Abstract: Objective To investigate the relationship between methyltransferase 16 (METTL16), Hematopoietic Scoring System, and the chemotherapy efficacy and prognosis in multiple myeloma (MM) patients. Methods A total of 126 MM patients who received chemotherapy at Jiaozhou Central Hospital of Qingdao from March 2018 to June 2020 were selected. Their clinical efficacy and survival outcomes were followed up. According to the therapeutic efficacy and survival outcomes, the patients were divided into the following groups: an effective group (n=81) and an ineffective group (n=45), as well as a survival group (n=96) and a death group (n=30). The groups were compared for their clinical data, METTL16 expression, and Hematopoietic Scoring System scores. The predictive value of METTL16 and the Hematopoietic Scoring System for chemotherapy efficacy, as well as the risk factors affecting prognosis were analyzed. Results The proportions of patients in the ineffective group with International Staging System (ISS) stage Ⅲ, lactate dehydrogenase (LDH) ≥220 U/L, high METTL16 expression, and a Hematopoietic Scoring System score of 2-3 were significantly higher than those in the effective group (P<0.05). The area under the ROC curve for METTL16, Hematopoietic Scoring System, and both in predicting chemotherapy efficacy in MM patients was 0.685, 0.638, and 0.844, respectively. There were statistically significant differences between the survival and death groups in terms of age, ISS stage, LDH levels, METTL16 expression, and Hematopoietic Scoring System (P<0.05). Age≥60 years, ISS stage Ⅲ, LDH≥220 U/L, METTL16 high expression, and high score in the Hematopoietic Scoring System were independent influencing factors of MM patients with poor prognosis (P<0.05). Conclusions METTL16 and the Hematopoietic Scoring System have certain predictive value for the chemotherapy efficacy in MM patients. High METTL16 expression and a high score on the Hematopoietic Scoring System are independent risk factors for poor prognosis in MM patients.