Introduction. A recent international genomic consensus staging has standardized the high-risk (HR) definition on the basis of an NGS-based definition plus serum beta-2-microglobulin level. Isa-VRd has become a standard-of-care for NDMM Transplant-Ineligible (TI). We studied the 12-24 months sustained MRD (sMRD) in high-risk patients using the genomic consensus staging in BENEFIT study.

Methods. BENEFIT is a multicenter, phase 3 study, that randomized NDMM TI to receive Isa-VRd or IsaRd (ClinicalTrials.gov identifier: NCT04751877). Data are presented in intention-to-treat. IMS/IMWG new HR definition was assessed centrally by NGS on sorted plasma cells.

Results. With a median follow-up of 33.4 months [95%CI, 33 - 34], 78 (29%) patients discontinued from the study, mostly for progressive disease. The HRMM (n=72, 27%) characterized 42/135 (31%) and 30/135 (22%) patients across Isa-VRd and IsaRd arms.

The 18-month MRD negativity rate at 10-5, the primary end point, was similar across HRMM and non-HRMM within the same arm, and Isa-VRd remained superior for HRMM, OR 2.75 (95%CI, 1 to 7.5). Similar differences were observed at 10-6 at 18 months.

The sustained MRD 12-24 months negativity rate at 10−5was higher for Isa-VRd than for IsaRd in HRMM, 31% and 13% respectively, OR 2.91 (95%CI, 0.8 to 10). There is no new safety signal observed across arms, including for HRMM.

Conclusion. The results from the BENEFIT study continue to demonstrate meaningful benefit of the quadruplet-based Isa-VRd regimen in NDMM TI patients, including sMRD negativity rates. The benefits of the Isa-VRd regimen are observed in HRMM. This data supports Isa-VRd as a new SOC for NDMM TI aged of 65 to 79 patients, including for HRMM.

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2025
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