Discussion
This Phase 1b study was designed to investigate Isa-VRd for the first time in adult patients with NDMM who were ineligible/had no intent for immediate transplantation. Treatment with isatuximab plus triplet bortezomib-lenalidomide-dexamethasone resulted in deep and durable responses, with an MRD- rate of 51% at a sensitivity of 10Median PFS in the overall population of the current study was not reached (NR; interquartile range [IQR], 28.6 months to NR). The PFS probability at 1 and 2 years for the entire cohort was 91.0% (95% CI: 81.0–95.9) and 83.1% (95% CI: 71.5–90.3), respectively. Examined separately, median PFS estimates were NR (IQR: 28.9 months to NR) for Part A (median follow-up, 35.8 months) and NR (IQR: 28.4 months to NR) for Part B (median follow-up, 25.3 months). Results from the Phase 3 SWOG S0777 study demonstrated significantly improved PFS with VRd vs Rd (43 vs 30 months; stratified HR 0.712 [95% CI: 0.56–0.906]) [Daratumumab is another anti-CD38 monoclonal antibody used for the treatment of patients with NDMM. In the Phase 3 MAIA study, after a median follow-up of 28.0 months, median PFS was NR in the daratumumab-Rd group vs 31.9 months in the Rd group (HR 0.56; 95% CI, 0.43–0.73) [In the MAIA and ALCYONE studies, daratumumab plus Rd or bortezomib-melphalan-prednisone (VMP) led to increased MRD- rates, assessed using NGS at a sensitivity of 10In the combined population of Parts A and B, there were no new safety concerns related to isatuximab compared with the results of the ICARIA-MM and IKEMA studies in RRMM [Overall, the incidence and severity of IRs were comparable to those reported with isatuximab in RRMM patients [Based on PK results from Parts A and B, when given in combination with VRd, isatuximab PK exposure was within the range of those previously reported, suggesting that VRd does not alter the PK of isatuximab [This study also evaluated isatuximab infusion duration. With the fixed-volume infusion, patients in Part A who switched from the weight-based infusion method and all patients in Part B exhibited a larger decrease in the median infusion time from ~3 h 40 min during the first infusion to ~1 h 20 min after the third infusion compared with patients in Part A with the weight-based infusion method ( ~ 3 h 40 min to ~2 h 35 min), with no increase in IRs reported.Stem cell collection showed adequate yield of cells/kilogram of body weight, which is required for further successful engraftment.Descriptive analysis of blood immune cell subpopulations in our study showed a decrease in CD3 and CD4 T cells, NK cells, regulatory T cells, and B cells at Cycle 3, in agreement with previous observations following single-agent treatment with an anti-CD38 antibody [In conclusion, this Phase 1b study demonstrated for the first time that a quadruplet regimen of isatuximab, an anti-CD38 monoclonal antibody, plus VRd led to deep responses in patients with NDMM ineligible/with no immediate intent for ASCT, including a 51% MRD- rate. In addition, Isa-VRd exhibited a safety profile consistent with that of each individual drug, suggesting that this quadruplet combination is both feasible and effective in this patient population. The ongoing Phase 3 BENEFIT study (NCT04751877) was designed to investigate isatuximab-based triplet (Isa-Rd) vs quadruplet (Isa-VRd) regimens in patients with NDMM ineligible for ASCT. This study will help determine any added value of the quadruplet vs triplet regimen in this patient population, considering the safety profile of each regimen.