RESUMEN
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.
RESUMEN
BACKGROUND: Treatment with Bortezomib (a proteasome inhibitor) and Daratumumab (DARA, a monoclonal anti CD38 antibody) are effective in patients with multiple myeloma (MM). However, these drugs impair cellular immunity, which may render the patients more prone to infection. OBJECTIVE: To investigate the effect of Bortezomib-based regimens and Daratumumab monotherapy on the lymphocyte subpopulations in MM patients. METHODS: Peripheral blood samples were collected from 32 patients, including 29 newly diagnosed who treated with bortezomib regimens and 3 patients with relapsed and refractory MM treated with Daratumumab as monotherapy. The immunophenotypic analysis was performed by flow cytometry at baseline and during the third cycle of Bortezomib regimen and fourth week of Daratumumab treatment. RESULTS: In the third cycle of Bortezomib, there was a significant decrease in CD3+ T cells, CD+4 T cells, memory T cells, and natural killer cells (NK cells). However, CD8+ T cells increased dramatically, followed by a significant reduction in the CD4/CD8 ratio. On the other hand, Daratumumab led to an increase in the T cell population after four weeks of treatment, with a significant increase in CD3+ T cells as well as CD4+ T cells, while NK cells were dramatically depleted in all patients. CONCLUSION: Bortezomib had a negative influence on subsets of T cells, while Daratumumab positively affected T cells subsets. In both treatments, NK cells decreased significantly. These results suggested that DARA is more specific to target myeloma cells than Bortezomib. Also, DARA expanded T cells especially CD3+ T cells and CD4+ T cells.
