Efficacy and Safety of Low-Frequency Daratumumab Regimen in Systemic Light-Chain Amyloidosis.

Introduction

Systemic immunoglobulin light‐chain (AL) amyloidosis is a rare clonal plasma‐cell neoplasm caused by the excess production and deposition of insoluble β‐pleated sheets of misfolded immunoglobulin light chains [ 1 ]. These are in turn responsible for significant organ dysfunction, infiltrating vital organs, which are most commonly the heart and kidneys [ 2 ]. AL amyloidosis is an uncommon hematologic disorder with an incidence of approximately 9–14 patients per million person‐years [ 3 ]. Owing to the rarity of this disease and the limited number of randomized clinical trials conducted so far, treatments for systemic AL amyloidosis are often adapted from multiple myeloma (MM) regimens [ 4 ].

A higher CD38 expression was observed in the clonal plasma cells (PCs) in AL amyloidosis, which was related to adverse survival [ 5 ]. Daratumumab, as a first‐in‐class human immunoglobulin IgG‐κ monoclonal antibody, binds the CD38 glycoproteins expressed on malignant PCs [ 6 ]. It induces the death of PCs through various mechanisms, including antibody‐dependent cell‐mediated cytotoxicity, complement‐dependent cytotoxicity, and apoptosis induction. After the encouraging phase III ANDROMEDA trial [ 7 , 8 , 9 , 10 ], daratumumab in combination with CyBorD (bortezomib + dexamethasone + cyclophosphamide) was granted approval by the Food and Drug Administration (FDA) for the treatment of patients with newly diagnosed AL amyloidosis.

The current dosage and administration frequency of daratumumab for AL amyloidosis treatment are based on the treatment regimen for MM, that is, it can be taken once a week in Weeks 1–8, once every 2 weeks in Weeks 9–24, and once every 4 weeks after Week 25 [ 11 ]. However, the number of CD38 + PCs and tumor load in patients with AL amyloidosis is much lower than those in patients with MM [ 12 , 13 ]. In addition, patients with cardiac amyloidosis have poor tolerance to frequent medication [ 14 ]. Based on these disease characteristics of AL amyloidosis, it is necessary to determine the suitable dosage and its frequency for affected patients. Therefore, we conducted this prospective, single‐arm, multicenter clinical study ( chictr.org.cn identifier: ChiCTR2100049253) to evaluate the efficacy and safety of low‐frequency daratumumab therapy for the treatment of AL amyloidosis.

Methods

Patients and Study Design

This study was a prospective, multicenter, single‐arm clinical trial including a total of 48 patients with AL amyloidosis confirmed by pathological biopsy from July 2021 to May 2024. These patients received low‐frequency daratumumab at the First Affiliated Hospital, Zhejiang University School of Medicine, at the Huzhou Central Hospital, at the Taizhou Hospital of Zhejiang Province, and at the Jinhua People's Hospital, China. Among these patients, 38 were newly diagnosed and 10 were relapsed and refractory patients.

The patients enrolled were over the age of 18 whose pathological biopsy of the system or organs (kidney, heart, liver, skin) involved in the primary disease clearly showed AL amyloidosis. Patients with local, genetic or secondary amyloidosis were excluded, as were those whose hematologic response could not be evaluated or those who exhibited plasma cell dyscrasias meeting the diagnostic criteria for multiple myeloma or other hematologic malignancies. This study was approved by the institutional review boards or ethics committees of three hospitals and conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization and Good Clinical Practice Guidelines. The Clinical Trial Registration Number is ChiCTR2100049253 ( chictr.org.cn identifier: ChiCTR2100049253). All patients provided written informed consent to participate in this study.

All patients received daratumumab‐bortezomib‐dexamethasone (DVD) as induction therapy. Maintenance therapy was daratumumab monotherapy, given that most enrolled patients were older, frail, or had advanced cardiac involvement. Induction therapy consisted of six cycles of 28 days each. Since the subcutaneous daratumumab preparation had not entered the Chinese market during this clinical trial, we used intravenous daratumumab in a dose of 16 mg/kg for our patients. In this trial, the frequency of daratumumab was once every 2 weeks in Weeks 1–8 and once every 4 weeks in Weeks 9–24. During induction, bortezomib (1.3 mg/m 2 ) and dexamethasone (20 mg) were administered weekly for the first 24 weeks. After Week 25, maintenance with daratumumab monotherapy was conducted every 8 weeks. According to the International Society of Amyloidosis (ISA) efficacy evaluation standards [ 15 ], evaluation was conducted once every treatment course. The primary endpoint was hematologic ORR, and the secondary endpoints were hematologic response, organ response, progression‐free survival (PFS), overall survival (OS), and safety. The evaluation was performed in accordance with the intention‐to‐treat principle.

