Abstract Background: Daratumumab has transformed the treatment landscape of AL amyloidosis. However, patients with severe cardiac involvement—particularly those classified as Mayo 2004 stage 3b—continue to face a dismal prognosis. Real-world data on the use of frontline daratumumab in this frail population remain limited to small patient cohorts. We conducted this systematic review to summarize the available evidence and evaluate the outcomes of first-line daratumumab-based therapies in this high-risk subgroup. Method: We conducted a comprehensive literature search using three databases: PubMed, Embase, and ASH publications. The search strategy incorporated both MeSH terms and relevant keywords, including “AL amyloidosis” and “daratumumab,” and covered the period from inception to May 5, 2025. We included only studies that reported clear hematologic response, cardiac response, or prognostic outcomes in newly diagnosed Mayo 2004 stage 3b patients who received frontline daratumumab-based therapy. Extracted data included the number of stage 3b patients, treatment regimens, median age, hematologic and cardiac responses, median overall survival (OS) or survival rate, and grade 3–4 adverse events. Results: After screening 620 studies, a total of 15 were included in this review—comprising 2 prospective trials and 13 retrospective analyses. These studies collectively reported outcomes for 289 patients with Mayo 2004 stage 3b AL amyloidosis. However, two pairs of studies originated from the same centers and may contain overlapping patient populations. Regarding hematologic response, the rate of very good partial response (VGPR) or better ranged from 42% to 100%, with most studies reporting rates around 60%. Cardiac overall response rates ranged from 29% to 80%, with the majority falling between 50% and 60%. Median overall survival (OS) ranged from 7.4 months to not reached at 2-year follow-up; however, outcomes were consistently more favorable than those historically observed with bortezomib-based regimens. In terms of safety, most studies reported either manageable toxicity profiles or toxicity comparable to that of bortezomib-based regimens, with the exception of one prospective trial by Kastritis et al., which reported 80% grade 3–4 adverse events, including 42.5% with severe cardiac toxicity. The most common grade 3–4 adverse events included infections and cytopenias. Conclusion: Daratumumab-based frontline therapy demonstrates promising hematologic and cardiac responses, with manageable toxicity comparable to that reported in the ANDROMEDA trial. Although survival in most studies is improved compared to bortezomib-based treatment, patients with Mayo 2004 stage 3b disease still have the poorest prognosis among all Mayo stages.
Gao et al. (Mon,) studied this question.