Multiple myeloma (MM) was characterized by frequent mutations in KRAS/NRAS/BRAF within the EGFR pathway that could induce resistance to EGFR inhibitors.
Deep genomic characterization of the extramedullary lesion prompted a personalized therapeutic approach.Acquisition of <i>CIC</i> mutation confers a mechanism of BRAF-MEK inhibitor drug resistance in multiple myeloma.The in silico interrogation of the CoMMpass clinical study revealed 10 patients with somatic mutations of <i>CIC</i> and its downregulation at gene expression level in multiple myeloma.
Of potential immediate clinical relevance, activating mutations of the kinase BRAF were observed in 4% of patients, suggesting the evaluation of BRAF inhibitors in multiple myeloma clinical trials.
Our data confirm and extend previous published evidence that MAPK pathway activation is recurrent in myeloma; the finding that it is mediated by BRAF mutations in a significant fraction of patients has potentially immediate clinical implications.
The spectrum of KRAS, NRAS, and BRAF codon mutations varied across subgroups with NRAS mutations at Q61 codon being common in hyperdiploid (HRD) and t(11;14) myeloma while being rare in MMSET and MAF.
We found a significant enrichment of RAS/BRAF mutations in rrMM compared to NDMM (P=0.011), which was mainly due to an increase of NRAS mutations (P=0.010).