Efficacy of venetoclax in the treatment of relapsed/refractory light-chain amyloidosis

Abstract Background Venetoclax (Ven) has shown promising efficacy in light-chain (AL) amyloidosis, particularly among patients with t(11;14). However, real-world data on Ven-based regimens in relapsed/refractory AL (RRAL) remain limited. We conducted a single-center, retrospective study to evaluate the efficacy and safety of Ven in RRAL. Methods AL patients with who received ≥1 prior line of therapy but either failed to achieve ≥very good partial response (VGPR) or experienced disease progression, therefore were subsequently treated with Ven-based therapy for more than 1 cycle were included. Best hematologic response, CR+VGPR rate, organ response, stringent FLC response rate which is defined as dFLC<10mg/L or involved FLC≤20mg/L, and adverse events (AE) were analyzed. The last follow up day was August 1, 2025. Event-free survival (EFS) was defined as the time of Ven initiation to disease progression, therapy change or death. Results Between July 18, 2022 and January 2, 2025, 29 RRAL patients were treated with Ven-based therapy. Median age at Ven initiation was 59 years (range 36–71), and 75.8% were male. Mayo 2004 stage distribution was: II (10.3%), IIIA (65.5%), IIIB (10.3%); 93.1% and 44.8% had cardiac and renal involvement, respectively. The median time from diagnosis to Ven initiation was 22 months (range 1–110) with a median of 1 (range 1–5) prior line therapy. Prior therapy included bortezomib (100%), daratumumab (72.4%), alkylators (58.6%), and immunomodulators (27.6%). Median t(11;14) proportion was 66% (range 0–96%), with 5 patients harboring <10% (low t(11;14)). Twenty-five patients (86%) received Ven+dexamethasone; 4 (14%) received daratumumab+Ven+dexamethasone regimen. The Ven dose was 400mg daily in 27 patients (93.1%); two patients required dose reduction due to side effects. After a median follow-up of 17 months (range 2–35), the overall hematologic response rate was 93%, with CR+VGPR achieved in 22/29 (79%), and stringent FLC response in 15/29 (51.7%). High t(11;14) was associated with superior CR+VGPR rates versus low t(11;14) (92% vs. 20%; OR 44.0; 95% CI, 4.3–1160.7). Cardiac ≥PR response occurred in 17/27 (63%), and renal ≥PR in 4/13 (31%). Two patients died from cardiac events and three discontinued Ven for lack of efficacy. Median OS and EFS were not reached at a median follow-up of 17 months. The 1-year OS and EFS rates were 96.6% (95% CI 90.1–100.0%) and 85.8% (95% CI 73.8–99.7%), respectively. A single grade 2 hematologic AE was reported. Non-hematologic AEs included gastrointestinal discomfort (27.6%), fatigue (10.3%), and infection (3.4%). Conclusions Venetoclax-based therapy achieved high rates of deep hematologic and organ responses in RRAL, with particularly favorable efficacy in patients with high t(11;14). Toxicity was minimal, supporting Ven as a promising option for RRAL.