OA – 49: Phase 3 study results of isatuximab, bortezomib, lenalidomide, and dexamethasone (Isa-VRd) versus VRd for transplant-ineligible patients with newly diagnosed multiple myeloma (IMROZ)
Professor and Chairman of the Department of Clinical Therapeutics National and Kapodistrian University of Athens, Greece
Introduction: First line of treatment (tx) is important for patients (pts) with newly diagnosed multiple myeloma (NDMM) as pts may not have a chance for subsequent therapy. VRd is currently a standard of care (SOC) in NDMM. Isa is an approved CD38 monoclonal antibody inducing myeloma cell death through multiple mechanisms. In the Phase 3 IMROZ study (NCT03319667), we investigate efficacy and safety of Isa-VRd vs VRd in transplant-ineligible NDMM pts.
Methods: IMROZ is a global, prospective, randomized, open-label study done at 102 study sites in 21 countries. Included pts were aged ≤80 and had active, measurable NDMM not considered for transplant due to elderly age or comorbidities. Pts were randomized 3:2 and stratified by age, R-ISS stage, and China vs non-China, to receive Isa-VRd induction followed by continuous Isa-Rd or VRd induction followed by continuous Rd. Isa-VRd pts received Isa (10 mg/kg IV); both arms received V (1.3 mg/m2 SC), R (25 mg PO), and d (20 mg IV/PO). Primary endpoint was progression-free survival (PFS). Key secondary endpoints were complete response (CR), minimal residual disease negativity (MRD-) (10-5 by NGS) in pts with CR, very good partial response or better, and overall survival. Adverse events (AEs) were graded with NCI CTCAE v4.03.
Results: 446 pts (265 Isa-VRd, 181 VRd) were randomized; pt characteristics were well balanced. At data cutoff (26 Sep 2023), 125 (47.2%) Isa-VRd and 44 (24.3%) VRd pts were still on tx. Median (mdn) tx duration was 53.2 (Isa-VRd) vs 31.3 (VRd) mo; addition of Isa did not significantly affect relative VRd dose intensity. At mdn follow-up of 59.7 mo, mdn PFS was not reached (Isa-VRd) vs 54.3 mo (VRd); HR 0.596 (98.5% CI 0.406–0.876; p=0.0005). Estimated 60-mo PFS was 63.2% (Isa-VRd) vs 45.2% (VRd). PFS benefit with Isa-VRd was consistent across prespecified subgroups. In the intention-to-treat population, Isa-VRd led to deep and sustained responses over VRd in MRD- CR (55.5% vs 40.9%; Stratified Odds Ratio 1.803 [95% CI: 1.229–2.646]; p=0.003), sustained MRD- for ≥12 mo (46.8% vs 24.3%; 2.729 [1.799–4.141]; p< 0.0001), and CR rate (74.7% vs 64.1%; 1.656 [1.097–2.500]; p=0.01). PFS benefit was maintained through subsequent line of therapy (PFS2: HR 0.697; 95% CI: 0.51–0.952). Grade ≥3 treatment-emergent AE (TEAE) incidence was 91.6% (Isa-VRd) and 84.0% (VRd). Definitive tx discontinuations from TEAE occurred in 22.8% Isa-VRd and 26.0% VRd pts.
Conclusions: IMROZ is the first Phase 3 study of an anti-CD38 with SOC VRd in transplant-ineligible NDMM to show significantly reduced risk of progression or death by 40.4% vs VRd and provide deep and sustained responses. Safety was consistent with addition of Isa to VRd. These results support Isa-VRd as a potential new SOC in pts not intended for transplant.
