Active Epstein–Barr virus infection and its association with multiple myeloma: evidence from a meta-analytical perspective

Objectives To clarify the association between active Epstein–Barr virus (EBV) infection and the risk of multiple myeloma (MM), given longstanding uncertainty regarding EBV’s etiologic contribution to plasma cell malignancies.Methods A meta-analysis was conducted using eight case–control studies comprising 795 MM patients and 367 controls. Active EBV infection was defined as EBV DNA positivity or EBER detection by in situ hybridization (EBER-ISH). Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using fixed-effects and random-effects models (DerSimonian and Laird method). Subgroup analyses were performed by geographic region, detection method, and study quality. Heterogeneity, sensitivity analyses, and trial sequential analysis (TSA) were conducted to assess robustness.Results Active EBV infection was significantly associated with an increased risk of MM (OR = 2.30; 95% CI: 1.72–3.08; P < 0.001), with moderate heterogeneity (I2 = 36.9%). Stronger associations were observed among studies conducted in East Asian populations (OR = 2.99; 95% CI: 2.05–4.36; I2 = 0%) and in those using EBER-ISH for viral detection (OR = 2.98; 95% CI: 1.63–5.43; I2 = 0%). Analyses restricted to high-quality studies (Newcastle–Ottawa Scale ≥7) yielded consistent results (OR = 2.90; 95% CI: 2.00–4.20). Sensitivity analyses and TSA supported the stability and sufficiency of the evidence.Discussion The findings provide quantitative support for a potential role of EBV in MM pathogenesis, particularly in specific populations and when assessed using sensitive histopathologic methods. Although causality cannot be inferred from case–control designs, the consistent effect sizes across subgroups and robustness analyses strengthen the plausibility of a biological link between EBV reactivation and clonal plasma cell expansion. Variations in viral detection approaches, population background, and study quality may partially explain interstudy differences.Conclusion This meta-analysis demonstrates a significant association between active EBV infection and increased MM risk. These results highlight the clinical relevance of monitoring EBV activity in patients with plasma cell dyscrasias and support further mechanistic and translational research to evaluate EBV-targeted preventive or therapeutic strategies in the context of MM.