Objective To investigate the expression of zinc finger protein transcription factor 10 (KLF10) in patients with multiple myeloma and its relationship with prognosis. Methods A total of 126 patients with multiple myeloma admitted to our hospital from January 2015 to January 2017 were gathered as the observation group. 120 healthy people who underwent physical examination in our hospital during the same period were gathered as the control group for the study. The serum KLF10 level of subjects was detected by enzyme-linked immunosorbent assay (ELISA). The quantitative real-time PCR (qRT-PCR) technology was applied to detect the serum miR-21 expression level of subjects. Pearson correlation analysis method was used for correlation analysis of serum KLF10 and miR-21 levels in patients with multiple myeloma. Kaplan-Meier method was applied to analyze the relationship between serum KLF10 and miR-21 levels and prognosis of patients. The multivariate COX regression was used to analyze risk factors affecting the prognosis of patients with multiple myeloma.Results The results of this study showed that the serum KLF10 level in the observation group was lower than that in the control group, and the serum miR-21 level in the observation group was higher than that in the control group (P<0.05). Pearson correlation analysis showed that serum KLF10 and miR-21 levels in the observation group were negatively correlated (r=-0.447,P=0.000). The serum KLF10 and miR-21 levels in patients with multiple myeloma were not related to patients′ gender, age, and immunoglobulin type (P>0.05), but were related to DS stage, severe anemia, ECOG score, and bone marrow plasma cell ratio of patients (P<0.05). Kaplan-Meier survival curve analysis showed that the survival rate of patients with multiple myeloma in the low-expression group of serum KLF10 was lower than that in the high-expression group (χ2=9.651,P=0.032). The survival rate of the high expression group of serum miR-21 was lower than that of the low expression group (χ2=12.056,P=0.0024). The multivariate COX regression analysis showed that low expression of serum KLF10, high expression of serum miR-21, DS stage III, severe anemia, ECOG score >3 points and bone marrow plasma cell ratio >30% were risk factors for poor prognosis in patients with multiple myeloma (P<0.05). Conclusion The expression of serum KLF10 in patients with multiple myeloma is down-regulated, and its expression level is related to the clinicopathological characteristics of patients, and it is a risk factor for poor prognosis in patients with multiple myeloma