Multiplexed imaging reveals immune-metabolic niches in multiple myeloma linked to progression and bone disease

Multiple myeloma (MM) is a plasma cell (PC) cancer that depends on the bone marrow (BM) microenvironment for disease establishment and progression. Here, we spatially mapped BM biopsies from patients with MM, smoldering MM, 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 IL-32 in patients with bone disease, consistent with their role in promoting bone loss in MM. 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 was an independent negative predictor for progression-free survival. Our work underscores spatial context as a key factor in understanding MM pathogenesis and the potential for spatial analyses to improve MM risk stratification.