Isatuximab, lenalidomide, dexamethasone and bortezomib in transplant-ineligible multiple myeloma: the randomized phase 3 BENEFIT trial

CD38-targeting immunotherapy is approved in combination with lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma (NDMM) that are transplant ineligible (TI) and is considered the best standard of care (SOC). To improve current SOC, we evaluated the added value of weekly bortezomib (V) to isatuximab plus lenalidomide and dexamethasone (IsaRd versus Isa-VRd). This Intergroupe Francophone of Myeloma phase 3 study randomized 270 patients with NDMM that were TI, aged 65–79 years, to IsaRd versus Isa-VRd arms. The primary endpoint was a minimal residual disease (MRD) negativity rate at 10⁻⁵ by next-generation sequencing at 18 months from randomization. Key secondary endpoints included response rates, MRD assessment rates, survival and safety. The 18-month MRD negativity rates at 10⁻⁵ were reported in 35 patients (26%, 95% confidence interval (CI) 19–34) in IsaRd versus 71 (53%, 95% CI 44–61) in Isa-VRd (odds ratio for MRD negativity 3.16, 95% CI 1.89–5.28, P < 0.0001). The MRD benefit was consistent across subgroups at 10⁻⁵ and 10⁻⁶, and was already observed at month 12. The proportion of patients with complete response or better at 18 months was higher with Isa-VRd (58% versus 33%; P < 0.0001), as was the proportion of MRD negativity and complete response or better (37% versus 17%; P = 0.0003). At a median follow-up of 23.5 months, no difference was observed for survival times (immature data). The addition of weekly bortezomib did not significantly affect the relative dose intensity of IsaRd. Isa-VRd significantly increased MRD endpoints, including the 18-month negativity rate at 10⁻⁵, the primary endpoint, compared with IsaRd. This study proposes Isa-VRd as a new SOC for patients with NDMM that are TI. ClinicalTrials.gov identifier: NCT04751877.

Xavier Leleu, Cyrille Hulin, Jerome Lambert, Arthur Bobin, Aurore Perrot, Lionel Karlin, Murielle Roussel, Lydia Montes, Brieuc Cherel, Thomas Chalopin, Borhane Slama, Marie-Lorraine Chretien, Kamel Laribi, Claire Dingremont, Christophe Roul, Clara Mariette, Sophie Rigaudeau, Claire Calmettes, Mamoun Dib, Mourad Tiab, Laure Vincent, Jacques Delaunay, Alberto Santagostino, Margaret Macro, Emmanuelle Bourgeois, Frederique Orsini-Piocelle, Julie Gay, Benoit Bareau, Noemie Bigot, François Vergez, Pierre Lebreton, Reza Tabrizi, Agathe Waultier-Rascalou, Laurent Frenzel, Ronan Le Calloch, Emilie Chalayer, Thorsten Braun, Florence Lachenal, Selim Corm, Celine Kennel, Rakiba Belkhir, Jean-Sebastien Bladé, Bertrand Joly, Valentine Richez-Oliver, Helene Gardeney, Helene Demarquette, Daniela Robu-Cretu, Laurent Garderet, Muriel Newinger-Porte, Amine Kasmi, Bruno Royer, Olivier Decaux, Bertrand Arnulf, Karim Belhadj, Cyrille Touzeau, Mohamad Mohty, Salomon Manier, Philippe Moreau, Hervé Avet-Loiseau, Jill Corre, Thierry Facon