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.