Accelerated Biological Aging and Immunosenescence as Drivers for Racial Disparities in Monoclonal Gammopathy of Undetermined Significance (MGUS)

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 compared to those with predominant European ancestry. In Aim 2, we will compare the immune tumor microenvironment in MGUS and MM patients with predominant African ancestry vs. those with predominant European ancestry to test the hypothesis that African ancestry patients exhibit increased immunosenescence. In Aim 3, we will evaluate whether MM tumors from patients with predominant African ancestry exhibit reduced immunoediting relative to those from patients with European ancestry. To mechanistically model this, we will use a mouse MM tumorigenesis model and apply unpredictable chronic mild stress to mimic chronic environmental and psychosocial stressors to test whether tumors arising under stress exhibit reduced immuno editing, evidenced by decreased genomic complexity and the reduced ability to engraft in immunocompetent recipient mice. Overall, this work will elucidate the role of accelerated biological aging and immunosenescence as potential drivers for increased MM incidence in individuals with African ancestry. Project Number: 1R01CA313650-01 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: LINDA BAUGHN (+1 co-PI) | Institution: MAYO CLINIC ROCHESTER, ROCHESTER, MN | Award Amount: $558,016 | Activity Code: R01 | Study Section: Basic Mechanisms of Cancer Health Disparities Study Section[BMCD] View on NIH RePORTER: https://reporter.nih.gov/project-details/11358776