Isatuximab for Treatment of Monoclonal Gammopathy of Renal Significance (MGRS) - Results from a Prospective Phase 2 Trial

Background: MGRS encompasses a group of heterogeneous disorders characterized by renal dysfunction caused by 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 end stage renal disease (ESRD) and lack a standard of care treatment approach. Novel treatment strategies targeting plasma cells have shown promise.

Objective: The objective of this phase 2 open-label trial is to evaluate the efficacy and safety of Isatuximab, an anti-CD38 monoclonal antibody, in patients with PNGMID or C3 glomerulopathy. Here we report outcomes of the patients (N=8) who have been treated on 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 estimated glomerular filtration rate (eGFR) ≥30 mL/min were eligible. Prior treatment with anti-CD38 antibody was an exclusion criteria. Patients received Isatuximab 10mg/kg given weekly for the first cycle and then every other week for another 5 cycles for a total of 6 cycles. Response assessment was based on change in proteinuria and serum creatinine with complete response defined as drop in proteinuria below 500 mg/day and partial response defined as ≥ 50% drop in 24-hr urine protein with stable creatinine (within 25% of baseline).

Results: A total of 12 patients have been enrolled to date, and response data is available for 8 patients, N=6 with PGNMID and N=2 with C3 glomerulopathy. Median age for patients was 52 years (range 27-72). Baseline median serum creatinine was 1.2 (range 0.8-1.7) and 24-hr urine protein 2932 mg/24hrs (range 1150-5130 mg). All patients were newly diagnosed. Monoclonal gammopathy was detectable by serum and bone marrow testing in 2/6 patients with PGNMID and 2/2 patients with C3 glomerulopathy. All patients have completed 6 cycles of therapy with Isatuximab and the median follow-up is 308 days (range 225-476 days). Therapy was well tolerated with three patients experiencing grade 3 toxicity. One patient who had history of prior renal transplant developed Epstein Bar viremia with lymphadenopathy 4 months after completing therapy on trial, which resolved with decrease of immunosuppression and rituximab therapy. Another patient developed an episode of pulmonary embolism during first cycle. . First-dose infusion reactions occurred in 3/8 patients and were grade 1 in two patients and grade 3 in one participant.

Renal response was seen in 87% (7/8) of patients with partial response seen in 5/8 and complete response in 2/8 patients. Among the responding patients, median time to response was 90 days (range 30-135 days). Mean reduction in proteinuria at best response was 67% (52-88%) among the responding patients. Among the responding patients 2/7 have shown renal progression with increase in proteinuria after completing the therapy. The one non-responding patient progressed from eGFR 40 ml/min at baseline to ESRD in 18 months.

Conclusion: Isatuximab monotherapy is overall well tolerated and effective in patients with MGRS among the patients treated in this ongoing clinical trial.