Immune signatures in older patients with newly diagnosed multiple myeloma are associated with survival outcomes of first‐line therapy irrespective of frailty levels

The treatment landscape for older patients with multiple myeloma (MM) has rapidly evolved with the introduction of CD38-targeting antibodies. Yet, outcomes remain highly variable and are only partially explained by frailty status. To address this, we investigated the impact of the immune system on survival outcomes of 89 newly diagnosed MM patients in the HOVON-143 trial, where frail or intermediate-fit patients received daratumumab-ixazomib-dexamethasone. Comprehensive immunophenotyping of lymphoid and myeloid subsets as relative or absolute counts in peripheral blood (PB) and bone marrow revealed comparable immune composition between frail and intermediate-fit patients at diagnosis, except for reduced naive CD4⁺ and CD8⁺ T-cells and increased effector memory CD4⁺ T-cells and CD56^bright NK-cells in frail patients. Among 36 T-cell and NK-cell subsets analyzed, 9 subsets-measured as absolute counts in PB-showed strong association with progression-free survival (PFS) and 5 with overall survival (OS). Four subsets were linked to both PFS and OS: higher absolute counts of naive CD8⁺ T-cells, CD38⁺CD4⁺ T-cells, and CD56^dimCD57⁺ NK-cells were associated with longer survival, whereas elevated EM CD8⁺ T-cell counts were linked to shorter survival. Using the most predictive immune parameters, we subsequently developed two immune risk scores-one for PFS and one for OS-which remained strongly associated with survival after adjusting for frailty status, disease stage, and cytogenetic risk. Our findings underscore the importance of a composite analysis of the immune system and demonstrate the association of baseline immune parameters with survival outcomes of first-line therapy in non-fit MM patients.