Evaluation of serum TIE-2 levels in newly diagnosed and untreated multiple myeloma patients

Abstract Background: Multiple myeloma (MM) is an incurable hematologic malignancy characterized by the clonal proliferation of plasma cells within the bone marrow. Angiogenesis plays a central role in MM pathogenesis, with increased vascular remodeling contributing to disease progression. The angiopoietin-TIE signaling system, particularly the TIE-2 receptor, is a key regulator of angiogenesis. Despite its biological relevance, clinical studies evaluating serum TIE-2 levels in MM are limited. Objective: This study aimed to evaluate serum TIE-2 levels in newly diagnosed, treatment-naïve MM patients and to assess its potential utility as a diagnostic biomarker. Methods: A total of 38 patients with newly diagnosed MM and 37 age- and sex-matched healthy controls were prospectively enrolled between September 2017 and June 2021. Serum TIE-2 levels were measured using a human-specific ELISA. Demographic, clinical, and laboratory data were recorded at diagnosis. Statistical analyses were performed using SPSS 20.0. ROC curve analysis was conducted to determine the diagnostic performance of serum TIE-2. Results: The median serum TIE-2 level was significantly higher in MM patients compared to healthy controls (1.4 vs. 0.9 ng/mL, p<0.001). ROC analysis demonstrated that a TIE-2 cutoff >0.99 ng/mL yielded a sensitivity of 89.5% and specificity of 59.5% (AUC >0.99). No correlation was found between TIE-2 levels and laboratory parameters such as total protein, albumin, hemoglobin, WBC, or LDH (p>0.05 for all). Patients with MM had significantly elevated total protein (9.1 ± 2.1 vs. 6.7 ± 0.6 g/L, p<0.001), and lower albumin (3.3 ± 0.7 vs. 3.8 ± 0.5 g/dL, p<0.001), hemoglobin (10.2 ± 2.2 vs. 12.8 ± 1.7 g/dL, p<0.001), and WBC counts (6.4 vs. 8.5 × 10⁹/L, p=0.001) than controls. No significant differences were observed in creatinine, calcium, or platelet counts between groups. Among MM patients, the most common immunoglobulin subtypes were IgG lambda (31.6%) and IgG kappa (31.6%). Median bone marrow plasma cell infiltration was 77.5% (range: 15–95%). Lytic bone lesions were present in 84.2% of patients at diagnosis. The median follow-up duration was 18 months, during which 3 patients (7.9%) died. Conclusion: In this study, serum TIE-2 levels were found to be significantly higher in newly diagnosed, treatment-naïve multiple myeloma (MM) patients compared to healthy individuals. This finding suggests that angiogenesis plays an important role in the early stages of MM pathogenesis and is reflected in detectable systemic biomarkers. Although TIE-2 appears to support MM diagnosis with high sensitivity, its limited specificity indicates that it is more appropriate to use it alongside other biomarkers rather than as a standalone diagnostic tool. Future studies with larger sample sizes, multicenter designs, and longitudinal follow-up data are needed. Such research will help clarify the potential role of TIE-2 in diagnosis, prognosis, and predicting treatment response. Keywords: Multiple myeloma, TIE-2, angiogenesis, biomarker, ELISA, plasma cell disorder