Objective: This study aimed to evaluate the relationship between CD27, CD28, CD81, and CD117 antigens and clinical, biochemical, and cytogenetic parameters in patients with multiple myeloma (MM) and to evaluate their prognostic significance.Material and Methods: A retrospective analysis was performed on data from 100 multiple myeloma patients. The analysis included available flow cytometry data (CD27, CD28, CD81, and CD117) and bone marrow biopsy results. Demographic data, laboratory parameters, cytogenetic analyses, treatment responses, and mortality were recorded. Multivariate logistic regression analysis was performed for variables associated with the R-ISS stages.Results: The median age of the patients was 67 years, and 64% were men. The positivity rates for CD27, CD28, CD81, and CD117 were 45%, 53%, 61%, and 51%, respectively. As the R-ISS stage increased, CD27 negativity significantly increased (p=0.021), while CD117 positivity also increased (p=0.046). In the multivariate analysis, CD28 positivity emerged as an independent risk factor for a higher R-ISS stage (aOR=0.324 for CD28 negativity, p=0.015). CKS1B positivity (p=0.039) and a high bone marrow plasma cell ratio (p=0.004) were independently associated with advanced disease stages. As the R-ISS stage increased, ECOG performance scores worsened, and the number of lytic lesions and mortality rates significantly increased.Conclusion: In multiple myeloma, CD27 loss and CD117 positivity are associated with poor prognosis, whereas CD28 positivity is associated with more advanced disease stage. The addition of these immunophenotypic markers to the R-ISS classification may contribute to a more accurate assessment of biological risk and the development of personalized treatment plans.