The diagnostic criteria for AL amyloidosis, as well as the standards for evaluating hematologic and organ involvement responses and disease progression were based on the Guidelines for non‐transplant chemotherapy for treatment of systemic AL amyloidosis [ 15 ] and Guidelines for the Diagnosis and Treatment of Systemic Light Chain Amyloidosis [ 16 ]. Detailed evaluation criteria are presented in the Supporting Information .

Statistical Analysis

The hematologic response rates and organ response rates at different time points were counted, and the best response rate, PFS, and OS. SPSS 25.0, Origin, SAS, and R language were used for statistical analysis and mapping. Data for non‐normal distribution were described as median (range), and intergroup comparisons were performed using the Wilcoxon rank‐sum test. Categorical variables were expressed as absolute numbers (ratios), and intergroup comparisons were performed using the χ 2 test or Fisher's exact test. PFS and OS were summarized descriptively using the Kaplan–Meier method, and comparisons between groups were made using the log‐rank test. All reported p values were two‐sided, with p < 0.05 considered a statistically significant difference.

Results

Clinical Features of Enrolled Patients

From July 2021 to May 2024, a total of 48 patients were enrolled, including 30 males (62.5%), 38 newly diagnosed patients (79.2%), and 10 relapsed and refractory patients (20.8%). The median age of newly diagnosed and relapsed and refractory patients was 64 years (range, 44–80) and 65 years (range, 57–72), respectively. Among the 48 enrolled patients, 5 patients (10.4%) had κ light chain type and 43 patients (89.6%) had λ light chain type. Bone marrow plasma cell percentage was stratified as follows: < 5% in 23 patients (47.9%), 5%–10% in 18 patients (37.5%), and 10%–20% in 7 patients (14.6%). The median number of involved organs was 2 (range, 1–4). A total of 29 patients (60.4%) had renal involvement, 39 patients (81.3%) had cardiac involvement, and 6 patients (12.5%) had hepatic involvement. Among all enrolled patients, 22 (45.8%) were diagnosed with European revised Mayo stage III AL amyloidosis, consisting of 18 newly diagnosed (47.4%) and 4 relapsed and refractory patients (40.0%). Of these, 12 patients (25.0%) were stratified into European revised Mayo stage IIIB AL amyloidosis group, including 11 newly diagnosed (28.9%) and 1 relapsed and refractory case (10.0%). Renal involvement was evaluated per the Palladini renal staging system [ 17 ]. Among newly diagnosed patients, 26 out of 38 (68.4%) presented with stage I renal impairment and 12 (31.6%) with stage II, while no patients had stage III disease. In relapsed and refractory cases, 4 (40.0%) were classified as stage I, 3 (30.0%) as stage II and 3 (30.0%) as stage III. The median number of cycles of the low‐frequency daratumumab regimen was 8 (range, 2–19) in newly diagnosed patients and 9 (range, 4–32) in relapsed and refractory patients. The baseline demographic and clinical characteristics are displayed in Table 1 .

For the 10 enrolled relapsed and refractory patients, 3 (30.0%) were primary refractory to prior first‐line therapy, and 7 (70.0%) were relapsed after achieving a durable hematologic response to prior treatment. The median number of prior systemic therapy lines was 1 (range, 1–3). Regarding prior treatment exposure, all 10 patients (100.0%) had previously received bortezomib‐based therapy, and 2 patients (20.0%) had received immunomodulatory drugs (lenalidomide or thalidomide) based therapy. The best hematologic response to prior systemic therapy was CR in 2 patients (20.0%), VGPR in 3 patients (30.0%), and partial response (PR) in 2 patients (20.0%).

Hematologic Efficacy

The details of the duration of on‐treatment and follow‐up, the best hematologic response, and the final disease progression or death status for each AL amyloidosis patient are depicted in a swimmer plot, stratified by “newly diagnosed” and “relapsed and refractory” groups (Figure 1 ).

