〔Abstract〕 Objective To investigate the clinical efficacy and safety of lenalidomide combined with VAD in the treatment of multiple myeloma. Methods 86 patients with multiple myeloma who were admitted to Nanyang Second General Hospital for treatment from May 2018 to May 2020 were selected as the research objects, and randomly divided into observation group and control group, with 43 cases in each group. The clinical efficacy, hemoglobin (HGB) and albumin (Alb) before and after treatment, the ratio of bone marrow plasma cells, and the incidence of adverse reactions were compared between the two groups. Results The total effective rate of the observation group was 81.40%, which was higher than 60.47% of the control group, the difference was statistically significant (P < 0.05). After 4 months of treatment, the ratio of marrow plasma cells in the two groups were significantly decreased, and HGB and Alb were significantly increased compared with before treatment, while the ratio of marrow plasma cells in the observation group was lower than that in control group, while HGB and Alb were higher than those in the control group, the differences were statistically significant (P < 0.05). There was no significant difference in the total incidence of adverse reactions between the two groups during treatment (P > 0.05). Conclusion Lenalidomide combined with VAD has a better clinical effect and higher safety than VAD alone in the treatment of multiple myeloma patients.