Subclonal evolution in disease progression from MGUS/SMM to multiple myeloma is characterised by clonal stability

• Published in: Leukemia Vol. 33; no. 2; pp. 457 - 468
• Main Authors: Dutta, Ankit K., Fink, J. Lynn, Grady, John P., Morgan, Gareth J., Mullighan, Charles G., To, Luen B., Hewett, Duncan R., Zannettino, Andrew C. W.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.02.2019; Nature Publishing Group
• Subjects: 13; 13/31; 45; 45/22; 45/23; 631/208/69; 631/67/1990/804; 631/67/69; 692/308/2056; Benign monoclonal gammopathy; Biomarkers, Tumor - genetics; Bone marrow; Cancer Research; Care and treatment; Cell proliferation; Cells, Cultured; Clonal Evolution; Cohort Studies; Critical Care Medicine; Development and progression; Disease Progression; Evolution; Follow-Up Studies; Genetic aspects; Genotypes; Health aspects; Hematology; Heterogeneity; Humans; Intensive; Internal Medicine; Longitudinal Studies; Malignancy; Medicine; Medicine & Public Health; Monoclonal Gammopathy of Undetermined Significance - genetics; Monoclonal Gammopathy of Undetermined Significance - pathology; Multiple myeloma; Multiple Myeloma - genetics; Multiple Myeloma - pathology; Oncology; Plasma cells; Prognosis; Smoldering; Stability; Whole Exome Sequencing
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/s41375-018-0206-x

Multiple myeloma (MM) is a largely incurable haematological malignancy defined by the clonal proliferation of malignant plasma cells (PCs) within the bone marrow. Clonal heterogeneity has recently been established as a feature in MM, however, the subclonal evolution associated with disease progression has not been described. Here, we performed whole-exome sequencing of serial samples from 10 patients, providing new insights into the progression from monoclonal gammopathy of undetermined significance (MGUS) and smouldering MM (SMM), to symptomatic MM. We confirm that intraclonal genetic heterogeneity is a common feature at diagnosis and that the driving events involved in disease progression are more subtle than previously reported. We reveal that MM evolution is mainly characterised by the phenomenon of clonal stability, where the transformed subclonal PC populations identified at MM are already present in the asymptomatic MGUS/SMM stages. Our findings highlight the possibility that PC extrinsic factors may play a role in subclonal evolution and MGUS/SMM to MM progression.