Multinational phase 3 trial of isatuximab, carfilzomib, lenalidomide, and dexamethasone for newly diagnosed multiple myeloma

Induction and consolidation with a quadruplet therapy (CD38-targeting monoclonal antibody, proteasome inhibitor, immunomodulatory drug, and dexamethasone) are standard of care treatments in transplant-eligible (TE) patients with newly diagnosed multiple myeloma (NDMM) with the optimal drugs to be used still under debate. The phase 3 EMN24IsKia trial, at 42 centers in 8 European countries, randomized 302 TE patients with NDMM aged ≤ 70 years 1:1 to isatuximab-carfilzomib-lenalidomide-dexamethasone (Isa-KRd) versus KRd pretransplant induction and post-transplant consolidation. The primary endpoint was the rate of measurable residual disease (MRD) negativity at sensitivity 10^-5 or better by next-generation sequencing (NGS) after consolidation. Post-consolidation MRD negativity was significantly higher with Isa-KRd versus KRd at the 10^-5 (77% versus 67%; OR 1.67; p=0.049) and 10^-6 (68% versus 28%; OR 2.36; p=0.0004) sensitivities. Deep MRD responses were rapid and durable. At current follow-up, PFS data were immature. Grade 3-4 non-hematologic adverse events, treatment discontinuations, and deaths due to adverse events were similar in the two arms. The authors conclude that Isa-KRd significantly improved NGS-MRD negativity in TE patients with NDMM, with a manageable safety profile.