Immune alterations in myeloma evolution and outcomes: quo vadis?

The pathogenesis of multiple myeloma (MM) and its precursor monoclonal gammopathy of undetermined significance (MGUS) is linked to an aging immune system. Chronic activation of B/plasma cells may contribute to the origin of MGUS, which is frequent in the older individuals. However, only 1% of individuals with MGUS annually experience progression to MM. The immune system can specifically recognize MGUS lesions, and preclinical MM models provide evidence for both innate and adaptive immune surveillance. Multiomic studies have identified several systemic alterations at the MGUS stage, suggesting accelerated immune aging prior to evolution into clinical malignancy. MM is further associated with spatial alterations in patterns of tumor growth and in situ regulation of regional immunity. Both tumor and microenvironment-related factors contribute to immune paresis, which facilitates the dissemination of clonal plasma cells, and increases the risk of infections in patients with MM. Immune profiles in blood or marrow exhibit considerable heterogeneity, and have been linked to outcomes following immune therapies, including T-cell redirection. Understanding how underlying systemic immune changes impact in vivo function and durability of natural or synthetic tumor/antigen-specific immunity needs further study. Preserving or restoring immune function may be critical for long-term outcomes both in the context of prevention of clinical MM and of treating active disease. Benchmarking of immune biomarkers followed by its prospective integration into current risk models, together with improved understanding of mechanisms underlying tumor immunity in vivo, are needed to optimize immune approaches and improve outcomes in MM.