Development of hyperdiploidy starts at an early age and takes a decade to complete

• First hyperdiploidy event occured within the first three decades of life and took a decade to complete

• A MM cell accumulated on median 0.56 mutations per mb pre-HMM and for every clonal pre-HMM mutation, 1.21 mutations accumulated post-HMM

Nearly half of multiple myeloma (MM) patients have hyperdiploidy (HMM) at diagnosis. Although HMM occurs early, the mutational processes before and after hyperdiploidy are still unclear. Here, we used 72 WGS samples from patients with HMM and identified pre and post HMM mutation to define the chronology of development of hyperdipoidy. A MM cell accumulated on median 0.56 mutations per mb pre-HMM and for every clonal pre-HMM mutation, 1.21 mutations accumulated post-HMM. This analysis using mutations before and after hyperdiploidy show that hyperdiploidy happens after somatic hypermutation, pre-hyperdipoidy muations are AID and age/Clock-like signature driven whereas post-hyperdiploidy mutations are from DNA damage and APOBEC. Interestingly, the first hyperdiploidy event occured within the first 3 decades of life and took a decade to complete. Copy number changes affecting chromosomes 15 and 19 occurred first. Finally, mutations pre initiating event affected chromosomes at different rates while post-initiating event mutational processes affect each chromosomes equally.