# Metabolic Heterogeneity and Niche Rewiring in Plasma Cells are Associated with Progression from MGUS to Multiple Myeloma

## TL;DR

This study uses advanced imaging and metabolomics to show how metabolic changes in plasma cells and their environment contribute to the progression from MGUS to multiple myeloma.

## Contribution

The study introduces spatial metabolomics of biopsies to dissect intramedullary metabolic heterogeneity in plasma-cell disorders.

## Key findings

- MM niches show elevated 3-hydroxykynurenine and altered tryptophan–kynurenine flux.
- Some MGUS samples have MM-like metabolic niches not detectable in plasma alone.
- Cross-compartment integration reveals conserved and redistributed metabolite signatures during progression.

## Abstract

Progression from monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM) is driven by 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, 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, some MGUS-like 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 during progression. 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.