Background: MGRS encompasses a group of heterogeneous disorders characterized by renal dysfunction caused by the interaction with an otherwise asymptomatic plasma cell or lymphoproliferative disorder. Two of the well-described types of MGRS are Proliferative Glomerulonephritis with Monoclonal Ig Deposition (PGNMID) and Paraprotein-Associated C3 Glomerulopathy. These disorders have a high risk of progression to ESRD and lack a standard treatment.

Objective: The objective of this phase 2 multicenter open-label trial is to evaluate the efficacy and safety of Isatuximab, an anti-CD38 monoclonal antibody, in patients with PGNMID or C3 glomerulopathy. Here, we report the outcomes of the patients (N=12) who have been treated in the clinical trial (NCT04614558).

Methods: Patients with newly diagnosed or previously treated PGNMID or C3 glomerulopathy with monoclonal gammopathy who had ≥1 g of proteinuria on 24-hour collection and an estimated glomerular filtration rate (eGFR) ≥30 mL/min were eligible. Prior treatment with an anti-CD38 antibody was an exclusion criterion. Patients received Isatuximab at 10 mg/kg, given weekly for the first cycle and then every other week for another 5 cycles. Response assessment was based on changes in proteinuria and serum creatinine. A complete response was defined as a drop in proteinuria below 500 mg/day, and a partial response was defined as a ≥50% reduction in 24-hour urine protein with stable creatinine (within 25% of baseline).

Results: A total of 12 patients were enrolled: N=9 with PGNMID and N=3 with C3 glomerulopathy. All patients had a renal biopsy confirming the diagnosis. One patient had received prior renal transplant. The median age 45 yrs (range 27–72). Median serum creatinine was 1.3 mg/dL (range 0.8–1.7), and median 24-hr urine protein was 3374 mg/24hrs (range 1150–6390). Three patients were previously treated (two patients with steroids, one patient with bortezomib + dexamethasone), while the rest were treatment naive. Monoclonal gammopathy was detectable by serum and bone marrow testing in 2/9 patients with PGNMID and 3/3 patients with C3 glomerulopathy. Among the 5 patients with monoclonal gammopathy, the median monoclonal protein size was 0.3 g/dL (range: 0.1–1.8 g/dL), and the median light chain ratio was 1.2 (range: 1–7.6).

All patients completed 6 cycles of therapy with Isatuximab, and the median follow-up was 12.2 months (range: 7.5-19.8). Therapy was well tolerated, with just 3 patients experiencing grade 3 toxicity. One patient, who had a history of prior kidney transplant, developed Epstein-Barr viremia with lymphadenopathy 4 months after completing therapy, which resolved with a decrease in immunosuppression and rituximab. Following this episode EBV was monitored in rest of the patients and no other patient developed ABV viremia. Another patient developed pulmonary embolism during the first cycle. First-dose infusion reactions occurred in 3/8 patients, with grade 1 reactions in two patients and a grade 3 reaction in one participant.

A renal response was observed in 75% (9/12) of patients, with partial responses noted in 5/9 and complete responses in 4/9 patients. All patients with C3 glomerulopathy had a response (complete response in one patient and partial response in 2 patients), while renal response rate in PGNMID was 66% (6/9 patients). Among the responding patients, the median time to response was 91 days (range: 19–273 days). The median reduction in proteinuria at the best response was 74% (range: 53–86%). Improvement in eGFR was observed in 2/4 patients who had decreased eGFR at enrollment. Among the responding patients, 3/9 progressed after discontinuation of isatuximab, with an increase in proteinuria at a median of 6.3 months (range: 2–8 months) after completing therapy on trial. None of the responding patients had worsening of eGFR after starting therapy. Among the non-responding patients, one progressed to ESRD from an eGFR of 35 mL/min at study enrollment, 3 months after completing the study treatment, while the other non-responding patients have stable eGFR. All patients are alive on the last follow-up.

Conclusion: Isatuximab monotherapy is well-tolerated and effective in patients with MGRS. However, a proportion of responding patients experience early progression after completing 6 months of therapy, suggesting the need for clinical trials testing a longer duration of therapy, and combination strategies with other anti-plasma cell therapies.

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2025
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