Daratumumab plus lenalidomide and dexamethasone (DRd) is the current standard of care (SOC) for transplant-ineligible (TI) newly diagnosed multiple myeloma (NDMM) patients. However, the need for improved treatment strategies to achieve deeper responses, particularly MRD negativity, and prevent early relapses remains. This study aimed to evaluate the efficacy and safety of adding weekly bortezomib to the isatuximab, lenalidomide, and dexamethasone (IsaRd) regimen in TI NDMM patients aged 65-79 years. Isatuximab targets CD38, inducing myeloma cell death. While DRd has shown promising results, including MRD negativity in 31%, there's a need for more effective quadruplet regimens to further improve outcomes. Bortezomib has been shown effective in NDMM but is commonly administered twice-weekly; the study explores the effectiveness of a weekly schedule. Two registration studies for quadruplet regimens incorporating CD38-targeting immunotherapies with VRd are underway, evaluating the added value to twice-weekly VRD. The BENEFIT study was therefore designed to assess the efficacy and safety of the quadruplet combination isatuximab plus weekly VRd (Isa-VRd) in comparison to IsaRd in a TI NDMM population, providing a timely assessment in this specific age group.

The MAIA study demonstrated the benefit of adding daratumumab to lenalidomide and dexamethasone (Rd) in TI NDMM patients, achieving a median progression-free survival (PFS) of 62 months and a complete response (CR) MRD negativity rate of 31%. However, novel quadruplet strategies are needed to enhance responses and prevent relapses. Isatuximab, a CD38-targeting monoclonal antibody, has shown benefits when added to SOC regimens. Bortezomib, a proteasome inhibitor, has also demonstrated efficacy but has predominantly been used on a twice-weekly schedule. Recent evidence indicates that a weekly schedule of bortezomib in combination with lenalidomide and dexamethasone is similarly effective and safer, especially in elderly TI NDMM patients.

This open-label, multicenter, phase 3 trial randomized 270 TI NDMM patients (aged 65-79) to either IsaRd or Isa-VRd arms (1:1 ratio). Randomization was stratified by age (<75 and ≥75 years), cytogenetic risk, and center type. Patients received treatment until progression. The primary endpoint was the MRD negativity rate at 10⁻⁵ at 18 months, assessed primarily by next-generation sequencing (NGS) and, if unavailable, by multiparametric flow cytometry. Key secondary endpoints included response rates (defined by International Myeloma Working Group criteria), MRD negativity at various time points and thresholds, PFS, OS, and safety. Treatment duration was cycle 1-12 for all drugs in both arms, cycle 13-18 for isatuximab and lenalidomide, with or without bortezomib, and cycle 19 and beyond for isatuximab and lenalidomide only. Bortezomib was permanently discontinued at cycle 18. Statistical analysis employed the intention-to-treat population and included adjusted logistic regression for binary endpoints and Cox proportional hazards models for time-to-event endpoints. The study adhered to ICH-GCP guidelines and was approved by an ethics committee.

At 18 months, the MRD negativity rate at 10⁻⁵ was significantly higher in the Isa-VRd arm (53%, 95% CI 44–61) compared to the IsaRd arm (26%, 95% CI 19–34) (OR 3.16, 95% CI 1.89–5.28, *P* < 0.0001). This benefit was consistent across subgroups. The proportion of patients achieving a CR or better at 18 months was also significantly higher in the Isa-VRd arm (58% vs 33%, *P* < 0.0001). The combined rate of MRD negativity and CR or better was also significantly better in the Isa-VRd arm (37% vs 17%, *P* = 0.0003). At a median follow-up of 23.5 months, PFS and OS data were immature, with no significant difference observed between the two arms. The most common adverse events were neutropenia, diarrhea, and infections. The incidence of thrombocytopenia was higher in the Isa-VRd arm. Peripheral neuropathy of grade 2 or higher was reported in 10% of patients in the IsaRd arm and 27% of patients in the Isa-VRd arm. The relative dose intensity of IsaRd was not significantly affected by the addition of weekly bortezomib.

The BENEFIT trial demonstrated a substantial improvement in MRD negativity and CR rates with the addition of weekly bortezomib to the isatuximab, lenalidomide, and dexamethasone regimen in TI NDMM patients aged 65-79 years. The consistent benefit across subgroups suggests the regimen may be beneficial for a broad range of patients within this population. While survival data were immature at the time of analysis, the high MRD negativity rates observed in the Isa-VRd arm suggest potential for improved long-term survival. The results are comparable to and potentially exceed those seen with daratumumab-based quadruplet regimens in similar patient populations, suggesting Isa-VRd as a new SOC. The difference in bortezomib administration schedule between BENEFIT (weekly for longer duration) and IMROZ (twice-weekly for shorter duration) warrants further investigation to optimize the balance between efficacy and toxicity.

The BENEFIT trial provides strong evidence supporting the superiority of the quadruplet regimen Isa-VRd over IsaRd in TI NDMM patients aged 65-79. The significantly improved MRD negativity and CR rates suggest Isa-VRd as a potential new standard of care. Future research should focus on longer-term follow-up to assess survival differences, exploring optimal bortezomib scheduling, investigating the use of Isa-VRd in patients older than 79 years, and evaluating the potential benefits of subcutaneous isatuximab.

The study was limited to patients aged 65-79 years, using intravenous isatuximab, and employed a prolonged bortezomib regimen. The upper age limit might restrict generalizability. The extended treatment schema (isatuximab and lenalidomide until progression) could affect long-term safety, and the lack of a fixed-duration treatment arm limits a precise assessment of the long-term effects. The current immature survival data needs longer-term follow-up.