Dissecting the risk of MGUS/MM in high-risk participants in the PLCO study
The proposed research will use novel methods to screen a large cohort of high-risk individuals to potentially help identify novel risk alleles and clinical factors that might predispose such high-risk populations to MM-related conditions. Findings stemming from the proposed project will serve as preliminary data for the development of deeper genomic analyses in larger patient samples. This program of research will contribute to our long-term goal of developing improved models that can be used to better understand the etiology and natural history of the disease among Black patients who are disproportionately impacted by the disease yet are understudied in clinical research. This research is positioned to contribute to our long-term research mission of informing the development and implementation of precision screening and prevention strategies in high-risk patient subsets to facilitate effective clinical surveillance and interventions. This will be the largest cohort of people at high risk for MGUS/SMM and will undoubtedly enable scientific discoveries that will benefit all patients with MGUS/MM. We expect that our approach will nominate germline variants of MGUS/MM risk, which will allow us to move past using self-reported race for risk stratification and potentially lead to the development of targeted diagnostics and therapeutics approaches.
Our overarching hypothesis is that (i) germline variants and (ii) aging of the individual’s immune system contribute to the risk of developing MGUS/MM.
Specific Aim 1. To screen all high-risk participants in the PLCO study for monoclonal protein using Mass Spectrometry. Black people and people with a family history of myeloma, lymphoma or leukemia have significantly higher risk of developing MGUS. Therefore, germline variants and/or the state of the individual’s immune system may play an important role in MGUS/SMM development in this population. Here, we plan to use Binding Site’s Mass Spectrometry platform to detect undiagnosed MGUS/SMM in serum samples of approximately 10,000 high-risk participants in the PLCO study (approximately 7,000 Black participants, and approximately 6,000 participants PLCO participants with a family history of leukemia, lymphoma or myeloma). We assume some of those participants may not have samples available or overlap between AA and familial cases, therefore, we expect to have 10,000 samples available for those 2 high-risk groups.
Based on the cohort’s age distribution and the prevalence of the disease (~10% of people over 50 years of age based on our preliminary data), we expect to discover at least ~1,000 positive cases of either African Americans or those with family history of blood cancers.
Specific Aim 2. To identify germline variants that predispose to developing MGUS/MM. Our understanding of the genetic factors that predispose an individual to develop MGUS/MM is very limited. This is largely due to the lack of large cohorts of Black people and/or people with positive family history. Here, we plan to leverage the positive cohort developed in Aim 1, as well as a control group of negative cases, and perform whole-genome sequencing at 30X on DNA extracted from their peripheral blood. Furthermore, we will integrate this data with data from the CoMMpass study (n=150) and two other screening cohorts we developed: the PROMISE cohort of Black patients over the age of 40 with or without a family history of MM and the MGB cohort.
Specific Aim 3. To assess the role of immune aging in developing MGUS/MM. Our preliminary data suggests potential differences in the immune system of healthy individuals who are at higher risk for MGUS/MM, due to their family history. Such individuals present a higher frequency of clonal T-cell expansion (~60%), a sign of immune aging, compared to age- and sex-matched healthy donors, and the presence of T-cell expansion is associated with inferior outcomes in patients with MM. Here, we plan to perform T-cell Receptor (TCR)-sequencing in peripheral blood mononuclear cells (PBMCs) or DNA extracted from PBMCs to profile the diversity of T-cell repertoire in the PLCO cohort of Aim 1. We expect to detect ~750 cases with TCR expansion overall, the majority of which we hypothesize may be coming from the positive cohort or from our own PROMISE/MGB samples. Furthermore, we plan to integrate this data with data from Aim 2 to explore the interplay of germline variants and immune aging in this population. This study will be the first to assess the state of the patients’ adaptive immunity and could lead to the development of immunodiagnostic and immunotherapeutic approaches for patients with MGUS/MM.
Irene Ghobrial (Dana-Farber Cancer Institute)
Habib El-Khoury (Dana-Farber Cancer Institute)
Romanos Sklavenitis Pistofidis (Dana-Farber Cancer Institute)
- Addendum for including serum samples from participants with multiple myeloma and monoclonal gammopathy of undetermined significance in a mass spectrometry screened cohort