Rescue treatment algorithm for AL amyloidosis. Relapsed/refractory patients should be enrolled in clinical trials whenever possible. Treating relapsed patients with a different class of agents than that used in upfront therapy is associated with prolonged PFS but has no impact on OS.¹⁰⁷ Thus, if response to the previous line of therapy lasted at least 12 to 18 months, retreatment with the same drugs can be considered. Eligible patients who did not perform ASCT can be transplanted at relapse. At present, many relapsing patients have not been exposed to daratumumab, and this agent alone or combined with bortezomib or lenalidomide can be used safely and effectively at relapse.^65,67,108 Immune modulatory drugs are commonly used in the treatment of relapsed/refractory patients with AL amyloidosis. Lenalidomide and pomalidomide grant hematologic response in approximately 50% of patients with generally low (∼15%) CR rates and can rescue patients who are refractory to alkylators, proteasome inhibitors, and other immunomodulatory drugs.^109,110 Immunomodulatory drugs cause an increase in cardiac biomarkers that interferes with the assessment of cardiac response, and lenalidomide may worsen renal function in subjects with elevated proteinuria.¹¹¹ The second-generation, orally available proteasome inhibitor ixazomib is active in patients previously exposed to bortezomib.^92,112 Recent studies reported high CR/VGPR rates (∼80%) in relapsed/refractory patients with t(11;14) treated with venetoclax.²⁷ Bendamustine can be considered in patients with IgM-AL amyloidosis. Dara, daratumumab; Dex, Dexamethasone; Ixa, Ixazomib; Len, lenalidomide; OS; overall survival; PFS, progression-free survival; Pom, pomalidomide.