PROJECT SUMMARY Multiple myeloma (MM) is an incurable plasma cell malignancy and the most common blood cancer among individuals who self-identify as African American, accounting for ~20% of newly diagnosed cases. The biological factors contributing to the increased risk of MM and its precursor condition, monoclonal gammopathy of undetermined significance (MGUS), in individuals of African ancestry remain poorly understood. Strikingly, when access to healthcare is equal, African American patients experience better clinical outcomes, and their MM tumors exhibit lower genomic complexity compared to those of European American patients. It is well established that the incidence of MGUS and MM increases with age, and aging is a primary determinant for progression from MGUS to MM. African American patients are diagnosed with MGUS and MM at younger average ages than European American patients, and emerging evidence suggests that individuals of African ancestry exhibit accelerated biological aging and immunosenescence. Together, these observations suggest that accelerated biological aging may contribute to the higher prevalence of MGUS and increased incidence of MM in African Americans. In support of this, we found that African American patients with MGUS and MM, as well as healthy donors, had increased CD57+ CD8+ T cells, a hallmark of immunosenescence. This altered immune function may reduce tumor immune surveillance, decreasing the selective pressure that drives tumor immunoediting. We hypothesize that individuals with predominant African ancestry who develop MGUS or MM experience accelerated biological aging and immunosenescence compared to those with predominant European ancestry, resulting in reduced tumor immunoediting and the development of tumors with less genomic complexity- a feature linked to more favorable clinical outcomes. In Aim 1, we will assess whether patients with MGUS and MM who have predominant African ancestry exhibit accelerated biological aging compar