Current management of non‐amyloidosis monoclonal gammopathy of renal significance: Clinical features, treatment selections, responses and renal outcomes

Monoclonal gammopathy of renal significance (MGRS) is currently defined as any clonal plasma or B-cell proliferation which causes kidney lesions related to a monoclonal immunoglobulin (Ig). Importantly, this clonal expansion must not meet the criteria for specific treatment of haematological malignancy.1, 2 This newly defined disease entity emerged due to the recognition of a distinct subset of patients who did not meet the criteria for treatment-eligible haematological malignancy based on standard guidelines yet still had clinically significant renal impairment related to a clonal cell population. It became clear that these patients had high rates of progression of kidney disease if left untreated.3, 4 Kidney disease caused by monoclonal cellular proliferation and subsequent paraproteinaemia is poorly responsive to conventional immunosuppression and instead has been shown to require clone-directed therapy.5, 6 One of the challenges of treating MGRS is the significant heterogeneity of the disease in terms of the histopathologic pattern seen on biopsy as well as the underlying clonal cell population driving the disease. MGRS can be driven by clonal expansion of either B-cell or plasma cell populations, and often the abnormal clone is not readily identified.7 Kidney lesions in MGRS are also characterized based on the types of immune deposits, which include organized, non-organized and absent deposits.8, 9 A final and definitive challenge in the treatment of MGRS is the relative rarity of the disease. There are few well-established guidelines for managing MGRS, and data on treatment outcomes are lacking.10 In this report, we present clinical features and response data across histological subtypes for a cohort of MGRS patients at a single quaternary care centre. For this retrospective study, all patients were evaluated at a single quaternary care centre between 1 January 2016 and 31 December 2023. Inclusion in this dataset required patients to have a renal biopsy with the presence of an organizing or non-organizing lesion typical of MGRS. Patients meeting the criteria for any treatment-eligible haematological malignancy were excluded. Renal AL-amyloidosis was excluded from our study, as its management is guided by established diagnostic and therapeutic paradigms. Complete renal response was defined as proteinuria of ≤0.5 g/24 h or ≤0.5 g/g on the urine protein-to-creatinine ratio and stabilized estimated glomerular filtration rate (eGFR) (no more than 10% decrease in eGFR from baseline value). Partial response was defined as a >50% drop in proteinuria to less than 3 g/24 h or less than 3 g/g on the urine protein-to-creatinine ratio and eGFR within 25% from baseline. Baseline characteristics were summarized using descriptive statistics. Continuous variables were reported as medians and range, and categorical variables as frequencies (percentages). Univariate analysis was conducted using Cox proportional hazards models, with variables achieving p < 0.2 considered for further analysis. Survival distributions were compared using Kaplan–Meier curves and log-rank tests. All analyses were performed using R version 4.2.2. A two-sided p-value less than 0.05 was considered statistically significant, unless otherwise specified. 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 monoclonal immunoglobulin deposition disease (MIDD, n = 7) and light chain proximal tubulopathy (LCPT, n = 3). Median age at diagnosis was 63 years, with a slight (55%) male predominance. Monoclonal deposits most commonly included an IgG heavy chain (59%) and a kappa LC (87%). Eighty-one per cent (25/31) of patients had a detectable plasma cell clone, 3% (1/31) had a lymphoma clone and 16% (5/31) had no detectable clone. The median eGFR (CKD-Epi 2021) was 29.0 mL/min/1.73 m2. The median 24-h urine protein at the time of diagnosis was 1.82 g. Eleven patients (35%) presented with nephrotic range proteinuria and 16 additional patients (52%) presented with proteinuria below nephrotic range (Table S1). All but one patient received treatment. Combination therapies incorporated bortezomib (90%), cyclophosphamide (52%), daratumumab (41%), lenalidomide (14%) and rituximab (7%). The most common first-line treatment was daratumumab + cyclophosphamide + bortezomib + dexamethasone (Dara-CyBorD) (n = 9). The remaining 22 patients received an assortment of different treatments, with the most common being bortezomib + dexamethasone (Vd) (n = 8) and bortezomib + lenalidomide + dexamethasone (VRd) (n = 3). Fifty-eight per cent 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. Ten patients progressed during the duration of the study period (7 renal progressions, 3 haematological progressions), all of whom continued to receive second-line therapy. Among these, five patients 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 the progression of MGRS. Patients achieved renal CR, PR or stable disease in 78.3% of cases. In patients with a detectable clone, the haematological overall response rate was 