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

Background: Treatment of relapsed/refractory multiple myeloma (RRMM) has greatly improved, yet relapse is inevitable and additional effective treatments are needed. Isatuximab (Isa), a monoclonal antibody targeting a specific epitope on CD38, is approved in combination with pomalidomide and dexamethasone (d) in the United States, the European Union, Canada, Australia, Switzerland, and Japan for the treatment of adult patients with RRMM who have received at least two prior therapies including lenalidomide and a proteasome inhibitor.

Aim: Demonstrate benefit of adding Isa to carfilzomib (K) plus d (Kd) vs Kd in RRMM.

Methods: In this Phase 3 study (NCT03275285), pts with RRMM and 1-3 prior lines of therapy were randomized 3:2 and stratified by number of prior lines and R-ISS to receive Isa-Kd or Kd. Isa-Kd arm received Isa (10mg/kg IV) weekly for 4 weeks, then every 2 weeks. Both arms received K (20mg/m² Days 1-2, 56mg/m² thereafter) twice-weekly for 3 of 4 weeks, and d (20mg) twice-weekly. Treatment continued until disease progression or unacceptable adverse events (AE). Primary objective: demonstrate an increase in progression free survival (PFS) of Isa-Kd vs Kd, determined by an Independent Response Committee (IRC). Comparison between arms conducted through log-rank testing. Key secondary objectives: evaluation of overall response rate (ORR), rate of very good partial response (VGPR) or better, complete response (CR) rate, minimal residual disease (MRD) negativity rate (10^-5 by NGS), and overall survival (OS). Key secondary endpoints tested with a closed test procedure. Safety data included treatment emergent adverse events (TEAE), and hematology and biochemistry results for all pts. Interim efficacy analysis was planned when 65% of the total expected PFS events were observed.

Results: 302 pts (179 Isa-Kd, 123 Kd) were randomized. Pt characteristics were well-balanced across arms. Median (range) age 64 (33-90) years; R-ISS I, II, III was 25.8%, 59.6%, 7.9% respectively; 44%, 33% and 23% had 1, 2 and ≥3 prior lines respectively; 90% and 78% had prior proteasome inhibitor and immunomodulatory drug (IMiD) respectively; 24% had high-risk cytogenetics. At a median follow-up of 20.7 months and with 103 PFS events per IRC, median PFS was not reached for Isa-Kd vs 19.15 months Kd; HR 0.531 (99% CI 0.318-0.889), one-sided p=0.0007. Thus, the pre-specified efficacy boundary (p=0.005) was crossed. PFS benefit was consistent across subgroups. ORR (≥partial response [PR]) was 86.6% Isa-Kd vs 82.9% Kd, one-sided p=0.1930. ≥VGPR rate was 72.6% Isa-Kd vs 56.1% Kd, p=0.0011. CR rate was 39.7% Isa-Kd vs 27.6% Kd. MRD negativity rate (10^-5) in the intent to treat population (ITT) was 29.6% (53/179) Isa-Kd vs 13.0% (16/123) Kd, descriptive p=0.0004. OS was immature (events 17.3% Isa-Kd vs 20.3% Kd). 52.0% Isa-Kd vs 30.9% Kd pts remain on treatment. Main reasons for treatment discontinuation were disease progression (29.1% Isa-Kd vs 39.8% Kd) and AEs (8.4% Isa-Kd vs 13.8% Kd). Grade ≥3 TEAEs were observed in 76.8% Isa-Kd vs 67.2% Kd. Treatment-emergent SAEs and fatal TEAEs were similar in Isa-Kd and Kd: 59.3% vs 57.4% and 3.4% vs 3.3%, respectively. Infusion reactions were reported in 45.8% (0.6% Grade 3-4) Isa-Kd and 3.3% (0% Grade 3-4) Kd. Grade ≥3 respiratory infections (grouping) were seen in 32.2% Isa-Kd vs 23.8% Kd. Grade ≥3 cardiac failure (grouping) was reported in 4.0% Isa-Kd vs 4.1% Kd. As per lab results, Grade 3-4 thrombocytopenia and neutropenia were reported in 29.9% Isa-Kd vs 23.8% Kd and 19.2% Isa-Kd vs 7.4% Kd, respectively.

Conclusions: Addition of Isa to Kd provided a superior, statistically significant improvement in PFS with clinically meaningful improvement in depth of response. Isa-Kd was well tolerated with manageable safety and a favorable benefit-risk profile, and represents a possible new standard of care treatment in pts with relapsed MM.