Analysis of Prognostic Significance of Biochemical Markers and Morphological Parameters in the Development of Bone Disease in Myeloma Patients. Summary of the Doctoral Thesis

Abstract

Analysis of prognostic significance of biochemical markers and morphological parameters in the development of bone disease in myeloma patients Introduction. Multiple Myeloma (MM) is a primary malignant bone marrow disease, in which lytic bone destruction is a widespread clinical manifestation that affects a patient's quality of life. Osteolytic lesions are seen in 70–80% of patients at the time of diagnosis, while up to 90% develop lytic lesions during their disease. Bone disease can cause skeletal-related events (SREs) with pathological fractures, spinal cord compression, and hypercalcemia. Currently, there are no methods with high sensitivity and specificity that could solve these clinical problems related to early diagnosis of the disease and dynamic control of patients with MM, because the conventional radiological investigation method does not provide us information about bone formation and resorption. Aim. To prove the prognostic significance of biochemical markers and morphological indicators of bone disease development in myeloma patients. Materials and methods. The thesis consists of two parts of research, which are united by the investigation of prognostic factors of bone disease in multiple myeloma patients. Two biochemical markers of bone metabolism as well as the grade of myeloma cell malignancy and the degree of DKK-1 expression, determined in the bone marrow trephine, were studied. The target population consisted of 123 patients diagnosed with MM for the first time, for whom the biochemical markers of bone metabolism were identified, i.e. the bone resorption marker β carboxy-terminal cross-linked telopeptide (β-CTX), and the marker of osteoblast activity and bone formation – alkaline phosphatase bone fraction (bALP). They were measured at the time of diagnosis and after 6 and 12 months. For 49 patients enrolled in the study, the morphological features of plasma cells and DKK-1 expression in myeloma cells were assessed during the routine bone marrow trephine biopsy at the time of diagnosis. Results. The β-CTX value in the study group is statistically significantly higher than in the control group (p < 0.001), while the median bALP for the control and study group did not differ statistically significantly (p = 0.55). The median β-CTX differed statistically significantly at different stages of bone damage (p = 0.001). In patients who responded to treatment, β-CTX decreased statistically significantly (p < 0.001) from baseline (Md = –0.77), but in patients who did not respond, β-CTX value increased after 6 months of treatment compared to the baseline value (Md = 0.28). The calculated cut-off value for β-CTX is 0.79 ng/ml and, when analyzed in association with bone lesion degree, a statistically significant association was found between the two traits (p < 0.001). In contrast, changes in bALP levels after 6 months of treatment differed statistically significantly (p < 0.001), however, after one year, bALP did not differ statistically significantly (p = 0.06). There was no statistically significant difference in bALP levels between different degrees of bone lesion severity (p = 0.95). Analyzing the suitability of bALP for the diagnosis of bone disease in MM patients using the ROC curve, it was found that bALP is not diagnostic (AUC = 0.5; p > 0.05). In turn, β-CTX is an excellent diagnostic indicator of MM bone disease (AUC = 0.91; p < 0.001; 95% CI: 0.88–0.94). A statistically significant association was found between the level of DKK-1 expression in patients with and without bone lesions (p = 0.02). DKK-1 expression level is higher in patients with bone lesions, who have more moderate to pronounced expression. In contrast, significant levels of DKK-1 expression were not observed in patients without bone lesions. Patients with bone lesions have a higher grade of plasma cell malignancy compared to patients without bone lesions. Conclusions. All this suggests that the biochemical marker of bone resorption (β-CTX), the level of DKK-1 expression in myeloma cells, and the morphological features of plasma cells in MM patients play an essential role in the diagnosis and treatment of bone disease and predict the course of the disease.