Genomic characterization of patient derived xenograft models of multiple myeloma reveals selection of multiple pre-existing high risk clones

Nathan J. Becker; Enze Liu; Riya Sharma; Parvathi Sudha; Sara Ortega‐Bertran; Oumaima Jaouadi; Sreejeta Mondal; Nelia Luviano Aparicio; Maurizio Affer; Kiran Kumar Mangalaparthi; Akhilesh Pandey; Marios Papadimitriou; Benjamin T. Diamond; David Glen Coffey; Abhishek Pandey; James Hoffman; Gil Hevroni; Dickran Gano Kazandjian; Kelvin Lee; Gareth John Morgan; Faith E. Davies; Attaya Suvannasankha; Aneta Mikulášová; Ola Landgren; Rafat Abonour; Brian A. Walker

doi:10.64898/2026.10.14.755992

Cancer BiologybioRxivOct 16, 2026

Preprint

Genomic characterization of patient derived xenograft models of multiple myeloma reveals selection of multiple pre-existing high risk clones

Nathan J. Becker iD, Enze Liu iD, Riya Sharma, Parvathi Sudha iD, Sara Ortega‐Bertran iD, Oumaima Jaouadi iD, Sreejeta Mondal iD, Nelia Luviano Aparicio iD, Maurizio Affer iD, Kiran Kumar Mangalaparthi iD, Akhilesh Pandey iD, Marios Papadimitriou iD, Benjamin T. Diamond iD, David Glen Coffey iD, Abhishek Pandey iD, James Hoffman, Gil Hevroni, Dickran Gano Kazandjian iD, Kelvin Lee iD, Gareth John Morgan iD, Faith E. Davies iD, Attaya Suvannasankha iD, Aneta Mikulášová iD, Ola Landgren iD, Rafat Abonour iD, Brian A. Walker iD

Abstract

Multiple myeloma (MM) is a genomically complex malignancy of terminally differentiated plasma cells. Here, we have utilized the SCID-rab patient derived xenograft (PDX) model as a platform to expand scarce primary MM samples across disease stages and major cytogenetic subgroups for comprehensive molecular analysis. The model generated abundant CD138+ cells while retaining key genomic, transcriptomic and proteomic features of corresponding patient tumors. Compared with human myeloma cell lines, PDX cells more closely resembled primary MM in proliferative state and expression of therapeutically relevant targets. WGS and single cell WGS showed that PDXs arose from the selection of pre-existing subclones, including clones harboring high-risk alterations and convergent mechanisms of tumor suppressor inactivation. These findings establish SCID-rab PDX models as a platform for multiomic profiling, studies of clonal evolution, and determining therapeutic response in MM.

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