Chromoanagenesis in Multiple Myeloma: A Comprehensive Overview

Chromoanagenesis, which includes chromothripsis, chromoplexy, and chromoanasynthesis, plays a significant role in cancer development, including multiple myeloma (MM). This process involves massive chromosomal rearrangements occurring during a single cellular event, leading to the shattering and random reassembly of chromosomes. In MM, a malignancy of plasma cells, chromothripsis has been associated with poor prognosis and aggressive disease progression, whereas chromoplexy has not shown the same correlation. The concept of chromoanasynthesis has not been explicitly introduced in MM and is most likely encompassed within the chromothripsis category. Recent studies suggest that chromothripsis may act as a driver event in MM and could predict disease evolution from an asymptomatic precursor state to symptomatic disease. In MM, as in other cancers, the technique for the detection of complex events is crucial to determine their true prevalence and to establish a differential diagnosis between chromothripsis, chromoplexy, and chromoanasynthesis, with whole genome sequencing being the gold standard for evaluating the standard Korbel and Campbell criteria. More affordable alternative techniques, such as optical genome mapping and long-read sequencing, have emerged. In this mini-review, we discuss, among other topics, the history of detection and analysis of complex genomic alterations in MM, highlighting the successive deviations that have led to a laxity in definitions since Korbel and Campbell, resulting in the loss of important information. It is essential to establish clear and consensus-based criteria for defining the various chromoanagenesis to enable more precise investigations in MM. Finally, understanding the role of chromothripsis, MM could offer new insights into the disease's pathogenesis and provide novel therapeutic targets. Approaches targeting the repair of chromothriptic damage or exploiting the vulnerability of cells with chromothripsis-induced genomic instability could potentially improve outcomes for patients with MM.