Abstract
Purpose
Daratumumab, a monoclonal anti-CD38 antibody, has been administered for relapsed refractory multiple myeloma (RRMM). The Pollux and Castor trials proved its efficacy, yet excluded patients with advanced-stage renal disease. Therefore, available experience in these patients is limited. Here, we aimed to emphasize the safety of daratumumab in 6 patients with kidney disease.
Methods
Six patients with RRMM diagnoses and renal impairment were included. Their mean ± standard deviation age was 63.6 ± 8.38 years. Three, two, and one patient(s) had immunoglobulin (Ig) G kappa, lambda light chain, and IgA lambda MM, respectively. All patients received 4 to 6 lines of anti-MM therapy before daratumumab treatment. Five had chronic kidney disease and 1 was admitted to the hospital with acute kidney injury due to myeloma relapse. Daratumumab was administered to all patients with close follow-up.
Results
Following treatment with daratumumab, kidney function was improved in 1 patient. In 1 patient, the glomerular filtration rate was slightly decreased and hemodialysis was initiated. In 2 patients already receiving hemodialysis, their dependency on hemodialysis continued. No adverse reactions were recorded. One patient achieved complete remission and 4 patients achieved very good partial remission.
Conclusion
Daratumumab can be administered safely, with improvements in kidney function possible in some patients. Studies involving larger patient groups are required to obtain more accurate data.
Introduction
Daratumumab, an immunoglobulin (Ig) G1 kappa monoclonal antibody directed toward CD38, is a widely accepted option for the treatment of relapsed refractory multiple myeloma (RRMM) patients. 1 The presence of renal disease at the initial diagnosis of MM has been reported in approximately 20% of patients, who require renal replacement therapy (RRT) at a rate of 1% to 13%. 2 Current data suggest the use of daratumumab is safe in patients in renal failure and may even improve renal function when creatinine clearance is reduced due to chronic kidney disease (CKD) or acute kidney injury caused by myeloma involvement.3,4 Here, we present the outcomes of 6 RRMM patients with renal disease who received daratumumab to underscore the safety of this drug in this group of patients.
Patients and Methods
We included 6 patients previously diagnosed with RRMM who were followed in the hematology department of Adnan Menderes University Hospital, Aydın, Turkey. Four and two patients were male and female, respectively, and their ages varied between 51 and 76 years (mean ± standard deviation age: 63.6 ± 8.38 years). Three, two, and one patient(s) had IgG kappa, lambda light chain, and IgA lambda MM, respectively. All patients received 4 to 6 lines of anti-MM therapy before daratumumab treatment. The glomerular filtration rate (GFR) for the patients with stable creatinine was calculated using the Cockcroft-Gault equation ([140-age] × lean body weight [kg])/(72 × serum creatinine [mg/dL]). 5 CKD was attributed to MM in 3 patients. Two patients (cases 1 and 6) formerly had CKD unrelated to MM and were already receiving RRT in the form of hemodialysis. One patient (case 2) received daratumumab during acute kidney injury due to myeloma relapse. Daratumumab therapy was initiated as a part of a combination regimen or monotherapy (with dexamethasone). Daratumumab (400 mg/20 mL vial) was administered at a dose of 16 mg/kg every week for a total of 8 doses, then every 2 weeks thereafter for another 8 doses, with additional plans for administration to continue every 4 weeks until disease progression. Premedication with steroids in addition to antihistaminic and antipyretic treatment was performed 30 min prior to administration. The infusion was performed intravenously, within 1000 mL of serum physiologic solution, with an initial dose of 50 mL/h, increasing the dose up to a maximum of 200 mL/h according to the tolerability of the patient. 6 All patients received acyclovir and trimethoprim-sulfamethoxazole for herpesvirus and pneumocystis jirovecii prophylaxis, respectively. The characteristics of the patients are described in Table 1.
The Characteristics of the Patients.
