IFM 2026 Recommendations for First-line Treatment of Newly Diagnosed Multiple Myeloma.

The treatment landscape of newly diagnosed multiple myeloma (NDMM) has changed considerably over the past 5 years. Anti-CD38-VRd quadruplets are now the standard of care for transplant-eligible patients and an important option for transplant-ineligible patients. This review presents unified, evidence-based first-line treatment recommendations from the Intergroupe Francophone du Myélome (IFM), covering transplant-eligible and transplant-ineligible NDMM within a single framework and common methodology. In transplant-eligible patients, daratumumab-VRd and isatuximab-VRd, informed respectively by the PERSEUS and GMMG-HD7 trials, are now the reference induction regimens, followed by autologous stem cell transplantation, optional consolidation, and daratumumab-lenalidomide maintenance. In transplant-ineligible patients, daratumumab-lenalidomide-dexamethasone (DRd), informed by the MAIA trial, remains the treatment backbone: in fit patients, adding bortezomib (isatuximab-VRd or daratumumab-VRd, informed by IMROZ, CEPHEUS, and BENEFIT) could further improve outcomes, while frail patients receive the same backbone without dexamethasone (DR), informed by IFM2017-03. Mathematical modeling projects a median progression-free survival of approximately 205 months with daratumumab-VRd in transplant-eligible patients (PERSEUS model) and approximately 100 months in transplant-ineligible/transplant-deferred patients (CEPHEUS model), approaching for the first time a normal life expectancy for a substantial subset of patients and supporting the emerging concept of functional cure. We discuss the role of measurable residual disease and NGS-based high-risk myeloma definition across both populations, and position these recommendations relative to the 2025 EHA-EMN evidence-based guidelines. Finally, we summarize ongoing trials investigating T-cell-redirecting immunotherapies (CAR-T cells and bispecific antibodies) as replacements for, or additions to, ASCT and maintenance therapy, which may further reshape the first-line treatment paradigm in the coming years.