Session: 651. Multiple Myeloma and Plasma Cell Dyscrasias: Basic and Translational: Poster I
Hematology Disease Topics & Pathways:
Plasma Cell Disorders, Diseases, Lymphoid Malignancies
Methods: We designed a novel CRBN splicing isoform probe with homology to both exon 9 and exon 11. This probe will thus capture CRBN mRNA sequences in which exon 10 is deleted and portions of exons 9 and 11 and juxtaposed. We also included probes to CRBN overall (Exons 5 and 6). These probes were combined with the MM-IP-7 probes to create a dual gene expression and genetic assay that was used to analyze 30 cases of newly diagnosed MM, 30 cases of end stage MM, and 3 MM cell lines (MM1.S, OPM2, XG1). To define increased exon 10 deleted allele frequency, we calculated the ratio of exon 10 deletion/total exon 10. Cases with apparent exon 10 deletion by expression profiling, were further evaluated with RT-PCR.
Results: 40% MM samples in the end stage group versus 23% of samples in the newly diagnosed group were identified with more than 20% exon 10 deleted mRNA as compared to total CRBN mRNA levels. Three cases were shown to have more than 45% exon 10 deleted mRNA, including two newly diagnosed cases and one end stage case. RT-PCR confirmed exon 10 deletion in a newly diagnosed patient sample with sufficient remaining RNA that was tested (cloning and sequencing for confirmation are underway). Cell line results showed very low exon 10 splicing variant, which correlated with our mRNAseq data for these lines.
Conclusions: Our findings demonstrate that inclusion of probes bridging CRBN exon 10 deletion with homology to exons 9 and 11, is feasible approach to use on the gene expression platform, which allows for combined evaluation of expression and genetic changes. CRBN exon 10 deletion is a known treatment resistance feature in MM, which may already be present at diagnosis and selected by subsequent therapy with possible therapeutic planning implications. Additional studies to confirm the results and expand the study set are underway.
Disclosures: Chesi: Pfizer, Novartis.: Consultancy, Research Funding; Abcuro, Palleon Pharmaceuticals,, Pi Therapeutics.: Patents & Royalties: Genetically engineered mouse model of myeloma.. Bergsagel: Janssen: Consultancy; GSK: Consultancy; Novartis: Consultancy; Oncopeptides: Consultancy; Pfizer: Consultancy. Fonseca: AbbVie, Amgen, Bayer, BMS/Celgene, GSK, H3 Therapeutics, Janssen, Juno, Karyopharm, Kite, Merck, Novartis, Oncopeptides, OncoTracker, Pfizer, Pharmacyclics, Regeneron, Sanofi, Takeda: Consultancy; Adaptive Biotechnologies, Caris Life Sciences, Oncomyx and OncoTracker: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies, Caris Life Sciences, OncoMyx and OncoTracker: Other: Scientific Advisory Board; Adaptive Biotechnologies: Divested equity in a private or publicly-traded company in the past 24 months; Genentech, Pfizer, Sanofi: Honoraria, Research Funding; FIH prognostication in myeloma: Patents & Royalties; Amgen, BMS, Celgene, Takeda, Bayer, Janssen, Novartis, Pharmacyclics, Sanofi, Merck, Juno, Kite, Aduro, OncoTracker, GSK, AbbVie, Pfizer, Karyopharm.: Consultancy.
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