85% (Figure 1). Five patients (16%) required renal replacement therapy during the course of their treatment. Of these, one was able to discontinue intermittent haemodialysis following recovery of renal function. An additional patient underwent renal transplant during the course of his therapy. Eight patients underwent melphalan-conditioned autologous stem cell transplantation, with a median eGFR for these patients being 31. Seven of these patients underwent transplant as second-line therapy while one patient received transplant as third-line therapy. No major transplant complications were reported. One hundred days following transplant, all eight patients were alive. Six achieved complete renal response, two achieved partial response and one was not evaluable for renal response. Survival analysis includes data from 29 patients for whom survival data were available at the time of the present report. At a median follow-up of 29 months, the median renal progression-free survival (rPFS) was not reached. Two-year rPFS was 86%. Renal PFS was impacted by the presence of PGNMID (HR = 8.8, CI 1.1–73, p = 0.013) as well as that of nephrotic-range proteinuria (HR = 9.3, 1.1–76.0, p = 0.013). 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) (Figure 2). 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. At the time of the current analysis, 22 of 29 (75%) evaluable patients demonstrated sustained response to treatment. The cohort of MGRS patients described here exhibited a wide range of histologies and clinical characteristics. Nearly all patients were initiated on treatment with daratumumab, bortezomib and cyclophosphamide being the most commonly used. Overall, renal outcomes tended to be favourable with prompt initiation of treatment. The choice of induction regimen did not have a significant effect on rPFS, although patients with PGNMID and those with proteinuria on presentation had worse outcomes. Due to the rarity of the disease, there have been only a limited number of studies published which describe treatment and outcomes of MGRS. A retrospective study by Cohen et al. described 38 MGRS patients across seven centres in which 53% of patients achieved a renal response after receiving treatment with bortezomib.5 Another study by Khera et al. followed 41 MGRS patients across five centres in the United Kingdom. They used renal survival, defined as the time to progression of renal replacement therapy, as one of their primary outcomes and showed 81.6% renal survival at 24-month follow-up.11 There are ongoing prospective clinical trials in MGRS; however, they generally include small numbers of patients and relatively immature follow-up. There is significant variability in clinical approaches to the diagnosis of MGRS and in how response to treatment is reported. A predictive score based on eight clinical parameters has been proposed to guide assessment of patients with suspected MGRS in the presence of a detectable monoclonal gammopathy.12 For patients who do not harbour a detectable clone by conventional methods, mass spectrometry, RNA-based Ig repertoire sequencing and single molecule real-time sequencing of monoclonal Igs represent novel approaches to verifying clonality and classifying nephritogenic protein.13-15 A clinical study at our institution to utilize ultra-low-pass whole genome sequencing to better elucidate the cell of origin and genomic underpinnings of these disorders is underway. There is not sufficient published data describing MGRS treatment outcomes to build a clear consensus around treatment strategies across histologies and clinical settings. To our knowledge, this dataset describes one of the largest cohorts of MGRS patients from a single centre in the era of anti-CD38 monoclonal antibody-based therapy. Continuing to rectify the deficiency in available data through co-operative studies represents a significant opportunity to improve the care of patients with this rare set of diseases and is being undertaken by our institution as well as organizations such as the International Kidney and Monoclonal Gammopathy Research Group. LW oversaw the project, contributed to data analysis and helped to develop the figures. DC analysed data and prepared the manuscript. DD collected and organized the patient data. XJ contributed to the statistical analyses. AM, HS, BF, FA, SM, DB, JK, CS, JV and SR provided extensive feedback and approved the final version of the manuscript. The authors wish to acknowledge the patients who participated in this study as well as all of the contributors of this work. There are no external funding sources to declare. The authors do not have any competing interests to declare. This study was conducted in accordance with the Declaration of Helsinki and was approved by the Cleveland Clinic Institutional Review Board. Informed consent was obtained whenever applicable. The data that support the findings of this study are not openly available due to reasons of sensitivity and are available from the corresponding author upon reasonable request. Data are located in controlled access data storage at Cleveland Clinic. Table S1. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.