P26 landscape of recurrent cytogenetic abnormalities in patients with newly diagnosed multiple myeloma as detected by chromosome microarray analysis (cma)

Background: Multiple myeloma (MM) is a plasma cell neoplasm clinically ranging from indolent to aggressive, and characterized by heterogeneous genetic makeup. Cytogenetic abnormalities play important role in myeloma tumorigenicity, and some recurrent abnormalities are known to have prognostic significance. Low proliferative rate of plasma cells limits the yield of conventional cytogenetics. Fluorescent in situ hybridization (FISH) performed on CD138 enriched sample is current standard for detection of clinically significant cytogenetic abnormalities, however it is limited by use of specific set of probes. Chromosome microarray analysis (CMA) allows detection of copy number changes and copy neutral loss of heterozygosity (cnLOH) across the entire genome with high resolution. Importantly, CMA does not detect balanced translocations, and therefore can supplement, but not replace FISH in MM. We previously reported landscape of CMA detected abnormalities and MRD detection by CMA in post-induction/ pre-transplant bone marrow samples. Here, we characterize cytogenetic abnormalities in patients with untreated symptomatic and smoldering MM using CMA. Methods: We analyzed 78 samples of patients with newly diagnosed, untreated active MM and 22 samples of patients with smoldering MM (sMM), who presented to our program in 2015-2021. CMA was performed on CD138-enriched material using ThermoFisher CytoScan HD microarrays for copy number and heterozygosity alterations. Results: 70 of 78 (89.7%)patients with active MM and 17 of 22 (77.3%) patients with sMM had CMA detected abnormalities. Abnormal findings detected by CMA included copy number changes (additions/ deletions), cnLOH and chromothripsis (CT). Total of 667 abnormalities were detected in 78 active MM samples (including 33 occurrences of cnLOH and 44 CT) and 72 abnormalities in 22 sMM samples (including 3 cnLOH). 53 types of recurrent abnormalities with frequency above 5% of samples were detected in active MM samples and 15 types in sMM samples (Figure 1, panel A: active MM, panel B: sMM). In the samples with active MM, in addition to the commonly tested MM abnormalities (trisomies of odd chromosomes, 1q+, 1p-, 13q-/13-, 17p-), we identified a number of less known recurrent abnormalities, among which 6q-, 6+, 8p-, 11q+, 12p-, 14q-, 16q-, 19p+, Xq+, X- were observed in above 10% samples. Conclusions: Our results demonstrate that CMA is a sensitive technique allowing to identify recurrent cytogenetic abnormalities (excluding balanced translocations) in multiple myeloma that cannot be detected by conventional karyotyping or standard FISH panels. In addition to copy number changes, we also detected multiple occurrences of cnLOH, that may promote tumorigenicity by gene inactivation, and chromothripsis, involving complex genomic abnormalities. Further investigation is required to determine clinical correlation and prognostic significance of those abnormalities. Lastly, our results demonstrate increased cytogenetic complexity of active MM compared to smoldering MM.