Genetic Abnormalities in Multiple Myeloma: Prognostic and Therapeutic Implications

Abstract

Some genetic abnormalities of multiple myeloma (MM) detected more than two decades ago remain major prognostic factors. In recent years, the introduction of cutting-edge genomic methodologies has enabled the extensive deciphering of genomic events in MM. Although none of the alterations newly discovered have significantly improved the stratification of the outcome of patients with MM, some of them, point mutations in particular, are promising targets for the development of personalized medicine. This review summarizes the main genetic abnormalities described in MM together with their prognostic impact, and the therapeutic approaches potentially aimed at abrogating the undesirable pathogenic effect of each alteration.

Keywords: chromosomal translocations; copy number changes; multiple myeloma; point mutations; prognosis; targeted therapy.

Figure 1

Multistep molecular pathogenesis of multiple myeloma (MM) Primary and secondary genetic events involved in the MM transformation and progression from the precursor disease entities, such as monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) to MM, and eventually to extramedullary myeloma/plasma cell leukemia (PCL). Adapted from Chesi M et al. and Manier S et al. [4,5].

Figure 2

Overview of the main signaling pathways dysregulated in multiple myeloma. Genetic alterations affect essential pathways and biological processes such as NF-κB and MAPK pathways, plasma-cell differentiation, RNA processing, cell cycle, apoptosis, and DNA-damage repair mechanisms. Some druggable targets are indicated.