab group vs 17.7 months (95% CI = 14.4–26.2 months) in the control group (HR = 0.76, 95% CI = 0.57–1.01, P = .028), with the P value failing to cross the prespecified stopping boundary.   

Updated progression-free survival analysis showed median durations of 11.1 months (95% CI = 7.8–13.8 months) in the isatuximab group vs 5.9 months (95% CI = 4.5–7.9 months) in the control group (HR = 0.60, 95% CI = 0.46–0.78, P < .0001).

A total of 92 patients (60%) in the isatuximab group and 110 (72%) in the control group received subsequent therapy after disease progression. Median time to next treatment was longer in the isatuximab group (P < .0001). Among these patients, 22 (24%) vs 64 (58%) received daratumumab as subsequent therapy. In a post hoc analysis, median overall survival was 19.9 months (95% CI = 15.7–27.5 months) among control group patients who received daratumumab and 17.4 months (95% CI = 10.0–29.1 months) among those who did not.

Overall, median progression-free survival on subsequent therapy or death was 17.5 months (95% CI = 14.9–19.2 months) in the isatuximab group vs 12.9 months (95% CI = 10.1–16.6 months) in the control group (HR = 0.76, 95% CI = 0.58–0.99, P = .020).

No new safety concerns were identified with isatuximab plus pomalidomide and dexamethasone with longer follow-up.

The investigators concluded, “Addition of isatuximab plus pomalidomide [and] dexamethasone resulted in a 6.9-month difference in median overall survival compared with pomalidomide and dexamethasone and is a new standard of care for lenalidomide-refractory and proteasome inhibitor–refractory or relapsed multiple myeloma. Final overall survival analysis follow-up is ongoing.”

Dr. Richardson, of the Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by Sanofi. For full disclosures of the study authors, visit

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