Daratumumab improves the hematological response and kidney function of patients with light chain deposition disease
Year: 2024
Type: article
Study design: Observational Study
Abstract: To the Editor: Light chain deposition disease (LCDD) is a rare systemic complication of plasma cell disorders that primarily affects the kidneys, and LCDD can lead to chronic kidney failure.[1] Before the development of novel anti-plasmacyte agents, the overall prognosis of LCDD patients was poor. The introduction of novel plasmacyte-targeted therapies, such as the proteasome inhibitor bortezomib, has improved kidney survival in LCDD patients.[2] However, the kidney response rate of LCDD patients to bortezomib-based treatment remains approximately 50%, and 25.7% of patients progress to end-stage kidney disease (ESKD) within 60 months. Daratumumab, an anti-CD38 monoclonal antibody that has been available in China since 2021, has shown promising results in both multiple myeloma (MM) and light-chain (AL) amyloidosis patients.[3,4] Several case series have demonstrated rapid hematological responses and preservation of kidney function of daratumumab in LCDD patients who were previously treated with bortezomib.[5,6] However, the efficacy of a combination of daratumumab and bortezomib compared to regimes involving bortezomib alone in newly diagnosed LCDD patients has yet to be systematically assessed. We retrospectively reviewed our database to address this issue and conducted a comparative study. Twenty patients who were referred to Peking University First Hospital between 2018 and 2023 were enrolled. The inclusion criteria were as follows: (1) confirmed diagnosis of LCDD, characterized by the presence of diffuse linear monoclonal light chain deposits lacking immunoglobulin heavy chains along the basement membranes of renal distal tubules, glomeruli, and/or surrounding arteriolar myocytes as detected by immunofluorescence; (2) punctate powdery electron-dense deposits on tubular or glomerular basement membranes as shown by electron microscopy when available; and (3) history of at least one cycle of bortezomib-based therapy or one cycle of daratumumab-based therapy, as first-line therapy or at relapse. All patients with myeloma cast nephropathy were excluded. The detailed treatment scheduals are as follows: bortezomib was administered subcutaneously at a set dose of 2 mg weekly for 24 weeks; daratumumab was administered intravenously at a set dose of 800 mg weekly for eight weeks, followed by every other week for eight doses, and then every four weeks. The detailed definitions, treatment regimens, and statistical methods are presented in detail in Supplementary Material, https://links.lww.com/CM9/C209. The study was approved by the Ethics Committees of Peking University First Hospital (No. 2022-261-002). Written informed consent was obtained from the patients. The included 20 LCDD patients had an equal female-to-male ratio (1:1), a median age of 55 years (range: 49–61 years), a mean baseline serum creatinine level of 283.1 ± 155.6 μmol/L, and a median eGFR of 16.3 (Q1, Q3: 10.9, 46.8) mL−1·min−1·1.73 m−2. Seventeen patients had kidney impairment, and eight had acute kidney injury (AKI) before kidney biopsy. Ten out of 20 patients had an eGFR below 15 mL−1·min−1·1.73 m−2, but none were receiving kidney replacement therapy before biopsy. The median baseline 24-h urinary protein concentration was 4.1 (Q1, Q3: 1.2–6.1) g/day, and the mean serum albumin concentration was 34.7 ± 7.1 g/L. The mean hemoglobin concentration was 111.7 ± 18.4 g/L, and anemia was observed in 11 patients. Monoclonal gammopathy (immunoglobulin G [IgG], n = 7; IgA, n = 1; IgD, n = 1; or light chain (LC) only, n = 8) was detected in the serum and/or urine of 17 patients. All the patients who were tested for serum free light chains (FLC) had an abnormal κ/λ ratio, with a median difference between involved free light chain (iFLC) and uninvolved free light chain (dFLC) of 315.9 (Q1, Q3: 146.9–699.9) mg/L. The LC isotype was κ in 16 patients. The hematological diagnoses were monoclonal gammopathy of renal significance (MGRS, n = 14) and MM (n = 6). The baseline hematological status and kidney function were similar between patients with MGRS and patients with MM. Among the 13 patients with available data, t (11,14) was the most common cytogenetic abnormality (n = 6), while two patients had a 1q21 abnormality. None of the patients had extra-kidney organ involvement due to LCDD at baseline. The patients were divided into two groups based on whether daratumumab was included in their treatment. Ten patients received bortezomib-based therapy as the initial treatment. Another 10 patients