Multiple Myeloma (MM) is a largely incurable haematological malignancy defined by the clonal proliferation of malignant plasma cells 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. We used whole exome sequencing to analyse 10 paired patient samples, providing new insights into the progression from Monoclonal Gammopathy of Undetermined Significance (MGUS) and Smouldering MM (SMM), to symptomatic MM. We confirm that clonal heterogeneity is a common feature at diagnosis and that the driving events involved in disease progression are more complex than previously reported. While we observe some previously identified known “drivers” of MM, we find that the driving events involved in progression are complex and not limited to the known SNVs or CNVs. The RAS/MAPK pathway was found to be the most frequently deregulated pathway, with recurrent mutations in KRAS and NRAS observed in patients at both MGUS/SMM and MM stages. We reveal that MM evolution ... (Show More)

Multiple Myeloma (MM) is a largely incurable haematological malignancy defined by the clonal proliferation of malignant plasma cells 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. We used whole exome sequencing to analyse 10 paired patient samples, providing new insights into the progression from Monoclonal Gammopathy of Undetermined Significance (MGUS) and Smouldering MM (SMM), to symptomatic MM. We confirm that clonal heterogeneity is a common feature at diagnosis and that the driving events involved in disease progression are more complex than previously reported. While we observe some previously identified known “drivers” of MM, we find that the driving events involved in progression are complex and not limited to the known SNVs or CNVs. The RAS/MAPK pathway was found to be the most frequently deregulated pathway, with recurrent mutations in KRAS and NRAS observed in patients at both MGUS/SMM and MM stages. We reveal that MM evolution is mainly characterised by the phenomenon of clonal stability, where the subclonal plasma cell populations identified at MM progression are already present in the asymptomatic MGUS/SMM stages. These subclonal populations could be amenable to therapeutic intervention to arrest transformation to MM.

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