After 3 months of treatment, the number of evaluable patients for hematologic efficacy decreased to 43. Two patients were transferred to local hospitals for further treatment, one discontinued treatment voluntarily, one's treatment was discontinued due to cardiac sudden death, and one died due to heart failure and pericardial effusion (Figure S1B ). Among the remaining 43 patients, the percentage of patients with hematologic VGPR or better was 72.1% (95% confidence interval [CI]: 58.1–86.1), including 37.2% (95% CI: 22.2–52.3) with CR and 34.9% (95% CI: 20.0–49.7) with VGPR, and the ORR was 90.7% (95% CI: 81.7–99.7) (Table S1 , Figure 2A ). At 3 months, the percentage of newly diagnosed patients with hematologic response ≥ VGPR was 75.8% (95% CI: 60.3–91.2), including 36.4% (95% CI: 19.0–53.7) CR and 39.4% (95% CI: 21.8–57.0) VGPR, with an ORR of 90.9% (95% CI: 80.6–99.6) (Table S1 , Figure 2A ). The CR, VGPR, and ORR rates of relapsed and refractory patients were 40.0%, 20.0%, and 90.0%, respectively.

After 6 months of treatment, the number of evaluable patients for hematologic efficacy decreased to 39. Among them, the percentage of patients with hematologic VGPR or better was 82.1% (95% CI: 69.4–94.7), including 56.4% (95% CI: 40.1–72.7) with CR and 25.6% (95% CI: 11.3–40.0) with VGPR, with an ORR of 87.2% (95% CI: 76.2–98.2) (Table S1 , Figure 2A ). At 6 months, the percentage of newly diagnosed patients with hematologic response ≥ VGPR was 86.7% (95% CI: 73.8–99.6), including 60.0% (95% CI: 41.4–78.6) CR and 26.7% (95% CI: 9.9–43.5) VGPR, with an ORR of 90.0% (95% CI: 78.6–100.0) (Table S1 , Figure 2A ). The CR, VGPR, and ORR rates of relapsed and refractory patients were 44.4%, 22.2%, and 77.8%, respectively.

Considering the best hematologic response at any time point, 45 patients (93.8%, 95% CI: 86.6–100.0) achieved hematologic response, and 40 patients (83.3%, 95% CI: 72.4–94.3) achieved hematologic VGPR or better (Figure 2A ).

A total of 18 patients were categorized as having newly diagnosed European revised Mayo stage III AL amyloidosis, of whom 14 patients were evaluated for hematologic response after 3 months of treatment. The percentage of European revised Mayo stage III patients with hematologic response ≥ VGPR at 3 months was 78.6%, including 21.4% CR and 57.1% VGPR, with an ORR of 85.7%. A total of 11 patients were categorized as newly diagnosed European revised Mayo stage IIIB, of whom hematologic response could be evaluated for 7 at 6 months after treatment. At 6 months, 57.1% of the Mayo stage IIIB patients achieved hematologic CR, 14.3% achieved VGPR, and the ORR was 71.4%.

In all patients, the median time to first hematologic response was 15 days (range, 10–57 days), and the median time to first hematologic CR was 57 days (range, 14–294 days). Among newly diagnosed patients, the median time to first hematologic response and first hematologic CR were 14 days (range, 13–57 days) and 59 days (range, 14–294 days), respectively. For relapsed and refractory patients, the corresponding median time was 21 days (range, 10–52 days) and 57 days (range, 27–108 days), respectively.

