Abstract
Multiple myeloma (MM) is a malignant neoplasm of terminally differentiated immunoglobulin-producing B lymphocytes called plasma cells. MM is the second most common hematologic malignancy, and it poses a heavy economic and social burden because it remains incurable and confers a profound disability to patients. Despite current progress in MM treatment, the disease invariably recurs, even after the transplantation of autologous hematopoietic stem cells (ASCT). Biological processes leading to a pathological myeloma clone and the mechanisms of further evolution of the disease are far from complete understanding. Genetically, MM is a complex disease that demonstrates a high level of heterogeneity. Myeloma genomes carry numerous genetic changes, including structural genome variations and chromosomal gains and losses, and these changes occur in combinations with point mutations affecting various cellular pathways, including genome maintenance. MM genome instability in its extreme is manifested in mutation kataegis and complex genomic rearrangements: chromothripsis, templated insertions, and chromoplexy. Chemotherapeutic agents used to treat MM add another level of complexity because many of them exacerbate genome instability. Genome abnormalities are driver events and deciphering their mechanisms will help understand the causes of MM and play a pivotal role in developing new therapies.
Highlights
The classic clonal evolution implies the sequential acquisition of mutations with a concomitant sequential selection of successive subclones, their expansion, and mutual interference [35,36]
No mutations in the DNA repair genes such as TP53, ATM, and ATR were identified in stable MGUS patients, and biallelic inactivation of TP53, RB1, DIS3, MAX, and CDKN2A were rare events for low-risk SMM, suggesting that these abnormalities are associated with tumor progression [48,51,52,62]
Recent studies suggest that MM at relapse has a more complex genetic landscape compared to primary tumors and highlights the biological role of TP53 inactivation and certain structural genome rearrangements (e.g., 1q gain, del(17p), and MYC translocations, see Section 5.1) rather than mutations in genes associated with resistance to PIs or IMiDs in acquired resistance to therapy [25,54,60]
Summary
MM patient management strategy differs significantly depending on age, comorbidities, cytogenetic parameters, disease stage, risk stratification, and other factors [87,88,89,90,91] (Figure 2). The therapeutic arsenal for MM treatment includes DNA damaging agents (melphalan, cyclophosphamide, etc.), immunomodulatory agents (IMiDs, e.g., thalidomide, lenalidomide, pomalidomide), proteasome inhibitors (PIs, e.g., bortezomib, carfilzomib, ixazomib), monoclonal antibodies (daratumumab, isatuximab, elotuzumab), and corticosteroids [1,87,91]. It is thought that fluctuations in the intracellular level of NAD+ might contribute to genome stability and response to DNA damage, and NAD+-depleting agents might potentiate the benefits of anti-CD38 agents [271,274,277] Another monoclonal antibody used to treat MM, elotuzumab, targets the signaling lymphocytic activation molecule F7 (SLAMF7), which is highly expressed in plasma cells [1,278,279,280,281]. It should be noted that corticosteroids are included in most schemes for MM treatment and may exert a certain effect on genome stability and mutagenesis, especially when used in combination with other drugs influencing DNA metabolism
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