Sustained minimal residual disease (sMRD) negativity in transplant ineligible newly diagnosed multiple myeloma treated with isatuximab plus lenalidomide and dexamethasone with bortezomib (Isa-VRd) versus isa-rd: 12-24-month data from the phase 3 benefit trial (IFM 2020-05) Free

Introduction. Sustained minimal residual disease (sMRD) negativity has shown a stronger correlation with survival outcomes than MRD negativity at a single time point or at best response. We evaluated MRD negativity between 12 and 24 months in newly diagnosed multiple myeloma (NDMM) transplant-ineligible (TI) patients enrolled in the BENEFIT study.

Methods. BENEFIT is a multicenter, phase 3 randomized trial comparing isatuximab-lenalidomide-dexamethasone with or without bortezomib (Isa-Rd ± V) in NDMM TI patients. In the Isa-VRd arm, bortezomib (V) was administered weekly for up to 18 months, dexamethasone was permanently discontinued after 12 months, and isatuximab-lenalidomide (Isa-R) was continued until progression. Data are presented in the intention-to-treat (ITT) population.

Results.With a median follow-up of 33.4 months (95% CI, 33.0–34.0), 78 patients (29%) discontinued treatment, primarily due to progressive disease.

At 24 months, the MRD negativity rate at 10⁻⁵ was significantly higher in the Isa-VRd arm (odds ratio [OR] 2.26; 95% CI, 1.35–3.79; p=0.002). Sustained MRD negativity at 10⁻⁵ was also more frequent in the Isa-VRd arm (OR 2.73; 95% CI, 1.50–4.80; p=0.0007). Similar results were observed for sMRD at the 10⁻⁶ threshold.

Importantly, MRD negativity at both 10⁻⁵ and 10⁻⁶ was evaluated in the t(11;14) NDMM TI subgroup. In this subgroup, MRD negativity rates were consistently lower at all time points up to 24 months, consistent with recent observations from the MIDAS study. Due to the small number of patients per group, no subgroup-specific analysis was feasible. Larger cohorts are required to determine whether t(11;14) MM in TI patients achieves delayed or less frequent MRD negativity, potentially reflecting a MGUS-like phenotype.

No new safety signals were observed in either treatment arm, including in high-risk multiple myeloma (HRMM) patients.

Conclusion. The BENEFIT study continues to support the efficacy of the quadruplet Isa-VRd regimen in NDMM TI patients, notably through improved sustained MRD negativity rates. These data support Isa-VRd as a new standard of care (SOC) for NDMM TI patients aged 65–79 years, including those with HRMM.

ClinicalTrials.gov Identifier: NCT04751877