Real-World Outcomes of Monoclonal Gammopathy of Renal Significance (MGRS) in the Era of Novel Therapies

Background Monoclonal gammopathy of renal significance (MGRS) is a rare complication of plasma cell disorders with various treatment options. Traditional therapies include proteasome inhibitors, immunomodulatory agents, and autologous stem cell transplantation. Recently, anti-CD38 antibodies have demonstrated high response rates. However, due to the rarity of MGRS, there is limited data on the long term outcomes with these novel therapies. This retrospective study aimed to characterize the clinical, histopathological, and treatment outcomes of MGRS patients from two institutions, the Ohio State University and the University of Illinois. Methods We included adult patients with a renal biopsy-proven MGRS-defining lesion, according to the International Kidney Working Group Criteria, who received clone-directed therapy between 2014 and 2024. Patients with myeloma cast nephropathy and systemic AL-amyloidosis were excluded. The primary outcome was relapse-free survival. Baseline characteristics reported included histopathologic subtype, percentage of bone marrow plasma cells, kidney function, and degree of proteinuria. Initial therapy, as well as hematologic and renal responses, were also reported. Hematologic response was defined by IMWG criteria, while renal response was defined as a reduction in proteinuria of >30%, with no decrease in estimated glomerular filtration rate (eGFR) of ≥25%. Overall survival (OS) and relapse-free survival (RFS) probabilities were estimated using the Kaplan-Meier method, with differences analyzed using the log-rank test. Results A total of 26 consecutive patients were included, with 15/26 (58%) being male, 23/26 (88.5%) being White, and 3 patients being African American; median age was 63 years (IQR 50-71). Most patients (n= 16, 61%) had no detectable monoclonal protein in peripheral blood. The median baseline involved free light chain concentration was 39 mg/dL (IQR 27-163). The median percentage of bone marrow plasma cells was 2% (IQR 1-4). The most common monoclonal component in the kidney was IgG (kappa /lambda), present in 23 patients (88%). The two most frequent histopathologic subtypes were proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID) in 17 patients (65.4%) and C3 glomerulopathy with monoclonal gammopathy in 5 patients (19.2%). Seventeen patients (65%) had a serum creatinine level greater than 1.77 mg/dL, with a median baseline eGFR of 31 ml/min (IQR 14-50). The median baseline proteinuria was 4.1 g/24 h (IQR 2.7-8). Of the patients, 13 (50%) had end-stage renal disease and received renal replacement therapy; 6 (23%) underwent kidney transplantation. Clone-directed therapy included bortezomib-dexamethasone (VD) or cyclophosphamide- bortezomib-dexamethasone (CyBorD) for 12 patients (46%), Daratumumab with VD or CyBorD for 11 patients (42%), and other therapies for 3 patients (12%). Six patients (23%) received high-dose chemotherapy with autologous stem cell transplantation as consolidation, and 12 patients (46%) received either maintenance or second-line treatment. Of 22 evaluable patients, 18 (70%) achieved a hematologic complete response (CR) or very good partial response (VGPR), while 4 (15%) had stable or progressive disease. Of 23 evaluable patients, 19 (83%) achieved a renal response. After a median follow-up of 5 years, the 5-year overall survival (OS) rate was 84%, and the 5-year relapse-free survival (RFS) rate was 50%. There was no significant difference in RFS or OS between patients who received Daratumumab plus Bortezomib versus Bortezomib alone, between those receiving maintenance versus no maintenance, or those undergoing autologous stem cell transplantation as consolidation. Conclusions Clone-directed therapy demonstrates high hematologic response rates in patients with MGRS and significant kidney function recovery; however, long-term follow-up reveals that relapse remains a significant challenge. Novel combination therapies are needed to improve long-term outcomes for this rare disease.