Safety and efficacy of daratumumab in patients with multiple myeloma and severe renal failure

Abstract

There has been considerable improvement in the treatment of multiple myeloma (MM), but severe renal impairment (RI) owing to cast nephropathy (CN) is still one of the frequent complications requiring prompt treatment. CN is caused by the precipitation of large amounts of monoclonal free light chain (FLC) in the renal tubules.4 Therefore, RI treatment in these patients mainly focusses on the rapid reduction of FLC in the circulation, thereby improving renal function;3, 9 however, there are some exceptions, depending on renal pathology. Daratumumab is an anti-CD38 monoclonal antibody with remarkable efficacy in patients with both newly diagnosed and relapsed/refractory MM in combination with dexamethasone, proteasome inhibitor or immunomodulatory drugs.1, 2 However, there are no studies of daratumumab in patients with severe renal failure [estimated glomerular filtration rate (eGFR) <15 ml/min/1·73 m2], except for a few case reports. In the present study, we report on the efficacy and safety of daratumumab in patients with end-stage renal failure at our institution. We retrospectively reviewed 13 consecutive patients with MM admitted to Kameda Medical Center between June 2017 and November 2020 who presented with severe renal failure (≤15 ml/min/1·73 m2) and received at least eight doses of daratumumab (16 mg/kg). One patient received four doses of daratumumab and then switched to isatuximab owing to insurance coverage. Daratumumab was used as part of an induction or intensification therapy in patients who did not achieve a complete response (CR). To assess the efficacy of daratumumab on FLC reduction, we measured FLC levels before and 3 and 7 days after daratumumab infusion. Diagnosis and treatment response were assessed using the International Myeloma Working Group (IMWG) criteria.2, 6 Renal responses were defined according to the IMWG criteria for renal responses to therapy.2 Cytogenetic abnormalities (CAs) were detected using interphase fluorescence in situ hybridisation. All patients or their family members provided written informed consent, and the study was conducted in accordance with the Declaration of Helsinki and approved by the review board of Kameda Medical Center. Clinical characteristics and previous treatments are shown in Table S1. Six patients were on dialysis at presentation, nine underwent kidney biopsies, and four were diagnosed with CN, three with CN and light chain deposition disease, one with tubular amyloidosis and CN, and one with immunotactoid glomerulopathy. The median (range) time from diagnosis to daratumumab infusion was 2·0 (0·2–8·1) months and patients 1, 2 and 8 received daratumumab with very good partial response (VGPR), CR and stringent CR (sCR), respectively, because they had high-risk CA, and significant number of MM cells remained in their bone marrow as shown by eight-colour flow cytometry. At the last follow-up of the patients [median (range) duration from diagnosis of 23·7 (3·5–44·5) months], the best haematological responses of partial response, VGPR, CR and sCR were observed in one, one, two and nine patients respectively. Renal responses of stable disease (SD), MRrenal and CRrenal, were observed in seven, four and two patients respectively. Dialysis independence was achieved in three of the six initially dialysis-dependent patients (Table S2). Table 1 shows the changes in involved FLC (iFLC), differences between iFLC and uninvolved FLC (dFLC), and eGFR at diagnosis and after eight infusions of daratumumab. Changes in dFLC during daratumumab use are shown in Fig 1A. There was no significant increase in eGFR between the completion of the first eight infusions and the final follow-up. In all, 10 of the 13 patients had >50% FLC reduction 3 days after the first dose of daratumumab, and the median (range) percentage FLC reduction after the first daratumumab infusion was 69·6 (14·3–89·2)% (Fig 1B). The most common adverse event (in four patients) was Grade 1/2 infusion reaction after the first dose. Grade 2–3 cytomegalovirus reactivation occurred in three patients and was successfully treated with ganciclovir. Two patients experienced Grade 3 congestive heart failure and pneumonia, respectively, and were successfully treated in the intensive care unit (Table S3). Both patients resumed daratumumab therapy upon recovery. Daratumumab yielded a favourable haematological response and was relatively well tolerated in all patients with severe renal failure. The present study describes 13 patients with MM and severe renal failure who were treated by daratumumab in combination with various novel agents. A rapid reduction of FLC was observed in 10 of the 13 patients after the first dose of daratumumab in combination with bortezomib, at which point the degree of iFLC reduction was most pronounced. This observation has significant implications, considering the importance of reducing the serum FLC level as soon as possible in cases of CN.3, 4 Daratumumab directly kills myeloma cells shortly after its infusion through a variety of mechanisms, including complement-mediated cytotoxicity, antibody-dependent cytotoxicity and antibody-dependent phagocytosis.5, 8 Our observations support the use of daratumumab as a first-line treatment for patients with CN. In general, adverse events of daratumumab in patients with severe RI are similar to those in patients without RI. Congestive heart failure in a dialysis patient may be related to excessive fluid infusion combined with the use of high doses of dexamethasone. The subcutaneous use of daratumumab will solve this problem.7 The limitations of the present study include its retrospective nature and a lack of predefined treatment regimens. Treatment was modified according to the response of iFLC. In summary, although daratumumab was not administered as a single agent in the present study, it showed strong anti-tumour effects and a rapid reduction in FLC when administered in combination with other agents, with a relatively similar safety profile to that in patients with MM without severe RI. Because a rapid reduction in toxic FLC is crucial to the reversibility of RI, the early use of daratumumab in combination with effective anti-myeloma agents, coupled with intensive monitoring of serum FLC, may improve the treatment of severe renal failure in patients with MM. We would like to thank Dr Tomo Suzuki (Department of Nephology, Kameda Medical Center) for performing the kidney biopsy and his contributions on the diagnosis of renal pathology. We would like to thank Editage (www.editage.com) for English language editing. The patients in this study provided consent for publication with removal of all identifying information to retain privacy. Ayumi Kuzume and Kosei Matsue planned and designed the study, collected data and wrote the manuscript. Both contributed equally to this study. Rikako Tabata, Toshiki Terao, Takafumi Tsushima, Daisuke Miura, Kentaro Narita and Masami Takeuchi provided patient care. All the authors reviewed and approved the manuscript. The authors declare that they have no conflict of interest. Table S1. Patients’ characteristics. Table S2. Treatment and response to daratumumab. Table S3. Treatment-related adverse events in 13 patients with severe renal failure. 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