Organ Efficacy

A total of 39 patients had cardiac involvement. At 3 months, the number of evaluable patients for cardiac response decreased to 29. The cardiac response rate at 3 months was 31.0%, including 6.9% cardiac‐CR, 10.3% cardiac‐VGPR and 13.8% cardiac‐PR (Table S2 , Figure 2B ). In newly diagnosed patients, the 3‐month cardiac response rate was 38.1%, including 9.5% cardiac‐CR, 9.5% cardiac‐VGPR and 19.0% cardiac‐PR. In relapsed and refractory patients, the 3‐month cardiac response rate was 12.5%. At 6 months after treatment, the number of evaluable patients for cardiac response was 26. The cardiac response rate at 6 months was 53.8%, including 3.8% cardiac‐CR, 15.4% cardiac‐VGPR and 34.6% cardiac‐PR (Table S2 , Figure 2B ). In newly diagnosed patients, the 6‐month cardiac response rate was 61.9%, including 4.8% cardiac‐CR, 14.3% cardiac‐VGPR and 42.9% cardiac‐PR. In relapsed and refractory patients, the 6‐month cardiac response rate was 20.0%. Among newly diagnosed patients, at 6 months the overall cardiac response rate for European revised Mayo stage III patients was 54.5%, while for the highest‐risk Mayo stage IIIB subgroup the 6‐month cardiac response rate reached 71.4%. The median time to first cardiac response was 44 days (range, 10–730 days). The median time to first cardiac response in newly diagnosed and relapsed and refractory patients was 44 days (range, 14–489 days) and 50 days (range, 10–730 days), respectively.

A total of 29 patients had renal involvement. After 3 months of treatment, the number of patients who could be evaluated for renal response reduced to 18. In these 18 patients, the renal response rate at 3 months was 50.0%, including 11.1% renal‐CR, 22.2% renal‐VGPR, and 16.7% renal‐PR (Table S2 , Figure 2C ). In newly diagnosed patients, the 3‐month renal response rate was 42.9%, including 14.3% renal‐CR, 21.4% renal‐VGPR, and 7.1% renal‐PR. In relapsed and refractory patients, the 3‐month renal response rate was 75.0%. At 6 months, the number of evaluable patients for renal response was 17. The renal response rate at 6 months was 47.1%, including 29.4% renal‐VGPR and 17.6% renal‐PR (Table S2 , Figure 2C ). In newly diagnosed patients, the 6‐month renal response rate was 46.2%, including 30.8% renal‐VGPR and 15.4% renal‐PR. Meanwhile, in relapsed and refractory patients, the renal response rate was 50.0% at 6 months. The median time to first renal response was 101 days (range, 13–504 days). The median time to first renal response in newly diagnosed and relapsed and refractory patients was 110 days (range, 29–504 days) and 47 days (range, 13–142 days), respectively.

Of the 6 patients with hepatic involvement, 2 (33.3%) achieved hepatic response, and the time to hepatic response in these two patients was 160 and 157 days, respectively.

Survival Analysis

During the follow‐up period, a total of 8 patients (16.7%) had disease progression according to the ISA consensus criteria, including 5 newly diagnosed patients and 3 relapsed and refractory patients. After 6 months of treatment, 4 patients (8.3%) had disease progression, including 2 newly diagnosed and 2 relapsed and refractory patients. At 12 months, 7 patients (14.6%) had disease progression, including 4 newly diagnosed and 3 relapsed and refractory patients. A total of 5 patients (10.4%) experienced all‐cause death during the follow‐up period, all of which occurred within 12 months after treatment initiation. The cumulative all‐cause mortality of the full cohort was 0% at 1 month, 4.2% (2/48) at 3 months, 6.3% (3/48) at 6 months, and 10.4% (5/48) at 12 months. In the newly diagnosed cohort ( n = 38), 4 patients (10.5%) died during the follow‐up period, including 2 patients who died of cardiac amyloidosis‐related heart failure and 1 patient who died of cardiac arrest. In the relapsed and refractory cohort ( n = 10), 1 patient (10.0%) died of grade 5 septic shock.

At the median follow‐up of 26.0 months (range, 1.6–39.4 months), the median PFS was not reached in either newly diagnosed patients or relapsed and refractory patients. The respective 1‐year and 2‐year PFS rates were 87.5% (95% CI: 77.8–97.2) and 83.3% (95% CI: 72.4–94.3) in all patients (Figure 3A ), 89.5% (95% CI: 79.3–99.7) and 86.8% (95% CI: 75.6–98.1) in newly diagnosed patients, and 80.0% (95% CI: 49.8–100.0) and 70.0% (95% CI: 35.4–100.0) in relapsed and refractory patients, respectively.

