Reduced-versus Standard-dose Melphalan as Single-agent Conditioning Regimen in Auto HSCT for Multiple Myeloma: A Systematic Review and Meta-Analysis.

Background: The optimal conditioning dose of melphalan for autologous hematopoietic stem cell transplantation (AHSCT) in multiple myeloma remains a subject of debate. While prior studies have presented conflicting evidence on whether standard-dose melphalan (SDM, 200 mg/m2) provides a statistically significant survival advantage over reduced-dose melphalan (RDM, 140 mg/m2), further investigation is necessary to clarify this. Aim: This systematic review and meta-analysis aimed to consolidate existing studies and assess whether standard-dose melphalan confers a significant benefit in terms of overall survival (OS) and progression-free survival (PFS) compared to reduced-dose melphalan, while also evaluating secondary outcomes non-relapse mortality (NRM), transplant-related mortality (TRM), and engraftment time (ET). Methods: A comprehensive literature search across four electronic databases (i.e., The Cochrane, ClinicalTrials.gov, PubMed, Google Scholar) identified six eligible studies published in the last 10 years, with a pooled sample size of 3,721 patients. The meta-analysis was conducted for the primary outcomes (OS and PFS) using hazard ratios (HRs) and their 95% confidence intervals (CIs), with effect sizes calculated based on reported p-values, population sizes, and Cohen's framework for effect size estimation. A fixed-effects model was employed, assuming relative homogeneity of effect sizes across studies. Results: For overall survival, no significant difference was seen between standard-dose and reduced-dose melphalan (95% CI: -0.025 to 0.217, p=0.119). Similarly, no significant difference in PFS was observed (95% CI: -0.021 to 0.088, p=0.353). The effect sizes for OS (0.0962) and PFS (0.0337) were small, indicating little clinical relevance despite trends to advantages in OS (16.9 months) and PFS (2.3 months) for the standard-dose group. The systematic review of secondary outcomes (NRM, TRM, and ET) demonstrated no significant differences between the two dose groups. Heterogeneity for primary outcomes was low (OS: I2 = 27.36%, p=0.316; PFS: I2 = 0.03%, p=0.567). Conclusions: Although standard-dose melphalan shows better survival trends, statistical analysis shows no significant difference in overall or progression-free survival. The small effect sizes also suggest these differences are not clinically meaningful. Due to lack of clear survival benefit between SDM and RDM, choice should be based on other important patient factors like risk of side effects and ability to tolerate treatment.