Renal recovery following daratumumab, lenalidomide, and dexamethasone therapy in a patient with newly diagnosed dialysis-dependent multiple myeloma

Abstract

An 81-year-old Japanese woman was diagnosed with Bence Jones protein κ-type multiple myeloma with acute kidney injury and severe anemia, complicated by congestive heart failure with triple vessel coronary artery disease. Her serum κ-free light-chain (FLC) level was 49,400 mg/L and κ/λ ratio was extremely high at 2373. Her kidney function deteriorated rapidly and required hemodialysis before initiating chemotherapy. A combination therapy of daratumumab (16 mg/kg), lenalidomide, and dexamethasone was initiated as a first-line treatment; the infusion rate of daratumumab was adjusted to reduce the heart load. The level of κ-FLC was rapidly reduced by 75% in only one week and by 99% after three weeks. Furthermore, she was dialysis-independent after the fourth dose of daratumumab. We report the first case of untreated patient with myeloma who had been successfully treated with daratumumab, lenalidomide, and dexamethasone therapy even in dialysis requiring state. Daratumumab may benefit patients with acute kidney injury caused by multiple myeloma, owing to the immediate need of FLC level reduction. Daratumumab and lenalidomide combination therapy could be a valuable treatment option for patients requiring dialysis when bortezomib may be hesitate to use due to severe heart disease.

Introduction

Renal impairment (RI) is a common complication of multiple myeloma (MM), diagnosed in 15–40% of patients; patients diagnosed with severe RI who require dialysis represent up to 10% of this population [1, 2]. The prognosis of patients on dialysis is poor, but can be improved in those who become dialysis-independent after successful treatment [3].

In recent years, combination therapies that include daratumumab, an anti-CD38 IgG-κ monoclonal antibody, are the preferred alternative for patients with newly diagnosed MM. Among all options for therapy, daratumumab and lenalidomide/dexamethasone (LEN/DEX) combination is one of the most successful regimens [4]. However, the efficacy and safety profiles of these drugs in patients with newly diagnosed MM and severe RI requiring dialysis have not been established because of exclusion of these patients from previous pivotal studies (MAIA trial [5] and ALCYONE trial [6]). Our study is the first to report the case of a patient with MM who was untreated and required dialysis and became dialysis-independent following successful treatment with daratumumab and LEN/DEX.

Case report

An 81-year-old Japanese woman with a medical history of hypertension and ischemic heart disease was admitted to a family hospital owing to acute exacerbation of chronic heart failure. She had a brain natriuretic peptide level of 1500 pg/mL caused by fluid overload and was diagnosed with anemia, with a hemoglobin level of 6.6 g/dL. A drug-eluting stent had been implanted in the left circumflex artery seven years ago for recovery from angina pectoris, and moderate stenosis in the left anterior descending artery and right coronary artery was observed one year prior. Her serum creatinine level was 1.0 mg/dL nine months ago but had worsened to 3.6 mg/dL at admission. Although a blood transfusion was performed, but her creatinine level rapidly worsened to 5.9 mg/dL. She was transferred to our hospital after one week owing to acute kidney injury. Her bone marrow biopsy revealed the presence of more than 70% CD138-positive monoclonal plasma cells. No osteolytic lesions were found in the whole-body bone computed tomography scan. Urinalysis revealed severe proteinuria (1.5 g/day), mostly of non-albuminuric type; Bence Jones protein-κ was also detected; the free light-chain (FLC) ratio was unusually high at 2373 (κ: 49,400 mg/L, λ: 20.8 mg/L). The cause of acute kidney injury was clinically diagnosed as light-chain cast nephropathy due to Bence Jones protein-κ-type MM. It was classified as stage II without any chromosomal abnormality, based on the Revised International Staging System for MM. Her urine output was 300–800 mL/day for the first few days after admission, but then decreased to 50–200 mL/day. Then, her renal functions further deteriorated, with creatinine level at 6.5 mg/dL. Her 24 h creatinine clearance was 7 mL/min. Her serum potassium level was 4.4 mEq/L and blood urea nitrogen level was 67 mg/dL. Arterial pH and HCO₃⁻ levels were 7.37 and 17.0 mEq/L. In addition, a chest radiograph indicated cardiac enlargement with congestion. We decided to start hemodialysis before chemotherapy to correct fluid management and improve metabolic acidosis. VPS-11HA (Asahi Kasei medical Co., Tokyo, Japan) was used as dialyzer in every hemodialysis. Dialysis was performed three times a week, and daratumumab and LEN/DEX were initiated as first-line therapy. Considering that she was an elderly patient with severe RI, the LEN dosage was reduced to 5 mg/day, and DEX was administered at 20 mg once a week simultaneously with a standard dose of daratumumab (16 mg/kg) on non-dialysis days (1, 8, 15, and 22) for eight weeks during the first two cycles, as reported in the MAIA trial schedule [5]. The infusion rate of daratumumab was 25 mL/h (standard rate 50 mL/h) initially and then increased by 25 mL/h every hour to reduce the heart load. Transient fever and chest discomfort with a non-ST segment change developed at the infusion rate of 75 mL/h; however, daratumumab administration was continued after adjusting the infusion rate. At the second dose, the infusion rate was initially 25 mL/h, and then increased to maximum rate of 125 mL/h (standard maximum rate 200 mL/h). Infusion-related reactions were not observed after the second dose. Her brain natriuretic peptide level decreased to 250–350 pg/mL due to fluid management on dialysis, and there was no exacerbation of heart failure with daratumumab and LEN/DEX therapy. A rapid decrease in the level of κ-FLC and an improvement in renal functions were observed, and she was dialysis-independent after the fourth dose of daratumumab (Fig. 1). Notably, the κ-FLC level reduced by 75% in only one week and by 99% after three weeks of initiation of daratumumab. Furthermore, the κ/λ ratio normalized to 1.36 after two cycles. Although LEN dosage was reduced owing to associated complication of neutropenia (< 1000/mm³) without infections, it was manageable with the administration of granulocyte-colony stimulating factor. Next, daratumumab and LEN/DEX were continued, and both the hematological response and renal functions remained stable, without the manifestation of severe adverse events.

