Oxidative Phosphorylation and mTOR Activation Drive Transcriptomic Divergence in Extramedullary Multiple Myeloma

Extramedullary disease (EMD) is an aggressive multiple myeloma (MM) variant marked by malignant plasma cells dissemination outside the bone marrow and poor overall prognosis. This study investigates EMD development via bulk and single cell transcriptomics of patient samples, providing insights into gene expression and cell signalling to guide targeted therapies. 

Bulk RNA was performed on 24 bone marrow mononuclear cell (BMNC) samples (medullary MM: n=9, extramedullary MM: n=15) and single-cell RNA-seq was also carried out on additional BMNCs (medullary MM: n=6, extramedullary MM: n = 8) to assess transcriptomic and cellular heterogeneity between cohorts.

Bulk transcriptomic profiling revealed a clear divergence between MM and EMD samples, including increased expression of oxidative phosphorylation genes and a distinct adipogenesis‑associated cluster, indicating a metabolic shift accompanying EMD progression. Gene set enrichment analysis (GSEA) highlighted enrichment of mTORC1 signalling and MYC target genes, consistent with enhanced proliferation, protein synthesis, and metabolic rewiring.

ScRNA-seq identified canonical immune cell types alongside non-canonical populations such as myeloid-derived suppressor cells (MDSCs), transitioning  cells, and NK-like T-cells reflecting microenvironment driven phenotypic plasticity in the EMD cohort. Stromal populations were also detected, including LEPR+ CAR cells, a mesenchymal subset, suggesting niche derived pro‑tumour support in the EMD cohort. GSEA of  individual cell types in the dataset corroborated bulk findings, with pathways such as epithelial-mesenchymal transition (EMT), cholesterol homeostasis and oncogenic signalling, including mTOR dominating EMD particularly in MSC cell population.

This transcriptomic divergence indicates that EMD represents a molecularly distinct disease subtype and not merely an advanced stage of MM. Given that mTORC1 signalling integrates mitochondrial energy status and drives lipid biosynthesis, lipid supported metabolism represents a downstream vulnerability of the OXPHOS–mTORC1 axis in EMD.