Single-Cell and Multi-Omics Profiling of the Multiple Myeloma Immune Niche: From Bone Marrow Architecture and Metabolic Reprogramming to Immunotherapy Response.

Multiple myeloma (MM) is increasingly understood as a spatially organized and dynamically evolving disease, in which malignant plasma-cell behavior is shaped by local immune, stromal, vascular, and metabolic contexts. Single-cell, spatial, and multi-omic technologies have resolved tumor-cell heterogeneity, bone marrow niche remodeling, immune dysfunction, and therapy-induced selection at unprecedented resolution, yet an integrated synthesis linking marrow architecture, extramedullary dissemination, circulating tumor cells, metabolic reprogramming, chimeric antigen receptor T (CAR-T) cell and T-cell-redirecting immunotherapy, and stem-cell transplantation remains lacking. Here, we review how malignant subclones occupy distinct marrow regions, focal lesions, and extramedullary sites with different transcriptional, antigenic, immune-interactive, and metabolic states. We discuss how spatial transcriptomics and multiplexed imaging reveal immune exclusion, stromal support, oxidative and glycolytic niches, and region-specific antigen heterogeneity. We further examine how circulating tumor cells serve as liquid readouts of tumor burden, high-risk genomics, and clonal evolution. Emphasis is placed on CAR T-cell and T-cell engager therapies, where response and resistance depend on antigen retention, effector-cell fitness, clonal T-cell expansion, myeloid suppression, and spatial accessibility. Finally, we consider autologous hematopoietic stem-cell transplantation as a clinical model of cytoreduction, lymphodepletion, and incomplete immune reconstitution. We propose that MM progression and relapse should be interpreted through an integrated spatial-temporal framework, in which therapeutic outcome reflects the interaction between malignant plasma-cell plasticity, immune competence, stromal persistence, metabolic adaptation, and residual disease localization.