Improving the Utility of a Cancer Gene Mutation Panel for Multiple Myeloma Patients

Abstract Multiple myeloma is a plasma cell malignancy that accounts for 1-2% of all cancer diagnoses and 10-15% of hematopoietic neoplasms. Clonal rearrangement of the IG locus suggests a monoclonal model for pathogenesis. The presence of cytogenetic abnormalities in >90% of cases suggests transformation by chromosomal instability and rearrangement. Classification and consensus guidelines by The International Myeloma Working Group (IMWG) and others reflect this by categorizing myeloma based on ploidy, translocations, and chromosomal abnormalities. Interestingly, a portion of Emory’s test volume for cancer gene mutation profiling by second generation short-read sequencing is for multiple myeloma cases. This suggests our 75-gene myeloid neoplasm panel (MMP75) is being utilized for medical purposes that are not met by cytogenetic and microarray characterizations performed during the diagnostic workup of multiple myeloma. Inspired by this observation, this study investigates providers motivations for ordering MMP75 and assesses the adequacy of our current implementation for their stated purposes. Anecdotes from ordering physicians indicate interest in MMP75 results when informing prognosis, selecting treatments, and evaluating for treatment associated secondary neoplasms. A more formal survey is underway that will statistically capture how the results of MMP75 testing were ultimately used: to inform diagnosis, determine prognosis, guide treatment, explain progression, identify/rule-out secondary neoplasia, or no effect on management. We also explore the variants called by MMP75 when performed using bone marrow from patients who received a cytogenetic workup for multiple myeloma at some point. A retrospective analysis of the 5-year interval between Jan 2019 and Jan 2024 identified 156 cases meeting this criterion. The number of pathogenic variants per case ranged between 1 and 8, with mutations detected across 42 genes. The genes most frequently identified with pathogenic mutations were TP53 (22.4%), DNMT3A (19.2%), TET2 (14.7%), and ASXL1 (12.2%). All four have been associated with adverse outcomes in patients with multiple myeloma. Activating events in therapeutic targets included mutations in the RAS/RAF pathway (16.7%), JAK/STAT signaling (2.6%), and the kinase KIT (0.6%). While these findings support the use of MMP75 for detection of relevant mutations, the genetic variants identified are not unique to multiple myeloma. Mutations detected in DNMT3A, TET2, and ASXL1 are common in clonal hematopoiesis of indeterminant potential (CHIP) and myeloid neoplasms. Hotspot mutations in TP53 and activating events in the RAS/RAF pathway also occur in various hematologic malignancies. This test therefore detects events that occur in both the plasma cell compartment and other cells of origin. This encumbers distinguishing variants that inform on a patient’s multiple myeloma from events that suggest a secondary neoplasm. Future directions include determining whether the effect of plasma cell enrichment on a mutations variant allele frequency (VAF) in repeat testing can help distinguish true multiple myeloma variants from events in other cells.