Grant Number:	5R01CA300518-02 Interpret this number
Primary Investigator:	Brown, Elizabeth
Organization:	University Of Alabama At Birmingham
Project Title:	Role of the Environment, Mutographs and T Cell Immunity on Mgus
Fiscal Year:	2026

ABSTRACT The goal of this investigation is to characterize the influence of macro-level exposures on associations of mutational signatures and T-cell immunity in high-risk monoclonal gammopathy of undetermined significance (MGUS). MGUS is a necessary precursor to multiple myeloma (MM) suggesting that driver events accumulated at the early precursor stage provide an evolutionary trajectory that predisposes to late-stage disease. Despite the importance of MGUS, our current understanding of its etiology is almost exclusively inferred from MM resulting in a knowledge gap of events driving the transition from early to late-stage disease. By directly evaluating MGUS, we will improve our understanding of the macro-level exposures and genomic mechanisms that drive risk. In this proposed investigation, we will test the overarching hypothesis that distinct mutational signatures and T-cell immunity are associated with the presence of MGUS and that macro-level exposures modify the effect of these factors that drive the risk of MGUS. Our objective to model the influence of macro- and micro- level factors relative to early genomic events underlying the evolutionary trajectory of MGUS is a critical step toward characterizing the biology that drives high-risk MGUS and may provide a clinically impactful tool for early detection, clinical monitoring and advancing interception strategies. The specific aims are to: (1) determine the influence of macro-level exposures on the risk of MGUS-MM, (2) identify mutographs and T-cell immune responses associated with MGUS risk, and (3) determine the extent to which macro-level exposures modify the effect of mutographs and T-cell immunity on the risk of MGUS. The proposal is highly innovative, timely and leverages existing resources and comprehensive, high-quality data together with biospecimens systematically collected in well-characterized populations to advance our understanding of MGUS etiology, and a biological basis for high-risk MGUS. Anticipated findings will uncover modifiable risk factors, identify populations at risk for MGUS-MM, and may provide a foundation to discover novel therapeutic targets and effective interception strategies to improve the health of all populations at risk for MGUS-MM.