In this issue of Blood, Chauvet et al reported the largest study to date of the treatment outcomes in patients with monoclonal gammopathy–associated C3 glomerulopathy (C3G). Renal outcomes were found to be dependent on hematological response for the first time in this disease. The data presented here could be used to help design future studies and trials.1
C3G is a rare group of kidney diseases characterized by predominate C3 deposits with little immunoglobulin deposition in the kidney.2 Two diseases are represented in this group: C3 glomerulonephritis (C3GN) and dense deposit disease (DDD), which can be distinguished by their ultrastructural characteristics on electron microscopy. These patients present with proteinuria, often in the nephrotic range, and renal impairment, which can be severe. Approximately half of the patients present with low C3 but normal C4, consistent with activation of the alternative pathway. In fact, in children and young adults, the majority of cases are due to dysregulation of the complement system resulting from mutations in one of the complement regulatory proteins. Infection preceding the kidney disease has also been identified in many patients.
Recently, it has been noted that a significant number of adults (≥50 years of age) with C3G also have a monoclonal gammopathy (MG). One study from the Mayo Clinic found 31% of patients with C3GN had an MG.3 Bone marrow biopsy revealed a diagnosis of monoclonal gammopathy of undetermined significance (MGUS) in 90% of these patients, whereas 10% were diagnosed with low-grade chronic lymphocytic leukemia (CLL). The age of patients with MG was significant higher than that of the patients without (54 vs 31 years, respectively). Another study of patients with DDD from the same institution found 71.4% of the patients >49 years of age had an MG.4 All had MGUS at the time of diagnosis, but one patient progressed to MM at 120 months of follow-up. These results are similar to those from the University of Utah, which found 83% of the patients with C3G over the age of 49, had an MG.5 In this cohort, 40% had multiple myeloma (MM) or smoldering MM, 40% had monoclonal gammopathy of renal significance (MGRS), and 10% had polyclonal plasmacytosis.
The relationship between the MG and the complement system remains poorly understood in C3G. No significant monoclonal immunoglobulin deposition is found in C3GN, even by mass spectrometry.3 Although C3 nephritic factor (C3nef) has been identified in some patients, <20% of patients in larger series have a C3nef.3,6,7 Disease-causing mutations are typically absent, but a minority of patients (10%-20%) carry the risk allele H402 (and rarely Y402) for factor H.3,4,6 Conversely, the high prevalence of MG in these patients makes it unlikely that the association is a mere coincidence.6 It is because of this that the monoclonal gammopathy in C3G with MG is considered an MGRS rather than an MGUS.8
Prognosis for these patients has been poor. End-stage renal disease (ESRD) or near ESRD is reported in 30% to 83% of patients. Among those who have not reached ESRD, many continue to have chronic kidney disease, with few ever achieving improvements in renal function.3-6 Recurrence is frequently reported in those who received a kidney transplant. The poor prognosis in part may be because of the inconsistent treatment these patients received. In one series, 40% were treated conservatively with renin-angiotensin system (RAS) inhibition.3 Only 20% received clone-directed therapy. In another series, only patients with MM received chemotherapy.5 The rest received RAS inhibition, and 1 patient received eculizumab. This is not uncommon in MGRS-associated renal diseases, where chemotherapy is avoided in patients who do not meet criteria for MM or malignant lymphoma.9
In this issue, Chavet et al reported the outcomes of 50 patients with C3G and MG treated after treatment. The patients were divided into groups based on the treatment received: clone-directed therapy (alkylator or bortezomib [or rituximab for CLL]), immunosuppressive therapy (corticosteroids, cyclophosphamide, rituximab, mycophenolate, and azathioprine), or RAS inhibition. In this study clone-directed therapy produced superior renal survival than immunosuppressive and RAS inhibition therapy. No differences in patient survival were noted, but this is not surprising, because an overwhelming majority of patients had a clone that would be classified as MGRS (MGUS, 60% and smoldering MM, 30%).9
What made this an important study was the incorporation of the International Myeloma Working Group criteria for MM for the assessment of hematological responses.1 The differences in hematological response helped explain why renal response was superior in patients treated with clone-directed therapy. Only 5% of patients treated with immunosuppressive or RAS inhibition therapy achieved a very good partial response (VGPR) or better vs 31% of patients treated with clone-directed therapy. In fact, 95% of the patients treated with immunosuppressive or RAS inhibition therapy had no hematological response (HR; P = .0002). The authors were also able to show renal function was only preserved in patients who achieved a VGPR or better, similar to other MGRS-associated kidney diseases (see figure). Interestingly, 83% of patients whose C3 normalized had an HR. In addition, 9 other patients with an HR had an improvement in C3 (that did not reach normalization), whereas no patient without an HR had an improvement in C3. These new data not only help guide treatment and design future studies but also provide further support that MG-associated C3G is truly an MGRS-related kidney disease.
Conflict-of-interest disclosure: Research support from Omeros Corporation has been provided to N.L.’s institution for the conduct of clinical trials on which N.L. serves as a principal investigator.