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Changes in serum inflammatory factors occur throughout the onset and multiple myeloma (MM) progression, the feedback loops make it harder to distinguish between causes and effects. In the present study, we performed a bidirectional summary‐level Mendelian randomization (MR) analysis to elucidate the causal relationships of C‐reactive protein (CRP) and inflammatory regulators with MM. Summary‐level data of genetic variants associated with inflammation were extracted from two genome‐wide association studies (GWASs) on CRP and human cytokines, while data on MM was from large meta‐analyses of GWASs among 372 617 UK Biobank participants. The inverse‐variance weighted (IVW) method was used as the primary MR analysis and MR‐Egger, weighted median, and MR‐pleiotropy residual sum and outlier (MR‐PRESSO) were used as the sensitivity analyses. Our results suggested that higher levels of monocyte‐specific chemokine‐3 (IVW estimate odds ratio [ORIVW] per SD genetic cytokines change: 1.24; 95% confidence interval [CI]: 1.03‐1.49; P =.02), vascular endothelial growth factor (1.14, 1.03‐1.27; P =.02), interleukin‐10 (1.33, 1.01‐1.75; P =.04) and interleukin‐7 (1.24, 1.03‐1.48; P =.02) were associated with increased risk of MM, while lower levels of tumor necrosis factor‐β (0.84, 0.74‐0.92; P <.001) was strongly associated with an increased risk of MM. And conversely, genetically predicted MM was related to increased levels of interleukin‐17 (IVW estimate β: 0.051, 95% CI: 0.018‐0.085; P = 2.7 × 10−3). Besides, we observed no such significant associations for other inflammatory factors in our study. Overall, our study provides genetic evidence on the relationships of CRP and systemic inflammatory regulators with MM. Targeted interventions of specific inflammatory factors may have implications to alleviate MM cancer risk. [ABSTRACT FROM AUTHOR]