Objective: To demonstrate benefit of adding Isatuximab (Isa) to (Kd) vs. Kd in relapsed/refractory multiple myeloma (RRMM).
Methodology: In this Phase-3 study (NCT03275285), patients 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: increase in PFS of Isa- Kd vs. Kd, determined by an Independent Response Committee (IRC). Comparison between arms conducted through log-rank testing. Key secondary objectives: overall response rate (ORR), rate of very good partial response (VGPR) or better, complete response (CR) rate, MRD negativity-rate (105 by NGS), and overall survival (OS). Key secondary endpoints tested with a closed test procedure. Safety data included treatment emergent adverse events (TEAE), hematological, and biochemistry results for all patients. Interim efficacy analysis is planned once 65% of total expected PFS events are observed.
Results: 302 patients (Isa-Kd: 179, Kd: 123) were randomized. Median 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 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 (≥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 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 (59.3% vs. 57.4%) and fatal TEAEs were similar in Isa-Kd and Kd (3.4% vs. 3.3%,) and 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): 32.2% Isa-Kd vs. 23.8% Kd. Grade ≥3 cardiac failure (grouping): 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.
Conclusion: Addition of Isa to Kd provided superior, statistically-significant improvement in PFS with clinically meaningful improvement in depth of response. Isa-Kd was well tolerated with manageable safety and favourable benefit-risk profile, and represents a possible new standard of care treatment in patients with relapsed MM. Data first presented at EHA 2020 virtual meeting, June 11–21st. Study sponsored by Sanofi.
