S120 CHRONOLOGY OF COPY NUMBER ALTERATIONS FROM PRECURSORS TO MULTIPLE MYELOMA: WHAT COMES FIRST?

Background: Multiple Myeloma (MM) is characterized by genomic heterogeneity with copy number alterations (CNA) as one of the most prominent genomic perturbation. CNAs are characterized by the trisomy of certain odd number chromosomes in a proportion of patients (HMM); while the other nonhyperdiploid MM (NHMM) patients typically display chromosomal rearrangements especially involving the IgH locus and deletion in chr 13 in some cases. Aims: Although aneuploidy is a hallmark of MM, no previous study has considered the sequence of occurrence of these complex genomic events during disease evolution from MGUS to newly diagnosed MM. Here, we use the largest available genomic dataset that covers the three progression stages in MM, to characterize when and in what sequence each CNAs occur in MM. Methods: Here, we have acquired one of the largest genomic datasets from 647 patients that combines data from MGUS to SMM to newly diagnosed MM (336 newly diagnosed MM, 147 SMM and 164 MGUS) to characterize when and in what sequence CNA occurs in MM development. We deduce the order of CNA events by identifying their pattern of clonality basically inferring that clonal genomic change suggest its origin at an earlier stage of the disease. We proposed a model and validated the proposed model using Whole Genome Sequencing data from 200 samples including MGUS to MM and SMM to MM pairs and newly diagnosed MM. Results: In HMM, the gain of chr 15 was the most frequent clonal event (86%), followed by chr 9 and 19 in 78% and 73% of the patients. 86% of HMM patients had concurrent clonal gains of at least 2 out of 3 most frequent chromosomes (9,15 and 19). Moreover, less frequent events such as chromosome 21 gain, 18p gain, and 1q gain showed higher frequency of clonal occurrence compared to other events indicating that when these events occur, they are early events. The majority of deletions occur as late subclonal events with few or none observed as clonal events. In the NHMM group, three events, del13, gain of 1q and gain of 11, had the highest frequency of clonal occurrence. Gain of 11, although detected only in 15% of NHMM patient, was clonal in 92% of cases; del13, observed in 60% of NHMM patients, was clonal in 95% of them. To confirm these observations in MM, we analyzed CNAs in purified plasma cells from SMM and MGUS patients. The clonal CNAs observed in MM are also observed at a similar frequency in SMM and MGUS. Interestingly, the majority of subclonal deletions observed in both HMM and NHMM patients at diagnosis were not observed in SMM and MGUS, suggesting late occurrence of these events. We have reconstructed a model representing the timeline of CNAs in MM development using combined clonality estimates with co‐occurrence analysis from all stages of plasma cell disorders. The reconstruction suggests 5 major copy number paths for HMM and NHMM. Summary/Conclusion: A major finding from our study is that the observed clonal CNAs in HMM are also clonal at the MGUS stage, suggesting that these events are early and may underlie initial transformation of normal plasma cells to MGUS cells. These changes may not be sufficient to provide the required proliferative capacity for MM; however, they do lead to clonal expansion of the plasma cells. In 15% of the patients in whom the complex deletion events observed in MM but not at MGUS stage may account for the changes responsible for progression to MM, but in the majority of the patients, CNAs may not be adequate for progression to MM. From this analysis, we can postulate that further mutational and/or epigenomic changes may drive progression in these patients.