Isatuximab, lenalidomide, dexamethasone and bortezomib in transplant-ineligible multiple myeloma: the randomized phase 3 BENEFIT trial

Abstract

CD38-targeting immunotherapy is approved in combination with lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma (NDMM) that are transplant ineligible (TI) and is considered the best standard of care (SOC). To improve current SOC, we evaluated the added value of weekly bortezomib (V) to isatuximab plus lenalidomide and dexamethasone (IsaRd versus Isa-VRd). This Intergroupe Francophone of Myeloma phase 3 study randomized 270 patients with NDMM that were TI, aged 65-79 years, to IsaRd versus Isa-VRd arms. The primary endpoint was a minimal residual disease (MRD) negativity rate at 10^-5 by next-generation sequencing at 18 months from randomization. Key secondary endpoints included response rates, MRD assessment rates, survival and safety. The 18-month MRD negativity rates at 10^-5 were reported in 35 patients (26%, 95% confidence interval (CI) 19-34) in IsaRd versus 71 (53%, 95% CI 44-61) in Isa-VRd (odds ratio for MRD negativity 3.16, 95% CI 1.89-5.28, P < 0.0001). The MRD benefit was consistent across subgroups at 10^-5 and 10^-6, and was already observed at month 12. The proportion of patients with complete response or better at 18 months was higher with Isa-VRd (58% versus 33%; P < 0.0001), as was the proportion of MRD negativity and complete response or better (37% versus 17%; P = 0.0003). At a median follow-up of 23.5 months, no difference was observed for survival times (immature data). The addition of weekly bortezomib did not significantly affect the relative dose intensity of IsaRd. Isa-VRd significantly increased MRD endpoints, including the 18-month negativity rate at 10^-5, the primary endpoint, compared with IsaRd. This study proposes Isa-VRd as a new SOC for patients with NDMM that are TI. ClinicalTrials.gov identifier: NCT04751877 .

Fig. 1. CONSORT patient flow diagram.

Patient disposition at the data cutoff date of 25 March 2024.

Fig. 2. Summary of MRD status and prespecified MRD subgroup analyses.

Shown are the results of MRD endpoints (a) and prespecified MRD subgroup analyses at 18 months (b). a, Parentheses indicate 95% CI. LP FISH, linear predictor interphase fluorescence in situ hybridization; Per−, not high-risk LP ≤ 1; Per+, high-risk score LP > 1; MRD−, MRD negativity; CR− MRD−, patients that are both in CR or better and MRD negativity.

Fig. 3. Responses in the ITT population at 18 months.

ORR, overall response rate.

Extended Data Fig. 1. Time to the first occurrence of a confirmed response in the ITT population.

(A) In patients with PR or better (p = 0.040) among patients in the intention-to-treat population. (B) In patients with VGPR or better (p=0.0002) among patients in the intention-to-treat population.

Extended Data Fig. 2. Progression-free survival and overall survival in the ITT population.

(A) Kaplan–Meier estimates of PFS among patients in the intention-to-treat population. (B) Kaplan–Meier estimates of OS among patients in the intention-to-treat population.