Metabolic heterogeneity and niche rewiring in bone marrow plasma cells from patients with MGUS, solitary bone plasmacytoma and multiple myeloma

Metabolic differences between plasma cell disorders reflect coordinated metabolic reprogramming within clonal plasma cells and the bone marrow microenvironment. We applied high-resolution MALDI-FT-ICR mass spectrometry imaging (MSI) to archived FFPE bone-marrow biopsies from patients with MGUS-like bone marrows (defined as <10% clonal plasma cells, including MGUS and solitary bone plasmacytoma with minimal marrow involvement (SBPmm)) and multiple myeloma (MM), integrated with matched bone marrow plasma metabolomics, to map spatial and systemic metabolic alterations. Spatial clustering delineated plasma-cell-rich niches, while Hill-based diversity and β-diversity metrics quantified intra- and inter-compartment heterogeneity. MM niches exhibited elevated 3-hydroxykynurenine, rewired tryptophan-kynurenine flux, and increased nucleotide and bioactive lipid metabolism associated with proliferation. Notably, SBPmm samples displayed MM-like metabolic niches undetectable in bone marrow plasma alone, underscoring spatial heterogeneity. Cross-compartment integration revealed conserved metabolic signatures and systemic redistribution of key metabolites, consistent with ecological reorganization and niche divergence between MGUS-like and MM. These findings establish spatial metabolomics of biopsies as a framework to dissect intramedullary metabolic heterogeneity and enable metabolite-based risk stratification in plasma cell disorders.