Isatuximab Plus Carfilzomib/Dexamethasone Maintains Survival Benefit in Relapsed Multiple Myeloma

The combination of Isatuximab (Sarclisa) plus carfilzomib (Kyprolis) and dexamethasone (Isa-Kd) continued to demonstrate a progression-free survival (PFS) benefit vs carfilzomib and dexamethasone (Kd) alone in patients with relapsed multiple myeloma, according to an updated analysis of the phase 3 IKEMA trial (NCT03275285) presented at the 19th International Myeloma Society Annual Meeting.¹

At a median follow-up of 44 months, the median PFS for Isa-Kd was 35.7 months (95% CI, 25.8-44.0) vs 19.2 months (95% CI, 15.8-25.0) with Kd, with a hazard ratio (HR) favoring Isa-Kd of 0.58 (95.4% CI 0.42-0.79).

“Results of this prespecified PFS updated analysis are consistent with the IA [interim analysis] and demonstrate improvement in PFS with addition of isatuximab to Kd with unprecedented median PFS of 3 years, the longest PFS on a PI [proteasome inhibitor] backbone in the relapsed multiple myeloma setting,” the investigators stated in their poster.

In the phase 3 IKEMA trial, 179 patients were randomly assigned to receive Isa-Kd and 123 to receive Kd. Patients had a median of 2 prior lines of therapy and were stratified between those with 1 prior line and those with more than 1 prior line, as well as by Revised International Staging System (R-ISS) status.

The experimental arm received 10 mg/kg of isatuximab intravenously once weekly in the first cycle, then once every 2 weeks of subsequent cycles. Both arms received carfilzomib at 20 mg/m2 on days 1 and, then 56 mg/m2 on days 8, 9, 15, and 16 of the first cycle, then 56 mg/m2 on days 1, 2, 8, 9, 15, and 16 in subsequent cycles, while 20 mg of dexamethasone was given on days 1, 2, 8, 9, 15, 16, 22, and 23 each cycle.

The primary end point was PFS, and secondary end points included overall response rate (ORR), rate of very good partial response (VGPR) or better, overall survival (OS), time to second progression (PFS2), minimal residual disease (MRD) negativity, and duration of response.

The preplanned primary IA at a median of 20.7 months demonstrated PFS favoring Isa-Kd over Kd with HR of 0.53 (99% CI, 0.32-0.89; one-sided P = .0007).2 The rate of VGPR or better was 72.6 with Isa-Kd vs 56.1 with Kd in the intent-to-treat (ITT) population. The complete response (CR) rate was 39.7% for Isa-Kd vs 27.6% for Kd.

With longer follow-up of 44 months, 49 patients (27.4%) who had received Isa-Kd continued to receive treatment vs only 11 (8.9%) in the Kd arm.1 Progressive disease was the most common reason for discontinuation, in 43.0% of the Isa-Kd arm and 52.0% of the Kd arm. Treatment discontinuation due to adverse events occurred in 12.3% of the Isa-Kd arm and 17.9% of the Kd arm.

In the updated analysis, the ORR and rates of VGPR or better had not changed significantly, but the CR rate was now improved to 44.1% for those who received Isa-Kd vs 28.5% with Kd alone (odds ratio [OR], 2.09; 95% CI, 1.26-3.48).

The PFS was superior for Isa-Kd in all subgroups, including those based on prior therapies, age, and ISS stage. The subgroup with the greatest HR favoring Isa-Kd was those who had not received prior PI (HR, 0.434; 95% CI, 0.286-0.657) while those who had received prior PI had the HR that favored Isa-Kd least (HR, 0.824; 95% CI, 0.506-1.343).

The MRD negativity rate was 33.5% for Isa-Kd vs 15.4% with Kd, with an OR of 2.78 (95% CI, 1.55-4.99). The rate of patients who had a CR and reached MRD negativity was 26.3% with Isa-Kd vs 12.2% with Kd, with an OR of 2.57 (95% CI, 1.35-4.88).

The median PFS2 in the ITT population was 47.2 months (95% CI, 38.1–not calculable [NC]) with Isa-Kd vs 35.6 months (95% CI, 24.0-40.5) with Kd (HR, 0.68; 95% CI, 0.50-0.94).

The time to next treatment after Isa-Kd was 44.9 months (95% CI, 31.6–NC) vs 25.0 months (95% CI, 17.9-31.3) after Kd, with a HR of 0.55 (95% CI, 0.40-0.76). In the Isa-Kd arm, only 44.1 patients had received another line of therapy, compared with 64.2% of those who had received Kd. OS had an HR favoring Isa-Kd of 0.78 (95% CI, 0.54-1.12); median OS was not reported.

Safety was consistent with prior IA results, with more frequent grade 3 or higher treatment-emergent adverse events (TEAEs) and serious TEAEs being reported in the Isa-Kd group. However, the rate of drug-related grade 3 or higher TEAEs, serious drug-related TEAEs, and fatal AEs were similar between the groups. When accounting for the longer duration of exposure in the Isa-Kd arm, the increase in grade 3 or higher TEAEs was lower in this analysis than in the IA. The most common any-grade AEs associated with Isa-Kd were infusion reaction, diarrhea, hypertension, and upper respiratory tract infection. Grade 3 or higher cardiac failure was reported in 8 patients (4.5%) in the Isa-Kd arm and in 5 (4.1%) in the Kd arm.

“With additional 2 years of follow-up and despite the COVID-19 pandemic, the safety profile remains similar to the IA results,” the authors wrote in the poster. “At median follow-up of ~44 months, median PFS of nearly 3 years and MRD negativity in 1 out of 3 patients further support Isa-Kd as a standard of care for relapsed multiple myeloma.”

References

1. Yong K, Moreau P, Dimopolous M, et al. Updated progression-free survival (PFS) and depth of response in IKEMA, a randomized Phase 3 trial of isatuximab, carfilzomib and dexamethasone (Isa-Kd) vs Kd in relapsed multiple myeloma (MM). Poster presented at: 19th Annual International Myeloma Society (IMS) Annual Meeting; August 25-27, 2022; Los Angeles, CA. Abstract P-284.
2. Moreau P, Dimopoulos MA, Mikhael J, et al. Isatuximab, carfilzomib, and dexamethasone in relapsed multiple myeloma (IKEMA): a multicentre, open-label, randomised phase 3 trial. Lancet. 2021;397(10292):2361-2371. doi:10.1016/S0140-6736(21)00592-4