Treatment with the investigational anti-CD38 monoclonal antibody isatuximab plus the combination of pomalidomide and low-dose dexamethasone (Pd) led to a median progression-free survival (PFS) of 11.5 months in patients with relapsed and refractory multiple myeloma (MM), according to findings from the phase III ICARIA-MM trial that were published in The Lancet. This was nearly twice as long as the median PFS in patients who were treated with Pd alone, reported lead author Michel Attal, MD, from the Institut Universitaire du Cancer Toulouse Oncopole in Toulouse, France, and colleagues.
“ICARIA-MM is the first positive randomized, phase III study adding an anti-CD38 antibody, isatuximab, to a pomalidomide-dexamethasone backbone therapy for relapsed and refractory MM,” Dr. Attal and authors wrote. In addition to the improvements in PFS and response rates, the addition of isatuximab “was well tolerated, with no increase in treatment discontinuations or incidence of fatal events,” they noted.
The randomized, open-label, multicenter ICARIA-MM trial included 307 patients with relapsed/refractory MM who had received at least two prior lines of therapy (including lenalidomide and a proteasome inhibitor [PI]). Patients whose disease was refractory to a previous anti-CD38 monoclonal antibody were excluded.
Participants were randomized 1:1 to receive isatuximab plus Pd (n=154) or Pd alone (n=153). Pd was administered in 28-day cycles of pomalidomide 4 mg on days 1 through 21 and dexamethasone 40 mg (20 mg if >75 years) weekly, until disease progression or unacceptable toxicity. Isatuximab 10 mg/kg was administered through intravenous infusion for the first 4 weeks, then every 2 weeks thereafter.
Patient characteristics were well-balanced between the treatment groups: Median age was 67 years (range = 59-74), and the median number of prior lines of therapy was 3 (range = 2-4). Nearly all patients in the isatuximab and Pd-alone groups were refractory to their last line of therapy (97% and 99%, respectively).
At a median follow-up of 11.6 months (interquartile range [IQR] = 10.1-13.9), the median PFS was 11.5 months in the isatuximab-treated group, compared with 6.5 months in the Pd-treated group (hazard ratio = 0.596; 95% CI 0.44-0.81; p=0.001).
The PFS benefit with isatuximab was observed across all prespecified subgroups, the authors noted, including those with high cytogenetic risk disease and those with lenalidomide-refractory disease (TABLE).
Isatuximab also appeared to increase the rates of response and depth of response, compared with Pd alone. More patients in the isatuximab-treated group achieved a complete response (5% vs. 1%), very good partial response (27% vs. 7%), or partial response (29% vs. 27%; p<0.0001 for all comparisons).
“Responses occurred faster and were more durable in the [isatuximab-Pd] group than the Pd group,” the investigators reported, with a median time to first response of 35 days (IQR=32-60) versus 58 days (IQR=32-87). In addition, responses lasted longer in the isatuximab group (13.3 months vs. 11.1 months).
Overall, safety results were similar between both treat-ment groups, with the exception of infusion reactions, which occurred exclusively in the isatuximab group (56%). Most of these were reversible and occurred with the first infusion of isatuximab.
There appeared to be more grade ≥3 adverse events (AEs) in the isatuximab group than the Pd group (86.8% vs. 70.5%). Incidence of hematologic AEs were similar between the groups, although grade 4 neutropenia was more frequent in the isatuximab group (61% vs. 31%). However, more patients in the Pd-alone group than the isatuximab group discontinued treatment due to AEs (12.8% vs. 7.2%).
Fatal AEs were reported in 12 patients (8%) in the isatuximab group and 14 (9%) in the Pd group. Deaths due to treatment-related AEs were reported in 1 patient (<1%) in the isatuximab group (sepsis) and 2 (1%) in the Pd group (pneumonia and urinary tract infection).
Together, these safety and efficacy results suggest that “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 PI,” the authors concluded. However, the study’s findings are limited by its open-label design, which introduces the potential for bias in primary outcome reporting. Also, because ICARIA-MM did not enroll patients with disease that was refractory to another anti-CD38 antibody, these results are not applicable to this subgroup of patients.
Study authors report relationships with Sanofi, which sponsored the trial.
Attal M, Richardson PG, Rajkumar SV, et al. Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): a randomised, multicentre, open-label, phase 3 study. Lancet. 2019;394:2096-2107.