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CD56 or neural cell adhesion molecule (NCAM) is a membrane glycoprotein expressed on neural cells, muscle tissues and myeloma cells. Expression of CD56 has been studied in patients with multiple myeloma (MM) with controversial results. The scope of this study was to examine the expression of CD56 in MM patients at diagnosis and investigate its association with clinicopathologic parameters. We retrospectively collected and analyzed data from 109 patients with MM diagnosed over the last decade (January 2010 to June 2020). Expression of CD56 was assessed by immunohistochemistry in bone marrow biopsies and investigated its association with a variety of clinicopathological parameters. For the statistical analysis chi(2) test and Mann-Whitney U tests were used to compare categorical and continuous variables in CD56+ and CD56- patients, respectively. Statistical analysis was performed using SPSS 21.0 for Windows (SPSS, Chicago, IL). Based on the expression of CD56 the patient population was divided to CD56+ patients and CD56- patients; Sixty-eight patients were CD56 + and 41 patients were CD56-. Absence of CD56 expression was associated with unfavorable prognostic parameters such as elevated lactate dehydrogenase (LDH) and beta 2-microglobulin levels, advanced stage according to the International Staging System (ISS) and clonal bone marrow plasma cell infiltration >= 60%, but no effect on outcome, while the expression of CD56 was associated with well differentiated neoplastic plasma cells. Our study confirmed that lack of CD56 expression is a possible marker of poor prognosis in patients with MM. The detection of CD56 expression by either immunohistochemistry or flow cytometry is simple and cheap, and it could be incorporated in future prognostic or predictive scores. Prospective studies are needed in order to evaluate the role of expression of CD56 as a predictive biomarker in the era of novel regimens.