Fig. 1.

Changes in serum Cr and κ-FLC levels in response to daratumumab, lenalidomide, and dexamethasone. The patient was dialysis-independent after the fourth dose of daratumumab by rapid reduction of κ-FLC levels. FLC free light chain, Cr creatinine

Discussion

RI is a well-known complication of MM and is associated with poor prognosis [1–3]. In MM patients with acute kidney injury, a 60% reduction in the FLC levels after an effective chemotherapy within 21 days contributes to improvement in renal function and prolonged survival time [7]; hence, agents with prompt tumor-suppressive effects are preferred. Proteasome inhibitor, such as bortezomib, is preferable in MM with RI because it has a shorter hematological and renal response time than immunomodulatory drugs [8]. However, proteasome inhibitors present a certain risk of cardiotoxicity. The frequency of cardiovascular adverse events in proteasome inhibitors has been reported to be 51% for carfilzomib and 17% for bortezomib [9]. The risk factors for cardiovascular adverse events are considered to be the use of carfilzomib, elevated baseline natriuretic peptide levels, and worsening of natriuretic peptide levels during one cycle of chemotherapy. Therefore, although the patient had severe RI requiring dialysis, she was treated with an LEN-based regimen rather than with bortezomib to minimize the risk of exacerbating heart failure complicated by triple vessel coronary artery disease. In the present case, we observed a rapid decrease in the level of involved FLCs within only one week of daratumumab and LEN/DEX therapy. Therefore, daratumumab could compensate for the inferior time for treatment response to immunomodulatory drugs.

The present case underwent hemodialysis during chemotherapy. The hemodialysis might have affected the decrease in FLCs, but VPS-11HA is a dialyzer with small membrane area and low dialysis efficiency. She was not receiving hemodiafiltration or plasma exchange. We therefore believe that the main cause of the rapid reduction in FLCs is not removal by hemodialysis.

MM is a disease that develops predominantly in the elderly [10]. Elderly patients often have various comorbidities, such as cardiovascular disease, chronic kidney disease, and metabolic syndrome. Thus, it is important to continue safe chemotherapy for such patients to avoid exacerbation of their condition from the viewpoint of onconephrology. In the present case, since the patient had severe RI and ischemic heart disease, the standard dose of daratumumab was administered by adjusting the infusion rate to reduce the heart load, thereby avoiding exacerbating heart failure. Infusion-related reactions, such as fever and chest discomfort, were observed, but they did not result in patient non-compliance with the treatment. We reported previously a similar case of MM where the patient required daratumumab therapy with a reduced infusion rate and dialysis [11]. We believe that daratumumab can be used safely and effectively in patients with severe RI and cardiac disorders. Recently, Mateos et al. reported a randomized, open-label, phase 3 trial (COLUMBA) in patients with myeloma, in which the subcutaneous administration of daratumumab was non-inferior to intravenous administration [12]. Although that study excluded patients with severe RI and an estimated creatinine clearance of < 20 mL/min/1.73 m², the subcutaneous administration of daratumumab in a clinical setting may be useful for fluid management in patients with severe RI complicated by heart disease in the near future.

Only few case reports of patients on dialysis treated with daratumumab are available [11, 13–17]. Among them, the patients who were able to become dialysis-independent or could manage with its reduced frequency showed a good hematological response [11, 13–16]. Cajalvo et al. reported the safety and efficacy of daratumumab monotherapy in 15 patients undergoing dialysis but did not demonstrate whether they recovered from RI [17]. In all of these cases, daratumumab was administered as a second-line therapy or beyond. To the best of our knowledge, our study is the first to use daratumumab as a first-line therapy in patients undergoing dialysis. The patient in our study had severe RI and was treated with daratumumab as a first-line treatment and showed favorable hematological and renal responses. Daratumumab-based regimens are currently one of the most effective treatments for MM, and we believe that extending their use to patients with severe RI could be beneficial. Additionally, our case report facilitates future research on treatment regimens for patients with MM requiring dialysis considering the complications of renal dysfunction. In the concept of onconephrology, the indication and adjustment of chemotherapy for cancer patients with severe RI are important topics. This is a valuable report in which a patient with acute kidney injury requiring dialysis was treated as aggressively as patients without renal impairment and showed favorable hematological effects and improvement in renal function.

In conclusion, we report the first case of an elderly untreated patient with MM who had been successfully treated with daratumumab and LEN/DEX therapy even in dialysis requiring state. Daratumumab may benefit patients with acute kidney injury who are newly diagnosed with MM and need immediate FLC level reduction owing to the drug’s rapid hematological response. Daratumumab and LEN/DEX regimen could be a valuable treatment option for untreated patients with MM requiring dialysis when bortezomib may be hesitate to use due to severe heart disease.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Declarations

Conflict of interest

The authors declare that they have no conflicts of interest associated with this manuscript.

Human and animal rights

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed consent

Informed consent was obtained from the patient in the study.