Adjunctive and post-transplant doxycycline in systemic light-chain (AL) amyloidosis.

e19551 Background: Systemic immunoglobulin light-chain (AL) amyloidosis has high early mortality. Doxycycline has been adopted based on preclinical anti-amyloid fibril activity, but clinical data remain inconsistent. Importantly, doxycycline is used in two clinically and biologically distinct contexts: adjunctive frontline plasma cell-directed therapy and antimicrobial prophylaxis after autologous stem cell transplantation (ASCT), which warrant separate evaluation. Methods: Systematic review/meta-analysis of comparative studies (PubMed, Embase, Web of Science, Cochrane) through Dec 2025. Eligible adults received doxycycline as frontline adjunct or post-ASCT prophylaxis, non-pooled analyses by context. Studies required a doxycycline-free comparator and extractable endpoints. Primary endpoint: all-cause mortality; secondary: deep hematologic response (≥VGPR) and cardiac organ response. Random-effects models used small-sample robust variance estimation; observational findings interpreted for confounding/selection bias. Analyses were prespecified by clinical context to mitigate indication bias and immortal time bias. Risk of bias (RoB 2; ROBINS-I) was incorporated into sensitivity analyses and evidence certainty. Protocol registered on PROSPERO. Results: We identified 1,450 records; after deduplication, 906 were screened and 31 underwent full-text review. Six comparative studies were included (one randomized controlled trial, five observational cohorts). Four evaluated adjunctive frontline therapy in newly diagnosed patients on bortezomib-based regimens with frequent cardiac involvement; two compared doxycycline versus penicillin as post-ASCT prophylaxis. In frontline analyses (n=307), adjunctive doxycycline did not reduce 6-month all-cause mortality (RR 0.80, 95% CI 0.46–1.39; I²=17%) or 12-month mortality (RR 0.81, 95% CI 0.16–4.22; I²=84%). ≥VGPR was similar (RR 0.99, 95% CI 0.77–1.27; I²=7%), and cardiac response was not improved (heterogeneous; RR 1.36, 95% CI 0.58–3.17; I²=88%). Among post-transplant landmark survivors, pooled analyses from two retrospective cohorts showed lower 5-year all-cause mortality with doxycycline (RR 0.70, 95% CI 0.52–0.93; I²=0%). In Hartung–Knapp random-effects sensitivity analysis (k=2), the pooled 12-month mortality estimate remained non-significant (RR 0.81; p=0.814). Ten-year mortality favored doxycycline but was heterogeneous and not statistically significant (RR 0.67, 95% CI 0.42–1.07; I²=79%). Conclusions: Adjunctive doxycycline during frontline therapy did not reduce early mortality or improve hematologic or cardiac responses in AL amyloidosis. Doxycycline use as post-ASCT prophylaxis was associated with improved 5-year survival among landmark survivors; however, this signal derives from observational data and should be considered hypothesis-generating pending randomized evaluation.