Impact of Genetic susceptibility along the continuum from MGUS to MM

ABSTRACT Monoclonal gammopathy of undetermined significance (MGUS), is a benign plasma cell disorder, common in the population (3-5% ≥50 years) and characterized by an asymptomatic clonal plasma cell expansion. Although MGUS precedes multiple myeloma (MM) with progression rates of 1% per year, most (>75%) MGUS never progress. MGUS is also associated with increased risk of infection, fracture, osteoporosis, renal impairment, and thrombosis, with resultant morbidity and mortality. Few risk factors are identified for either the development of MGUS or MGUS progression to MM, with African American (AA) ancestry being one of the strongest. Identifying individuals who are more likely to progress is important given that individuals with MGUS who are closely monitored prior to development of MM have better outcomes. Prior work identified genetic variations associated with MM through family studies and, more recently, through genome wide association studies (GWAS). However, no well-powered genetic epidemiology studies of MGUS have been performed, particularly in AAs; and to our knowledge, none have investigated whether detection of genetic variation improves the identification of high-risk MGUS, including those that progress to MM. Therefore, we propose a comprehensive evaluation of genetic susceptibility to MGUS (Aim 1) and MGUS progression to MM (Aim 2) using established epidemiologic and genomic studies among European Americans (EA). Given the racial predisposition for MGUS and MM among AAs, for the first time, we propose to evaluate the known MM susceptibility variants and novel variants identified in Aims 1-2 in AAs (Aim 3). Using both GWAS and transcriptome-wide association studies (TWAS), we will answer the questions: (1) What are the genetic variations and genes predisposing to MGUS (Aim 1)? (2) How do these compare to genetic predisposition associated with progression from MGUS to MM (Aim 2)? (3) Do these identified genetic factors (and consequent polygenic risk scores, PRS) differentiate between MGUS patients that do and do not progress to active MM (Aim 2)? and finally, (4) Are these genetic factors for MGUS risk and progression similar across populations of EA and AA ancestries (Aim 3)? We will utilize established EA and AA studies of MGUS and MGUS progression to MM (MM vs. MGUS), the majority with GWAS, to allow for discovery and validation. We will also leverage genomic data, including RNA-sequencing of both whole blood (peripheral blood mononuclear cells, PBMCs) and sorted CD138+ bone marrow plasma cells (BMPCs) from MGUS patients to inform gene expression for the TWAS. Further, we will perform functional characterization of the new genes or variants validated in both EA and AA populations. Upon completion, our study will validate and characterize germline genetic factors associated with risk of MGUS and progression to MM in both EAs and AAs. It will have high impact, providing insight to MGUS and MM etiology and informing genetic contributions to clinical risk models for progression for the millions of people living with MGUS.