PROJECT SUMMARY This Career Transition Award will position the candidate to achieve her career goal of becoming a successful independent investigator in multiple myeloma (MM) prevention. The candidate's current program of research is focused on elucidating the impact of energy balance factors on MM risk and survival. The research proposed in this K22 will focus on monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM), which are premalignant conditions that progress to MM in a subset of patients for reasons that are poorly understood. Evidence-based strategies are unavailable for preventing the progression of MGUS/SMM to MM, underscoring the importance of research in this area. A promising pharmacologic intervention to reduce the risk of progression of MGUS/SMM to MM is metformin, an inexpensive, safe, and widely-available drug with demonstrated anti-myeloma properties in laboratory and epidemiologic studies. The study hypothesis is that metformin use will be associated with: (1) a significant reduction in clinical symptoms of disease progression, and (2) altered expression of bone marrow niche cells implicated in the malignant transformation of MGUS/SMM to overt MM. To test these hypotheses, we will conduct a 6-month, double-blind placebo- controlled trial enrolling 86 MGUS/SMM patients who currently have no available strategies for cancer risk reduction. The research outlined in this proposal is expected to contribute to a paradigm change in the clinical follow-up of MGUS and SMM, from a watch and wait approach, to a paradigm focused on the prevention and interception of disease progression. The training plan that complements this research will provide the candidate with the depth and breadth of expertise needed to translate etiologic and epidemiologic discoveries into efficacious interventions for MM and precursor MM patients. Specifically, the training is designed to provide advanced knowledge of precursor MM biology, single-cell sequencing approaches, and intervention research in cancer prevention in preparation for an independent career of research focused on the prevention of MM. Together, the innovative research and strategic training activities will promote the career development of the candidate.