As reported in The Lancet by Michel Attal, MD, and colleagues, the phase III ICARIA-MM trial has shown that the addition of the CD38-targeted antibody isatuximab to pomalidomide and low-dose dexamethasone significantly improved progression-free survival in patients with relapsed and refractory multiple myeloma.

Michel Attal, MD

Isatuximab targets a specific epitope on the CD38 receptor and is reported to exert antitumor activity via multiple biological mechanisms, immunomodulatory effects, and a direct induction of apoptosis. To the authors’ knowledge, the trial is the first phase III trial to evaluate an anti-CD38 antibody in combination with pomalidomide/dexamethasone.

Study Details

The open-label trial included 307 patients with relapsed and refractory disease from 102 sites in 24 countries in Europe, North America, and the Asia-Pacific region. Patients were randomly assigned between January 2017 and February 2018 to receive isatuximab plus pomalidomide/low-dose dexamethasone (n =154) or pomalidomide/low-dose dexamethasone (n = 153). Patients had received at least two previous lines of treatment, including lenalidomide and a proteasome inhibitor. Patients were excluded if they were refractory to previous treatment with an anti-CD38 antibody.

Treatment consisted of 28-day cycles of isatuximab 10 mg/kg given intravenously (IV) on days 1, 8, 15, and 22 in the first cycle and days 1 and 15 in subsequent cycles plus pomalidomide 4 mg on days 1 to 21, and IV or oral dexamethasone 40 mg (20 mg in patients aged ≥ 75 years) on days 1, 8, 15, and 22. Treatment continued until disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint was progression-free survival on independent response committee assessment in the intention-to-treat population.

Progression-Free Survival

At a median follow-up of 11.6 months, median progression-free survival was 11.5 months in the isatuximab group vs 6.5 months in the control group (hazard ratio [HR] = 0.596, 95% confidence interval [CI] = 0.44–0.81, P = .001). In prespecified subgroup analyses, hazard ratios consistently favored the isatuximab group (HRs generally in the 0.5 to 0.6 range), including among patients with poor prognostic features; those refractory to lenalidomide, a proteasome inhibitor, or both; and those refractory to lenalidomide as the last line of treatment before study entry. Among patients refractory to lenalidomide and a proteasome inhibitor, the HR was 0.58 (95% CI = 0.40–0.84).

Partial response was observed in 60% of the isatuximab group vs 35% of the control group (P < .0001), with very good partial response or better occurring in 32% vs 9% (P < .0001). Median duration of response was 13.3 months vs 11.1 months.

Interim analysis of overall survival at the time of progression-free survival analysis—when 43 patients in the isatuximab group and 56 in the control group had died—yielded a hazard ratio of 0.69 (P = .063).

Adverse Events

The most common adverse events of any grade in the isatuximab vs control groups were infusion reactions (38% [including 3% grade 3 or 4] vs 0%), upper respiratory tract infection (28% vs 17%), and diarrhea (26% vs 20%). Adverse events led to death in 12 patients (8%) in the isatuximab group and 14 (9%) in the control group, with deaths being considered related to treatment in one (sepsis) vs two patients (pneumonia and urinary tract infection).

The investigators concluded, “The addition of isatuximab to pomalidomide/dexamethasone significantly improves progression-free survival in patients with relapsed and refractory multiple myeloma. Isatuximab is an important new treatment option for the management of relapsed and refractory myeloma, particularly for patients who become refractory to lenalidomide and a proteasome inhibitor.”

Dr. Attal, of the Institut Universitaire du Cancer Toulouse Oncopole, is the corresponding author for The Lancet article.

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