received a combination of daratumumab and bortezomib as first-line therapy. The demographic, kidney, pathological, and hematological characteristics were similar between the two groups [Supplementary Table 1, https://links.lww.com/CM9/C209]. The median dose of bortezomib was 1.15 mg/m2 body surface area, and the median dose of daratumumab was 13 mg/kg body weight. All the patients received a median of six cycles of bortezomib-based therapy, and those who were treated with daratumumab received a median of 16 infusions. During the study, patients were followed up for a median duration of 12.5 (12.0–16.75) months. Both groups were monitored for a comparable period and administered equal cycles of bortezomib. After treatment, the overall hematological response rate was 75%. Of these, 11 patients achieved complete remission (CR) (n = 5) or very good partial remission (VGPR) (n = 6). The hematological response was similar between patients with MGRS and those with MM. There was a significant reduction in dFLC in the daratumumab group compared to the bortezomib group (–405.2 [Q1, Q3: –734.8, –247.1] mg/L vs. –76.5 [Q1, Q3: –117.1, 37.3] mg/L, respectively, P = 0.005). The daratumumab group exhibited a significantly higher rate of overall hematological response (CR + VGPR + PR) and a significantly shorter median time to overall hematological response than the bortezomib group [Supplementary Figure 1, https://links.lww.com/CM9/C209]. Multivariate Cox regression analysis revealed that daratumumab combination therapy (odds ratio [OR] = 20.361, 95% confidence interval [CI] = 3.249–127.614, P = 0.001) and female sex (OR = 10.624, 95% CI = 2.187–51.615, P = 0.001) were associated with a higher probability of achieving an overall hematological response. At the end of the follow-up period, the kidney response rate was higher in the daratumumab group than in the bortezomib group (80% vs. 10%, P = 0.005) [Supplementary Table 2, https://links.lww.com/CM9/C209]. The baseline characteristics of the patients who achieved a kidney response and those who did not were comparable. Univariate ordinal logistic regression analysis revealed that daratumumab combination therapy was associated with a higher probability of achieving a kidney response (OR = 36.000, 95% CI = 2.321–476.2; P = 0.007). During the follow-up period, seven patients reached the kidney endpoint within a median of 1.5 (Q1, Q3: 0.9–7.5) months. In the bortezomib group, five patients developed ESKD, and one experienced a decrease in the eGFR of more than 50%. In comparison, only one patient in the daratumumab group developed ESKD; however, the difference did not reach statistical significance (P = 0.057). The median kidney survival time was 50 months [Supplementary Figure 2, https://links.lww.com/CM9/C209]. Daratumumab treatment preserved kidney function [Supplementary Figure 3A, https://links.lww.com/CM9/C209], and the eGFR improved in the daratumumab group and deteriorated in the bortezomib group compared to the baseline group (0.57 mL−1 · min−1·1.73 m−2 per month vs. −1.33 mL−1·min−1·1.73 m−2 per month, P = 0.023, Supplementary Figure 3B, https://links.lww.com/CM9/C209). Kaplan–Meier curve analysis revealed that the kidney survival time was significantly longer in the daratumumab combination treatment group (26 months in the bortezomib group vs. an undefined value in the daratumumab group) and kidney responder group (12 months for those without a kidney response vs. an undefined value for those with a kidney response), as shown in Supplementary Figure 4, https://links.lww.com/CM9/C209. All the patients survived throughout the follow-up period. The treatment was well tolerated in both groups. No infusion-related reactions (IRRs) or life-threatening events were reported. The most prevalent side effect observed during therapy was lymphocytopenia (n = 8), which resulted in longer intervals between treatments. Five patients had pneumonia during follow-up, resulting in extended hospital stays and temporary treatment discontinuation. There was no discernible difference in the occurrence of adverse effects between the two groups (P = 0.370) [Supplementary Table 2, https://links.lww.com/CM9/C209]. LCDD patients typically present with hypertension, microhematuria, proteinuria, and kidney insufficiency.[1] Similar to AL amyloidosis and other plasma cell disorders, the management of LCDD relies on chemotherapy that targets the causative clones. Recent studies have confirmed the effectiveness of proteasome inhibitor-based regimens in treating LCDD and highlighted the utility of serial serum-free light chain measurements in assessing hematological responses.