Introduction: In the phase 3 IMROZ study (NCT03319667), isatuximab (Isa) given intravenously (IV) with bortezomib, lenalidomide and dexamethasone (VRd) followed by Isa-Rd was associated with a significant progression-free survival (PFS) benefit in patients (pts) with newly diagnosed multiple myeloma (NDMM) not eligible for autologous stem cell transplant (ASCT). Although frail pts often have worse outcomes, a post-hoc subgroup analysis of frailty in the IMROZ study found Isa-VRd to be an effective option in these pts, with PFS benefit. The efficacy and safety of Isa-VRd was also demonstrated in a phase 1b study (TCD13983; NCT02513186) in NDMM pts not eligible or with no immediate intent for ASCT. In addition, long-term efficacy and safety data from the phase 1b study showed PFS benefit in the subgroup of pts ≥75 years (yrs). Here we report on a pooled post hoc analysis of IMROZ and phase 1b studies exploring the efficacy and safety of Isa-VRd in pts ≤75 yrs and >75 yrs with and without frailty criteria, to evaluate the consistent efficacy of Isa-VRd in hard to treat pt populations.

Methods: Pts in the Isa-VRd arm (n=265) from IMROZ, a global, randomized, phase 3 study, and pts from the multicenter, phase 1b study (n=73) were included in this analysis. In both studies, pts received Isa 10mg/kg IV weekly in cycle 1, then every 2 weeks (Q2W), and then Q4W from cycle 18 onwards in combination with VRd and then Rd. A subgroup analysis was performed by baseline age (≤75 yrs, >75 yrs) and further by frailty [defined according to the simplified International Myeloma Working Group (Intergroupe Francophone du Myélome) score]. PFS and overall response rate (ORR) were examined. Minimal residual disease (MRD) negativity was evaluated by central-laboratory testing (next-generation sequencing (clonoSEQ®)) at 10-5 sensitivity level. Safety was also evaluated.

Results: In this pooled analysis (N=336), median age was 71 (range, 49-87) yrs. Of the pts ≤75 yrs (n=271) and >75 yrs (n=65), 14.4% and 64.6% were frail, respectively. Median PFS was not reached in the overall population or in the ≤75 and >75 yrs subgroups. Similarly, median PFS was not reached in non-frail and frail pts within each age subgroup. Pts ≤75 yrs experienced greater PFS than those >75 yrs [hazard ratio=1.630 (95% confidence interval (CI): 1.041–2.550; p=0.033)]. Within each age subgroup, however, no PFS difference was observed between non-frail and frail pts. ORR was similar between the two age groups: ≤75 yrs, 93.0% and >75 yrs, 92.3%, with complete response or better (≥CR) in 72.0% and 67.7% of pts, respectively. However, ORR was generally greater in the non-frail vs frail pts within each age subgroup (non-frail vs frail: ≤75 yrs, 95.7% vs 76.9%; >75 yrs, 100% vs 88.1%) as was ≥CR (non-frail vs frail: ≤75 yrs, 72.9% vs 66.7%; >75 yrs, 87.0% vs 57.2%). Rates of MRD- with CR/stringent CR (CR/sCR) were 53.5% vs 50.8% in the ≤75 yrs and >75 yrs subgroups, respectively. The 24-month sustained MRD- rates were 32.8% vs 23.1% in the ≤75 and >75 yrs subgroups, respectively. In the ≤75 yrs subgroup, rates of MRD- with CR/sCR were 53.9% in non-frail and 51.3% in frail pts, with 24-month sustained MRD- rates of 34.9% and 20.5%, respectively. In the >75 yrs subgroup, rates of MRD- with CR/sCR were 60.9% in non-frail and 45.2% in frail pts, with 24-month sustained MRD- rates of 34.8% and 16.7%, respectively. Grade ≥3 treatment-emergent adverse events (TEAEs) were reported in 87.8% pts ≤75 yrs (non-frail, 87.6%; frail, 89.5%) and 95.4% pts >75 yrs (non-frail, 95.7%; frail, 95.2%). Serious TEAEs occurred in 66.8% pts ≤75 yrs (non-frail, 64.4%; frail, 81.6%) and 73.8% pts >75 yrs (non-frail, 65.2%; frail, 78.6%). Isa-VRd was well tolerated with definitive treatment discontinuation due to AE in 21.8% pts ≤75 yrs (non-frail, 20.2%; frail, 31.6%) and 26.2% pts >75 yrs (non-frail, 21.7%; frail, 28.6%).

Conclusions: Thispooled analysis of the IMROZ and phase 1b studies further supports the broad applicability of the Isa-VRd regimen in NDMM pts not eligible for ASCT, demonstrating consistent efficacy in pts ≤75 yrs and >75 yrs with and without frailty criteria. This was evidenced by median PFS not being reached with Isa-VRd in all subgroups analyzed and the similarity of sustained MRD- among pts ≤75 yrs and >75 yrs old.

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2025
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