Whole-genome sequencing reveals progressive versus stable myeloma precursor conditions as two distinct entities

Abstract

Multiple myeloma (MM) is consistently preceded by precursor conditions recognized clinically as monoclonal gammopathy of undetermined significance (MGUS) or smoldering myeloma (SMM). We interrogate the whole genome sequence (WGS) profile of 18 MGUS and compare them with those from 14 SMMs and 80 MMs. We show that cases with a non-progressing, clinically stable myeloma precursor condition (n=15) are characterized by later initiation in the patient's life and by the absence of myeloma defining genomic events including: chromothripsis, templated insertions, mutations in driver genes, aneuploidy, and canonical APOBEC mutational activity. This data provides evidence that WGS can be used to recognize two biologically and clinically distinct myeloma precursor entities that are either progressive or stable. The factors that are associated with myeloma precursor condition progression are not well understood. Here the authors find that monoclonal gammopathies of undetermined significance and smoldering myelomas that did not progress to multiple myelomas have a distinct genomic profile and emerge later in the patient's life. ; We want to thank Dr. Vincent S Rajkumar for important and useful scientific feedback on the final draft. This work was supported by the Society of Memorial Sloan Kettering, by the Sylvester Comprehensive Cancer Center NCI Core Grant (P30 CA 240139), by the Memorial Sloan Kettering Cancer Center NCI Core Grant (P30 CA 008748), by the Multiple Myeloma Research Foundation (MMRF), by the Perelman Family Foundation, and by the Riney Family Multiple Myeloma Research Program Fund. F.M. is supported by the American Society of Hematology, the International Myeloma Foundation and The Society of Memorial Sloan Kettering Cancer Center. N.B. is funded by the European Research Council under the European Union's Horizon 2020 research and innovation program (grant agreement no. 817997). K.H.M. is supported by the Royal Australasian College of Physicians Dr. Helen Rarity McCreanor Traveling Fellowship. This study is part of the Limburg Clinical Research Center (LCRC) UHasselt-ZOL-Jessa, supported by the foundation Limburg Sterk Merk (LSM), Hasselt University, Ziekenhuis Oost-Limburg and Jessa Hospital. Additionally, this research is supported by Limburgs Kankerfonds, and LiveALife. ; Maura, F (corresponding author), Mem Sloan Kettering Canc Ctr, Dept Med, Myeloma Serv, 1275 York Ave, New York, NY 10021 USA. Landgren, O; Maura, F (corresponding author), Univ Miami, Sylvester Comprehens Canc Ctr, Myeloma Program, Miami, FL 33124 USA. col15@miami.edu; fxm557@med.miami.edu