Cytogenetic and molecular aberrations at diagnosis and in prognosis of multiple myeloma

Abstract

Multiple myeloma accounts for ∼10 % of all hematologic malignancies. It is genetically a highly heterogeneous disease. Cytogenetic aberrations can be found in only one-third of myeloma cases by karyotyping, in contrast to >90 % by interphase fluorescence in situ hybridization analysis, especially when performed on CD138-enriched plasma cells. Next generation sequencing has shown that mutations affecting the MAP kinase pathway, including KRAS, NRAS and BRAF are the most frequent driver mutations in myeloma detected in up to 40 % of cases. Biallelic TP53 inactivation is one of the most important high-risk factor that is associated with poor survival, frequency of which increases in relapsed/refractory myeloma and is rare in MGUS and SMM. De novo plasma cell leukemia is associated with frequent MYC translocations and t(11;14) while plasma cell leukemia associated with a pre-existing myeloma (so-called secondary plasma cell leukemia) more commonly harbors del(17p). Early or primary cytogenetic alterations (such as trisomies and/or one of the IGH translocation) lead to formation of a founder clone which over time expands, and evolves by acquiring additional genetic abnormalities such as copy number and epigenetic changes and secondary mutations contributing to intratumoral heterogeneity seen in myeloma. Thus, presence of clonal heterogeneity at baseline, subsequent linear and branching clonal evolution that occurs with disease progression and therapeutic selection of resistant mutant clones underscores the need for a comprehensive cytogenetic and molecular testing over time. This testing allows for a better understanding of disease pathogenesis and can inform therapeutic options for better patient care and outcomes.