Daratumumab for Anti-CD20-Refractory Membranous Nephropathy

Introduction: Rituximab (RTX) is a cornerstone of therapy for primary membranous nephropathy (MN). However, up to 35-40% of patients do not achieve remission despite depletion of circulating B cells. We discuss a patient with refractory MN who was successfully treated with daratumumab, a plasma cell-directed anti-CD38 monoclonal antibody (mAb). Case Description: An 80-year-old man presented with anasarca, creatinine (Cr) 1.1 mg/dL, 24-hour urine protein 11.2g, and anti-phospholipase A2 receptor (PLA2R) level 481 relative units (RU)/mL. Kidney biopsy showed subepithelial deposits with basement membrane spikes and diffuse IgG, C3, and PLA2R staining, confirming PLA2R+ MN. He began therapy with RTX 1gx2 in addition to supportive care. At 8 months, he had persistent edema with urine protein to creatinine ratio (UPCR) 11.65 g/g and anti-PLA2R 383 RU/mL. Due to his frailty and age, we elected against treatment with cyclophosphamide (CYC). He was treated with tacrolimus followed by obinutuzumab (OBI) 1gx2. However, despite total depletion of CD19+ B cells, he achieved only partial remission with Cr 2.04 mg/dL, UPCR 7.033 g/g, and anti-PLA2R 78 RU/mL at 6 months. We arranged for daratumumab (DARA) 1800mg weekly injections. At 6 weeks, his edema had resolved, with undetectable PLA2R level, Cr 1.68 mg/dL, and UPCR 4.49 g/g. At 4 months, PLA2R remained undetectable with UPCR 4.03 g/g (Figure 1) Discussion: Treatment of patients with RTX-resistant MN who are unable to tolerate CYC remains a challenge. Recent reports have demonstrated the potential of newer anti-CD20 mAbs such as OBI for patients with refractory disease. Plasma cell-directed agents like bortezomib or DARA, first approved for B cell malignancies, are now being investigated for autoimmune disease. For our patient, more than 18 months of B cell-depleting therapy led to only partial improvement in PLA2R titers and failed to produce clinical improvement. DARA was able to achieve rapid serologic remission and reversal of his Cr trend, suggesting that anti-CD38 therapy holds promise for multidrug-resistant MN.Clinical course