Advanced cardiac involvement in systemic light chain amyloidosis (AL) carries a dismal prognosis, particularly in stage IIIb patients (median survival: 3–6 months), who are often excluded from clinical trials [1, 2]. While daratumumab-based regimens (e.g., D-VCd) have shown efficacy in non-stage IIIb AL [3], data in high-risk stage IIIb patients remain scarce. Here, we present a retrospective analysis comparing daratumumab based regimens and bortezomib based regimens in 16 AL patients with cardiac involvement, including 6 stage IIIb cases.

From May 2018 to August 2023, 16 AL patients with cardiac involvement (Mayo 2004 stage IIIa: n = 4; IIIb: n = 6) were treated at our center, as shown in Table 1. Nine received bortezomib-based regimens, and seven received daratumumab-based therapy. Hematological response (≥ partial response) and cardiac organ response rates were higher with daratumumab (71% vs. 33%; 57% vs. 11%, respectively). In stage IIIb patients (n = 6), daratumumab achieved superior outcomes: 66% hematological/cardiac responses versus 0% with bortezomib. After a median follow-up of 12 months, daratumumab prolonged progression-free survival (median not reached vs. 6 months; *P* = 0.022), though overall survival did not differ significantly (27.8 vs. 21.7 months; *P* = 0.232).Five bortezomib non-responders switched to daratumumab, achieving stable disease or better. Safety profiles were comparable between groups.

We specifically focused on 6 stage IIIb patients, as shown in Fig. 1. In the bortezomib group, all 3 patients died during the 1st, 4th, and 5th treatment cycles due to disease progression. In contrast, in the daratumumab group, 2 out of 3 patients achieved hematologic VGPR/CR by the 2nd/3rd cycle and cardiac PR/VGPR by the 5th cycle, respectively. One patient in the daratumumab group died due to a cardiac event. With a median follow-up of 10.5 months (range: 2–15 months), the two responding patients remained alive at the last follow-up. The hematological and cardiac response rates were higher in the daratumumab group compared to the bortezomib group (66% vs. 0% for both endpoints). These results suggest that daratumumab demonstrates promising efficacy in stage IIIb patients.

Efficacy and survival outcomes in six Patients with stage IIIb disease treated with daratumumab or bortezomib

Stage IIIb amyloidosis patients face poor treatment responses and high early mortality, with no established standard therapy. In our study, two patients achieved hematological VGPR/CR and cardiac PR/VGPR with the D-VCD regimen. One patient achieved stable disease after one course but died during the second course due to a cardiac event. Balancing treatment efficacy and tolerability to reduce early mortality and adverse events remains a critical challenge in stage IIIb patients.

Multiple studies confirm daratumumab's efficacy in relapsed/refractory AL amyloidosis [4]. Our study also demonstrated that switching to a daratumumab-based regimen in non-responders to bortezomib can still improve efficacy and thus prolong patient survival. This may also explain the lack of statistical difference in OS between the two groups.

In conclusion, daratumumab may benefit high-risk stage IIIb AL patients, a population with urgent unmet needs. Notably, even bortezomib-refractory patients derived clinical benefit after switching to daratumumab, supporting its role in salvage therapy. However, limitations include the small sample size and retrospective design. Larger prospective trials are warranted to validate these observations.