Phase 3 study results of isatuximab, bortezomib, lenalidomide, and dexamethasone (Isa-VRd) versus VRd for transplant-ineligible patients with newly diagnosed multiple myeloma (IMROZ).

person Thierry Facon University of Lille, CHU Lille, Lille, France info_outline Thierry Facon, Meletios Athanasios Dimopoulos, Xavier P Leleu, Meral Beksac, Ludek Pour, Roman Hajek, Zhuogang Liu, Jiri Minarik, Philippe Moreau, Joanna Romejko-Jarosinska, Ivan Spicka, Vladimir I. Vorobyev, Michele Cavo, Hartmut Goldschmidt, Thomas G. Martin, Salomon Manier, Marie-France Brégeault, Sandrine Macé, Christelle Berthou, Robert Z. Orlowski

Authors person Thierry Facon University of Lille, CHU Lille, Lille, France info_outline Thierry Facon, Meletios Athanasios Dimopoulos, Xavier P Leleu, Meral Beksac, Ludek Pour, Roman Hajek, Zhuogang Liu, Jiri Minarik, Philippe Moreau, Joanna Romejko-Jarosinska, Ivan Spicka, Vladimir I. Vorobyev, Michele Cavo, Hartmut Goldschmidt, Thomas G. Martin, Salomon Manier, Marie-France Brégeault, Sandrine Macé, Christelle Berthou, Robert Z. Orlowski Organizations University of Lille, CHU Lille, Lille, France, Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece, Service d'Hématologie et Thérapie Cellulaire, CHU and CIC Inserm 1402, Poitiers Cedex, France, Department of Hematology, Ankara University, Ankara, Turkey, Istinye University Ankara Liv Hospital, Ankara, Turkey, University Hospital Brno, Brno, Czech Republic, Shengjing Hospital of China Medical Unversity, Shenyang, China, Palacky University Olomouc and University Hospital Olomouc, Olomouc, Czech Republic, University Hospital Hôtel-Dieu, Nantes, France, Marie Sklowdoska-Curie National Research Institute of Oncology, Warszawa, Poland, Charles University and General Hospital in Prague,, Prague, Czech Republic, SP Botkin Moscow City Clinical Hospital, Moscow, Russian Federation, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seràgnoli", Università di Bologna, Bologna, Italy, University Hospital Heidelberg, Heidelberg, Germany, University of California, San Francisco, San Francisco, CA, University Hospital Center of Lille, Lille, France, Sanofi R&D, Vitry-Sur-Seine, France, The University of Texas MD Anderson Cancer Center, Houston, TX Abstract Disclosures Research Funding Sanofi Background: The 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 anti-CD38 monoclonal antibody (mAb) inducing myeloma cell death through multiple mechanisms. In the Phase 3 IMROZ study (NCT03319667), we investigate the 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 had active, measurable NDMM not considered for transplant due to elderly age or comorbidities. Pts aged ≥80 were excluded. Pts were randomized 3:2 and stratified by age, R-ISS stage and China vs non-China, to receive Isa-VRd or VRd. Isa-VRd arm 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). The 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) and laboratory parameters 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%) and 44 (24.3%) pts in Isa-VRd and VRd arms were still on tx, respectively. Median (mdn) tx duration was 53.2 (Isa-VRd) vs 31.3 (VRd) mo; addition of Isa did not significantly affect relative dose intensity of VRd. 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), log-rank p=0.0005. From the current trend, projected Isa-VRd mdn PFS will reach ~90 mo. PFS benefit was consistent across subgroups and maintained through subsequent line of therapy (PFS2 HR 0.697; 95% CI: 0.51-0.952). Isa-VRd led to deep and sustained responses and was well-tolerated (Table). Exposure-adjusted Grade 5 TEAE rate was 0.03 (Isa-VRd) vs 0.02 (VRd). Conclusions: IMROZ is the first Phase 3 study of an anti-CD38 mAb with SOC VRd in this pt population to show a significantly reduced risk of progression or death by 40.4% vs VRd while providing deep and sustained responses. The safety profile was consistent with addition of Isa to VRd. Numerical differences in TEAEs are largely explained by longer exposure in the Isa-VRd arm. These results support Isa-VRd as a potential new SOC in pts not intended for transplant. Clinical trial information: NCT03319667. % pts Isa-VRd (n=265) VRd (n=181) Stratified Odds Ratio (95% CI) 1-Sided p-value CR 74.7 64.1 1.656 (1.097–2.500) 0.008 MRD- CR 55.5 40.9 1.803 (1.229–2.646) 0.0013 Sustained MRD- for at least 12 mo 46.8 24.3 2.729 (1.799–4.141) <0.0001 Grade ≥3 TEAE 91.6 84.0 - Grade 5 TEAE 11.0 5.5 Any TEAE leading to definitive tx discontinuation 22.8 26.0

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