Dysregulation of the Bone Marrow Immune Microenvironment and Clinical Outcomes in Multiple Myeloma

Multiple myeloma (MM) is characterized not only by malignant plasma cell proliferation but also by progressive dysregulation of the bone marrow immune microenvironment (BMIME). Increasing evidence suggests that disease progression, therapeutic resistance, and clinical outcomes are associated with dynamic interactions between tumor cells, immune populations, stromal elements, and inflammatory signaling pathways within the marrow niche. Although many of these observations derive from high-dimensional immune profiling, spatial transcriptomics, and single-cell transcriptomic studies, emerging mechanistic and functional evidence supports an important role for immune dysregulation in shaping disease evolution, immune escape, and therapeutic responsiveness. Recent advances in spatial profiling, immune phenotyping, and multi-omic approaches have revealed profound remodeling of the immune ecosystem across the evolution from monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) to symptomatic MM. This remodeling is characterized by progressive T-cell exhaustion, immunosenescence, dysfunction of natural killer (NK) cells, expansion of immunosuppressive myeloid populations, and altered cytokine and ligand–receptor signaling networks associated with adverse clinical outcomes. Importantly, emerging studies demonstrate that immune signatures derived from the BMIME may improve prognostic stratification beyond conventional tumor cytogenetics and staging systems. In this review, we discuss the mechanisms underlying immune dysregulation in MM, summarize recent discoveries regarding immune remodeling associated with clinical outcomes, and explore the translational implications of immune-based biomarkers and therapeutic strategies. Understanding the dynamic interplay between tumor genetics, immune-cell states, immunosenescence, and microenvironmental remodeling may facilitate the development of clinically actionable biomarkers and more personalized immunotherapeutic approaches and novel risk-adapted treatment strategies in MM.