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N6-methyladenosine (m6A) methyltransferase-like 3 (METTL3) has been confirmed to be involved in multiple myeloma (MM) progression, and basic leucine zipper and W2 domains 2 (BZW2) is considered to be a regulator for MM development. However, whether METTL3 mediates MM progression by regulating BZW2 remains unclear. The messenger RNA (mRNA) and protein levels of METTL3 and BZW2 in MM specimens and cells were determined using quantitative real-time PCR and western blot analysis. Cell proliferation and apoptosis were assessed by cell counting kit 8 assay, 5-ethynyl-2′-deoxyuridine assay, colony formation assay, and flow cytometry. Methylated RNA immunoprecipitation-qPCR was used to detect the m6A modification level of BZW2. Xenograft tumor models were constructed to confirm the effect of METTL3 knockdown on MM tumor growth in vivo. Our results showed that BZW2 was upregulated in MM bone marrow specimens and cells. BZW2 downregulation reduced MM cell proliferation and promoted apoptosis, while its overexpression enhanced MM cell proliferation and inhibited apoptosis. METTL3 was highly expressed in MM bone marrow specimens, and its expression was positively correlated with BZW2 expression. BZW2 expression was positively regulated by METTL3. Mechanistically, METTL3 could upregulate BZW2 expression by modulating its m6A modification. Additionally, METTL3 accelerated MM cell proliferation and restrained apoptosis via increasing BZW2 expression. In vivo experiments showed that METTL3 knockdown reduced MM tumor growth by decreasing BZW2 expression. In conclusion, these data indicated that METTL3-mediated the m6A methylation of BZW2 to promote MM progression, suggesting a novel therapeutic target for MM. [ABSTRACT FROM AUTHOR]