Abstract
Simple SummaryThe proteasome inhibitor bortezomib is currently commonly used for the treatment of multiple myeloma (MM). MicroRNAs (miRNAs) are small non-coding RNAs that play a crucial role in messenger RNA silencing and post-transcriptional regulation of gene expression. In MM, the expression of several miRNAs is markedly dysregulated suggesting their role in MM pathogenesis and drug resistance. The aim of our study was to assess miRNA expression patterns in the serum of MM patients treated with bortezomib. We have identified 21 serum miRNAs differentially expressed in patients refractory to bortezomib-based chemotherapy. A miRNAs-based prediction model was developed to assess the probability of refractoriness to bortezomib. Our findings, indicating the differential expression of miRNAs between bortezomib-refractory and bortezomib-sensitive patients, suggest that these circulating miRNAs may play an important role in personalized treatment of MM patients.Bortezomib is the first-in-class proteasome inhibitor, commonly used in the treatment of multiple myeloma (MM). The mechanisms underlying acquired bortezomib resistance in MM are poorly understood. Several cell-free miRNAs have been found to be aberrantly regulated in MM patients. The aim of this pilot study was to identify a blood-based miRNA signature that predicts bortezomib-based therapy efficacy in MM patients. Thirty MM patients treated with bortezomib-based regimens were studied, including 19 with refractory disease and 11 who were bortezomib sensitive. Serum miRNA expression patterns were identified with miRCURY LNA miRNA miRNome PCR Panels I+II (Exiqon/Qiagen). Univariate analysis found a total of 21 miRNAs to be differentially expressed in patients with MM according to bortezomib sensitivity. Multivariate logistic regression was created and allowed us to discriminate refractory from sensitive patients with a very high AUC of 0.95 (95%CI: 0.84–1.00); sensitivity, specificity and accuracy were estimated as 0.95, 0.91, and 0.93. The model used expression of 3 miRNAs: miR-215-5p, miR-181a-5p and miR-376c-3p. This study is the first to demonstrate that serum expression of several miRNAs differs between patients who are bortezomib refractory and those who are sensitive which may prove useful in studies aimed at overcoming drug resistance in MM treatment.
Highlights
Multiple myeloma (MM) is a hematological malignancy characterized by the clonal proliferation of plasma cells in the bone marrow (BM) microenvironment [1,2]
Serum miRNAs, with their noticeable stabilityand andunique uniqueexpression expression pattern pattern are robust non-invasive biomarkers that can be used for cancer detection and identifying disease characteristics non-invasive biomarkers that can be used for cancer detection and identifying disease characteristics
The present study identifies 21 serum miRNAs differentially expressed in patients with MM according to the bortezomib sensitivity based on univariate analysis
Summary
Multiple myeloma (MM) is a hematological malignancy characterized by the clonal proliferation of plasma cells in the bone marrow (BM) microenvironment [1,2]. It is the second most prevalent hematological malignancy, accounting for 1.3% of all malignancies and 15% of hematological neoplasms, with an annual incidence of 4.5–6 cases per 100,000 people [3]. Bortezomib inhibits the proteasomal degradation of several regulatory ubiquitinated proteins and exerts substantial anti-myeloma activity in previously untreated and relapsed/refractory MM patients. The therapeutic resistance of these agents, which emerges soon after the onset of therapy in some cases, limits the efficacy of the treatment in most patients, even if they initially responded to therapy [9]
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