The Myeloma Genome in Drug Refractory Extra-Medullary Disease Identifies Mutations in Proteasome, Cereblon and Glucocorticoid Pathways

Abstract 3968

To better understand the genetic events associated with extra-medullary multiple myeloma (MM) we completed whole exome, long-insert whole genome and RNA sequencing on a patient with t(14;16) and neck adenopathy, as well as whole genome sequencing on two additional patients with respectively: t(4;14) and plasma cell leukemia, and del 17 with chest wall mass. All patients had multi-drug resistant disease and del 13. The frequency of somatic non-synonymous single nucleotide variants (SNV) ranged from 119 to 498, including an average of 15 truncating SNV, as well an average of 75 structural variants (range 2–147). Importantly, in one patient a truncating mutation, Q99*, on one allele and minor clone point mutation, R283K, on the second allele was observed in CRBN, a gene whose expression is required for effective lenalidomide and pomalidomide anti-myeloma activity. In the same patient a non-synonymous mutation, E171K, was also observed in PSMG2, a proteasome assembly protein, and a non-synonymous mutation, G369A, in NR3C1, a glucocorticoid receptor. Subsequently we have sequenced CRBN in 27 patients and 7 cell lines and have found no further examples of mutation in CRBN but have previously reported a bi-alleleic focal deletion in the MM.1Sres cell line. Mutations in NR3C1 have not previously been described in other MM genomes. Other, potentially clinically relevant mutations in the three patients were observed in FGFR3, PRDM1, STAT5B, NRAS, KRAS, PIK3CA, NF1, ATM, NFKB2, CKS1B and ERBB4. Although the three patients did not share a unifying event, a number of mutated genes observed were shared with other published myeloma genomes including RB1, TP53, MLL3, JAG2, VAV3 and SETD2. We also looked at pathway activation across the three genomes with the most statistically mutated pathways including VEGF signaling and activation, cell adhesion and chemokines, cytoskeleton remodeling, integrins in carcinoma progression, TP53 signaling and NOTCH signaling. In conclusion, we have identified, for the first time, the presence of a mutation in CRBN in a myeloma patient as well as mutations in PSMG2 and NR3C1, likely associated with drug resistance.