The leucine-rich-2-glycoprotein-1 levels in patients with multiple myeloma

Introduction: Angiogenesis is considered important in the pathogenesis of multiple myeloma (MM), as well as in the targeted treatment of the disease. Leucine-rich-alpha 2-glycoprotein 1 (LRG1) is a protein that participates in angiogenesis and its effect on solid organ tumors has been investigated recently. This study aimed to investigate the relationship between MM and LRG1. Methods: The MM patients who admitted to Hatay Mustafa Kemal University Hematology Clinic between September 2021 and October 2022 were included in the study. The study consists of a total of 4 groups: newly diagnosed MM (NDMM), relapsed refractory MM (RRMM), MM in remission (Rem-MM), and control group. Demographic data were retrieved from hospital records. Blood samples of our study groups were centrifuged at 1500 x g for 10 minutes and serum were collected. LRG1, IL-6, IL-8, TGF-ss 1, HIF-1 alpha, FGF-2, and VEGF levels were analyzed in all groups by ELISA method and statistical analysis was performed. Results: A total of 112 individuals, including NDMM (n:27), RRMM (n:18), Rem-MM (n:42), and control group (n:25), were enrolled in the study. Based on the analyses, the NDMM group exhibited significantly elevated levels of LRG1 (p<0.001), TGF-1 (p<0.001), and HIF-1 alpha (p=0.046, p<0.001, and p=0.003 compared to the RRMM, Rem-MM, and Control groups, respectively) compared to the other groups. LRG1 levels were positively correlated with creatinine (r:0.363, p=0.001), calcium (r:0.344, p=0.001), total protein (r:0.473, p<0.001), erythrocyte sedimentation rate (r:0.547, p<0.001), lactate dehydrogenase (r: 0.321, p=0.003), beta-2-microglobulin (r:0.312, p=0.017), IL-6 (r:0.478, p<0.001), IL-8 (r:0.240, p=0.03), TGF-ss 1 (r:0.521, p<0.001), and HIF-1a (r:0.321, p=0.003) levels, and were negatively correlated with hemoglobin (r:-0.512, p<0.001) and albumin (r:-0.549, p<0.001) levels. Receiver Operating Characteristics (ROC) analysis revealed the association of LRG1 with the highest AUC value of 0.959 (95% CI: 0.904-1, p<0.001) and the optimal cut-off value of 534.95 ng/mL (sensitivity: 93% and specificity: 99%) in the NDMM group compared to the control group. Discussion/Conclusion: In this study, providing data for the first time on LRG1 levels in the setting of MM. LRG1 levels were found to be significantly higher in NDMM patients and in our study discriminate this patient population from significant difference in FGF-2 and VEGF levels was observed in any group. While the results of TGF-ss 1, HIF-1 alpha, IL-6, and IL-8 analysis in our study's NDMM group were similar to previous studies [44-47], the results of FGF-2 and VEGF analysis appear to be conflicting [48-50]. Another result that contradicted previous studies was observed in the RRMM group. It is puzzling that only IL-6 levels were found to be higher than the control group in the results of cytokine analysis in the RRMM group, where a more aggressive disease course was expected compared to the NDMM group. We think the main reason for the differences is because the samples were analyzed from peripheral blood samples, and the study group numbers were not entirely uniform. There are certain limitations of our study. Analyses based on peripheral blood samples can be considered as a limitation. However, there are contradicting studies on the matter. A randomized controlled study of cytokines in MM found no difference between bone marrow and peripheral blood results [50], nevertheless, another comparative study found that bone marrow cytokine levels were higher than peripheral blood [51]. Another limitation of our study can be considered that bone marrow (BM) microvascular density measurements were not performed for the evaluation of angiogenesis. Another limitation of our study is the small sample size in the control group. However, we conducted a pilot study with 7 healthy individuals before the main study, and the mean LRG1 value we obtained was 188.9 +/- 50.8. Subsequently, when the control group was expanded to include 25 individuals, the calculated mean LRG1 value was 189.4 +/- 50.2. Based on these findings, we believe that increasing the sample size in the control group will not result in statistically significant changes in the observed results. Although the lack of data on survival analysis can be considered as a final limitation, the aim of this study was to reveal the descriptive features of MM within the study period, rather than evaluating the effect of LRG1 and other cytokines on survival in MM. Conclusion To our knowledge, this study was the first to analyze LRG1 in MM patients. In this way, we found that the LRG1 level was significantly increased in NDMM. In addition, we found that increase in LRG1 levels was correlated with laboratory parameters which are of considerable importance in the diagnosis, treatment, and prognosis of myeloma. In ROC curves analysis, we found that LRG1 showed a reasonable ability with high sensitivity and specificity in NDMM. These results suggested that LRG1 may play an important role in MM. Therefore, we consider that LRG1 should be evaluated in terms of diagnosis, stage, follow-up, prognosis, and treatment goal in future studies.