The present study investigated the interactions between decitabine (DAC) and bortezomib (BTZ) in RPMI 8226 multiple myeloma (MM) cells. Cells were exposed to DAC alone and in combination with BTZ for 48 h. A Cell Counting Kit‑8 assay was performed to assess the rate of proliferation inhibition in the cells. Cell apoptosis was investigated by Annexin V-fluorescein isothiocyanate and propidium iodide staining. Flow cytometry was used to detect the different cell cycle stages. Western blotting was performed to analyze the protein expression levels of poly(ADP‑ribose) polymerase 1 (PARP‑1), caspase‑3, ‑9 and DNA (cytosine‑5‑)‑methyltransferase 1 (DNMT1). Reverse transcription‑quantitative polymerase chain reaction was used to assess DNMT1 gene expression. The combination of DAC and BTZ increased the proliferation inhibition, apoptotic rate and G0‑G1 arrest compared with use of a single therapeutic agent. In addition, the combination treatment enhanced PARP‑1 cleavage, caspase‑3 and caspase‑9 activation and downregulated the protein and mRNA expression levels of DNMT1. Therefore, the current study determined that the combination of BTZ and the epigenetic agent DAC may be a novel therapeutic strategy to improve the efficacy of BTZ in patients with MM.