Objective To investigate the levels of serum N-terminal propeptide of type Ⅰ procollagen (PINP), dickkopf Wnt signaling pathway inhibitor 1 (DKK1), and secreted frizzled related protein 3 (SFRP3) in patients with multiple myeloma (MM), and their clinical significance. Methods A total of 150 MM patients (the MM group) and 150 healthy check-up individuals (the control group) were enrolled. The levels of serum DKK1, PINP, and SFRP3 were compared between research subjects of the two groups, between MM patients with different clinical stages, and between MM patients with different clinical efficacy. The relation of pre-treatment serum DKK1, PINP, and SFRP3 levels with MM patients' clinical efficacy was analyzed by employing the Logistic regression model. The receiver operating characteristic (ROC) curve was used to analyze the efficiency of serum DKK1, PINP, and SFRP3 levels for predicting clinical efficacy in MM patients. Results The MM group exhibited higher levels of serum DKK1, PINP, and SFRP3 as compared with the control group (P<0.05), and pre-treatment serum DKK1, PINP, and SFRP3 levels of MM patients were elevated successively in stages Ⅰ, Ⅱ, and Ⅲ (P<0.05). The effective group yielded lower levels of serum DKK1, PINP, and SFRP3 as compared with the ineffective group before treatment (P<0.05). The elevations of pre-treatment serum DKK1, SFRP3, and PINP levels were the independent risk factors for affecting MM patients' clinical efficacy (P<0.05). There was no predictive value of pre-treatment serum DKK1 and SFRP3 levels for MM patients' clinical efficacy (area under the curve<0.5, P>0.05), while pre-treatment serum PINP level exerted predictive value on MM patients' clinical efficacy to a certain extent (area under the curve=0.663, P<0.05). Conclusion Serum DKK1, PINP, and SFRP3 levels of MM patients are higher than those of healthy population, and are related to disease severity, which are the influencing factors for MM patients' clinical efficacy. Pre-treatment serum PINP level exerts a value for predicting MM patients' clinical efficacy to a certain extent.