Similar to PFS, after a median follow‐up of 26.0 months, the median OS was not reached in either newly diagnosed or relapsed and refractory patients. The 1‐year and 2‐year OS rates were both 89.6% (95% CI: 80.6–98.5) for all patients (Figure 3B ), 89.5% (95% CI: 79.3–99.7) for newly diagnosed patients, and 90.0% (95% CI: 67.4–100.0) for relapsed and refractory patients. The 6‐month OS rate for newly diagnosed European revised Mayo stage III patients was 88.9%, with 1‐year and 2‐year OS rates both at 77.8%, and for newly diagnosed Mayo stage IIIB patients the 6‐month OS rate was 81.8%, with 1‐year and 2‐year OS rates both at 72.7%.

Of the 48 patients, 33 (68.8%) received maintenance therapy, while 15 (31.3%) did not. These 15 patients comprised 13 newly diagnosed and 2 relapsed and refractory cases. Among the newly diagnosed patients, 2 patients died of disease‐related complications during the induction phase before the start of maintenance; 3 patients had incomplete treatment records following transfer back to their local hospitals; 1 patient underwent regimen modification due to suboptimal therapeutic response; and 7 patients declined subsequent maintenance therapy due to social or personal factors. Of the 2 relapsed and refractory patients, 1 patient died during induction therapy and 1 patient refused further treatment for personal reasons. The respective 1‐ and 2‐year PFS rates were 97.0% (95% CI: 90.8–100.0) and 93.9% (95% CI: 85.3–100.0) in patients receiving maintenance, and 66.7% (95% CI: 39.6–93.7) and 60.0% (95% CI: 31.9–88.1) in patients without maintenance. There was a statistical difference in PFS between these two groups ( p = 0.004) (Figure 3C ). The 1‐ and 2‐year OS rates were both 100.0% for patients receiving maintenance, and 66.7% (95% CI: 39.6–93.7) for patients without maintenance. There was also a statistical difference in OS between the two groups ( p < 0.001) (Figure 3D ). In the subgroup analysis of patients with different hematologic responses, significant differences in PFS and OS were observed between those who received maintenance therapy and those who did not (all p < 0.05) (Figure 4 ). These findings remained consistent when patients were further stratified into newly diagnosed and relapsed and refractory subgroups.

Drug Safety

In terms of safety endpoints, 86.8% of newly diagnosed patients and 100% of relapsed and refractory patients experienced at least one adverse event (AE), and 31.6% of newly diagnosed patients experienced at least one grade ≥ 3 AE. The most prevalent higher‐grade adverse events were anemia (7/48, 14.6%), thrombocytopenia (5/48, 10.4%), neutropenia (4/48, 8.3%), cardiac arrest (4/48, 8.3%), and infusion reaction (4/48, 8.3%) (Table 2 ). Among these, two patients experienced grade 5 cardiac arrest and one patient developed grade 5 septic shock, all of which resulted in death. Additional safety analyzes are presented in the Supporting Information .

Discussion

To our knowledge, this study is the first prospective, multicenter phase 2 clinical trial to explore a low‐frequency daratumumab treatment regimen and evaluate its efficacy and safety in the treatment of AL amyloidosis. Currently, the internationally recognized treatment regimen for daratumumab in the ANDROMEDA trial is 1800 mg of daratumumab administered subcutaneously weekly in cycles 1 and 2, once every 2 weeks in cycles 3–6, and once every 4 weeks thereafter until disease progression, with each cycle lasting for 28 days [ 7 ]. Many clinical trial designs are based on this standard dose for the treatment of AL amyloidosis. Chakraborty et al. evaluated 84 AL patients who received first‐line daratumumab‐based treatment [ 18 ], among which 48% achieved CR, 74% achieved VGPR or better, and the 2‐year OS was 79.4%. Eleven out of 84 patients (13.4%) had an infection in the first 6 months that was either≥grade 3 or led to treatment discontinuation, similar to the results of the ANDROMEDA trial [ 7 ]. Bazarbachi et al. enrolled 100 patients with newly diagnosed AL who received prior treatment based on standard daratumumab, and the median follow‐up time was 22.3 months. Nearly half (46.4%) of patients achieved CR, 21.4% achieved VGPR, and 3.6% achieved low dFLC‐PR [ 4 ]. In our study, we employed a daratumumab regimen at half the standard dosing frequency. Encouragingly, the hematologic and organ response rates were consistent with the above results. Importantly, this low‐frequency treatment strategy also conferred a favorable safety profile, with a relatively low incidence of grade ≥ 3 adverse events.

