Multicenter phase 2 study of subcutaneous isatuximab plus bortezomib , lenalidomide and dexamethasone (Isa Sc-VRd) in transplant ineligible newly diagnosed multiple myeloma: Final analysis of the isasocut study (IFM 2022-05)

Introduction: Isa-VRd has emerged as a new standard of care (SOC) in NDMM TI based on the BENEFIT and IMROZ studies. A subcutaneous (SC) formulation of isatuximab at a fixed dose demonstrated non-inferiority in the phase 3 IRAKLIA study (IsaPd regimen) in relapsed/refractory multiple myeloma (RRMM). We report the efficacy and tolerability of Isa SC-VRd in NDMM TI. Methods: ISASOCUT is a prospective, multicenter, open-label, phase 2 study in NDMM TI patients aged ≥65 years. During cycles 1–12, isatuximab was administered SC at a fixed dose of 1400 mg weekly during cycle 1, then on days 1 and 15 of subsequent cycles. Lenalidomide (25 mg/day, oral) was given on days 1–21, dexamethasone (20 mg/week, oral), and bortezomib (1.3 mg/m² SC) was given biweekly during cycle 1, then weekly. From cycle 13 onward, isatuximab was given monthly (day 1), and lenalidomide was continued. One cycle = 28 days. The primary objective was to evaluate the ≥very good partial response (VGPR) rate at 8 months. Secondary endpoints included survival, response rates and durations, MRD (NGS + PET-CT), and safety (NCI CTCAE v5.0). Data are presented in the intention-to-treat (ITT) population. Results: As of data cutoff (January 13, 2025), 74 patients were enrolled across 23 IFM centers. Median age was 73 years (IQR, 66–83); 25 patients (34%) were >75 years. High-risk cytogenetics (IMS score) were present in 16 patients (22%), ISS stage III in 14 (19%), R-ISS stage III in 13 (18%), and gain(1q)+ in 22 (30%). The ≥VGPR rate was 87.8% (n=65; 95% CI, 78–94), consistent with IMROZ and BENEFIT and across weight subgroups. The ≥CR rate was 24% (n=18). MRD negativity rates were 35.1% (n=26) at 10⁻⁵ and 27% (n=20) at 10⁻⁶. With a median follow-up of 11.7 months, 4 patients (5%) discontinued therapy, no relapses occurred, and 2 (3%) had died. Survival data are immature. Treatment compliance was high, with relative dose intensity ≥90%; for Isa SC it was 91.8% (range 53.3–111). Isa SC injections using the On-Body Injector (OBI) were completed in 99.7% of cases without interruption. No new safety signals were observed. Infusion reactions occurred in 7 patients (9.5%), mostly grade 1. Injection site reactions occurred in 20 patients (27%); 89.5% were grade 1 and the rest grade 2. The addition of a twice-weekly bortezomib schedule in cycle 1 did not impact relative dose intensity or increase toxicity. Neurological adverse events were reported in 35 patients (47.3%), all grades. Conclusion: The ISASOCUT study met its primary endpoint, confirming the efficacy and safety of Isa SC-VRd. These results support Isa SC-VRd as a new SOC in NDMM TI, offering a less intensive and more convenient option compared to IV-based regimens such as IMROZ