Impact of Genetic susceptibility along the continuum from MGUS to MM (Supplement)

ABSTRACT This application is being submitted in response to the Notice of Special Interest (NOSI), NOT-CA-22-057. Racial disparities exist for multiple myeloma (MM) and its precursor, monoclonal gammopathy of undetermined significance (MGUS); both MGUS and MM are at least twice as common in Black compared with White

populations, including at younger ages. A similar two-fold increase in MGUS has been seen in a population- based sample of Black men in Ghana compared to a White reference population, suggesting that the disparity is similar outside of the US. MGUS also is familial, with 2-3-fold increased prevalence in first-degree relatives

of MM or other hematologic malignancies. Although MGUS is usually benign, it is common in those ages 50 and older, progresses to MM or other lymphoproliferative proliferative disorders at rates of 1-1.5% per year, and is associated with increased risk of infection, fracture, osteoporosis, renal impairment, and thrombosis,

with resultant morbidity and mortality. Thus, understanding the development of MGUS and MGUS progression to MM is important, particularly among those with the highest risk, including people of African ancestry (AA) and first-degree relatives of MM and hematologic disorders. Our parent grant (U01 CA271014) proposes a

comprehensive evaluation of genetic susceptibility to MGUS and MGUS progression to MM using established epidemiologic and genomic studies. Due to the importance of racial predisposition, for the first time, we propose to evaluate known MM susceptibility variants and identified novel variants for MGUS and MGUS

progression in an AA population (Parent U01, Aim 3). In this supplement application, we establish a new global collaboration with Dr. Rotimi at Covenant University in Nigeria to conduct complementary studies of MGUS in West Africa to enhance the genetic investigations of MGUS and MGUS progression among people of

AA. In Aim 1, we will estimate the prevalence of MGUS using a novel mass spectrometry assay, in two risk groups ages 40 and older in Nigeria [a community-based sample (N=300) and first-degree relatives of MM and hematologic cancer patients (N=100)] and compare to US population-based rates. This aim leverages the experience and existing infrastructure of the Prostate Cancer Transatlantic Consortium network

that recruited over 1000 participants and first-degree relatives, including ten Nigerian clinical sites. In Aim 2, we will conduct genotyping (GWAS) of MM (N=25), MGUS identified through screening Aim 1 samples (N=66), and a sample of unaffected participants (N=100) to contribute to the validation of genetic risk factors for

MGUS risk and MGUS progression to MM in AA populations, as proposed in our parent U01. Finally, we will establish a family study of MGUS, MM and related disorders and perform whole exome sequencing on 25 relatives to identify rare variants. Understanding the prevalence of MGUS and genetic determinants of MGUS

and progression will have high impact for West African populations, as life expectancies continue to see a steady rise, and more individuals will develop MGUS, MM, and other diseases associated with aging.