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Neutral tumor evolution in myeloma is associated with poor prognosis

David C. Johnson, Oleg Lenive, Jonathan Mitchell, Graham Jackson, Roger Owen, Mark Drayson, Gordon Cook, John R. Jones, Charlotte Pawlyn, Faith E. Davies, Brian A. Walker, Christopher Wardell, Walter M. Gregory, David Cairns, Gareth J. Morgan, Richard S. Houlston and Martin F. Kaiser

Key Points

  • A significant proportion of MM is dominated by neutral evolutionary dynamics.

  • Neutral MM tumors are characterized by shorter survival, consistent with reduced sensitivity to drugs targeting the MM microenvironment.

Abstract

Recent studies suggest that the evolutionary history of a cancer is important in forecasting clinical outlook. To gain insight into the clonal dynamics of multiple myeloma (MM) and its possible influence on patient outcomes, we analyzed whole exome sequencing tumor data for 333 patients from Myeloma XI, a UK phase 3 trial and 434 patients from the CoMMpass study, all of which had received immunomodulatory drug (IMiD) therapy. By analyzing mutant allele frequency distributions in tumors, we found that 17% to 20% of MM is under neutral evolutionary dynamics. These tumors are associated with poorer patient survival in nonintensively treated patients, which is consistent with the reduced therapeutic efficacy of microenvironment-modulating IMiDs. Our findings provide evidence that knowledge of the evolutionary history of MM has relevance for predicting patient outcomes and personalizing therapy.

  • Submitted November 9, 2016.
  • Accepted August 7, 2017.
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