BENEFIT: Isatuximab Plus Lenalidomide, Dexamethasone, and Bortezomib Versus Isatuximab Plus Lenalidomide and Dexamethasone in Transplant-Ineligible NDMM

The IMROZ study aimed to assess the additional benefits of immunotherapy targeting CD38 in conjunction with the standard of care (SOC) bortezomib, lenalidomide, and dexamethasone (VRd) administered biweekly. Research has indicated that in patients with newly diagnosed multiple myeloma (NDMM) who are treated with thalidomide, a weekly regimen, particularly in conjunction with VRd, resulted in reduced instances of peripheral neuropathy and has subsequently been integrated into clinical practice. To improve the current SOC for patients with transplant-ineligible NDMM, weekly bortezomib to isatuximab plus lenalidomide and dexamethasone (Isa-VRd vs Isa-Rd) was evaluated in the BENEFIT/IFM2020-05 (NCT04751877) study.

BENEFIT is the first academic French phase 3 study investigating the efficacy and safety of Isa-VRd versus Isa-Rd in transplant-ineligible patients with NDMM, and it is also the first phase 3 study to read out with minimal residual disease (MRD) as a primary endpoint in transplant-ineligible NDMM. Two hundred seventy patients with transplant-ineligible NDMM were randomized 1:1 to receive either Isa-VRd (n=135) or Isa-Rd (n=135). The primary endpoint was MRD, and key secondary endpoints were complete response (CR) rate, MRD-CR (next- generation sequencing, 10⁻⁵) rate, very good partial response (VGPR) rate or better, progression-free survival, overall survival, and safety. Patient characteristics were well-balanced in both arms.

Isa-VRd resulted in deep response rates, with a significant improvement in MRD at 12 months at 10^–5 (odds ratio [OR], 3.88) and at 10^–6 (OR, 2.97) and at the primary endpoint of 18 months at 10^–5 (OR, 3.16) and at 10^–6 (OR, 2.74) in the intent-to-treat (ITT) population. Isa-VRd resulted in a significant improvement in the MRD-CR rate. Improvements were seen at 12 months at 10^–5 (OR, 3.86) and 10^–6 (OR, 3.43) and at 18 months at 10^–5 (OR, 2.91) and 10^–6 (OR, 2.85) in the ITT population. A consistent MRD advantage was observed with Isa-VRd over Isa-Rd in most subgroups, encompassing difficult-to-treat populations characterized by negative prognostic factors. Isa-VRd resulted in deep response rates compared with Isa-Rd, particularly the CR or better rate at 18 months (58% vs 31%, respectively), and a shorter time to the first occurrence of a confirmed response of VGPR or better (2.1 months vs 3.7 months, respectively) in the ITT population. At a median follow-up of 23.5 months, survival is still immature. A similar relative dose intensity of isatuximab, lenalidomide, and dexamethasone was observed in both arms. Treatment-emergent adverse events (TEAEs) were observed in 99% of patients in the Isa-VRd arm and 95% of patients in the Isa-Rd arm. Serious TEAEs were observed in 34% of patients in the Isa-VRd arm and 35% of patients in the Isa-Rd arm. Isa-VRd was well-tolerated, however, and the safety profile was consistent with the known safety profiles of treatment.

A consistent MRD advantage for Isa-VRd versus Isa-Rd was observed across various subgroups, particularly among difficult-to-treat patients who exhibit negative prognostic factors. Isa-VRd was found to be well-tolerated, and its safety profile is consistent with that of the individual agents involved. The BENEFIT study supports an alternative dosing schedule for frontline multiple myeloma management, demonstrating enhanced effectiveness of Isa-VRd compared with Isa-Rd, along with a reliable safety profile in patients with transplant-ineligible NDMM.

Source:

Leleu X, Hulin C, Jerome L, et al. Isatuximab plus lenalidomide and dexamethasone with weekly bortezomib versus isatuximab plus lenalidomide and dexamethasone in newly diagnosed transplant ineligible multiple myeloma. The BENEFIT (IFM 2020-05) study. Presented at: International Myeloma Society 21st Annual Meeting & Exposition. September 25-28, 2024; Riocentro, Rio de Janeiro, Brazil.