Defining the landscape of structural alterations in African American Multiple Myeloma

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Summary Multiple Myeloma is a malignancy of long-lived plasma cells of the bone marrow and is the second most common hematologic malignancy, with over 34,000 new cases and nearly 13,000 deaths expected in the US in 2021. However, amongst African Americans, myeloma is the most common hematologic malignancy with the incidents rate between 2-3 times higher than that observed in Caucasians. Consistent with this finding, the precursor to myeloma, Monoclonal Gammopathy of Undetermined Significance (MGUS) is also observed at a higher frequency in African Americans. Thus, the increased frequency of myeloma is likely to due to underlying factors that result in both the development of MGUS as well as its progression to myeloma. Translocations that juxtapose oncogenes to the potent enhancers of the immunoglobulin heavy chain (IgH) or trisomies of odd- numbered chromosomes (hyperdiploidy) are the initiating events in nearly all myelomas. However, these are rarely sufficient to cause myeloma, which almost always have additional copy number alterations (e.g., del17p, amp1q21) and/or mutations (e.g. KRAS, TP53) observed at diagnosis and these influence outcome. Interestingly African Americans tend to have genomic alterations that would predict a superior outcome, however we have found that in patients treated identically with the current standard of care at our institution, there is no difference in the patient outcomes. Additionally, in the MMRF CoMMpass study, African Americans do worse than Caucasians despite no difference in the treatment and being diagnosed at a significantly earlier age, which is typically considered a good prognostic marker. Together these data suggest that our current approaches are either not accurately predicting risk or our therapeutic approaches are not optimized for the African American population. Our recent finding suggest that these events could be related. Utilizing whole genome sequencing that is part of the MMRF CoMMpass study, we performed an analysis of the structural landscape of newly diagnosed multiple myeloma. We found that patients that have translocations in the immunoglobulin lambda light chain locus (IgL) have a significantly worse outcome than other patients in the study. IgL translocations were found in 10% of the population and 70% were associated with hyperdiploid myeloma, a good prognostic marker routinely tested for clinically whereas IgL events are not. Thus, these patients were misdiagnosed with lower risk disease. We also demonstrated that the likely cause of misdiagnosis was resistance to one of the backbone myeloma drugs, lenalidomide. African American patients with IgL translocations experienced strikingly worse outcomes than their European American counterparts. Based on these findings we hypothesize that there are additional structural events that are not routinely tested for which can influence outcomes and that these may differ in African American myeloma. These events may also contribute to the early onset of disease. We propose two Specific Aims to test this hypothesis as well as the development of a test to detect these changes.