Current Management of Non-Amyloidosis Monoclonal Gammopathy of Renal Significance: Clinical Features, Treatment Selection, Response, and Renal Outcomes in a Recently Treated Patients

Background:

Monoclonal gammopathy of renal significance (MGRS) is defined by a series of kidney disorders caused by the renal deposition of monoclonal immunoglobulins (Ig) or Ig fragments secreted by a clonal cell population that does not otherwise meet criteria for a specific hematologic malignancy. MGRS presents a clinical challenge due to the relative rarity of these disorders, heterogeneity in both pathological characteristics and underlying clonal cell populations, lack of reliable biomarkers, and a paucity of outcomes data. Here we present the salient clinical features and response data across histologic subtypes for a cohort of MGRS patients treated in the modern therapeutic era.

Methods:

All patients were evaluated at a single tertiary care center between 1/1/2016 and 12/31/2023. Inclusion in this data set required patients to have a renal biopsy with the presence of a an organizing or non-organizing lesion typical of MGRS. Patients meeting the criteria for any hematologic malignancy were excluded. Renal AL-amyloidosis was excluded from our study, as its management is guided by established diagnostic and therapeutic paradigms. Renal response was defined as a reduction in proteinuria of 30% in the absence of a decline of eGFR of 25%. The clinical characteristics of the patient population were assessed using descriptive statistics. Analysis of time to event endpoints was undertaken via the Kaplan Meier approach and the cox proportional hazards model where applicable. Medan follow up was calculated using the reverse KM method.

Results:

A total of 31 patients met inclusion criteria. Among these, the most common underlying histology was proliferative glomerulonephritis with monoclonal immune deposits (PGNMID, n =15) followed by light chain deposition disease (LCDD, n = 6), and light chain proximal tubulopathy (LCPT, n = 3). Median age at diagnosis was 63 years, with a slight (52%) male predominance. Monoclonal deposits were most commonly included an IgG heavy chain (49%) and a kappa light chain (87%). Fifty two percent of patients had a population of clonal cells in the bone marrow among which the median clonality was 9.5%. The median eGFR (Cockcroft Gault) was 30.5 mL/min/173.m², the median serum creatinine was 1.10 mg/dL, and the average 24 hour urine protein was 1.64g. Twelve patients (39%) presented with nephrotic range proteinuria.

All but one patient received treatment. Combination therapies incorporated bortezomib (83%), cyclophosphamide (52%), daratumumab (39%), lenalidomide (13%) and rituximab (9.6%). Fifty-eight percent of patients achieved a renal response to first line therapy and an additional 20% persisted with stable disease after first line therapy. Median time on initial therapy was 6 months. Seven patients underwent melphalan-conditioned autologous stem cell transplantation. Ten patients progressed after treatment, all of whom continued to receive second line therapy. Among these, 5 pts also received third line treatment. A single patient received a renal allograft during the follow up period. There was one death during the follow up period that was unrelated to progression of MGRS.

At a median follow up of 29 months, the median renal progression free survival (rPFS) was not reached. Two-year rPFS was 77%. Renal PFS was impacted by the presence of PGNMID (HR = 8.8, CI 1.1 - 73, p = 0.013) as well as the presence of nephrotic range proteinuria (HR 10, 1.2 - 83, p <0.001). Two-year rPFS was likewise impacted by the presence of nephrotic range proteinuria (93% vs 53%, p = 0.008) and PGNMID (94% vs 55%, p = 0.015). Age, baseline creatinine, presence of a clone, and induction regimen did not impact rPFS. Multivariable analysis was not attempted due to a low number of events per variable relative to sample size and concerns for multicollinearity. Time to response analysis is in process at the time of abstract submission.

Conclusion:

In this cohort of patients, MGRS exhibits substantial clinical heterogeneity. Combination therapeutic strategies incorporating daratumumab, bortezomib and cyclophosphamide were most commonly used. Renal outcomes tend to be favorable with prompt treatment, although patients with PGNMID and heavy proteinuria experience suboptimal outcomes. Collaborative approaches to generate larger data sets and biomarker development to guide treatment selection will be essential to the increased standardization of management strategies in MGRS.

Williams:Janssen: Honoraria; Bristol Myers Squibb: Honoraria; Abbvie Inc.: Research Funding. Mehdi:Novartis: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Calliditas: Membership on an entity's Board of Directors or advisory committees. Anwer:BMS: Consultancy. Khouri:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Consultant; Prothena: Honoraria; Legend: Membership on an entity's Board of Directors or advisory committees; GPCR Therapeutics, Inc.: Honoraria. Raza:Pfizer: Consultancy, Honoraria; Prothena Biosciences: Consultancy; Kite Pharma: Consultancy.

This abstract includes data regarding the use of daratumumab, bortezomib, cyclophosphamide and rituximab for off-label uses.