Outcomes of Therapy of Monoclonal Gammopathy of Renal Significance (MGRS)

Background: MGRS encompasses a group of heterogeneous 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) and lack a standard of care treatment approach. The most common types of therapies used include plasma cell directed therapies and immunosuppressive therapy.

Objectives: The primary objective of this study was to evaluate the efficacy of the therapies used to treat these disorders. The secondary objectives included rate of progression to ESRD and to study the risk factors for ESRD in this patient population.

Methods: This was a retrospective analysis of patients treated at two National Cancer Institute (NCI)-designated cancer centers in the United States. Medical records of adult patients seen between January 2010 and March 2023 were screened for MGRS. Patients were eligible if they had renal biopsy-confirmed histopathologic findings compatible with MGRS. AL amyloidosis and monoclonal immunoglobulin deposition disease and concurrent multiple myeloma were excluded as the therapies for these disorders are we defined based. Baseline characteristics including diagnosis, eGFR, degree of proteinuria, presence of detectable monoclonal gammopathy in serum, urine or bone marrow monoclonal plasmacytosis, and types of therapy used and response to therapy were recorded. Response assessment was based on change in proteinuria and serum creatinine with renal response defined as ≥ 50% drop in 24-hr urine protein with stable creatinine (within 25% of baseline).

Results: We identified a total of 35 patients with a diagnosis of biopsy proven MGRS. The distribution of underlying diagnoses was proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) in 20, C3 glomerulopathy in 6, Immunotactoid glomerulopathy in 4 and light chain proximal tubulopathy (LCPT) in 3 and type 1 cryoglobulinemia in 2 patients. Median age of the patients was 63 y (range 19-84), M/F ratio 16/19, Median eGFR at diagnosis was 40 ml/min (range 11-80), and median 24-hr proteinuria 2876 mg/d (range 325-19030 mg). Monoclonal gammopathy was identified in 57% of patients and was present in nearly all patients with C3 glomerulopathy, immunotactoid glomerulopathy and type 1 cryoglobulinemia and LCPT but only in 23% of patients with PGNMID. Among the patients with MGUS the size of M protein was small at median of 0.3 g/dl (range 0.01-1.7 g/dl) with majority being IgG kappa type in 72%. Median light chain ratio among patients with identified MGUS was 4.5 (1.5-30.8). None of the patient in the cohort had evidence of B cell lymphoproliferative disorder.

All patients were newly diagnosed and plasma cell directed therapy was used in 62% (22/35) and B-cell-directed (rituximab based) therapy was used in 38% (13/35) of patients. Among the plasma cell-directed therapy, bortezomib, cyclophosphamide and dexamethasone (CyBorD) was the most common regimen used in 68%, daratumumab-based therapy was used in 20%, and lenalidomide was used in 8% of patient. Renal response was achieved in 71% of patients overall and rate was similar in patients who received plasma cell-directed vs. B-cell-directed therapy (64 vs 83%, p=0.2). Median time to response was 10 months (range 4-48 months). Over a median follow-up of 4.8 years (range 0.8-11 years) 31% (11/35) have progressed to ESRD. Baseline eGFR (OR 0.94, P =0.02) and lack of renal response (OR 66, P <0.001) were predictors of progression to ESRD.

Conclusion: Plasma cell-directed as well as B-cell directed therapies are effective in treatment of patients with MGRS disorders. Even with effective therapies a significant number of patients proceed to ESRD and achieving a renal response with therapy is the strongest predictor of good long term renal outcomes.

Bhutani:Sanofi: Consultancy, Research Funding. Chakraborty:Sanofi: Consultancy; Adaptive: Consultancy; Janssen: Consultancy. Lentzsch:RedMed: Speakers Bureau; Magenta: Current holder of stock options in a privately-held company; Peerview: Speakers Bureau; BMS: Consultancy; Regeneron: Consultancy; Clinical Care Options (COO): Speakers Bureau; GSK: Consultancy; Poseida: Current holder of stock options in a privately-held company; Janssen: Consultancy; Angitia: Consultancy; Aptitude: Speakers Bureau; Sanofi: Research Funding; Pfizer: Consultancy; Caelum Bioscience: Patents & Royalties; Adaptive: Consultancy; Takeda: Consultancy; Bio Ascend: Speakers Bureau; Medscape: Speakers Bureau; Sanofi: Consultancy; Zentalis: Research Funding; Alexion: Consultancy; Karyopharm: Consultancy. Rubinstein:Johnson & Johnson: Consultancy; Sanofi: Consultancy; LAVA Therapeutics: Consultancy; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Other: Abemca.

Bortezomib, Lenalidomide, Daratumumab, and Rituximab for therapy of MGRS