Results and discussion
MGRS is a new diagnostic classification encompassing patients who meet criteria for MGUS and otherwise have only renal disease caused by monoclonal gammopathy rather than clonal proliferation1,2. The spectrum of renal pathologies that fall under MGRS is evolving and are largely due to deposition of monoclonal Ig fragment in renal glomeruli4. Immunotactoid glomerulopathy (ITG) is defined by the pathognomonic finding of organized microtubular deposits with diameters of 10 to 60 nm4,5, as observed in our patient. ITG is frequently caused by IgG paraproteins and associated with CLL clones5,6. Our patient’s workup revealed a CD5-, CD23-, B-cell clone, which precludes a CLL-related pre-malignancy. Further, IgM κ light chain was found to be the unifying lesion in our patient’s studies, making her case even more unusual.
Clinicians currently have no firm guidelines for treatment of MGRS or suspected MGRS. The hematologic outcomes of this disease entity were only recently described. A large retrospective analysis by Steiner and colleagues found decreased PFS and OS in pathologically proven MGRS patients compared to MGUS patients2. Despite an imbalanced cohort number due to the rareness of MGRS cases, the authors clearly demonstrated that MGRS patient have increased risk of progression to more advanced monoclonal gammopathies such as multiple myeloma or smoldering myeloma. They also found MGRS patients to have a higher risk of progression to end stage renal disease (ESRD) as compared to MGUS patients. This observation is in line with older data from Heilman and colleagues showing that 82% of MGUS with light chain deposition patients progressed to (ESRD) despite therapy7. Thus, MGRS likely represents a distinct entity from MGUS with higher rates of both hematologic and renal disease progression. Under-recognition of the increased risk of progression of MGRS as compared to MGUS can lead to undertreatment and even misclassification. Our patient presented with MGRS, ITG, and classic signs of nephrotic syndrome. Based on currently available literature, she is at increased risk for progression to myeloma or ESRD as compared to MGUS patients. Given her minimal burden of comorbidities, we determined that it was in her best interest to treat her disease aggressively to prevent these outcomes.
Very little prospective data are available to guide treatment for MGRS. Expert opinion currently recommends a clone-directed approach1,5,8. Gumber and colleagues reported in a recent case series over a dozen MGRS patients treated by this approach9. Notably, nearly all of their patients had an IgG paraprotein or renal deposit identified, and most had no clonal involvement by bone marrow biopsy. Their treatment outcomes were encouraging, with most patients demonstrating at least partial response to rituximab-based treatment regimens. We discussed upfront aggressive treatment with our patient and opted for rituximab monotherapy first in an attempt to avoid more toxic therapies. Due to the minimal renal response to rituximab, marked by persistent massive proteinuria, we proceeded with a bortezomib-based regimen. We had also discussed employing a cyclophosphamide regimen given the patient’s IgM paraprotein and renal dysfunction8, however due to the patient’s desire to avoid toxic therapies and take a step-wise approach, we chose bortezomib, dexamethasone, and rituximab first3. Currently available anti-plasma cell and anti-B-cell regimens would likely all have some activity against the broad spectrum of MGRS clones, and more studies are needed to define which regimens are best for each pathology.
In summary, we present a rare case of MGRS with ITG caused by IgM κ paraprotein from a non-CLL B-cell clone. Our patient has achieved a very good partial response to bortezomib, dexamethasone, and rituximab, and will be monitored for continued improvement. We strongly recommend that patients with MGUS and unexplained nephrotic range proteinuria be referred to nephrology for renal biopsy. MGRS is an under-recognized disease, but aggressive management can likely delay hematologic and renal progression of disease, leading to better long-term outcomes for patients.