Determinants of renal survival in patients treated for monoclonal gammopathy of renal significance

Abstract Background: Monoclonal gammopathies of renal significance (MGRS) are a heterogeneous category of disorders characterized by renal dysfunction caused by interaction with an otherwise asymptomatic plasma cell or lymphoproliferative disorder. These disorders have a high risk of progression to end stage renal disease (ESRD), especially if diagnosed late in the disease process. Historically these diseases were treated with nonspecific immunosuppression, but recent consensus has emerged in preference of clone-directed therapy, usually targeting plasma cells. Comparisons of these strategies are limited, and correlates of long-term renal survival with therapy have not been established. Methods This was a retrospective analysis of patients treated at three National Cancer Institute (NCI)-designated cancer centers in the United States. Patients were eligible if they had renal biopsy-confirmed histopathologic findings compatible with MGRS, other than those with monoclonal immunoglobulin deposition disease (MIDD) and AL amyloidosis, who were excluded from the analysis. Baseline characteristics including age, specific MGRS histology according to renal biopsy, baseline serum creatinine, and baseline proteinuria were collected. Therapy was classified as plasma cell-directed or non-plasma cell-directed. For patients with measurable paraprotein, hematologic response status (defined as a 50% or greater reduction in the concentration of causal paraprotein) within the first six months of therapy was recorded. Renal response status (defined as a 30% or greater reduction in proteinuria or 30% or greater improvement in serum creatinine) within the first six months of therapy was recorded. The association between these factors and progression to end-stage renal disease (ESRD) was performed using Fisher's exact test (for categorical variables) or Wilcoxon signed-rank test (for continuous variables). The association with therapy type and time-to dialysis was examined using the log-rank test. Results A total of 46 patients were included. Median age was 64, and a majority (n=25, 54%) of patients were female. Median baseline serum creatinine was 1.76 mg/dL (IQR 1.40-2.58 mg/dL) and median baseline proteinuria was 3253 mg/24h (IQR 1165-5271 mg/24h). Most patients (n=28, 60%) had PGNMID. Other diagnoses included immunotactoid glomerulonephritis (n=5, 11%), C3 glomerulonephritis (n=5, 11%), light chain proximal tubulopathy (n=4, 9%) and dense deposit disease (n=3, 7%). A total of 11 patients (24%) progressed to ESRD, with median time to ESRD of 510 days (IQR 116 – 1408 days). Most patients (n=31, 67%) received plasma cell-directed therapy. Most patients receiving plasma cell-directed therapy received bortezomib (n=29, 93%) and four (13%) received daratumumab. Most patients receiving non-plasma cell directed therapy were treated with regimens including rituximab (n=13, 93%). The rate of progression to ESRD was similar in patients who received plasma cell-directed and non-plasma cell-directed therapy (24% v. 27%), as was the rate of renal response (67% v. 71%), and there was no difference in renal survival between these groups by time-to-event analysis. Of 26 patients with measurable paraprotein, 20 (77%) had a hematologic response. Hematologic response rate among patients treated with plasma cell-directed therapy was 81% (17/21), and among 5 patients treated with non-plasma cell-directed therapy who had measurable paraprotein, 3 (60%) achieved a hematologic response. Compared to nonresponders, achieving hematologic response was associated with lower rate of progression to ESRD (10% v. 83%, p<0.01). Between patients progressing to ESRD and those not progressing, there were not statistically significant differences in baseline serum creatinine (median 2.1 v. 1.6 mg/dL, p=0.14 and baseline proteinuria (median 3800 v. 2923 mg/24H, p=0.29). Most patients (n=31, 67%) had a renal response to therapy. Compared to nonresponders, achieving renal response was associated with lower rate of progression to ESRD (7% v. 36%, p<0.01). Conclusion Even with modern clone directed therapy, the rate of progression to ESRD in patients with MGRS remains high. Achievement of renal response, and where measurable, hematologic response is of paramount importance in preserving renal survival. Developing therapies that result in high rates of rapid responses is of paramount importance.