Abstract
Plasma cell dyscrasias are a heterogeneous group of diseases characterized by the expansion of bone marrow plasma cells. Malignant transformation of plasma cells depends on the continuity of events resulting in a sequence of well-defined disease stages, from monoclonal gammopathy of undetermined significance (MGUS) through smoldering myeloma (SMM) to symptomatic multiple myeloma (MM). Evolution of a pre-malignant cell into a malignant cell, as well as further tumor progression, dissemination, and relapse, require development of multiple driver lesions conferring selective advantage of the dominant clone and allowing subsequent evolution under selective pressure of microenvironment and treatment. This process of natural selection facilitates tumor plasticity leading to the formation of genetically complex and heterogenous tumors that are notoriously difficult to treat. Better understanding of the mechanisms underlying tumor evolution in MM and identification of lesions driving the evolution from the premalignant clone is therefore a key to development of effective treatment and long-term disease control. Here, we review recent advances in clonal evolution patterns and genomic landscape dynamics of MM, focusing on their clinical implications.
Highlights
Next-generation DNA sequencing (NGS) techniques have provided a broad insight into the genomics of cancer, contributing to our current view of malignancies as continuous evolutionary processes
smoldering myeloma (SMM) was found to be a genetically mature entity; in all cases of no progression from SMM to MM, clonal evolution with subclonal cancer fractions changing over time was detected
Johnson et al (Table 1) [64] showed that in nearly every fifth patient exposed to IMiDs, the clonal dynamics followed the model of neutral evolution, which means that in these cases the selection pressure did not play a significant role in shaping the subclonal architecture of the tumor
Summary
Next-generation DNA sequencing (NGS) techniques have provided a broad insight into the genomics of cancer, contributing to our current view of malignancies as continuous evolutionary processes. Highly active agents, such as proteasome inhibitors (PIs) [2,3,4], immunomodulatory drugs (IMiDs) [5,6,7], monoclonal antibodies [8,9,10], together with the high-dose melphalan conditioning regimen followed by autologous stem cell transplantation (autoHSCT) [11] have undeniably improved the MM patients prognosis, the emergence of drug resistance still remains a major treatment complication Often, it leads to adverse outcomes, and most patients die of relapsed disease. We briefly present the current state of knowledge about the clonal evolution of MM and discuss its clinical and diagnostic implications
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