Objective To investigate the clinical efficacy of daratumumab versus bortezomib in patients with systemic light chain amyloidosis (pAL) with cardiac involvement, particularly those at stage IIIb. Methods Retrospective analysis of 16 AL patients with cardiac involvement, two groups of patients received treatment primarily with bortezomib and daratumumab, respectively. The hematologic remission rate, cardiac response rate, survival and adverse reactions of the two groups were analyzed. Results Among the 16 patients, 4 were classified as Mayo 2004 stage IIIa and 6 as stage IIIb. The hematological response rate and cardiac organ response rate were higher in the daratumumab group compared to the bortezomib group (71% vs. 33%; 57% vs. 11%). With a median follow-up of 12 months, the median progression-free survival (PFS) and overall survival (OS) were superior in the daratumumab group (not reached vs. 6 months, P = 0.022; 27.8 months vs. 21.7 months, P = 0.232).Specifically, among the 6 stage IIIb patients, the daratumumab group demonstrated higher hematological and cardiac response rates (66% vs. 0%; 66% vs. 0%). Conclusions For patients with AL amyloidosis and cardiac involvement,including those at stage IIIb, daratumumab-based regimens offer benefits in terms of hematological remission, cardiac response, and progression-free survival, with comparable tolerability to bortezomib.