Isatuximab Combo Improves Progression-Free Survival in Pretreated Myeloma

In an update from the phase III ICARIA-MM trial, researchers reported that the combination of the anti-CD38 monoclonal antibody isatuximab with pomalidomide and dexamethasone (Pd) extended progression-free survival (PFS) to 11.5 months in patients with relapsed/refractory multiple myeloma (MM) – nearly five months longer than with Pd alone. Paul G. Richardson, MD, from the Dana-Farber Cancer Institute in Boston, presented the findings at the 2019 ASCO Annual Meeting.

“The PFS observed with [the isatuximab combination] is the longest observed in this patient population,” Dr. Richardson reported, “demonstrating consistent improvement in PFS among subgroups, including lenalidomide-refractory patients.”

The phase III 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]). Participants also had disease that was refractory to their last therapy.

Patients were randomized 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 1-21 and dexamethasone 40 mg (20 mg if >75 years) weekly, until disease progression or unacceptable toxicity.

Isatuximab 10 mg/kg weekly was administered through intravenous infusion for the first few weeks, then every two weeks thereafter.

Across the entire treatment population, median age was 67 years (range = 36-86 years) and 19.5% of participants had high-risk cytogenetics. The researchers noted that patient characteristics were well balanced across the treatment arms. The median number of prior lines of therapy was 3 (range = 2-11), with most patients (92.5%) refractory to lenalidomide and 75.9% refractory to a PI.

After a median follow-up of 11.6 months (range not provided), the median PFS was 11.5 months in the isatuximab group, compared with 6.5 months in the Pd-alone group (ranges not reported; p=0.001).

The PFS benefit was consistent across all major subgroups, the authors reported, including in patients whose MM was refractory to lenalidomide (hazard ratio [HR] = 0.59; 95% CI 0.43-0.82) and those with high-risk cytogenetics (HR=0.66; 95% CI 0.33-1.28). P values for these comparisons were not provided.

Median overall survival (OS) was not reached in either group, but rates of 12-month OS appeared to be higher in the isatuximab group (72% vs. 63%; p value not provided).

“The addition of isatuximab to Pd resulted in significant improvement in overall and depth of response,” Dr. Richardson said. Responses occurred more rapidly in the isatuximab group (median time to response = 35 days vs. 58 days; ranges and p value not reported), and more patients in the isatuximab group achieved at least a partial response (60.4% vs. 35.3%; p<0.0001).

No patients in the Pd-alone group reached a measurable residual disease–negative state, while 5.2% of evaluable patients in the isatuximab-treated group achieved this state (p value not reported).

Dr. Richardson also highlighted the renal response associated with isatuximab. Among patients with renal impairment at baseline and at least one post-baseline assessment (32 in the isatuximab arm and 21 in the Pd arm), the monoclonal antibody appeared to increase the reversal of renal impairment: 71.9% of patients experienced a complete renal response, compared with 38.1% of patients in the Pd alone group (p value not reported).

Treatment appeared to be well tolerated, Dr. Richardson and colleagues reported, with patients receiving isatuximab for a median of 41 weeks, compared with 24 weeks in the Pd alone group.

There appeared to be more grade ≥3 adverse events (AEs) observed in the isatuximab group than the Pd group (86.8% vs. 70.5%); the most common of these were infection (42.8% vs. 30.2%) and neutropenia (84.9% vs. 70.1%; p values not reported). However, more patients in the Pd-alone group than the isatuximab group discontinued treatment due to AEs (12.8% vs. 7.2%).

At the time of data presentation, 7.9% of isatuximab-treated patients and 9.4% of Pd-treated patients died due to AEs.

Together, these safety and efficacy results suggest that isatuximab plus Pd is “an important new treatment option for the management of relapsed/refractory MM,” Dr. Richardson concluded. However, these results will need to be confirmed in longer-term follow-up, and also compared with other monoclonal antibody–based regimens for MM.

The authors report relationships with Sanofi, which sponsored the study.

Reference

Richardson PG, Attal M, Rajkumar SV, et al. A phase III randomized, open label, multicenter study comparing isatuximab, pomalidomide, and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed/refractory multiple myeloma (RRMM). Abstract #8004. Presented at the 2019 ASCO Annual Meeting, June 2, 2019; Chicago, IL.

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