Multicenter Open Label Phase 3 Study of Isatuximab Plus Lenalidomide and Dexamethasone with/without Bortezomib in the Treatment of Newly Diagnosed Non-Frail Transplant Ineligible Multiple Myeloma Elderly Patients (≥ 65; < 80 Years). IFM2020-05/Benefit

Background. The addition of the anti-CD38 monoclonal antibody (mAb) daratumumab to lenalidomide-dexamethasone (Rd) (MAIA) as part of the upfront treatment regimen for non-transplant eligible (NTE) newly diagnosed multiple myeloma (NDMM) has considerably increased survival. Interestingly, while median PFS reached 5 years, the sustained minimal residual disease (MRD) negativity rate was lower than 15%. To continue improving the treatment of NTE NDMM and allow most patients to survive with only one line of treatment, sustained MRD negativity rates need to further increase. Two randomized phase III studies are investigating the quadruplet combination of anti-CD38 mAb + bortezomib + Rd in the same NTE NDMM population, IMROZ (NCT03319667) and CEPHEUS (NCT03652064), with isatuximab and daratumumab, respectively, and VRd as the comparator arm. The design of these studies is expected to demonstrate the added value of an anti-CD38 mAb to VRd. However, VRd might be considered suboptimal SOC in NTE NDMM compared to the triplet-based regimen Dara-Rd until progression, given the results of the median PFS in the MAIA trial, with an unprecedented 5-year median PFS. We hypothesized that adding a proteasome inhibitor (PI) to the anti-CD38 mAb + Rd combination would significantly increase the sustained MRD negativity rate compared to the anti-CD38 mAb + Rd combination, the optimal standard of care (SOC) today in the NTE NDMM. We therefore have conducted the present study of Isa-VRd compared to Isa-Rd (IFM2020-05/Benefit). Benefit has fully enrolled as of August 2022, and there has been no safety warnings from the safety committee with the prolonged use of bortezomib on a weekly basis in combination to Isa-Rd. Study Design and Methods. 270 NTE NDMM patients, aged 65-79 years old and non-frail, were randomized and assigned in a 1:1 ratio to either the anti-CD38 mAb isatuximab + Rd (Isa-Rd) or isatuximab + VRd (Isa-VRd lite) (NCT04751877). Stratification across arms was done according to high-risk MM, age cutoff of 75 years and study centers. Patients receive isatuximab IV 10 mg/kg on days 1, 8, 15, and 22 of cycle 1, days 1 and 15 from cycle 2 to 12 and day 1 from cycle 13 onward, 28-day cycles. Lenalidomide and dexamethasone were given orally as approved. Bortezomib was administered weekly and subcutaneously on days 1, 8, 15 at 1.3 mg/m² from cycle 1 to 12 and on days 1, 15 from cycle 13 to 18, and then stopped. All patients will discontinue dexamethasone after cycle 12. Patients will then continue receiving Isa-Rd until progression in both arms. The primary objective is to evaluate the MRD negativity rate at 10-5 at 18 months in both arms. The study will be considered positive if the MRD negativity rate at 10-5 at 18 months is >30% in the Isa-VRd arm, and twice as much at the same time point in the Isa-Rd arm. Key secondary objectives include the survival analysis (OS, PFS, EFS, TTNT), response rates, duration of response, and safety. The study is estimated to read out December 2023, 18 months after the last patient enrolls.