INTRODUCTION: Many reports indicate that the occurrence of multiple myeloma (MM) is closely related to inflammation and immunity. Although the survival rates have been gradually improving in recent years, the cure rate is still not optimistic enough. Therefore, it is necessary to continue exploring the causes of MM. METHODS: This study utilizes Mendelian randomization (MR) analysis to establish the connection between inflammatory factors, immune cells, and the occurrence of MM. RESULTS: In MR studies, a significant correlation was observed between interleukin-1 receptor antagonist (IL-1Ra), tumor necrosis factor receptor 1 (TNFR1), memory B-cell percentage of B cells (memory B-cell %B cells), and immunoglobulin D-positive, CD24-negative percentage B cells (IgD+ CD24- %B cells) with the onset of MM. In particular, IgD+ CD24- %B cells showed a statistically significant inverse relationship with the development of MM (p <
0.05, OR <
1), whereas IL-1Ra, TNFR1, and memory B-cell %B cells displayed a positive association with the onset of MM (p <
0.05, OR >
1). These findings contribute valuable insights to the understanding of the pathogenesis of MM. CONCLUSION: This study emphasizes the significant role of inflammatory factors and immune cells in multiple myeloma (MM) progression. IL-1Ra, TNFR1, and memory B-cell percentages are identified as risk factors, while IgD+ CD24- %B cells may protect against progression, suggesting new immunomodulatory treatment strategies. However, research on IgD+ CD24- %B cells and MM is limited, necessitating future studies to clarify their mechanisms and effects on the tumor microenvironment. There is also an urgent need for clinical trials to assess therapies targeting these cells, as well as long-term follow-ups to understand their dynamic changes in relation to disease progression. Further investigation using animal models is warranted to validate their functional role in MM development.