BackgroundUpfront high-dose therapy (HDT) followed by autologous stem cell transplantation (ASCT) remains a profitable strategy for newly diagnosed multiple myeloma (MM) patients in the context of novel agents. However, current knowledge demonstrates a discrepancy between progression-free survival (PFS) and overall survival (OS) benefit with HDT/ASCT.MethodsWe conducted a systematic review and meta-analysis that included both randomized controlled trials (RCTs) and observational studies evaluating the benefit of upfront HDT/ASCT published during 2012 to 2023. Further sensitivity analysis and meta-regression were also performed.ResultsAmong the 22 enrolled studies, 7 RCTs and 9 observational studies had a low or moderate risk of bias, while the remaining 6 observational studies had a serious risk of bias. HDT/ASCT revealed advantages in complete response (CR) with an odds ratio (OR) of 1.24 and 95% confidence interval (CI) 1.02 ~ 1.51, PFS with a hazard ratio (HR) of 0.53 (95% CI 0.46 ~ 0.62), and OS with an HR of 0.58 (95% CI 0.50 ~ 0.69). Sensitivity analysis excluding the studies with serious risk of bias and trim-and-fill imputation fundamentally confirmed these findings. Older age, increased percentage of patients with International Staging System (ISS) stage III or high-risk genetic features, decreased proteasome inhibitor (PI) or combined PI/ immunomodulatory drugs (IMiD) utilization, and decreased follow-up duration or percentage of males were significantly related to a greater survival advantage with HDT/ASCT.ConclusionsUpfront ASCT remains a beneficial treatment for newly diagnosed MM patients in the period of novel agents. Its advantage is especially acute in high-risk MM populations, such as elderly individuals, males, those with ISS stage III or high-risk genetic features, but is attenuated with PI or combined PI/IMiD utilization, contributing to divergent survival outcomes.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12885-023-10907-1.