The molecular make up of smoldering myeloma highlights the evolutionary pathways leading to multiple myeloma

Eileen M. Boyle, Shayu Deshpande, Ruslana Tytarenko, Cody Ashby, Yan Wang, Michael A. Bauer, Sarah K. Johnson, Christopher P. Wardell, Sharmilan Thanendrarajan, Maurizio Zangari, Thierry Facon, Charles Dumontet, Bart Barlogie, Arnaldo Arbini, Even H. Rustad, Francesco Maura, Ola Landgren, Fenghuang Zhan, Frits Rhee, Carolina Schinke, Faith E. Davies, Gareth J. Morgan () and Brian A. Walker ()
Additional contact information
Eileen M. Boyle: Myeloma Center, University of Arkansas for Medical Sciences
Shayu Deshpande: Myeloma Center, University of Arkansas for Medical Sciences
Ruslana Tytarenko: Myeloma Center, University of Arkansas for Medical Sciences
Cody Ashby: Myeloma Center, University of Arkansas for Medical Sciences
Yan Wang: Myeloma Center, University of Arkansas for Medical Sciences
Michael A. Bauer: Myeloma Center, University of Arkansas for Medical Sciences
Sarah K. Johnson: Myeloma Center, University of Arkansas for Medical Sciences
Christopher P. Wardell: Myeloma Center, University of Arkansas for Medical Sciences
Sharmilan Thanendrarajan: Myeloma Center, University of Arkansas for Medical Sciences
Maurizio Zangari: Myeloma Center, University of Arkansas for Medical Sciences
Thierry Facon: Lille University Hospital
Charles Dumontet: INSERM 1052/CNRS 5286 Cancer Research Center of Lyon
Bart Barlogie: The Mount Sinai Hospital
Arnaldo Arbini: Perlmutter Cancer Center, NYU Langone Health
Even H. Rustad: Perlmutter Cancer Center, NYU Langone Health
Francesco Maura: Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center
Ola Landgren: Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center
Fenghuang Zhan: Myeloma Center, University of Arkansas for Medical Sciences
Frits Rhee: Myeloma Center, University of Arkansas for Medical Sciences
Carolina Schinke: Myeloma Center, University of Arkansas for Medical Sciences
Faith E. Davies: Perlmutter Cancer Center, NYU Langone Health
Gareth J. Morgan: Perlmutter Cancer Center, NYU Langone Health
Brian A. Walker: Indiana University

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: Abstract Smoldering myeloma (SMM) is associated with a high-risk of progression to myeloma (MM). We report the results of a study of 82 patients with both targeted sequencing that included a capture of the immunoglobulin and MYC regions. By comparing these results to newly diagnosed myeloma (MM) we show fewer NRAS and FAM46C mutations together with fewer adverse translocations, del(1p), del(14q), del(16q), and del(17p) in SMM consistent with their role as drivers of the transition to MM. KRAS mutations are associated with a shorter time to progression (HR 3.5 (1.5–8.1), p = 0.001). In an analysis of change in clonal structure over time we studied 53 samples from nine patients at multiple time points. Branching evolutionary patterns, novel mutations, biallelic hits in crucial tumour suppressor genes, and segmental copy number changes are key mechanisms underlying the transition to MM, which can precede progression and be used to guide early intervention strategies.

Date: 2021
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DOI: 10.1038/s41467-020-20524-2

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