Considering newly diagnosed patients with advanced AL amyloidosis, low‐frequency daratumumab therapy also induced a rapid and profound response. In a prospective study of standard‐frequency daratumumab in combination with bortezomib and dexamethasone in the treatment of newly diagnosed Mayo 2004 Phase III AL amyloidosis [ 11 ], the percentage of patients with hematologic VGPR or better at 3 months was 67.5%, with an ORR of 82.5%, and the percentage of patients with cardiac response at 6 months was 47.5%, which was similar to our results. Oubari et al. evaluated the addition of standard‐frequency daratumumab to first‐line therapy in patients with newly diagnosed stage IIIB AL amyloidosis. At 6 months, the cardiac response rate in the daratumumab group was 45.8%, the hematologic ORR was 66.7%, and the OS rate was 70% [ 19 ]. In our study, among newly diagnosed European revised Mayo stage IIIB patients treated for 6 months, the hematologic ORR was 71.4%, the cardiac response rate was 71.4%, and the OS rate was 81.8%, with these outcomes being numerically similar to those of standard treatment. Our patients exhibited longer survival times, which may be attributed to the better tolerance of low‐frequency therapy in advanced‐stage cases and lower early mortality rates.

Low‐frequency daratumumab therapy also has promising efficacy in relapsed and refractory patients. Bomsztyk et al. evaluated the efficacy of daratumumab‐bortezomib‐dexamethasone (DVD) in patients with relapsed and refractory AL amyloidosis [ 20 ]. The optimal overall hematologic response was CR in 42 (36.2%), VGPR in 39 (33.6%), and PR/NR in 35 (30.2%) patients, with a 1‐year OS of 83.7% [ 20 ]. In our study, evaluating the best hematologic response attained at any follow‐up time point, all 10 relapsed and refractory patients achieved hematologic response; 7 (70.0%) achieved hematologic VGPR or better, 5 (50.0%) achieved CR, and the 1‐ and 2‐year OS rates were both 90.0%, which were all similar to their results.

Given the characteristically low plasma cell tumor burden in systemic AL amyloidosis, there has been growing interest in treatment de‐escalation relative to the standard ANDROMEDA regimen. Contemporary studies increasingly focus on streamlining combination regimens and reducing treatment intensity, with the aim of preserving efficacy while minimizing treatment‐related toxicity. Khwaja J et al. evaluated the DVTD (daratumumab‐bortezomib‐thalidomide‐dexamethasone) regimen in systemic AL amyloidosis [ 21 ]. They administered 1800 mg of daratumumab weekly during cycles 1–2 and every 2 weeks during cycles 3–4, with each cycle lasting for 28 days. At 3 and 6 months, the hematologic CR, VGPR, and PR rates were 41%, 38%, 15%, and 56%, 18%, 15%, respectively. These results were similar to ours. Kastritis et al. assessed the use of daratumumab monotherapy in newly diagnosed stage IIIB AL amyloidosis patients. Among the 29 patients, 21 (72.4%) achieved their best hematologic response (PR or better), including 6 (20.7%) with CR, 8 (27.6%) with VGPR, and 7 (24.1%) with PR [ 22 ]. The efficacy outcomes in our study were relatively higher than those from a European cohort including 346 stage III AL amyloidosis patients receiving daratumumab‐free regimens [ 23 ]. In parallel, Jian Li et al. discontinued cyclophosphamide‐based protocols and evaluated the efficacy of daratumumab with bortezomib and dexamethasone in newly diagnosed Mayo 2004 stage IIIA or IIIB AL amyloidosis patients [ 11 ]. This reduced‐dose regimen demonstrated an effectiveness equivalent to the standard regimen in this population. Taken together, these findings support the feasibility of de‐escalated treatment strategies for systemic AL amyloidosis, and our low‐frequency daratumumab scheduling approach further expands this established paradigm.

