Background: Daratumumab (Dara)-based therapy is the standard for upfront treatment in systemic light-chain (AL) amyloidosis and is preferred in the relapsed setting. However, outcomes of patients who relapse on dara remain unclear. In such circumstances, optimal sequencing of subsequent drugs is also not well-established. Here, we describe outcomes of AL patients who progressed on dara-based treatments. Methods: We conducted a retrospective review of AL patients treated at our center from 2015 to 2022. Patients were eligible if they progressed on dara at any time during disease course. We recorded all standard metrics, including serologic and biomarker data. Patients with incomplete follow-up or missing data were excluded. Descriptive statistics were performed with Prism 5.0 (GraphPad; San Diego, CA). Results: A total of 11 patients were identified. Median age was 73. Nine were male, and 8 had AL, λ-type (2–κ, 1–heavy chain). Median iFLC at baseline was 342 mg/L (55.6–9780) and NT-proBNP was 1166 pg/mL (147–5000). Cardiac involvement was most common (82%); 64% had ≥2 organs involved. Six had t(11;14) by FISH and/or cyclin D1 overexpression by IHC, 3 had gain 1q, 2 had del 17p, and 4 had complex cytogenetics. Five patients received ≥2 prior lines of therapy, including 3 ASCT. Three (27%) received dara in induction, whereas the most common indications for later use were hematologic/organ progression (45%), suboptimal response (18%), and refractory disease (9%). At a median follow-up of 82 weeks, all patients had progressed. Median time to next therapy was 15 weeks (7–151). Six (55%) continued dara at salvage, while other agents used were bortezomib (n=5), ixazomib (n=6), pomalidomide (n=5), cyclophosphamide (n=4), bendamustine (n=4), and belantamab mafodotin (n=3). All patients with t(11;14) or cyclin D1 overexpression received venetoclax, of whom 4 also received HMG-CoA reductase inhibitors (statins). ORR was 100%. Hematologic VGPR and CR rates were each 36%, PR 18%, and 1 patient had low dFLC PR. Rate of VGPR or better was higher in patients with t(11;14) and/or cyclin D1 overexpression (83% vs 60%; P=0.55). Of the 4 patients who received venetoclax and statins for t(11;14) disease, 3 had CR and 1 had VGPR. One renal and 3 cardiac responses were observed. At last follow-up, 2 patients with VGPR had died while the rest had ongoing responses. Conclusions: In our study, most patients had t(11;14) and progressed on dara within 20 weeks. Salvage therapy incorporating novel agents yielded impressive responses. The combination of venetoclax and statins was effective in overcoming the negative impact of t(11;14) although further studies are needed for validation.