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)

Introduction:
The anti-CD38 antibody Isa in combination with Kd is approved in various countries for patients (pts) with relapsed MM after ‚â•1 prior therapy, based on primary interim analysis (IA) of the Phase 3 IKEMA study (NCT03275285). Here we report updated efficacy and safety results from IKEMA.
Methods:
This prespecified final analysis (179 pts randomized to Isa-Kd, 123 to Kd) evaluated updated PFS (primary endpoint), PFS2, minimal residual disease negativity (MRD-) rate, complete response (CR) rate, MRD- and CR rate in ITT population, and safety with 2 additional years of follow-up. Isa 10 mg/kg was given IV weekly for 4‚Äâweeks and then every 2‚Äâweeks; Kd (20/56 mg/m , twice weekly, 3/4‚Äâweeks) was administered in both arms.
Results:
At cutoff (14-Jan-2022) with a median (m) follow-up of 44-months, 49 (27.4%) pts in Isa-Kd and 11 (8.9%) in Kd were still on treatment. The updated PFS was consistent with the IA results, which showed significant benefit in favor of Isa-Kd (vs Kd): HR 0.58 (95.4% CI 0.42–0.79) with median (m) PFS 35.7 mo (95% CI: 25.8-44.0) vs 19.2 mo (95% CI: 15.8-25.0) in Isa-Kd vs Kd. PFS2 HR was 0.68 (95% CI 0.50–0.94) with mPFS2 47.2 mo (95% CI: 38.1-NC) vs 35.6 mo (95% CI: 24.0-40.5) in Isa-Kd vs Kd. Primary PFS analysis as per FDA request/sensitivity analysis for other countries (censoring PFS event occurring >8 weeks after last valid assessment) was 41.7 vs 20.8-months (HR: 0.59, 95.4% CI: 0.42-0.83). With additional follow up and using the Hydrashift Isa immunofixation assay to rule out potential Isa interference in CR determination, final CR rate was 44.1% (95% CI: 0.37–0.52) in Isa-Kd vs 28.5% (95% CI: 0.21-0.37) (OR: 2.09, 95% CI: 1.26–3.48); ORR was 86.6% (95% CI: 0.81–0.91) vs 83.7% (95% CI: 0.76–0.90); MRD- was reached in 33.5% (95% CI: 0.27–0.41) vs 15.4% (95% CI: 0.10–0.23) pts (OR: 2.78, 95% CI: 1.55–4.99); rate of MRD- CR pts was 26.3% (95% CI: 0.20–0.33) vs 12.2% (95% CI: 0.07–0.19) (OR: 2.57, 95% CI: 1.35–4.88). Addition of Isa to Kd (vs Kd) also delayed time to next treatment, with HR 0.55 (95% CI: 0.40–0.76). Safety profiles in both arms remain consistent with prior IKEMA findings. Serious TEAEs were reported in 70.1% of Isa-Kd pts vs 59.8% in Kd. The most common, any-grade non-hematologic TEAEs in Isa-Kd were infusion reaction (45.8%), diarrhea (39.5%), hypertension (37.9%) and upper respiratory tract infection (37.3%).
Discussion:
These results show unprecedented mPFS, CR rate, MRD- and MRD- CR rates in a non-lenalidomide containing regimen with benefit maintained through subsequent therapies and a manageable safety profile. The PFS analysis using FDA censoring rules showed consistent results with the IA as well. Our findings support Isa-Kd as a standard of care treatment for pts with relapsed MM.