Multiplexed Imaging Reveals Immune-Metabolic Niches in Multiple Myeloma Linked to Progression and Bone Disease

Multiple myeloma is a plasma cell (PC) cancer that depends on the bone marrow (BM) microenvironment for disease establishment and progression. In this study, we spatially mapped BM biopsies from patients with multiple myeloma, smoldering multiple myeloma, and monoclonal gammopathy of undetermined significance by imaging mass cytometry. We found that PCs near bone surfaces displayed markers of quiescence and demonstrated a distance-to-bone-dependent expression of IL32 in patients with bone disease, consistent with their role in promoting bone loss in multiple myeloma. We identified two distinct PC neighborhoods termed PC OXPHOS, characterized by focal PC growth, enrichment of endothelial cells, and oxidative phosphorylation, and PC MYELOID, characterized by PCs interspersed with immune cells, featuring a glycolytic phenotype. Notably, imaging-inferred interactions between PCs and CD4+ T cells were an independent negative predictor for progression-free survival (PFS). Our work underscores spatial context as a key factor in understanding multiple myeloma pathogenesis and the potential for spatial analyses to improve multiple myeloma risk stratification.

This study demonstrates that multiple myeloma cells in different neighborhoods experience unique metabolic conditions and immune environments, and that neighbor preference of CD4+ T cells and PCs is associated with poorer PFS. These data highlight the value of spatially resolved analyses in uncovering potential pathophysiologic mechanisms of multiple myeloma.