Abstract Objective The purpose of this study was to investigate the predictive relevance of CD27 and CD117 expression and the prognostic value in newly diagnosed multiple myeloma (NDMM) patients. Methods This retrospective cohort study analyzed 160 newly diagnosed multiple myeloma (NDMM) patients at Beijing Chaoyang Hospital (2016–2023), evaluating CD27 (TNF receptor family member regulating plasma cell differentiation) and CD117 (c-KIT proto-oncogene product mediating hematopoietic cell survival) expression patterns via pretreatment flow cytometry. Patients were stratified by CD27/CD117 membrane positivity to assess their combined prognostic significance on disease progression, with survival outcomes tracked through standardized clinical surveillance protocols. Results The CD27 negative cohort demonstrated severe disease burden, evidenced by elevated β2-MG, increased bone marrow plasma cell infiltration, reduced hemoglobin levels, percentage of high ISS III. Kaplan-Meier analysis demonstrated that CD27 positive cohort showing significantly prolonged median PFS versus CD27 negative counterparts (78 vs. 33 months, P = 0.0078). While CD117 alone lacked prognostic significance, combined CD27(+)CD117(+) status was associated with superior PFS (P = 0.0041 vs. subgroups), earlier ISS\MASS staging (P = 0.005, P = 0.021), deeper therapeutic remission rates(Protease inhibitor-based therapy, P = 0.009), and lower frequency of high-risk cytogenetic abnormalities compared to all other combinations, and particularly outperforming CD27(−)CD117(−) patients. Among CD27-expressing patients, CD117 positive patients had better survival performance (P = 0.0424). Multivariate Cox regression confirmed CD27 positivity as an independent protective factor (HR 0.50, P = 0.009) and thrombocytopenia (PLT