Moving From Cancer Burden to Cancer Genomics for Smoldering Myeloma

Abstract

IMPORTANCEAll patients who develop multiple myeloma have a preceding asymptomatic expansion of clonal plasma cells, clinically recognized as monoclonal gammopathy of undetermined significance or smoldering multiple myeloma (SMM). During the past decade, significant progress has been made in the classification and risk stratification of SMM.OBSERVATIONS This review summarizes current clinical challenges and discusses available models for risk stratification in the context of SMM. Owing to several novel, more effective, and less toxic drugs, these aspects are becoming increasingly important to identify patients eligible for early treatment. However, all proposed criteria were built around indirect markers of disease burden and therefore are generally able to identify a fraction of patients with SMM in whom transformation to multiple myeloma and genomic subclonal diversification are already happening. In contrast, next-generation sequencing approaches have the potential to identify myeloma precursor disease that will progress even before the major clonal expansion and progression, providing a potential base for more effective treatment and better precision regarding the optimal timing of treatment initiation. CONCLUSIONS AND RELEVANCEOwing to modern technologies, in the near future, prognostic models derived from genomic signatures independent of the disease burden will allow better identification of the optimal timing to treat a plasma cell clonal disorder at the very early stages, when the chances of eradication are higher.

Revealing the impact of recurrent and rare structural variants in multiple myeloma

“…A common feature of these 3 classes of SVs is the simultaneously deregulation of multiple driver genes as part of a single event. Such multi-driver events are of particular importance in myeloma progression as they can provide an explanation for the rapid changes in clinical behavior that are frequently seen in the clinic 57 . Such changes may be the result of “punctuated evolution” that occurs as a result of catastrophic intracellular events leading to the complex SVs we describe.…”

Accelerated single cell seeding in relapsed multiple myeloma

“…In line with its activity early in disease development, SBS9 (AID) was detected mostly in the trunk of the phylogenetic trees, while APOBEC activity was detected in both clonal and subclonal clusters. 4,8,19,20 SBS35 was only detected in the branches of the two post-platinum relapsed patients from WGS. SBS-MM1 showed a heterogenous landscape.…”

“…The pathogenesis of multiple myeloma is characterized by a long and complex evolutionary process through two clinically defined precursor stages: monoclonal gammopathy of uncertain significance and smoldering multiple myeloma. [1][2][3][4] The progression of precursor disease to invasive multiple myeloma is characterized by branching evolutionary patterns, clonal sweeps together with local evolution and expansion of cancer cells in varying anatomical sites. 5,6 Divergence and progression at distinct sites of disease -spatial evolution -magnifies the genomic heterogeneity of multiple myeloma, where a range of clones compete for dominance and are positively selected according to their genetic driver landscape reflected in their ability to best adapt to the local environment.…”

Revealing the Impact of Structural Variants in Multiple Myeloma

“…The vast majority of established genomic drivers in multiple myeloma are single nucleotide variants (SNVs) and copy number alterations (CNAs), identified by whole exome sequencing and arraybased approaches (18)(19)(20)(21)(22). However, important aspects of tumor biology and evolution remain poorly explained by known genomic drivers, such as progression from precursor stages to active multiple myeloma and the development of drug resistance (12,(23)(24)(25).…”