Investigating the role of incretin mimetics in reducing the risk of development and progression of multiple myeloma and its precursor conditions

The prevalence of monoclonal gammopathy of undetermined significance (MGUS), a clinically asymptomatic bone marrow (BM) clonal plasma cell disorder, increases with age and is present in 5% of individuals over the age of 70 years. The risk of transformation to multiple myeloma (MM), a cancer requiring therapy due to clinical symptoms such as bone lesions, renal impairment, bone marrow suppression and frequent infections is approximately 1% per year. Currently no therapeutic intervention is offered to individuals with MGUS, instead they are monitored closely so that chemotherapy may be given swiftly if there is evidence of disease progression. Epidemiological and animal models link obesity with the development of MGUS and the transition from MGUS to MM. Clonal MGUS/MM cells are reliant on interactions with the BM microenvironment for cell growth and survival. Recent murine studies have shown that obesity and the resulting increase in BM adipocytes creates a permissive BM microenvironment enabling clonal MGUS/MM cells to survive and proliferate. The success of incretin mimetics in decreasing obesity rates and improving the prevalence of obesity-related diseases opens up the possibility that their use may be able to decrease the risk of MM progression, decrease the incidence of MGUS and the overall population burden of plasma cell dyscrasias. In order to investigate this, we will utilize two murine models of disease; one where MM does not develop in the normal fed state, but when animals are fed a high fat diet the BM becomes permissive and disease develops; the other where the BM is permissive and MM develops independent of diet/weight. We will determine whether weight loss alone, and/or treatment with incretin mimetics reduces the disease incidence and burden. In the same models we will determine the effects of weight loss and incretin mimetics therapy on the cellular composition of the BM microenvironment, including tumor cells, immune cells, adipose cells, and niche cells and determine how the permissive microenvironment is normalized following intervention. We will confirm findings and further define biological effects using a functional in-vitro model. Finally, we will determine if any differences are observed between the two main incretin mimetics classes, GLP-1 and dual GLP-1/ GIP-1 receptor agonists. The resulting data will provide supporting evidence for the development of clinical interception studies of incretin mimetics for individuals with MGUS with the aim of decreasing the amount of disease and the risk of transformation to MM. Project Number: 1R21CA301170-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Faith Davies | Institution: NEW YORK UNIVERSITY SCHOOL OF MEDICINE, NEW YORK, NY | Award Amount: $466,125 | Activity Code: R21 | Study Section: Cancer Prevention Study Section[CPSS] View on NIH RePORTER: https://reporter.nih.gov/project-details/11303823