Molecular and Immunological Determinants of Long-Term Survival in Multiple Myeloma Open Access

Long-term survival (LTS) in multiple myeloma (MM), defined as survival of ≥10 years post-diagnosis following a single line of therapy, is an increasingly observed outcome due to significant therapeutic advancements. The introduction of proteasome inhibitors, immunomodulatory drugs, monoclonal antibodies, autologous stem cell transplantation (ASCT), and novel immunotherapies has transformed MM treatment. Importantly, only a subset of patients achieves long-term, durable disease control, suggesting that both myeloma-intrinsic and immune-mediated mechanisms play critical roles. Therapeutic advancements, including chimeric antigen receptor T-cell (CAR-T) therapy and bispecific antibodies, have primarily benefited standard-risk patients. Beyond therapeutic interventions, LTS appears to be driven by distinct features of the immune bone marrow environment (IBME), where enhanced T cell function, increased NK cell cytotoxicity, and reduced immunosuppressive myeloid populations contribute to disease control. Understanding these immune adaptations in LTS MM provides a foundation for developing next-generation treatment strategies. Future research integrating genomic and immune profiling, along with IBME modulation, will be critical in shifting MM treatment paradigms from disease management to sustained remission and functional cures.