Circulating miRNAs as Auxiliary Diagnostic Biomarkers for Multiple Myeloma: A Systematic Review, Meta-Analysis, and Recommendations

Abstract

Multiple myeloma (MM) is a hematologic malignancy characterized by aberrant expansion of monoclonal plasma cells with high mortality and severe complications due to the lack of early diagnosis and timely treatment. Circulating miRNAs have shown potential in the diagnosis of MM with inconsistent results, which remains to be fully assessed. Here we updated a meta-analysis with relative studies and essays published in English before Jan 31, 2021. After steps of screening, 32 studies from 11 articles that included a total of 627 MM patients and 314 healthy controls were collected. All data were analyzed by REVMAN 5.3 and Stata MP 16, and the quality of included literatures was estimated by Diagnostic Accuracy Study 2 (QUADAS-2). The pooled area under the curve (AUC) shown in summary receiver operating characteristic (SROC) analyses of circulating miRNAs was 0.87 (95%CI, 0.81-0.89), and the sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR) were 0.79, 0.86, 5, 0.27, 22, respectively. Meta-regression and subgroup analysis exhibited that "miRNA cluster", patient "detailed stage or Ig isotype" accounted for a considerable proportion of heterogeneity, revealing the importance of study design and patient inclusion in diagnostic trials; thus standardized recommendations were proposed for further studies. In addition, the performance of the circulating miRNAs included in MM prognosis and treatment response prediction was summarized, indicating that they could serve as valuable biomarkers, which would expand their clinical application greatly.

Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=234297, PROSPERO, identifier (CRD42021234297).

Keywords: biomarker; diagnosis; meta-analysis; microRNAs; multiple myeloma.

Figure 1

Study selection flow diagram.

Figure 2

Quality assessment of qualified studies by QUADAS-2 tool.

Figure 3

Pooled diagnostic parameters of all microRNA studies. (A) Forest plot of Sensitivity and Specificity; (B) SROC curve; (C) Forest plot of DOR.

Figure 4

Clinical utility of circulating miRNAs. (A) Summary LRP & LRN for Index Test showed that a few miRNAs (No. 9/18/19/20/21/31/32) had relatively good clinical diagnostic value. LLQ, left lower quadrant; LRN, likelihood ratio negative; LRP, likelihood ratio positive; LUQ, left upper quadrant; RLQ, right lower quadrant; RUQ, right upper quadrant; (B) Fagan nomogram of Pre-test probability and post-test probability.

Figure 5

Sensitivity analysis and Heterogeneity exploration. (A) Sensitivity Analysis showed that the combination results were stable; (B) Bivariate Boxplot revealed that No.18/21/31 studies presented strong heterogeneity; (C) Deek’s Funnel Plot Asymmetry Test found no publication bias.

Figure 6

Subgroup analysis. (A) Subgroup analysis based on DOR sorted by “miRNA cluster”; (B) Subgroup analysis based on DOR sorted by “detailed stage or Ig isotype”. NA, not available.