SOHO State of the Art Updates and Next Questions | Treatment of Myeloma Early Relapse: Non-CAR T Cell

Multiple myeloma increasingly presents with multi-class drug resistance after frontline treatment. Although chimeric antigen receptor (CAR) T-cells have emerged as a highly effective treatment modality available at first relapse, their widespread adoption has been hindered by high costs and complicated logistics. We collected evidence from randomized phase III clinical trials, subgroup analyses, and recent guidelines to form an evidence-based, non CAR-T treatment framework. The main determinant of second-line therapy selection includes refractoriness, particularly to lenalidomide and anti-CD38 monoclonal antibodies, followed by cytogenetic risk, relapse aggressiveness, frailty, and patient preferences. In lenalidomide-sensitive or naive patients, regimens that combine an anti-CD38 monoclonal antibody with an immunomodulatory drug (IMiD) or a proteasome inhibitor provide the most consistent benefit. In lenalidomide-refractory patients, non-lenalidomide containing combinations are preferred. Moreover, anti-CD38 antibody refractory relapse excludes further anti-CD38 antibody use in second-line combinations. Due to anti-CD38 antibody incorporation in frontline regimens, refractoriness to this drug class is becoming increasingly prevalent, necessitating the use of novel approaches. Combinations based on belantamab mafadotin, an antibody drug conjugate targeting B cell maturation antigen (BCMA), are currently the leading non CAR-T options in this setting, while exportin-1 inhibitors, such as selinexor, and next-generation proteasome inhibitors offer additional options. Ongoing trials assessing T-cell redirecting bispecific antibodies targeting B cell maturation antigen or GPRC5D may further improve outcomes at first relapse as access and safety profiles evolve. In conclusion, early-relapse multiple myeloma care should be individualized in order to optimize patient outcomes and achieve long-term remissions with acceptable toxicity profile.