Human IL-6 fosters long-term engraftment of human patient derived myeloma cells in immunodeficient mice

Multiple myeloma is a largely incurable and life-threatening malignancy of antibody-secreting plasma cells. An effective and widely available animal model that recapitulates human myeloma and related plasma cell disorders is lacking. We show that busulfan-conditioned hIL-6 transgenic NSG mice (NSG+hIL6) reliably support the engraftment of malignant and pre-malignant human plasma cells including from patients diagnosed with pre- and post-relapse myeloma, plasma cell leukemia, and AL amyloidosis. Consistent with human disease, NSG+hIL6 mice engrafted with patient-derived myeloma cells developed blood M spikes, and a majority developed anemia, hypercalcemia, and/or bone lesions. Singe cell RNAseq analyses showed non-malignant and malignant cell engraftment, the latter expressing a wide array of mRNAs associated with myeloma cell survival and proliferation. Myeloma-engrafted mice given CAR T-cells targeting plasma cells or bortezomib experienced reduced tumor burden. Our results establish that NSG+hIL6 mice provide an effective patient derived xenograft model for study and preclinincal drug development for myeloma and related plasma cell disorders. NSG+hIL6 mice were engrafted with primary bone marrow mononuclear cells from a patient with relapsed t(4;14) (MMSET-FGFR3 fusion) IgG lambda multiple myeloma through intraosseous injection of cells into the left femur after prior busulfan conditioning. After 52 weeks, bone marrow was harvested from both femurs and processed through the Parse Biosciences Evercode Fixation and Whole Transcriptome mini kits for library preparation and then submitted to Azenta LifeSciences for paired end illumina sequencing. Two libraries were prepared, one with 10,000 cell input and a second with 5,000 cell input. They were sequenced at equimolar concentrations to allow for deeper sequencing of the 5,000 cell fraction. Raw data was processed through the Parse Biosciences Pipeline using Python R.