(OA-46) Multicenter Phase 2 Study of Subcutaneous Isatuximab Plus Bortezomib, Lenalidomide, and Dexamethasone in Newly Diagnosed Transplant-Ineligible Multiple Myeloma: Results from ISASOCUT (IFM 2022-05)

Introduction: Isa-VRd has emerged as a new standard of care (SOC) in transplant-ineligible (TI) newly diagnosed multiple myeloma (NDMM) based on the BENEFIT and IMROZ studies. A subcutaneous (SC) formulation of Isatuximab is currently being evaluated in the phase 3 IRAKLIA study (Isa SC-Pd vs. Isa IV-Pd) in relapsed/refractory multiple myeloma. Here, we present the first report on the efficacy and safety of Isa SC-VRd in NDMM TI patients.

Methods: ISASOCUT is a prospective, multicenter, open-label, phase 2 study in NDMM TI patients (≥65 years). The initial treatment regimen (cycles 1 to 12) included fixed-dose SC isatuximab administered weekly during cycle 1, then on days 1 and 15 of subsequent cycles. Lenalidomide (25 mg daily, orally) was given on days 1 to 21, dexamethasone (20 mg weekly, orally), and bortezomib (1.3 mg/m2 SC) biweekly in cycle 1, then weekly thereafter. From cycle 13 onward, isatuximab was administered once monthly (day 1) while lenalidomide dosing remained unchanged. Each cycle lasted 28 days. The primary objective was to assess the ≥ very good partial response (VGPR) rate at 8 months post-cycle 1 day 1. Key secondary endpoints included survival outcomes, response rates and durations, MRD assessments at 8 months (NGS + PET-CT), and safety. Data were analyzed using an intention-to-treat (ITT) approach.

Results: At data cutoff (January 13, 2025), 74 patients had been enrolled across 23 IFM centers. The median age was 73 years (IQR: 66–83); 25 patients (34%) were >75 years old, 16 (22%) had high-risk (HR) cytogenetics (per the new IMS consensus), 14 (19%) had ISS stage 3 disease, 13 (18%) had R-ISS stage 3 disease. The ≥VGPR rate at 8 months, the primary endpoint, was 87.8% (n=65) [95% CI, 78–94], consistent with the IMROZ and BENEFIT studies, and observed across all weight subgroups. The ≥CR rate was 24% (n=18), while MRD negativity rates were 35.1% (n=26) at 10⁻⁵ and 27% (n=20) at 10⁻⁶. At a median follow-up of 11.73 months, 4 patients (5%) had discontinued therapy, no relapses had occurred, and 2 patients (3%) had died. Survival data remain immature. Treatment adherence was high, with a relative dose intensity ≥90% for Isa SC (91.8% [range: 53.3–111]). Nearly all Isa SC administrations (99.7%) using the on-body delivery system (OBDS) were successfully completed without injection interruptions. Isa SC did not introduce any new safety concerns. Infusion related reactions occurred in seven patients (9.5%), mostly grade 1. Injection site reactions were reported in 20 patients (27%), with 89.5% being grade 1 and the remaining cases grade 2. Neurological adverse events (all grades) were reported in 35 patients (47.3%).

Conclusions: The ISASOCUT study met its primary endpoint, demonstrating consistent efficacy of isatuximab in NDMM TI patients, regardless of SC or IV administration. These results support Isa SC-VRd as a new SOC for NDMM TI, offering a longer but less dose-intensive induction regimen compared to IMROZ.