[7] Moreover, these investigations demonstrated that the criteria that define hematological response in AL amyloidosis can be applied to LCDD with equivalent prognostic value for long-term outcomes. Daratumumab, an anti-CD38 monoclonal antibody, has demonstrated high efficacy and safety in treating AL amyloidosis and MM.[3,4,8] In the context of LCDD, a study by Milani et al[6] demonstrated that adding daratumumab to bortezomib improved the hematological response rate and quality in refractory patients and overcame resistance to bortezomib. Another study in bortezomib-treated patients with AL amyloidosis and LCDD indicated an improvement in the depth of response after consolidation therapy with a short course of daratumumab.[9] However, in these studies, daratumumab was used as a second-line therapy. Kastritis et al[5] reported the use of daratumumab for managing 25 patients with MGRS (20 LCDD patients), 12 of whom were previously untreated. The results favored the use of daratumumab as primary therapy. The patients who were included in previous studies were mainly of Caucasian descent. Our study confirmed the superior efficacy of daratumumab combined with bortezomib compared to bortezomib alone as a first-line therapy for Chinese LCDD patients. Previous studies have demonstrated that the outcomes of systemic AL amyloidosis depend on the extent of the hematological response and the speed of response. Patients who achieved at least a VGPR and had a serum FLC concentration <20 mg/L within one month had better survival.[10] For LCDD, the need to reduce the FLC in early stages is more urgent since LCDD patients usually have worse kidney function at baseline and rapid progression of kidney disease. In our study, four patients in the bortezomib group developed ESKD within 1.25 months despite achieving hematological response at six months. The discrepancy between the timing of the hematological response and the timing of the organ response led to kidney deterioration. The combination of daratumumab and bortezomib as first-line therapy significantly reduced the time to hematological response by approximately five months, providing additional opportunity for kidney recovery. The optimal dosage and duration of daratumumab for treating patients with LCDD still need to be defined. We administered a lower-than-standard dose, which resulted in a satisfactory hematological response. Kastritis et al[9] proved that a short course of daratumumab consolidation (four infusions) after bortezomib therapy could improve the extent of the response. Among our patients, two patients received less than eight infusions of daratumumab due to economic issues. These patients were followed for 12 months, and the short course of daratumumab therapy still resulted in a hematological response and preserved kidney function. However, whether the reduced dosage and short course of daratumumab can continuously improve the hematological response in most patients remains unclear. The toxicity of the daratumumab regimens was low and consistent with previous descriptions and expectations. Adding daratumumab did not increase the risk of severe adverse events. In our center, we systematically used prophylactic antibiotics, which may have reduced the risk of infection in these patients. There are limitations in this study. This was a small retrospective study, and the follow-up duration was short. More data are needed for kidney survival analysis, and the small size of the population limits the statistical efficacy of these methods. In conclusion, our findings demonstrate that the combination of daratumumab and bortezomib-based regimens as primary treatment for LCDD yields superior hematological and renal responses and improves kidney function compared to bortezomib-based regimens alone while maintaining acceptable tolerability. Therefore, this combination should be considered a first-line treatment option for LCDD. However, further prospective multicenter studies investigating daratumumab-based therapies in patients with LCDD are warranted. Funding This study was supported by grants from the National High Level Hospital Clinical Research Funding (Scientific Research Seed Fund of Peking University First Hospital) (No. 2022SF37), National High Level Hospital Clinical Research Funding (No. 2022CR07), National Natural Science Foundation of China (No. 82070747), and CAMS Innovation Fund for Medical Sciences (No. 2019-I2M-5-046). Conflicts of interest Minghui Zhao reports consultancy agreements with AstraZeneca, GSK, INFLARX, Novartis, and Roche.
Source: Chinese Medical Journal
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,000
Awards: G1930372441, G6787137170
OpenAlex ID: W4404334183