Session: 652. Multiple Myeloma: Clinical and Epidemiological: Poster I
Hematology Disease Topics & Pathways:
Research, adult, epidemiology, Clinical Research, Plasma Cell Disorders, genomics, Diseases, Lymphoid Malignancies, computational biology, Biological Processes, Technology and Procedures, Study Population, Human, omics technologies
We observed recurrent selection of subclones harbouring 17p loss of heterozygosity (LOH) or 1pLOH with disease progression and therapy resistance acquisition in tumour phylogenies. In addition, clonal timing analysis of the longitudinal dataset suggested that sequential acquisition of 1pLOH and 1qGain in the same clone was a common selected trajectory (22% of cases). To validate this finding, the same trajectory analysis was undertaken in a much larger IMiD-refractory rrMM WGS as a validation dataset (N=386, Myeloma Genome Project), albeit with single time-point samples and compared with a set of unrelated newly diagnosed WGS dataset (N=198, IFM 2009) [Ansari-Pour et al. 2023, PMID: 36223594]. Strikingly, 1pLOH was found to be the only event that showed evidence for clonal selection in this case-control analysis (timing rank fold-change = 3.7, P<2.2x10-16). Interestingly, the 1pLOH-1qGain trajectory (27% of cases; co-occurrence OR = 2.3 (95% CI 1.5-3.8), P=2x10-4) was also identified in the validation dataset, corroborating the potential driverness of the dual chromosome 1 copy number events in subclonal expansion during therapy resistance acquisition.
While this WGS-based analysis of selected evolutionary trajectories in relapsed/refractory myeloma patient tumours needs further confirmation with sequential WGS datasets from uniformly treated cohorts, these findings suggest potential collaborative genetic interaction between 1pLOH and 1qGain in the same cell as emerging co-drivers of resistance/disease progression, conferring a greater selective advantage under therapeutic exposure than either event on its own. If confirmed, these biomarkers may define a new ‘double hit’ in relapsed/refractory myeloma, with biological consequences that will require novel and directed therapeutic approaches.
Disclosures: Ansari-Pour: Bristol Myers Squibb: Consultancy. Flynt: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Ramasamy: Amgen, Celgene (BMS), GSK, Janssen, Takeda: Research Funding; AbbVie, Adaptive Biotechnologies, Amgen, Celgene (BMS), GSK, Janssen, Karyopharm, Oncopeptides, Pfizer, Sanofi, Takeda Recordati pharma, Menarini Stemline: Honoraria; Pfizer, GSK: Membership on an entity's Board of Directors or advisory committees; AbbVie, Adaptive Biotechnologies, Amgen, Celgene (BMS), GSK, Janssen, Karyopharm, Oncopeptides, Pfizer, Sanofi, Takeda, Recordati pharma, Menarini Stemline: Speakers Bureau. Gooding: Bristol Myers Squibb: Research Funding. Thakurta: Antenegene, Bristol Myers Squibb: Consultancy, Current Employment, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company, Honoraria, Research Funding.
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