New Standard for Relapsed/Refractory Multiple Myeloma?

Isatuximab (Sarclisa) added to carfilzomib and dexamethasone (Isa-Kd) extended progression-free survival (PFS) compared with carfilzomib and dexamethasone (Kd) alone in patients with relapsed/refractory multiple myeloma (MM) previously treated with one to three lines of therapy.

In the first planned interim analysis of the multinational phase III IKEMA study, at a median duration of follow-up of 20.7 months, median PFS in the intent-to-treat population (ITT) with the experimental Isa-Kd regimen had not been reached, compared with a median PFS of 19.15 months in the Kd arm, corresponding to a hazard ratio of 0.531 (99% CI 0.318-0.889, P=0.0007) in favor of the triplet regimen, reported Philippe Moreau, MD, of University Hospital Hôtel-Dieu in Nantes, France.

As he noted during the virtual program of the European Hematology Association (EHA25), an interim analysis was prespecified when 65% of PFS events occurred.

The depth of response with Isa-Kd compared with Kd was “profound,” said Moreau. In the ITT population, 30% of patients in the Isa-Kd arm were negative for minimal residual disease (MRD) compared with 13% in the Kd arm (P=0.0004).

Based on these results, “Isa-Kd may represent a new standard of care for patients with relapsed MM,” he said.

In March 2020, the FDA approved isatuximab, an immunoglobulin G1 monoclonal antibody targeting CD38, in combination with pomalidomide and dexamethasone for adult patients with MM who have received at least two prior therapies including lenalidomide and a proteasome inhibitor.

IKEMA enrolled 302 patients with relapsed/refractory MM across 69 centers from 16 countries. Patients with MM previously treated with one to three lines of therapy, not including carfilzomib, and not refractory to prior anti-CD38 therapy, were eligible.

Participants were randomized 3:2 to isatuximab at 10 mg/kg on days 1, 8, 15, and 22 of the first cycle, then on days 1 and 15 of subsequent cycles, in combination with IV carfilzomib (20/56 mg/m²) on days 1, 2, 8, 9, 15, and 16, plus 20 mg of dexamethasone (intravenous or orally) on days 1, 2, 8, 9, 15, 16, 22, and 23 of a 28-day cycle or Kd alone.

The median age of patients in the entire cohort was 64; about 9% were age 75 or older. About one fourth of patients in each arm had high-risk cytogenetics at baseline, defined as 17p deletion or t(4,14) and t(14,16).

A total of 18.4% of patients in the Isa-Kd arm and 24.4% in the Kd arm had three prior lines of therapy; the median in each arm was two prior lines. About one third of patients in each arm were refractory to lenalidomide at study entry, and 49.7% in the triplet arm and 59.3% in the doublet arm were refractory to their last regimen. About 90% of patients had prior exposure to proteasome inhibitors, and about 80% had prior exposure to immunomodulatory drugs.

As of the data cut-off of Feb. 7, 2020, a higher percentage of patients were still on treatment in the Isa-Kd arm than in the Kd arm (52.0% vs 30.9%). The rates of discontinuation due to progressive disease or adverse events were 37.4% in the Isa-Kd arm and 53.7% in the Kd arm.

The primary endpoint was PFS as assessed by an independent review committee. Moreau said median PFS in the control arm was estimated at 19 months using the results from the ENDEAVOR study, which served as the basis for approval of Kd for relapsed/refractory MM, and was nearly identical to the 19.15 months observed in IKEMA.

“Kd is a good control arm … and if you are adding isatuximab on top of Kd, you are definitely highly improving the outcome of patients, with a very good PFS and a hazard ratio of 0.53 that is associated with a 47% reduction in the risk of death or progression with the addition of isatuximab,” he said.

Isa-Kd demonstrated a consistent benefit on PFS across all prespecified subgroups, including by stage at study entry, prior lenalidomide treatment, and high-risk cytogenetic status, he added.

Moreau noted that overall response rates were similar at 86.6% in the Isa-Kd arm and 82.9% in the Kd arm (P=0.19), but deeper responses were observed with Isa-Kd, as evidenced by the superior MRD rate in this arm. Median time to next treatment also favored Isa-Kd over Kd (not reached in either arm; HR 0.56, 95% CI 0.35-0.841).

Overall survival (OS) data are not yet mature, Moreau said; death rates at the time of analysis were 17.3% in the patients randomized to Isa-Kd and 20.3% in those assigned to Kd. Median treatment duration was longer in patients assigned to Isa-Kd versus Kd (80.0 vs 61.4 weeks) indicating that the triplet is feasible, he said.

No new safety signals were identified in the study. The rates of grade 3 or greater treatment-emergent adverse events (TEAEs) were 76.8% in the Isa-Kd arm vs 67.2% in the Kd arm, and the rates of serious drug-related TEAEs were similar at 24.8% and 25.4%, respectively.

The rates of any TEAE leading to definitive discontinuation from the study were 8.5% in patients randomized to Isa-Kd and 13.9% in those assigned to Kd. The rates of fatal TEAEs were not different (3.4% vs 3.3%, respectively). Some 44.6% of the Isa-Kd arm experienced infusion-related reactions, almost all grade 1 or 2 and occurring mainly during the first infusion.

The 0.53 hazard ratio for PFS in IKEMA compared favorably with the 0.63 hazard ratio for a daratumumab-carfilzomib-dexamethasone triplet vs carfilzomib and dexamethasone in a similar patient population with relapsed/refractory MM in the CANDOR study, which was reported in December at the American Society of Hematology 2019 annual meeting. “The meaning of these two trials is that we can add on top of the full dose of Kd, a monoclonal antibody targeting CD38 … with a benefit in terms of PFS,” Moreau explained.

Asked for her perspective, Sarah A. Holstein, MD, PhD, of the University of Nebraska in Omaha, who was not involved with the study, said the Isa-Kd combination, “like daratumumab/carfilzomib/dexamethasone, represents a reasonable option for R/R myeloma, particularly in those who are refractory to lenalidomide.”

“Isatuximab is currently only approved in combination with pomalidomide/dexamethasone. The data available to date would suggest that isatuximab and daratumumab are fairly equivalent,” Holstein told MedPage Today via email. “Thus I would suspect that physicians are deciding on which anti-CD38 antibody to use based on approved indication/s, schedule, and pricing.”

Last Updated June 15, 2020