Genetic and molecular mechanisms in multiple myeloma: a route to better understand disease pathogenesis and heterogeneity

Marie-Christine Kyrtsonis^1,2, Vassiliki Bartzis^1,2, Xenophon Papanikolaou¹, Efstathios Koulieris^1,2, George Georgiou², Maria Dimou², Tatiana Tzenou^1,2, Panayiotis Panayiotidis^2
1First Department of Propedeutic Internal Medicine, ²Department of Hematology, National and Kapodistrian University of Athens, Laikon Hospital, Greece

Abstract: Multiple myeloma (MM) is a heterogeneous plasma cell neoplasm presenting with a wide range of clinical manifestations. In spite of the availability of very performing treatment modalities, survival is highly varying, ranging from a few months to several years. Underlying genetic and microenvironmental mechanisms are thought to be responsible for clinical heterogeneity. Disease etiology is unknown but progresses in the understanding of its pathogenesis have shown that MM precursor cell transformation into a malignant one occurs in a multistep process. Possibly during class switch recombination a primary genetic event takes place. With the occurrence of additional events and the support of bone marrow microenvironmental cells, neoplastic plasma cells actively proliferate and disease behavior may change. Recurrent translocations involving the IgH locus (11q13, 4p16, 16q23, 21q12, and 6p21), deletions of chromosome 13, trisomies of chromosomes 3, 5, 9, 11, 15, 19, and 21, and dysregulated expression of cyclin D genes, are considered initiating or primary events. Alterations related to further disease transformation and adverse prognosis are deletion of 17p13, c-myc translocations, and gains of chromosome 1q21. In relation to the underlying genetic defects, disease subgroups are recognized. Accordingly treatment effectiveness may differ among groups. Intense research is ongoing in this field.

Keywords: myeloma, pathogenesis, genetic abnormalities, heterogeneity, prognosis