Multiple myeloma is the second most common hematologic malignancy in older patients. The standard front-line VRD regimen (bortezomib/lenalidomide/dexamethasone) achieves high efficacy but is associated with significant toxicity, leading to infections, bone marrow suppression, and treatment discontinuation in approximately 20% of patients. Alternative regimens with reduced toxicity are needed for this demographic. Prior studies suggest adding arsenic trioxide to bortezomib/dexamethasone (BD) enhances remission depth with acceptable safety, while bortezomib/thalidomide/dexamethasone (VTD) offers reduced toxicity, but lower efficacy compared to VRD. This study evaluates the efficacy, safety, and cost-effectiveness of an arsenic trioxide-VTD regimen (AVTD) versus VRD in newly diagnosed multiple myeloma (NDMM) patients. Among 116 participants, AVTD demonstrated comparable efficacy to VRD but significantly reduced infection rates (14.0% vs. 40.7%, P < 0.001) and severe bone marrow suppression (0% vs. 11.9%, P = 0.013). Subgroup analysis of patients >60 years yielded consistent results. Additionally, AVTD was associated with lower treatment costs. In conclusion, the AVTD regimen offers a safer, more cost-effective alternative to VRD for NDMM, particularly in older adult patients, without compromising treatment efficacy.