Phillipe Moreau, MD from the University Hospital of Nantes discusses the ASH 2020 abstract – 2316 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.
Context:
Relapsed/refractory multiple myeloma (RRMM) care has improved dramatically, but relapse is unavoidable, and additional successful therapies are required. Isatuximab (Isa), a monoclonal antibody targeting a particular CD38 epitope, is approved in conjunction with pomalidomide and dexamethasone (d) for the treatment of adult RRMM patients who have undergone at least two prior therapies, including lenalidomide and a proteasome inhibitor, in the United States, the European Union, Canada, Australia, Switzerland, and Japan.
Objective: To show the value of the addition of Isa in RRMM to carfilzomib (K) plus d (Kd) vs Kd.
Methodology:
In this Phase 3 (NCT03275285) study, pts with RRMM and 1-3 prior lines of therapy were randomized to 3:2 and stratified to Isa-Kd or Kd by a number of prior lines and R-ISS. For 4 weeks, Isa-Kd obtained Isa (10mg/kg IV) regularly, then every 2 weeks. K (20mg/m2 Days 1-2, 56mg/m2 thereafter) was issued to both arms twice weekly for 3 of 4 weeks, and d (20mg) twice weekly for 3 of 4 weeks. Therapy continued until the worsening of the disease or undesirable adverse events (AE). Primary objective: to demonstrate an improvement in Isa-Kd vs Kd progression-free survival (PFS) determined by an Independent Response Committee (IRC). Comparison of weapons made by log-rank examination. Main secondary objectives: Overall Response Rate (ORR) assessment, Very Good Partial Response Rate (VGPR) or better, Full Response Rate (CR), Minimum Residual Disease (MRD) Negativity Rate (10-5 by NGS), and Overall Survival Rate (10-5 by NGS) (OS). A closed test protocol evaluated the main secondary endpoints. Protection data included the treatment of emerging adverse reactions (TEAE) and the findings of hematology and biochemistry for all sections. When 65 percent of the total predicted PFS events were observed, an interim efficacy review was scheduled.
Outcomes:
302 pts is randomized (179 Isa-Kd, 123 Kd). The features of Pt were well distributed around the weapons. R-ISS I, II, III was 25.8 percent, 59.6 percent, 7.9 percent, respectively; 44 percent, 33 percent, and 23 percent had the previous row, respectively; 90 percent and 78 percent had previous proteasome inhibitor and an immunomodulatory drug (IMiD) respectively; 24 percent had high-risk cytogenetics. Median (range) age 64 (33-90) years; Median PFS for Isa-Kd vs 19.15 months Kd was not achieved with a median follow-up of 20.7 months and with 103 PFS events per IRC; HR 0.531 (99 percent CI 0.318-0.889), one-sided p=0.0007. The pre-specified boundary for efficacy (p=0.005) was thus crossed. The PFS gain across subgroups was consistent. ORR (partial answer [PR]) was 86.6% Isa-Kd vs 82.9% Kd, p=0.1930 one-sided. The VGPR rate was 72.6% Isa-Kd vs 56.1% Kd, p=0.0011. The CR rate was 39.7% Isa-Kd vs 27.6% Kd. Intention to treat population (ITT) MRD negativity rate (10-5) was 29.6 percent (53/179) Isa-Kd vs 13.0 percent (16/123) Kd, descriptive p= 0.0004. OS had been inexperienced (events 17.3 percent Isa-Kd vs 20.3 percent Kd). On care, 52.0 percent Isa-Kd vs 30.9 percent Kd pts remain. Disease progression (29.1 percent Isa-Kd vs 39.8 percent Kd) and AEs were the key reasons for discontinuing care (8.4 percent Isa-Kd vs 13.8 percent Kd). In 76.8% of Isa-Kd vs 67.2% of Kd, grade 3 TEAEs were observed. In Isa-Kd and Kd, treatment-emergent SAEs and fatal TEAEs were similar: 59.3 percent vs 57.4 percent and 3.4 percent vs 3.3 percent. 45.8 percent (0.6 percent grade 3-4) Isa-Kd and 3.3 percent (0 percent grade 3-4) Kd reported infusion reactions. In 32.2 percent Isa-Kd vs 23.8 percent Kd, grade ~3 respiratory infections (grouping) were seen. In 4.0% of Isa-Kd vs 4.1% of Kd, Grade 3 cardiac failure (grouping) was registered. Grade 3-4 thrombocytopenia and neutropenia were identified in 29.9% of Isa-Kd vs. 23.8% of Kd and 19.2% of Isa-Kd vs. 7.4% of Kd, respectively, as per laboratory findings.
Findings:
A superior, statistically significant improvement in PFS with clinically significant improvement in response depth was provided by the addition of Isa to Kd. With manageable protection and a favorable benefit-risk ratio, Isa-Kd has been well-tolerated and represents a potential new standard of care treatment in relapsed MM pts.