Abbreviations: ASCT, Autologous Stem Cell Transplantation; B, Bendamustine; C, Carfilzomib; CKD, Chronic kidney disease; CR, Complete response; Cy, Cyclophosphamide; D, Daratumumab; GFR, Glomerular filtration rate; I, Ixazomib; Ig, Immunoglobulin; Min, minute; ml, milliliter; N/A, not applicable; P, Pomalidomide; R, Lenalidomide; T, Thalidomide; V, Bortezomib; VAD, Vincristine + Adriamycin + dexamethasone; VGPR, very good partial response.
Acute renal injury demonstrating myeloma relapse.
With dexamethasone (d).
Results
No adverse events occurred during or after daratumumab infusion in any case and all patients tolerated the infusion. Regarding GFR, one patient (case 5) was evaluated within 1 month of data collection after initiating the therapy, whereas the others were evaluated after 3 months. After daratumumab infusion, the GFR was improved in 2 patients (cases 2 and 3). Dependency on RRT persisted for 2 patients. Deterioration of kidney function was observed in one CKD-diagnosed patient (case 5), who was admitted to the clinic with myeloma relapse and required RRT. One patient achieved complete remission and 4 patients had very good partial remission after 3 months of daratumumab therapy.
Discussion
Limited data concerning the safety of daratumumab in patients with kidney disease is possibly due to the exclusion of CKD patients (GFR < 20-30 mL/min) from the Pollux and Castor studies.7,8 An ongoing phase II trial (NCT03450 057), evaluating daratumumab combination therapy in myeloma requiring dialysis may be helpful by providing illustrative data. However, a few studies to date have already offered data on its efficacy and safety.4,9 Cejalvo et al reported a disease control rate of 87% and an overall response rate of 40% after administering daratumumab to 15 patients with CKD and RRMM who required RRT. These authors also reported that none of their dialysis non-dependent patients became independent and the median duration of response was 6.1 months. 4 Lovas et al 9 suggested that the progression-free survival rate of 11 (11.1%) CKD patients (GFR < 30 mL/min) among 99 patients who received daratumumab was comparable to that of patients without CKD and underscored the safety of the drug, which did not provide any increase in adverse reactions. Kuzume et al evaluated 13 patients with severe renal failure (≤15 mL/min/1.73 m2) due to MM and assessed daratumumab efficacy based on free light chain (FLC) reduction. A rapid decrease in FLC amount after the first dose of daratumumab was observed in 10 patients, and the median %age of FLC reduction was 69.6%. Notably, 3 of 6 previously dialysis-dependent patients achieved independence from dialysis. 10 The safety of daratumumab and its contribution to renal function improvement have also been emphasized in some case reports.2,3,11 In our study, we similarly observed a degree of anti-myeloma efficacy, reporting complete remission in 1 patient and very good partial remission in 4 patients, respectively. This assessment (performed at the end of 3 months for 5 patients) was performed earlier than in Cejalvo et al's study, which suggested the median duration of response was approximately 6 months. 4 As compared with in the research by Kuzume et al, the limitation of our study can be considered the absence of FLC measurements and follow-up as a reflection of kidney function. Regarding safety, we did not observe any adverse reactions or progression of renal disease except in one patient, supporting the use of daratumumab in patients with renal impairment. The slight decrease in renal function (from 15 to 8 mL/min) that occurred in case 5 was not thought to be related to daratumumab and was attributed to the kidney involvement of MM and the short time (1 month) between drug initiation and assessment.
Conclusion
Although daratumumab appears to be safe in patients with renal dysfunction based on reports from different centers, trials with greater numbers of patients should be performed to demonstrate the accuracy of this finding. To date, no potential mechanism of the drug in reversing renal impairment except the anti-myeloma efficacy has been reported. Also, according to our research, there were no adverse reactions that clearly accumulated in this group of patients. Until a novel algorithm has been described, centers may continue to use daratumumab with caution among patients with kidney disease.
Footnotes
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Author’s Note
This work was has been carried out in Adnan Menderes University Hospital, Aydın, Turkey.