EMN24 IsKia phase III: Isa-KRd vs KRd for TE NDMM

Results from the ongoing, randomized, open-label, multicenter, phase III EMN24 IsKia trial (NCT04483739), comparing outcomes with isatuximab + carfilzomib + lenalidomide + dexamethasone (Isa-KRd) vs carfilzomib + lenalidomide + dexamethasone (KRd) in transplant-eligible (TE) patients with newly diagnosed multiple myeloma (NDMM), were published in Nature Medicine by Gay et al. Patients aged 18–70 years were randomized 1:1 to receive pre-autologous hematopoietic stem cell transplantation (auto-HSCT) induction and post-auto-HSCT consolidation with Isa-KRd (n = 151) or KRd (n = 151). The primary endpoint was next-generation sequencing (NGS)-measurable residual disease (MRD) negativity at a sensitivity of 10⁻⁵ or better after consolidation. Key secondary endpoints included post-induction NGS-MRD negativity and progression-free survival (PFS).

Key data: The MRD negativity rate after post-auto-HSCT full-dose consolidation was higher with Isa-KRd vs KRd at both 10⁻⁵ (77% vs 67%; odds ratio [OR], 1.67; 95% confidence interval [CI], 1.00–2.80; p = 0.049) and 10⁻⁶ (68% vs 48%; OR, 2.36; 95% CI, 1.47–3.79; p = 0.0004). The MRD negativity rate after induction was higher with Isa-KRd vs KRd at both 10⁻⁵ (46% vs 27%; OR, 2.32; 95% CI, 1.43–3.78; p = 0.0007) and 10⁻⁶ (28% vs 14%; OR, 2.44; 95% CI, 1.36–4.40; p = 0.0029). The 1-year sustained MRD negativity rate was also higher with Isa-KRd vs KRd at 10⁻⁶ (52% vs 38%; OR, 1.82; 95% CI, 1.14–2.91; p = 0.012). Treatment discontinuation, deaths due to adverse events (AEs), and Grade 3–4 non-hematologic AEs were comparable. PFS data were immature at the current follow-up.

Key learning: Adding isatuximab to KRd as induction and consolidation therapy improved the depth and durability of MRD negativity in TE NDMM, including high-risk and ultra-high-risk subgroups, with a manageable safety profile.