Isatuximab, Bortezomib, Lenalidomide, and Dexamethasone (Isa-VRd) in Patients with Newly Diagnosed Multiple Myeloma (NDMM) Not Eligible or with No Immediate Intent for Transplant: Long-Term Efficacy and Safety in a Phase 1b Study

Introduction The anti-CD38 antibody isatuximab (Isa) mediates anti-myeloma activity through multiple mechanisms of action and it is approved with carfilzomib-dexamethasone or pomalidomide-dexamethasone for the treatment of patients (pts) with relapsed and/or refractory MM. A multi-center Ph. 1b study (TCD13983; NCT02513186) showed preliminary efficacy of Isa in quadruplet combination with VRd followed by Isa-Rd maintenance therapy in pts with NDMM not eligible or with no immediate intent for autologous stem cell transplantation (ASCT), with a manageable safety profile (Ocio et al. Leukemia 2023;37:1521-29). In a prespecified interim analysis of the randomized, global Ph. 3 IMROZ study (NCT03319667), treatment with Isa-VRd followed by Isa-Rd demonstrated a significant progression-free survival (PFS) benefit (HR, 0.60; 98.5% CI, 0.41-0.88; p<0.001) and deep responses in transplant-ineligible NDMM pts compared with VRd followed by Rd (Facon et al. N Engl J Med 2024;June 3). In this analysis, we evaluated long-term efficacy and safety of treatment with Isa-VRd followed by Isa-Rd in the overall Ph. 1b pt population and in the subgroups of pts ≥75 yrs of age or with no immediate intent for ASCT (noIInt-ASCT pts included in Part B of the study). Methods NDMM pts without age restriction received four 6-week cycles of Isa-VRd (Isa 10 mg/kg IV, bortezomib 1.3 mg/m2 SC, lenalidomide 25 mg PO, dexamethasone 20 mg IV/PO) followed by Isa-Rd maintenance in 4-week cycles. Primary study endpoint was complete response (CR). The efficacy population included pts who had completed cycle 1 and received >2 weekly Isa administrations, with investigator-assessed response. MRD negativity was evaluated by central-laboratory next-generation sequencing (NGS) at 10-5 sensitivity in pts with ≥VGPR as best response at any point on study. PFS was analyzed with the Kaplan-Meier method. Adverse events (AEs) were graded by NCI-CTCAE v4.03. Results 73 NDMM pts received Isa-VRd followed by Isa-Rd. Median age was 71.0 (range, 49-87) yrs, including 15 (20.5%) pts ≥75 yrs and 4 (5.5%) >80 yrs of age. Nine (12.3%) pts had a creatinine clearance ≥30 to <60 mL/min/1.73 m2. Thirteen (17.8%) noIInt-ASCT pts did not receive an ASCT in frontline (4/13 received an ASCT in 2nd line). The overall response rate was 98.6% in all efficacy-evaluable pts (n=71), 100% in pts ≥75 yrs (n=14), and 100% in noIInt-ASCT pts (n=13), with ≥CR in 63.4%, 64.3%, and 53.8% of pts, respectively. Median PFS was not reached in the overall population nor in the noIInt-ASCT pt subgroup (data cutoff 3May23; median follow-up, 44.3 mo and 30.7 mo, respectively), and it was 51.9 mo in pts ≥75 yrs (median follow-up, 46.3 mo). Rates of PFS in all efficacy-evaluable pts (n=71) were 77.5% at 3 yrs and 71.9% at 5 yrs, 64.3% at 3 yrs and 48.2% at 5 yrs in pts ≥75 yrs (n=14), and 90.0% at 3 yrs in noIInt-ASCT pts (n=13), consistent with IMROZ Isa-VRd observations of 76.1% at 3 yrs and 63.2% at 5 yrs. MRD negativity by NGS (at 10-5 in pts with ≥VGPR) was achieved by 56.3% of pts overall (n=71), 57.1% of pts ≥75 yrs (n=14), and 30.8% of noIInt-ASCT pts (n=13). 34.2% of all pts, 33.3% of pts ≥75 yrs, and 30.7% of noll-ASCT pts were still on treatment, with a median duration of exposure of 41.5 mo (43.3 mo in pts ≥75 yrs; 16.5 mo in noIInt-ASCT pts). Grade ≥3 treatment-emergent AEs (TEAEs) were reported in 80.8% of all treated pts (n=73), 100% of pts ≥75 yrs (n=15), and 61.5% of noIInt-ASCT pts (n=13); serious TEAEs occurred in 58.9%, 80.0%, and 61.5% of pts, respectively. Grade ≥3 infections were observed in 26.0% of all treated pts, 40.0% of pts ≥75 yrs, and 23.1% of noIInt-ASCT pts (44.9% in IMROZ Isa-VRd, 38.1% in VRd pts). Treatment was well tolerated with definitive treatment discontinuations due to AE in 21.9% of all treated pts, 33% of pts ≥75 yrs, and 15.4% of noIInt-ASCT pts. Conclusions Our findings demonstrate long-term efficacy and safety of treatment with Isa-VRd followed by Isa-Rd maintenance in the overall population of NDMM pts without age restriction and in the subgroups of pts ≥75 yrs old or with no immediate intent for ASCT. The PFS results observed in this study are consistent with those reported in transplant-ineligible pts in the IMROZ trial, suggesting that the longer-term benefit with Isa-VRd extends to this broader population of pts with NDMM. Clinical trial registration: NCT02513186. Funding: Sanofi.