Exonic variants in multiple myeloma patients associated with relapsed/ refractory and response to bortezomib regimens

Abstract

Novel treatment in multiple myeloma represented by proteasome inhibitors, immunomodulatory drugs and monoclonal antibodies have produced a deep response. However, relapses are possible, and all classes of drugs are refractory to patients. Next-generation sequencing has improved our understanding of the multiple myeloma genome related to drug resistance and has discovered many genomic variants. Therefore, this study was conducted to investigate new variants associated with drug resistance in MM patients who relapsed and refractory to bortezomib regimen and daratumumab treatment using next-generation sequencing for whole-exome sequencing. Peripheral blood samples were collected in EDTA tubes from six patients; four were in relapsed and refractory to bortezomib regimens and daratumumab; two patients responded to bortezomib regimens. Whole-exome sequencing was performed by the MGI-DNBSEQ-G400 instrument. We identified 21 variants in multiple myeloma patients. Seventeen variants were found in relapsed and refractory multiple myeloma in 11 genes (GNAQ, PMS1, CREB1, NSUNS2, PIK3CG, ROS1, PMS2, FIT4, KDM5A, STK11 and ZFHX3). And four variants were identified in two patients with response to bortezomib regimens in 4 genes (RAF1, CREB1, ZFHX3 and INSR). We have observed several genetic variants in many genes that may have been associated with the poor prognosis and poor response to treatment in these patients. These values should be further confirmed in large sample studies using the RNA-seq technique to identify genome expression.

Keywords: BCL-2, B-cell lymphoma 2; BWA, Burrows-Wheeler Aligner; GATK, Genome Analysis Toolkit; IGV, Integrative Genomic Viewer; MAPK, mitogen-activated protein; MCL-1, myeloid cell leukaemia-1; MM, multiple myeloma; MMR, mismatch repair; Multiple myeloma; M−CSF, macrophage colony-stimulating factor; NF-кB, nuclear factor kappa B; NGS, Next-generation sequence; Next-generation sequencing; RANKL, receptor activator of nuclear factors-кB ligand; RTKs, tyrosine kinases receptors; SNP, single nucleotide polymorphism; VEGF-C, vascular endothelial growth factors receptors; VUS, variant unknown significant; WES, whole exome sequence; drug resistance.