Phase 3 randomized study of isatuximab (Isa) plus lenalidomide and dexamethasone (Rd) with bortezomib versus isard in patients with newly diagnosed transplant ineligible multiple myeloma (NDMM TI).

person Xavier P. Leleu Université de Poitiers et Centre Hospitalier Universitaire de Poitiers, INSERM U1313 and CIC 1082, Poitiers, France info_outline Xavier P. Leleu, Cyrille Hulin, Jerome Lambert, Arthur Bobin, Salomon Manier, Aurore Perrot, Arnaud Jaccard, Lydia Montes, Lionel Karlin, Pascal Godmer, Thomas Chalopin, Borhane Slama, Kamel Laribi, Marie-Lorraine Chretien, Mohamad Mohty, Cyrille Touzeau, Philippe Moreau, Herve Avet-Loiseau, Jill Corre, Thierry Facon

Authors person Xavier P. Leleu Université de Poitiers et Centre Hospitalier Universitaire de Poitiers, INSERM U1313 and CIC 1082, Poitiers, France info_outline Xavier P. Leleu, Cyrille Hulin, Jerome Lambert, Arthur Bobin, Salomon Manier, Aurore Perrot, Arnaud Jaccard, Lydia Montes, Lionel Karlin, Pascal Godmer, Thomas Chalopin, Borhane Slama, Kamel Laribi, Marie-Lorraine Chretien, Mohamad Mohty, Cyrille Touzeau, Philippe Moreau, Herve Avet-Loiseau, Jill Corre, Thierry Facon Organizations Université de Poitiers et Centre Hospitalier Universitaire de Poitiers, INSERM U1313 and CIC 1082, Poitiers, France, Hôpital Haut Leveque, University Hospital, Pessac, France, ECSTRA, Centre de Recherche en Epidémiologie et Statistiques, INSERM UMR 1153, Paris, France, Paris, France, Lille University Hospital, Lille, France, CHU de Toulouse, IUCT-O, Université de Toulouse, UPS, Service d’Hématologie, Toulouse, France, CHU Limoges, Limoges, France, CHU Amiens, Amiens, France, Department of Urology, Centre Hospitalier Lyon Sud, Pierre-Benite, France, GHBA, Vannes, France, CHU Tours, Tours, France, CH d'Avignon, Avignon, France, Department of Hematology, Centre Hospitalier Le Mans, Le Mans, France, CHu Dijon, Dijon, France, Sorbonne University, Hôpital Saint-Antoine, APHP, Paris, France, University of Nantes Hôtel Dieu Hospital Center, Nantes, France, Hematology Clinic, University Hospital Hotel-Dieu, Nantes, France, Unit for Genomics in Myeloma, IUCT-Oncopole, INSERM U1037, Toulouse, France, Hematology Department, University Cancer Institute IUCT oncopôle, Toulouse, France, Hôpital Claude Huriez, Lille, France Abstract Disclosures Research Funding Sanofi Background: CD38 targeting immunotherapy is approved in combination with lenalidomide and dexamethasone in NDMM TI and considered the current standard of care (SOC). The best treatment combinations are important in NDMM TI, as outcomes worsen with successive line of therapy. To improve current SOC, we evaluated the added value of prolonged use of bortezomib for 18 months with reduced intensity weekly schedule to IsaRd, with the intent to demonstrate the impact of a PI in a quadruplet regimen to improve depth of response. In BENEFIT/IFM2020-05 study (NCT04751877), we investigated efficacy and safety of IsaRd vs Isa-VRd in NDMM TI. Methods: BENEFIT is a prospective, multicenter, randomized, parallel trial. Patients aged 65-79, non-frail, with NDMM TI were randomized 1:1 and stratified by age, high-risk cytogenetic and center. Isa-VRd arm received V (1.3 mg/m2 SC weekly up to c12 (c), bimonthly up to c18); both arms received Isa (10 mg/kg IV weekly and bimonthly up to c12, then monthly), R (25 mg), and d (20 mg up to c12). The primary endpoint was minimal residual disease (MRD) 10-5 negative rate (NGS) at 18 months from treatment start analyzed in ITT. Key secondary endpoints included survival times (OS, PFS, EFS, TTNT), response rates and durations, MRD endpoints, and safety (using NCI CTCAE v5.0). Results: At data cutoff date (02 Feb 2024), 270 patients (135 per arm) were recruited. Patients baseline characteristics were well balanced across arms, overall median age was 73.2 years [IQR. 71;76], 90 patients (33%) were >75 years, 23 (9%) had high-risk cytogenetic (IFM score >1), 181 (76%) had R-ISS2+3, and 47 (17%) had impaired renal function (eGFR <60 mL/min). MRD negativity rates at 10-5 at 18 months were significantly higher in Isa-VRd arm compared to IsaRd arm (47% vs 24%, OR for negative MRD =2.96 [95%CI. 1.73 – 5.07, p<0.001]. The MRD benefit was consistent across subgroups. At 21.2 months median follow-up, 33 (12%) patients had relapsed and 20 (7%) had died, and no significant difference were observed across arms, yet. The addition of weekly “light” schedule of bortezomib did not significantly affect relative dose intensity of IsaRd. Forty-four (33%) patients presented with neurological adverse events grade ≥2 in the Isa-VRd vs 27 (20%) in IsaRd arm. Conclusions: Isa-VRd significantly deepened responses including a significant increase of the MRD negative rate at 10-5 vs IsaRd. The safety profile is consistent with addition of bortezomib. This study supports Isa-VRd as a new standard of care for NDMM TI non-frail patients. Clinical trial information: NCT04751877. N (%) (ITT Population) [95%CI] at 18 Months IsaRd(n=135) Isa-VRd (n=135) p-value ≥CR 24 (18) [12 – 25] 54 (40) [32 – 49] 0.0001 ≥CR- MRD- 10-5 16 (12) [7 – 19] 29 (21) [15 – 29] 0.04 MRD- 10-6 20 (15) [9 – 22] 46 (34) [26 – 43] 0.0004 PFS at 18 months 86% [80 – 92] 87.2% [82 – 93] 0.47 OS at 18 months 93.6% [90 – 98] 92.4% [88 – 97] 0.77

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