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Abstract Introduction AL amyloidosis is a rare plasma cell disorder characterized by the deposition of misfolded light chain proteins in organs, resulting in significant morbidity and mortality. Patients with high-risk cytogenetic abnormalities represent a particularly challenging subgroup due to poor prognosis and limited therapeutic options. Venetoclax, a BCL-2 inhibitor, has shown promise in targeting plasma cell clones, especially in the context of high-risk features. This systematic review and meta-analysis evaluate the efficacy and safety of venetoclax in patients with relapsed/refractory (R/R) AL amyloidosis, with a focus on those harboring adverse cytogenetic profiles and the impact of prior lines of therapy. Methods: A systematic review and meta-analysis was conducted according to PRISMA 2020 guidelines. Pubmed, Embase, and Cochrane were searched through April 2025 for original studies evaluating venetoclax in patients with R/R AL amyloidosis. Eleven studies reporting baseline characteristics and clinical outcomes were included. Outcomes assessed included overall response rate (ORR), complete response rate (CR), very good partial response rate (VGPR), partial response rate (PR), mortality, and adverse events. Meta-analyses were performed using R version 4.4.0 with the “meta” and “metasens” packages, using the inverse variance method and Freeman-Tukey double arcsine transformation to calculate pooled proportions and 95% confidence intervals Results: A total of 215 participants were included across the 11 analyzed studies. The median age was 66 years (range, 64–73), and 64.4% were male. The median number of previous lines of therapy was 2.5 (range, 1–4), and concurrent multiple myeloma was reported in 15.2% of cases. The median duration of treatment was 5.6 months (range, 2–15). Cardiac involvement was the most common organ manifestation (72.7%), followed by renal (50.6%), neurological (25%), gastrointestinal (24%), soft tissue (14.6%), and liver involvement (12.7%). Among 179 patients with R/R amyloidosis treated with venetoclax, the pooled ORR was 83% (95% CI: 0.71 to 0.93). The CR, VGPR, and PR rates were 45% (95% CI: 0.32 to 0.58), 28% (95% CI: 0.23 to 0.34), and 7% (95% CI: 0.03 to 0.11), respectively. Subgroup analysis by prior lines of therapy showed ORR of 85% (95% CI: 0.66 to 0.98) in patients who received ≤2 prior lines compared to 81% (95% CI: 0.52 to 0.99) in those who received >2 lines. CR, VGPR, and PR rates were 47%, 30%, and 6% in patients with ≤2 prior therapies, and 41%, 26%, and 8% in those with >2 lines, respectively. The pooled all-cause mortality was 14% (95% CI: 0.04 to 0.28), with disease-related and infection-related mortality rates of 9% (95% CI: 0.02 to 0.19) and 1% (95% CI: 0.00 to 0.07), respectively. Subgroup analysis revealed higher all-cause (19% vs. 11%) and disease-related mortality (13% vs. 9%) in patients with >2 prior lines compared to ≤2 lines, while infection-related and treatment-related mortality remained low in both groups. Pooled overall survival was 79% at 1 year (95% CI: 0.36 to 1.00) and 74% at 2 years (95% CI: 0.00 to 1.00).Conclusion: Venetoclax is associated with a high overall response rate and favorable survival outcomes in patients with high-risk R/R AL amyloidosis. While efficacy was observed across all patients, outcomes were more favorable in those who received venetoclax after fewer prior lines of therapy. These findings support the use of venetoclax as a promising therapeutic option, particularly when introduced earlier in the treatment course, though further prospective studies are needed to validate these results and optimize patient selection