ABSTRACT
To comprehensively unravel the temporal relationship between initiating and driver events and its impact on clinical outcomes, we analyzed 421 whole-genome sequencing profiles from 382 patients. Using clock-like mutational signatures, we estimated a time lag of 2-4 decades between initiating events and diagnosis. In patients with hyperdiploidy, we demonstrate that trisomies of odd-numbered chromosomes can be acquired simultaneously with other chromosomal gains, such as 1q gain. We provide evidence that hyperdiploidy is acquired after canonical IGH translocation when both events are present. Finally, patients with early 1q gain had adverse outcomes similar to those with 1q amplification (>1 extra-copies), but faring worse than those with late 1q gain. This underscores that the prognostic impact of 1q gain/amp depends more on the timing of acquisition than on the number of extra copies gained. Overall, this study contributes to a better understanding of the life history of MM and may have prognostic implications.
Competing Interest Statement
OL has received research funding from: National Institutes of Health (NIH), National Cancer Institute (NCI), U.S. Food and Drug Administration (FDA), Multiple Myeloma Research Foundation (MMRF), International Myeloma Foundation (IMF), Leukemia and Lymphoma Society (LLS), Myeloma Solutions Fund (MSF), Paula and Rodger Riney Multiple Myeloma Research Program Fund, the Tow Foundation, Perelman Family Foundation, Rising Tide Foundation, Amgen, Celgene, Janssen, Takeda, Glenmark, Seattle Genetics, Karyopharm; Honoraria/ad boards: Adaptive, Amgen, Binding Site, BMS, Celgene, Cellectis, Glenmark, Janssen, Juno, Pfizer; and serves on Independent Data Monitoring Committees (IDMCs) for clinical trials lead by Takeda, Merck, Janssen, Theradex. GJM has received funding from National Institutes of Health (NIH), National Cancer Institute (NCI), Multiple Myeloma Research Foundation (MMRF), Leukemia and Lymphoma Society (LLS), Perelman Family Foundation, Amgen, Celgene, Janssen, Takeda; Honoraria/ad boards: Adaptive, Amgen, BMS, Celgene, Janssen; and serves on Independent Data Monitoring Committees (IDMCs) for clinical trials lead by Takeda, Karyopharm and Sanofi. EKM reports consulting or advisory role, honoraria, research funding, travel accommodation, and expenses from Bristol Myers Squibb (Celgene), GlaxoSmithKline, Janssen-Cilag, Sanofi, Stemline, and Takeda. KCW reports research grant from Abbvie, Amgen, BMS/ Celgene, Janssen, GSK Sanofi. Honoraria and Consulting fees from Abbvie, Amgen, Adaptive Biotech, Astra Zeneca, BMS/Celgene, BeiGene, Janssen, GSK, Karyopharm, Novartis, Oncopeptides, Pfizer, Roche Pharma, Sanofi, Stemline, Takeda. RF reports consulting or advisory role, honoraria, travel accommodation, and expenses from Amgen, Bristol Myers Squibb (Celgene), GlaxoSmithKline, Janssen-Cilag, Sanofi, Stemline and Takeda. KHS has served on an advisory board for AbbVie, Amgen, Bristol Myers Squibb (BMS), GlaxoSmithKline (GSK), and Janssen; received Honoraria for Adaptive Biotechnologies Corporation, Amgen, BMS, GSK, Janssen, and Sanofi Genzyme; received research funding from AbbVie and Karyopharm Therapeutics. H.G. Grants and/or provision of Investigational Medicinal Product: Amgen, Array Biopharma/Pfizer, BMS/Celgene, Chugai, Dietmar-Hopp-Foundation, Janssen, Johns Hopkins University, Mundipharma GmbH, Sanofi. Research Support/ Forschung und Studien: Amgen, BMS, Celgene, GlycoMimetics Inc., GSK, Heidelberg Pharma, Hoffmann-La Roche, Karyopharm, Janssen, Incyte Corporation, Millenium Pharmaceuticals Inc., Molecular Partners, Merck Sharp and Dohme (MSD), MorphoSys AG, Pfizer, Sanofi, Takeda, Novartis. Advisory Boards: Amgen, BMS, Janssen, Sanofi, Adaptive Biotechnology. Honoraria / Nebentatigkeiten: Amgen, BMS, Chugai, GlaxoSmithKline (GSK), Janssen, Novartis, Sanofi, Pfizer. Support for attending meetings and/or travel / Reisekosten: Amgen, BMS, GlaxoSmithKline (GSK), Janssen, Novartis, Sanofi, Pfizer. KHM has received funding from the Multiple Myeloma Research Foundation, The American Society of Hematology and the International Myeloma Society. F.M.: consulting for Medidata and Sanofi. All other authors have no conflicts of interest to declare
