Sustained MRD negativity in patients with newly diagnosed multiple myeloma treated with carfilzomib-lenalidomide-dexamethasone with or without isatuximab (phase III IsKia trial).

7502 Background: The phase III IsKia trial assessed the efficacy and safety of isatuximab-carfilzomib-lenalidomide-dexamethasone (IsaKRd) as pre-ASCT induction and post-ASCT consolidation vs KRd. The rate of measurable residual disease (MRD) negativity was significantly higher in IsaKRd vs KRd patients (pts) after both induction and consolidation (Gay et al. ASH 2023). Here we report the rates of 1-year sustained (sust)MRD negativity and findings about the light consolidation phase. Methods: Transplant-eligible NDMM pts aged <70 years were enrolled. IsaKRd pts received 4 full-dose IsaKRd induction cycles, MEL200-ASCT, 4 full-dose IsaKRd consolidation cycles and, thereafter, 12 28-day light consolidation cycles [Isa 10 mg/kg IV on days (dd) 1, 15; K 56 mg/m 2 IV dd 1; R 10 mg PO daily dd 1–21; d 20 mg PO dd 1, 15]. Pts in the KRd arm received the same KRd schedule used in the other arm. MRD was tested by NGS in all pts who achieved ≥VGPR. 1-year sustMRD was defined as 2 sequential MRD-negative evaluations at least 1 year apart. Analyses were based on the ITT principle (pts with missing MRD data or who did not achieve VGPR were considered as MRD positive). The data cut-off was Jul 22, 2024. Results: 151 vs 151 pts were randomly assigned to the IsaKRd vs KRd arms. Pt characteristics were well balanced: 43% vs 41% had R2-ISS stage III/IV disease; 9% vs 11% had ≥2 high-risk cytogenetic abnormalities [CA; including del(17p), t(4;14), t(14;16), 1q+]. The median follow-up was 35 months (IQR 32–38). In the ITT analysis, the MRD negativity rates at the 10 -5 cut-off after full-dose consolidation were 77% vs 67% (OR 1.67; p=0.049) with IsaKRd vs KRd; the rates of 10 -5 1-year sustMRD after light consolidation were 66% vs 59% (OR 1.36; p=0.21). The MRD negativity rates at the 10 -6 cut-off after full-dose consolidation were 67% vs 48% (OR 2.29; p<0.001) with IsaKRd vs KRd; the rates of 10 -6 1-year sustMRD after light consolidation were 52% vs 38% (OR 1.82; p=0.012). The 10 -6 1-year sustMRD negativity advantage with IsaKRd was retained in all subgroups. In particular, the 10 -6 1-year sust MRD negativity rates were: 62% vs 20% in pts with ≥2 high-risk CA (OR 6.3, 95% CI 1.11–35.66) and 47% vs 35% in pts with R2-ISS III/IV (OR 1.62, 95% CI 0.77–3.41). During light consolidation, in the IsaKRd vs KRd arms, the main grade 3–4 hematologic AEs were neutropenia (17% vs 18%) and thrombocytopenia (2% vs 3%); the main grade 3–4 non-hematologic AEs included infections (8% vs 5%), gastrointestinal (4% vs 4%) and vascular AEs (3% vs 1%); discontinuation for toxicity occurred in 3% vs 2%; treatment-related deaths were 2 (1 cerebral ischemia, 1 pulmonary embolism) vs 0. Conclusions: The addition of isatuximab to KRd induction-consolidation and the prolonged light consolidation significantly increased the rates of 10 -6 sustMRD negativity in NDMM pts, including those with high-risk disease. Clinical trial information: NCT04483739 .