FDA Approves Isatuximab Plus Carfilzomib/Dexamethasone for Relapsed/Refractory Multiple Myeloma

FDA

The FDA has approved isatuximab-irfc (Sarclisa) in combination with carfilzomib (Kyprolis) and dexamethasone (Kd) for the treatment of adult patients with relapsed or refractory multiple myeloma who have previously received 1 to 3 lines of therapy.

The regulatory decision was based on data from the phase 3 IKEMA trial (NCT03275285), which showed that the triplet reduced the risk of disease progression or death by 45% vs Kd alone in this patient population (HR, 0.548; 95% CI, 0.366-0.822; P = .0032). At the time of the preplanned interim analysis, the median progression-free survival (PFS) had not yet been reached with the isatuximab combination.

Additionally, no statistically significant difference in objective response rate (ORR) was observed with the triplet vs the doublet, at 86.6% vs 82.9%, respectively (P = .03859); complete response (CR) rates were 39.7% vs 27.6%, respectively, and very good partial response (VGPR) rates were 33.0% and 28.5%, respectively. At the time of the interim analysis, data for overall survival (OS) were still immature.

“Treatment of patients with relapsed or refractory multiple myeloma remains challenging and the prognosis for patients experiencing multiple relapses unfortunately is poor,” Peter C. Adamson, MD, Global Development Head, Oncology and Pediatric Innovation at Sanofi, stated in a press release. “With this approval, [isatuximab] is now included in 2 standard-of-care regimens for the treatment of patients with multiple myeloma as early as first relapse. Today’s milestone further supports our ambition for [isatuximab] to become the anti-CD38 of choice for patients with relapsed or refractory multiple myeloma.”

The open-label phase 3 trial enrolled a total of 302 patients with relapsed/refractory myeloma who had received 1 to 3 prior lines of treatment. Participants were randomized 3:2 to receive either intravenous isatuximab at 10 mg/kg with Kd (n = 179) or Kd alone (n = 123).

Isatuximab was given on days 1, 8, 15, and 22 in cycle 1, and then every 2 weeks thereafter. Twice-weekly carfilzomib was administered at a dose of 20 mg/m² on days 1 and 2 and then at 56 mg/m² thereafter for 3 to 4 weeks. Dexamethasone was given at a twice-weekly dose of 20 mg. Treatment continued until progressive disease, intolerable toxicity, or the patient decided to withdraw.

Notably, patients who previously received carfilzomib and/or were refractory to previous anti-CD38 therapy were ineligible to participate. Patients were stratified based on line of therapy (1 vs more than 1) and Revised Multiple Myeloma International Staging System (R-ISS stage; I or II vs III vs not classified).

The primary end point of the trial was PFS per independent review committee assessment. Secondary outcome measures included ORR, VGPR rate or better, CR rate, minimal residual disease (MRD) negativity rate, and OS. Safety was evaluated via treatment-emergent adverse effects (TEAEs).

Baseline characteristics were comparable between the arms. The median age of patients was 64 years (range, 33-90), and 8.8% of were 75 years of age or older. The percentages of those with R-ISS I, II, and III disease were 53.2%, 30.2%, and 15.4%, respectively. Additionally, 44.4% of patients previously received 1 line of therapy, 32.5% had 2, and 21.4% had 3 or more. About 90% of patients (89.1%) had previously received a proteasome inhibitor, while 78.7% received a prior immunomodulatory drug (IMiD); 33% of patients were refractory to lenalidomide (Revlimid). Twenty-four percent of patients had high-risk cytogenetics.

Regarding safety, the most commonly experienced toxicities in the investigative arm vs the control arm included upper respiratory tract infection (67% vs 57%, respectively), infusion-related reactions (46% vs 3.3%), fatigue (42% vs 32%), hypertension (37% vs 32%), diarrhea (36% vs 29%), pneumonia (36% vs 30%), dyspnea (29% vs 24%), bronchitis (24% vs 13%), and cough (23% vs 15%).

Serious adverse effects that were reported in more than 5% of patients who received the isatuximab triplet included pneumonia (25%) and upper respiratory tract infections (9%). Eight percent of patients who received the isatuximab combination permanently discontinued treatment due to toxicities; 2.8% of patients discontinued because of an infection.

References

1. FDA approves Sarclisa (isatuximab) in combination with carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma. News release. Sanofi. March 31, 2021. Accessed March 31, 2021. https://bit.ly/39za7X4
2. Moreau P, Dimopoulos MA, Mikhael J, et al. Isatuximab plus carfilzomib and dexamethasone vs carfilzomib and dexamethasone in relapsed/refractory multiple myeloma (IKEMA): interim analysis of a phase 3, randomized, open-label study. Presented at: 2020 European Hematology Association Congress; June 11-21, 2020; Virtual. Abstract LB3603.