Abstract
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.
Keywords: Cardiac, Amyloidosis, Efficacy analysis
Introduction
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.
Table 1.
Clinical characteristics of patients n (%)
| Bz (n = 9) | Dara (n = 7) | ||
|---|---|---|---|
| Ages (years)median (range) | 62 (48–74) | 62.5 (53–79) | |
| Gender | Male | 4 (44.4) | 4 (57.1) |
| Female | 5 (55.6) | 3 (42.9) | |
| Mayo2004 | I | 1 (11.1) | 0 (0.0) |
| II | 3 (33.3) | 2 (28.6) | |
| IIIa | 2 (22.2) | 2 (28.6) | |
| IIIb | 3 (33.3) | 3 (42.9) | |
| Mayo2012 | I | 1 (11.1) | 0 (0.0) |
| II | 1 (11.1) | 0 (0.0) | |
| III | 3 (33.3) | 3 (42.9) | |
| IV | 4 (44.4) | 4 (57.1) | |
| Organ involvement | Kidney | 5 (55.6) | 7 (100.0) |
| Liver | 2 (22.2) | 1 (14.3) | |
| Nerve | 2 (22.2) | 0 (0.0) | |
| Pleura | 1 (11.1) | 1 (14.3) | |
| Intestinal | 0 (0.0) | 1 (14.3) | |
| NT-proBNP (ng/L) median (range) | 2626(1280–20800) | 7450(69.6–35,000) | |
| TNT (ng/ml) median (range) | 0.057(0.009–0.207) | 0.078(0.012–2.620) | |
| dFLC (mg/L) median (range) | 326.9 (52–7189) | 557.5 (33–1852) |
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.
Fig. 1.
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.
Author contribution
Jing Wang, Shaojie Ye and Hua Xue wrote the main manuscript text and Huimei Guo, Songying Zhao, Jia Liu,JiangBo Zhang,Jianmei Xu, Xi Su,Luoming Hua prepared figures. All authors reviewed the manuscript.
Funding
The authors have not disclosed any funding.
Data availability
The datasets generated and analysed during the current study are available from the corresponding author on reasonable request.
Declarations
Conflict of interest
The authors declare no competing interests.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Jing Wang and Shaojie Ye have contributed equally to this work.
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets generated and analysed during the current study are available from the corresponding author on reasonable request.