Metabolic Mechanisms in Multiple Myeloma

Multiple myeloma is characterised by the clonal expansion of malignant plasma cells within the bone marrow, and mounting evidence has revealed that these cells undergo profound metabolic rewiring to sustain their growth, survival and resistance to therapy. Central to this rewiring is enhanced glycolysis, whereby glucose is rapidly converted to lactate even in the presence of oxygen, supporting both biosynthetic demands and redox balance. Concurrently, myeloma cells exploit glutaminolysis, using glutamine to fuel the tricarboxylic acid (TCA) cycle and generate ATP and anabolic precursors. This dual reliance on glucose and glutamine is regulated by oncogenic drivers such as c-Myc and PGC1β, which coordinate expression of transporters and enzymes including hexokinase 2, lactate dehydrogenase A and glutaminase. Lactate exported via monocarboxylate transporters alters the bone-marrow microenvironment and fosters immunosuppression, while anaplerotic replenishment of TCA intermediates ensures continuous mitochondrial respiration and biosynthesis. Metabolic plasticity also underlies resistance to proteasome inhibitors, with resistant clones displaying increased mitochondrial glutamine catabolism and augmented oxidative phosphorylation. Therapeutic strategies that disrupt these pathways—by inhibiting key enzymes or blocking nutrient transport—have shown promise in preclinical models, pointing to metabolism as a fertile target for overcoming drug resistance and improving patient outcomes.

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Metabolic Mechanisms in Multiple Myeloma publication trend

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Technical terms

Glycolysis: The enzymatic breakdown of glucose to pyruvate, yielding ATP and NADH to support rapid cell proliferation.

Glutaminolysis: The metabolic pathway where glutamine is deaminated and its carbon skeleton enters the TCA cycle to produce energy and biosynthetic precursors.

Tricarboxylic acid (TCA) cycle: A series of mitochondrial reactions that oxidise acetyl-CoA to carbon dioxide while generating NADH and FADH₂ for ATP synthesis.

Monocarboxylate transporters (MCTs): Membrane proteins that export lactate and protons from cells, regulating intracellular pH and linking tumour metabolism to the microenvironment.

Anaplerosis: The replenishment of TCA cycle intermediates through the entry of nutrients like glutamine, ensuring continuous energy production and biosynthesis.

References

1. Glutaminase inhibitor CB-839 synergizes with carfilzomib in resistant multiple myeloma cells. Oncotarget (2017).
2. Cyclin D1 targets hexokinase 2 to control aerobic glycolysis in myeloma cells. Oncogenesis (2020).
3. In vivo assessment of glutamine anaplerosis into the TCA cycle in human pre-malignant and malignant clonal plasma cells. Cancer & Metabolism (2020).
4. PGC1β regulates multiple myeloma tumor growth through LDHA‐mediated glycolytic metabolism. Molecular Oncology (2018).