Abstract: LB2603

Type: Oral Presentation

Presentation during EHA25: All oral abstract presentations will be made available on the on-demand Virtual Congress platform as of Friday, June 12 at 08:30 CEST and will be accessible until October 15, 2020.

Session title: Late-breaking Oral Session

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, received positive CHMP opinion and FDA-approval in combination with pomalidomide and low-dose dexamethasone (d) for patients (pts) with RRMM.

Aims
Demonstrate benefit of adding Isa to 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 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, 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 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 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.

Conclusion
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.

Session topic: 14. Myeloma and other monoclonal gammopathies - Clinical

Keyword(s): CD38, Monoclonal antibody, Multiple myeloma, Phase III