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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 multiple myeloma (MM) is dominated by neutral evolutionary dynamics.

  • Neutral MM tumors are characterised by shorter patient survival, consistent with reduced sensitivity to drugs targeting the MM micro-environment.

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 outcome we analysed whole exome sequencing tumor data for 333 patients from Myeloma XI, a UK phase III trial and 434 patients from the CoMMpass study, all of which had received immunomodulatory therapy (IMiD). By analysing mutant allele frequency distributions in tumors we found that 17-20% of MM is under neutral evolutionary dynamics. These tumors are associated with poorer patient survival in non-intensively treated patients, consistent with reduced therapeutic efficacy of micro-environment modulating IMiD drugs. Our findings provide evidence that knowledge of the evolutionary history of MM has relevance for predicting patient outcome and personalising therapy.

  • Submitted November 10, 2016.
  • Accepted August 7, 2017.