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