Clinical reasoning for starting second-line therapy after initial response to frontline therapy in AL amyloidosis. Persistent or worsening organ involvement and/or relapse of clonal disease should be the triggers for resuming therapy. Non–amyloid-related causes of organ damage and/or dysfunction should be excluded, in order to avoid unnecessary exposure to chemotherapy. The presence of clonal disease should also be verified before resuming chemotherapy. In some cases, persistence of MRD is sufficient to maintain organ disease or cause organ progression. In the absence of clinically significant organ involvement, clonal relapse should be interpreted based on disease severity and amyloid free light chain level at diagnosis. For instance, clones that were associated with cardiac involvement and those that were able to cause organ involvement at low amyloid free light chain concentration should be treated earlier. Patient’s frailty remains a key issue also at relapse in AL amyloidosis, and the decision to resume chemotherapy should be carefully balanced in light of patient performance status and expected toxicity. NGF, next-generation flow cytometry.