Objective To investigate the genetic characteristics and prognostic influencing factors of the middleˉhighˉrisk patients with multiple myeloma (MM) based on Mayo Stratification of Myeloma and RiskˉAdapted Therapy (mSMART) consensus guidelines. Methods A total of 179 hospitalized MM patients in Fujian Provincial Hospital from June 2009 to October 2017 were collected. Eventually, 49 patients were included except for the patients who were unable to perform mSMART stratification. According to the mSMART stratification criteria, the patients were divided into lowˉrisk group (24 cases) and middleˉhighˉrisk group (25 cases). The genetic characteristics of the two groups were analyzed to explore the relationship between mSMART stratification and clinical features. KaplanˉMeier method and logˉrank test were used to make survival analysis; logistic regression analysis was used to analyze the prognostic influencing factors in highˉrisk patients. Results The incidence of CSK1B gene amplification was the highest in the lowˉrisk group (41.7%, 10/24), while in the middleˉhighˉrisk group, the incidence of RB1 gene deletion was the highest (88.0%, 22/25). In the lowˉrisk group and the middleˉhighˉrisk group, there were no statistical differences in bone destruction, hypercalcemia, renal damage, anemia, β2 microglobulin abnormality, albumin abnormality, lactate dehydrogenase abnormality, and plasma cell ratio abnormality (all P> 0.05). Survival analysis showed that the median survival time of the middleˉhighˉrisk group was lower than that of the lowˉrisk group (23.19 months vs. 39.71 months, P＝ 0.043). Multivariate logistic regression analysis found that anemia and bone destruction were risk prognostic influencing factors for mSMART stratification as a middleˉhighˉrisk group (P＝ 0.044, P＝ 0.002). Conclusion mSMART stratification could indicate the poor prognosis for the patients with middleˉhighˉrisk, and the anemia and bone destruction are risk prognostic influencing factors for patients with middleˉhighˉrisk stratification.