Objective: To investigate the intrinsic associations between the immunophenotype of bone marrow plasma cells, the status of circulating plasma cells (CPCs), and bone marrow infiltration patterns in patients with multiple myeloma (MM), thereby elucidating the molecular mechanisms underlying CPCs formation. Methods: A total of 83 patients with newly diagnosed MM were enrolled and divided into a CPCs-positive group (n=34) and a CPCs-negative group (n=49) based on peripheral blood flow cytometry results. Flow cytometry was employed to detect the expression of CD56, CD27, CD81, CD45, and CD19 in bone marrow and peripheral blood plasma cells, as well as to assess cytoplasmic light chain restriction. Bone marrow biopsy pathology was performed to determine the bone marrow infiltration patterns (interstitial, nodular, or diffuse). Differences in immunophenotype and infiltration patterns between the two groups were compared. The correlation of CD56, CD27, and CD81 expression in the CPC-positive group was analyzed, and multivariate Logistic regression was used to identify independent influencing factors for CPCs positivity. Results: In the CPCs-positive group, the proportion of Lambda light chain restriction was higher than that in the negative group, while the proportion of Kappa light chain restriction was lower than that in the negative group (P<0.05), and the proportion of diffuse infiltration was also higher than that in the negative group (P<0.05). The positivity rates of CD56 and CD27 in bone marrow plasma cells in the CPCs-positive group were lower than those in the negative group (P<0.05), whereas the positivity rate of CD81 was higher than that in the negative group (P<0.05). CD56 expression was positively correlated with CD27 (P <0.05) and negatively correlated with CD81 (P <0.05). Gradient differences in immunophenotypes were observed among different bone marrow infiltration patterns: within the CPCs-positive group, patients with diffuse infiltration exhibited lower positivity rates of CD56 and CD27 compared to those with nodular and interstitial infiltration (P<0.05), conversely, the positivity rate of CD81 in patients with diffuse infiltration was higher than that in patients with nodular and interstitial infiltration (P <0.05). Multivariate Logistic regression analysis indicated that only the reduced positivity rate of CD56 in bone marrow plasma cells was an independent influencing factor for CPC positivity (P<0.05). Conclusion: The loss of CD56 expression in bone marrow plasma cells is a key driving factor for the emergence of CPCs in MM patients, and this aberrant molecular expression is closely associated with the diffuse bone marrow infiltration pattern. CD56 can serve as a molecular marker to identify high-risk MM patients with “migration-prone” characteristics, providing a novel basis for risk stratification and targeted therapy in multiple myeloma.