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1999 Acquisition of 1pLOH-1qGain Is a Frequent Trajectory in Expanding Relapsed/Refractory Myeloma SubclonesClinically Relevant Abstract

Program: Oral and Poster Abstracts
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
Saturday, December 9, 2023, 5:30 PM-7:30 PM

Naser Ansari-Pour, PhD1*, Mohammad Kazeroun1*, Evie Fitzsimons2*, Selina J Chavda, MBBS, BSc, MRCP3*, Alessandro Lagana, PhD4, Erin Flynt, PhD5*, Udo Oppermann, PhD1*, Karthik Ramasamy1,6, Kwee Yong7,8, Sarah Gooding6,9* and Anjan Thakurta, PhD1

1Oxford Translational Myeloma Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (NDORMS), University of Oxford, Oxford, United Kingdom
2Cancer Institute, University College London, London, United Kingdom
3University College London, London, GBR
4Department of Medicine, Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York
5Bristol Myers Squibb, Summit, NJ
6Department of Haematology, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
7Department of Haematology, University College London, London, United Kingdom
8University College London, London, United Kingdom
9MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom

Genetic clonal heterogeneity is common in multiple myeloma (MM). However, the specific drivers of subclonal evolution associated with disease progression under therapeutic selection has not been fully characterized with the resource of sequential samples to accurately observe changes in relation to drug exposures. To address this gap, we generated whole-genome sequencing data for 2-4 sequential samples of 50 UK relapsed/refractory MM (rrMM) patients taken before, during and after acquisition of therapy resistance. These patients were exposed to a real-world range of multi-agent therapy combinations between 2011 and 2020 all of which included IMiDs. We undertook high-resolution subclonal heterogeneity analysis using Battenberg and multi-dimensional DPClust as gold-standard methods [Salcedo et al. 2020, PMID: 31919445] and implemented the Plackett-Luce model of partial rankings to time genomic events based on their cancer cell fraction and identify alternative evolutionary trajectories [Ansari-Pour et al. 2021, PMID: 34836952]. This approach enabled the identification and tracking of recurrent genomic aberrations gaining dominance amongst the evolving subclones of the disease in relation to therapeutic exposure and resistance acquisition, and to our knowledge is the first time that has been applied to analyze multi-timepoint myeloma WGS datasets.

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.

*signifies non-member of ASH