Single-arm meta-analysis of melflufen-based regimens in relapsed/refractory multiple myeloma: Efficacy and safety insights from clinical trials

Abstract Introduction: Multiple Myeloma (MM) poses a significant challenge in clinical settings, especially among patients with resistant disease. Melflufen is a novel, first-of-its-kind peptide-drug, exclusively available across Europe. This drug works by targeting aminopeptidases and has demonstrated promising results in relapsed-refractory multiple myeloma (RRMM) patients. However, there is limited stratified data on safety and efficacy of this drug. By carrying out this single-arm meta-analysis, we aim to provide a more comprehensive evaluation of efficacy and safety outcomes of melflufen-based regimens. Methods: Following PRISMA, A comprehensive literature search was conducted on PubMed, Scopus, and Embase for studies published up to June 2025 evaluating melflufen-based regimens in relapsed/refractory multiple myeloma (RRMM). Eligible studies included clinical trials reporting outcomes of interest such as overall response rate (ORR), overall survival (OS), and progression-free survival (PFS). Safety outcomes, including any-grade and serious treatment-emergent adverse events (TEAEs), were also extracted. Outcome definitions were consistent across studies, and OS/PFS were standardized at 6- and 9-month time points. Meta-analyses were conducted using a random-effects model (DerSimonian–Laird) in RStudio (v5.4.1). Subgroup analyses were performed based on treatment regimen (triplet vs. doublet), cytogenetic risk (high vs. standard), and refractory status (double-class vs. triple-class). Results: A total of 6 studies comprising a total of 485 patients were used in this single-arm meta-analysis, out of which three were randomized controlled trials, and 3 were non-randomized trials. Non-randomized were included because of the small number of studies and their sample sizes. The follow-up duration, reported in four studies, ranged from 3.8 to 19.8 months. The age of patients across the included studies ranged from 35 to 86 years. The number of prior lines of therapy patients received ranged from 1 to 12. The pooled 6-month and 9-month OS was 79% (95% CI: 0.70–0. 86%; I² = 69.9%, p = 0.010) and 73% (95% CI: 0.62–0.81%; I² = 74.6%, p = 0.0034), respectively. The OS was higher in triplet regimens as compared to double regimens (94% vs. 75%, p = 0.0064). Between double and triple class refractory disease, OS was notable in the first group (84% vs. 69%, p = 0.0259). The 6- and 9-months pooled results showed PFS of 63% (95% CI: 0.41–0.80%, I² = 92.2%, p < 0.0001) and 50% (95% CI: 0.29–0.72%, I² = 92.7%, p < 0.0001). At the 6-month mark, PFS was significantly higher in patients with double-class refractory status (75% vs. 32%, p = 0.0044) and those receiving triplet regimens compared to doublet regimens (84% vs. 42%, p = 0.0006) respectively. The pooled estimate of ORR was 44% (95% CI: 0.27–0.62%; I² = 84.0%, p < 0.0001). Triplet regimens had notably higher ORR in contrast to doublets (67% vs. 31%, p < 0.0001). While non-significant trend favored double-class over triple-class refractory patients (54% vs. 29%, p = 0.06). In context of safety, pooled incidence of serious TEAEs was 43% (95% CI: 0.36–0.50%; I² = 38.3%, p = 0.1819), while any-grade TEAEs occurred in 96% (95% CI: 0.92–0.98%; I² = 40.6%, p = 0.1680). Conclusion: Meflufen showed significant efficacy in RRMM, especially when used as triplet regimen and in double-class refractory disease. Triple therapies were particularly linked with higher overall response and better survival. This supports the use of Meflufen in previously treated RRMM and provides nuanced evidence to guide clinicians to make informed decisions in heavily pretreated RRMM.