PROJECT SUMMARY Multiple myeloma (MM) is a devastating clonal plasma cell (cPC) malignancy responsible for over 13,000 deaths in the US per year. It is always preceded by pre-malignant, asymptomatic plasma cell disorders such as monoclonal gammopathy of undetermined significance (MGUS) or smoldering multiple myeloma (SMM). Despite the availability of various clinical, genomic, and imaging-based risk stratification models, accurate classification of precursor cPC disorders and their risk of progression to MM remains elusive. The fundamental roadblock remains in the inability of existing clinical and laboratory-based biomarkers to distinguish between the presence of premalignant or malignant cPCs in patients. In contrast, recent advances in mass- spectrometry based metabolomics offers new opportunities to characterize intra- and extracellular metabolites that could serve as novel biomarkers reflective of the presence of malignant cPCs. This is especially promising since oncogenic drivers of progression of premalignant to malignant cPCs, such as c-Myc, has known downstream effects on multiple intracellular metabolic pathways resulting in altered extracellular metabolite levels. These resultant metabolite profiles can be exploited to more accurately assess the risk of progression of precursor cPC disorders to MM in the future and ultimately affect management and treatment. Thus, this research proposal will test the hypothesis that the levels of select metabolites within the bone marrow (BM) plasma are reflective of the qualitative and quantitative presence of c-Myc-activated malignant cPCs in patients with PC disorders. This research proposal will specifically validate the presence of differences in the levels of select metabolites in the BM plasma between MGUS and MM patients (Aim 1). It will also evaluate the effect of c-Myc activation in cPCs on their extracellular levels of these select metabolites (Aim 2). Finally, it will evaluate how depleting the malignant cPCs with systemic therapy affects the BM plasma levels of these select metabolites in MM (Aim 3). These studies will provide an opportunity to advance our understanding of the metabolic rewiring associated with the pathogenesis of MM. This could allow us to better determine the transition from MGUS to symptomatic MM for the development of potential early diagnostic or preventative strategies. The expertise and resources of the members of the team, the availability of the Myeloma SPORE biobank and a NIH-designated comprehensive metabolomics core at the Mayo Clinic ensures the viability and execution of the proposed experiments.
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