Clonal Heterogeneity and Genetic Instability of Multiple Myeloma and Impact on Treatment

Multiple myeloma is a pathological definition for a series of distinct genetic entities with similar phenotypic and clinical characteristics. Multiple studies have now identified distinct subtypes of the disease, which are associated with different clinical outcomes. The genetic complexity underlying these different subtypes is very diverse. Some subtypes like those characterized by immunoglobulin translocations targeting cyclin D1 are associated with very minimal changes or no copy number changes. Conversely, subtypes defined by translocations targeting WHSC1/MMSET or the MAF and MAFB transcription factors often have highly complex and diverse copy number changes. With the substantial advances in DNA sequencing technology we now know there is a diverse array of somatic mutations in multiple myeloma tumors. Through the integration of copy number changes and somatic mutations multiple groups have now shown the existence of multiple co-existing subclones within individual tumors. Additional studies following patients through their individual disease courses have shown these subclones can ebb and flow with time through multiple rounds of therapeutic selection. This session will highlight our current understanding of how the interplay between tumor evolution and clonal heterogeneity should influence our treatment decisions, particularly when applying a personalized medicine approach.