In recent years, the survival benefit of daratumumab maintenance therapy in AL amyloidosis has been confirmed by high‐level evidence. Our findings demonstrate that a halved‐frequency daratumumab maintenance regimen similarly confers favorable survival benefits. In the ANDROMEDA Phase 3 trial, the 2‐year OS rate of patients receiving maintenance treatment with daratumumab at a standard frequency of once every 4 weeks was 86.2% [ 7 ], while in our study, the 2‐year OS rate of patients receiving the same agent at a halved frequency was 100.0%. In our cohort, long‐term survival was significantly improved among patients who received maintenance therapy compared to those who did not. The survival improvement with maintenance therapy was consistent across all subgroups, regardless of the depth of hematologic response achieved after induction (CR, VGPR, or PR), and regardless of whether patients were newly diagnosed or relapsed and refractory. Our study is the first prospective multicenter trial to demonstrate that an every‐8‐week low‐frequency daratumumab maintenance regimen still confers profound and consistent survival benefits, which aligns with our core hypothesis that reduced‐frequency dosing is sufficient to maintain clonal control in AL amyloidosis, while minimizing treatment burden and toxicity. For patients with advanced cardiac amyloidosis, frequent hospital visits, intravenous infusions, and treatment‐related adverse events (such as infection and infusion reactions) can exacerbate cardiac decompensation and worsen quality of life. Our low‐frequency maintenance regimen reduced the number of annual infusions by 50% compared with the standard regimen, while maintaining excellent long‐term disease control and survival outcomes.

Notably, 8 patients refused subsequent maintenance treatment due to social or personal reasons in this study, which is a relatively high proportion. Due to the large heterogeneity of AL amyloidosis, some patients have insidious onset and no obvious clinical symptoms in the early stage. After achieving hematological remission, they may feel subjectively well, which may reduce their willingness to continue long‐term treatment. Secondly, in real‐world clinical practice, treatment decisions are often influenced by various non‐medical factors such as economic burden, inconvenient transportation, and family support. These factors collectively contribute to a higher rate of treatment refusal, reflecting the complexity of real‐world research, but also suggesting that potential selection bias should be considered when interpreting the benefits of maintenance treatment.

There are several limitations of this research. First, some patients discontinued treatment or were lost to follow‐up during the study period, leading to partial loss of patient‐level data, which may introduce a certain degree of bias to the long‐term survival analysis. Second, the overall sample size of our study is relatively small, especially for the relapsed and refractory patient cohort, which limits the generalizability of our findings to this population. Most importantly, the limited sample size significantly hampers the statistical power of all subgroup analyzes, particularly the analyzes stratified by different categories of hematologic response (CR, VGPR, and PR), and these subgroup analysis results should be interpreted as exploratory rather than confirmatory. Future large‐scale, multicenter randomized controlled trials are needed to validate the efficacy of this low‐frequency daratumumab regimen. Despite the above limitations, our trial is the first prospective multicenter study to explore a low‐frequency daratumumab regimen for systemic AL amyloidosis and demonstrates that this regimen is an effective, safe, and clinically feasible treatment strategy for both newly diagnosed and relapsed and refractory AL amyloidosis patients.

Author Contributions

Xinyi Meng: conceptualization, methodology, software. Li Huang: conceptualization, methodology. Jinuo Wang: conceptualization, methodology. Qiu Fang: conceptualization, methodology. Jintao Lin: conceptualization, methodology, data curation, investigation, formal analysis, visualization, writing – original draft, writing – review and editing, software. Jian Shen: conceptualization, methodology. Xiaoyan Han: conceptualization, methodology. Gaofeng Zheng: conceptualization, methodology. Yi Zhao: conceptualization, methodology. Jingsong He: conceptualization, methodology. Li Yang: conceptualization, methodology. Yi Li: conceptualization, methodology. Zhen Cai: conceptualization, methodology, writing – review and editing, funding acquisition, supervision, project administration, validation. Jing Chen: conceptualization, methodology. Haimeng Yan: conceptualization, methodology. Donghua He: conceptualization, methodology, resources, writing – review and editing, project administration, supervision, validation. Xing Guo: conceptualization, methodology. Hui Yan: conceptualization, methodology, software. Wenjun Wu: conceptualization, methodology.

Funding

The study was supported by the Natural Science Foundation of Zhejiang Province (LY22H080003).

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Table S1: Summary of confirmed hematologic responses.

Table S2: Summary of cardiac, renal and hepatic response assessments.

Figure S1: Trial profile. (A) Distribution of patients receiving induction and maintenance therapy. (B) Number of patients who could be evaluated for hematologic efficacy. The survival status of all patients was monitored throughout the trial.

Data Availability Statement

The datasets generated and/or analyzed during the current study are available from the corresponding author upon reasonable request.

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