Head of MM-MRD Diagnostics University Hospital Würzburg 97078 Würzburg, Bayern, Germany
Introduction: Junction adhesion molecule A (JAM-A), is a protein expressed in various cell types, including endothelial cells, leukocytes, and plasma cells (PCs). The interactions between JAM-A expressing endothelial cells and malignant PCs influence tumor growth and dissemination in multiple myeloma (MM). Previous reports have demonstrated that high JAM-A expression on bone marrow (BM) tumor PCs in newly diagnosed MM patients correlates with patient outcomes, suggesting JAM-A as a potential target and biomarker in MM. However, studies on JAM-A expression in circulating tumor cells (CTCs) remain lacking, which is crucial for a comprehensive understanding of the dynamics and interactions between malignant PCs and the tumor microenvironment, as well as the mechanisms underlying disease dissemination. In this study, we examined the dynamics of JAM-A expression on CTCs in MM and explored its association with cytogenetics and disease prognosis.
Methods: Sample processing protocols were performed after adapting Euroflow guidelines. NDMM patients were classified as JAM-Ahigh/low based on the median value of fluorescence intensity on CTCs by FACS. Statistical analyses were performed using GraphPad software. The study was conducted in conformity to the Good Clinical Practice Guidelines (study n° 7411, prot. n° 0073322). All enrolled patients provided their informed consent.
Results: In this study, we investigated the expression of JAM-A on BM-PCs and CTCs in different disease settings. In BM, a group of 135 patients showed heterogeneous levels of JAM-A+ malignant PCs at diagnosis, followed by a decrease on JAM-A levels after therapy and an increase on JAM-A at relapse. JAM-A levels in the BM do not seem to be associated to high-risk (HR) cytogenetic abnormalities while in peripheral blood, high JAM-A expressing CTCs (n = 144 NDMM: 24 1q gain/amp, 22 other HR factors and 98 standard risk subjects) correlated with high-risk cytogenetics, showing statistically significant differences between the 1q gain/amp group, compared to patients with other HR abnormalities and with no cytogenetic abnormalities. Patients with low JAM-A on CTCs at diagnosis showed superior survival compared with patients with high JAM-A expressing CTCs (n = 67). Therefore, we analyzed the expression and distribution of JAM-A on CTCs, evaluating the relationship between JAM-A levels and progression free survival (PFS): The median PFS in NDMM with higher JAM-A expression levels was 19 months and differed significantly from the median PFS in patients with the lower JAM-A which was 23 months. These results demonstrate that JAM-A expressing CTC frequencies are associated with cytogenetic risk factors and disease outcome.
Conclusions: These results underscore the potential clinical utility of JAM-A as both a prognostic biomarker and a therapeutic target in MM, suggesting that JAM-A levels on CTCs could help stratify patients according to risk and guide more personalized treatment approaches.
