As reported in The Lancet by Michel Attal, MD, of the Institut Universitaire du Cancer Toulouse Oncopole, France, 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.¹

Michel Attal, MD

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

Study Details

In the open-label trial, 307 patients with relapsed and refractory multiple myeloma from 102 sites in 24 countries in Europe, North America, and Asia-Pacific regions were randomly assigned between January 2017 and February 2018 to receive isatuximab plus pomalidomide and low-dose dexamethasone (n =154) or pomalidomide plus low-dose dexamethasone (n = 153) alone. Patients had received at least two previous lines of treatment, including lenalidomide and a proteasome inhibitor. Randomization was stratified by the number of previous lines of treatment (2–3 vs > 3) and age < 75 years vs ≥ 75 years. Patients were excluded if they were refractory to previous treatment with an anti-CD38 antibody or had received prior pomalidomide.

Treatment consisted of 28-day cycles of isatuximab at 10 mg/kg given intravenously on days 1, 8, 15, and 22 of the first cycle and days 1 and 15 in subsequent cycles plus pomalidomide at 4 mg on days 1 to 21, and intravenous or oral dexamethasone at 40 mg (20 mg in patients aged ≥ 75 years) on days 1, 8, 15, and 22. All patients in the isatuximab group received premedication prior to infusions. 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.

For the isatuximab vs control groups: the median age was 68 vs 66 years (61% vs 54% ≥ 65 years, 21% vs 19% ≥ 75 years); 42% vs 54% were female; 10% vs 11% had a history of asthma or chronic obstructive pulmonary disease; 39% vs 34% had an estimated glomerular filtration rate < 60 mL/min/1.73 m²; 54% vs 59% had previous autologous stem cell transplantation; International Staging System stage at study entry was I in 42% vs 33%, II in 34% vs 37%, and III in 22% vs 28%; 16% vs 24% had high-risk cytogenetics; the median number of prior lines of therapy was three (range = 2–4) in both (including an alkylating agent in 90% vs 97%, a proteasome inhibitor in all patients, and lenalidomide in all patients); and 97% vs 99% were refractory to the last line of therapy.

Progression-Free Survival

At median follow-up of 11.6 months, the 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).

Subgroup analyses showed a consistent progression-free survival benefit for the isatuximab group, with hazard ratios including 0.48 (95% CI = 0.24–0.95) in patients aged ≥ 75 years, 0.64 (95% CI = 0.39–1.06) in those aged 65 to 74 years, and 0.66 (95% CI = 0.40–1.07) in those aged < 65 years; 0.59 (95% CI = 0.40–0.88) in 203 patients with two or three or prior lines of therapy and 0.59 (95% CI = 0.36–0.98) in those with more than three prior lines; 0.58 (95% CI = 0.40–0.84) in 218 patients refractory to both lenalidomide and a proteasome inhibitor; 0.50 (95% CI = 0.34–0.76) in 181 refractory to lenalidomide in the last previous line of therapy; and 0.48 (95% CI = 0.29–0.77) in 138 refractory to a proteasome inhibitor in the last previous line of therapy.

Overall response rates were 60% in the isatuximab group vs 35% in the control group (P < .0001), with a very good partial response or better occurring in 32% vs 9% (P < .0001). The median duration of response was 13.3 months vs 11.1 months.

At interim analysis (at the time of primary progression-free survival analysis), the hazard ratio for overall survival was 0.69 (P = .063) in favor of the isatuximab group. The median overall survival had not been reached in either group; the overall survival rate at 12 months was 72% vs 63%.

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%). Grade ≥ 3 adverse events occurred in 87% vs 71% of patients, with the most common in the isatuximab group being pneumonia (16% vs 14%), fatigue (4% vs 0%), and dyspnea (4% vs 1%). Grade 3 or 4 hematologic toxicity included neutropenia in 85% vs 70%, thrombocytopenia in 31% vs 25%, and anemia in 32% vs 28%. Second primary malignancies occurred in six patients (4%; myelodysplastic syndrome in one, post-radiation angiosarcoma in one, and squamous cell carcinoma of the skin in four) vs one patient (< 1%; squamous cell carcinoma of the skin).

Serious adverse events occurred in 62% vs 54% of patients. Treatment was discontinued due to adverse events in 7% vs 13%. Adverse events led to death in 12 patients (8%) vs 14 patients (9%), with deaths being considered related to treatment in 1 (sepsis) vs 2 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.” 

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

REFERENCE

1. Attal M, Richardson PG, Rajkumar SV, et al: Isatuximab plus pomalidomide and low-dose dexamethasone vs pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): A randomised, multicentre, open-label, phase III study. Lancet 394:2096-2107, 2019.