The term monoclonal gammopathy of renal significance (MGRS) was introduced by the International Kidney and Monoclonal Gammopathy Research Group (IKMG) in 2012. The IKMG met in April 2017 to refine ...the definition of MGRS and to update the diagnostic criteria for MGRS-related diseases. Accordingly, in this Expert Consensus Document, the IKMG redefines MGRS as a clonal proliferative disorder that produces a nephrotoxic monoclonal immunoglobulin and does not meet previously defined haematological criteria for treatment of a specific malignancy. The diagnosis of MGRS-related disease is established by kidney biopsy and immunofluorescence studies to identify the monotypic immunoglobulin deposits (although these deposits are minimal in patients with either C3 glomerulopathy or thrombotic microangiopathy). Accordingly, the IKMG recommends a kidney biopsy in patients suspected of having MGRS to maximize the chance of correct diagnosis. Serum and urine protein electrophoresis and immunofixation, as well as analyses of serum free light chains, should also be performed to identify the monoclonal immunoglobulin, which helps to establish the diagnosis of MGRS and might also be useful for assessing responses to treatment. Finally, bone marrow aspiration and biopsy should be conducted to identify the lymphoproliferative clone. Flow cytometry can be helpful in identifying small clones. Additional genetic tests and fluorescent in situ hybridization studies are helpful for clonal identification and for generating treatment recommendations. Treatment of MGRS was not addressed at the 2017 IKMG meeting; consequently, this Expert Consensus Document does not include any recommendations for the treatment of patients with MGRS.
Multiple myeloma is the most frequent monoclonal gammopathy to involve the kidney; however, a growing number of kidney diseases associated with other monoclonal gammopathies are being recognized. ...Although many histopathologic patterns exist, they are all distinguished by the monoclonal immunoglobulin (or component) deposits. The hematologic disorder in these patients is more consistent with monoclonal gammopathy of undetermined significance (MGUS) than with multiple myeloma. Unfortunately, due to the limitations of the current diagnostic schema, they are frequently diagnosed as MGUS. Because treatment is not recommended for MGUS, appropriate therapy is commonly withheld. In addition to end-stage renal disease, the persistence of the monoclonal gammopathy is associated with high rates of recurrence after kidney transplantation. Preservation and restoration of kidney function are possible with successful treatment targeting the responsible clone. Achievement of hematologic complete response has been shown to prevent recurrence after kidney transplantation. There is a need for a term that properly conveys the pathologic nature of these diseases. We think the term monoclonal gammopathy of renal significance is most helpful to indicate a causal relationship between the monoclonal gammopathy and the renal damage and because the significance of the monoclonal gammopathy is no longer undetermined.
Monoclonal gammopathy is a common condition, particularly in the elderly. It can indicate symptomatic multiple myeloma or another overt malignant lymphoid disorder requiring immediate chemotherapy. ...More frequently, it results from a small and/or quiescent secreting B-cell clone, is completely asymptomatic, and requires regular monitoring only, defining a monoclonal gammopathy of unknown significance (MGUS). Sometimes, although quiescent and not requiring any treatment per se, the clone is associated with potentially severe organ damage due to the toxicity of the monoclonal immunoglobulin or to other mechanisms. The latter situation is increasingly observed but still poorly recognized and frequently undertreated, although it often requires rapid specific intervention to preserve involved organ function. To improve early recognition and management of these small B-cell clone–related disorders, we propose to introduce the concept of monoclonal gammopathy of clinical significance (MGCS). This report identifies the spectrum of MGCSs that are classified according to mechanisms of tissue injury. It highlights the diversity of these disorders for which diagnosis and treatment are often challenging in clinical practice and require a multidisciplinary approach. Principles of management, including main diagnostic and therapeutic procedures, are also described. Importantly, efficient control of the underlying B-cell clone usually results in organ improvement. Currently, it relies mainly on chemotherapy and other anti–B-cell/plasma cell agents, which should aim at rapidly producing the best hematological response.
Monoclonal gammopathy of undetermined significance (MGUS) is, in many ways, a unique hematologic entity. Unlike most hematologic conditions in which the diagnosis is intentional and credited to ...hematologists, the discovery of MGUS is most often incidental and made by nonhematologists. MGUS is considered an obligate precursor to several lymphoplasmacytic malignancies, including immunoglobulin light-chain amyloidosis, multiple myeloma, and Waldenström macroglobulinemia. Therefore, long-term follow-up is generally recommended. Despite its high prevalence, there is surprisingly limited evidence to inform best clinical practice both at the time of diagnosis and during follow-up. We present 7 vignettes to illustrate common clinical management questions that arise during the course of MGUS. Where evidence is present, we provide a concise summary of the literature and clear recommendations on management. Where evidence is lacking, we describe how we practice and provide a rationale for our approach. We also discuss the potential harms associated with MGUS diagnosis, a topic that is rarely, if ever, broached between patients and providers, or even considered in academic debate.
A revision of the nearly 8-year-old World Health Organization classification of the lymphoid neoplasms and the accompanying monograph is being published. It reflects a consensus among ...hematopathologists, geneticists, and clinicians regarding both updates to current entities as well as the addition of a limited number of new provisional entities. The revision clarifies the diagnosis and management of lesions at the very early stages of lymphomagenesis, refines the diagnostic criteria for some entities, details the expanding genetic/molecular landscape of numerous lymphoid neoplasms and their clinical correlates, and refers to investigations leading to more targeted therapeutic strategies. The major changes are reviewed with an emphasis on the most important advances in our understanding that impact our diagnostic approach, clinical expectations, and therapeutic strategies for the lymphoid neoplasms.
Recently, the term monoclonal gammopathy of renal significance (MGRS) was introduced to distinguish monoclonal gammopathies that result in the development of kidney disease from those that are ...benign. By definition, patients with MGRS have B-cell clones that do not meet the definition of multiple myeloma or lymphoma. Nevertheless, these clones produce monoclonal proteins that are capable of injuring the kidney resulting in permanent damage. Except for immunoglobulin light chain amyloidosis with heart involvement in which death can be rapid, treatment of MGRS is often indicated more to preserve kidney function and prevent recurrence after kidney transplantation rather than the prolongation of life. Clinical trials are rare for MGRS-related kidney diseases, except in immunoglobulin light chain amyloidosis. Treatment recommendations are therefore based on the clinical data obtained from treatment of the clonal disorder in its malignant state. The establishment of these treatment recommendations is important until data can be obtained by clinical trials of MGRS-related kidney diseases.
Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant plasma cell dyscrasia that consistently precedes multiple myeloma (MM) with a 1% risk of progression per year. Recent ...advances have improved understanding of the complex genetic and immunologic factors that permit progression from the aberrant plasma cell clone to MGUS and overt MM. Additional evidence supports bidirectional interaction of MGUS cells with surrounding cells in the bone marrow niche that regulates malignant transformation. However, there are no robust prognostic biomarkers. Herein we review the current body of literature on the biology of MGUS and provide a rationale for the improved identification of high-risk MGUS patients who may be appropriate for novel clinical interventions to prevent progression or eradicate premalignant clones prior to the development of overt MM.
A panel of members of the 2009 International Myeloma Workshop developed guidelines for standard investigative workup of patients with suspected multiple myeloma. Both serum and urine should be ...assessed for monoclonal protein. Measurement of monoclonal protein both by densitometer tracing and/by nephelometric quantitation is recommended, and immunofixation is required for confirmation. The serum-free light chain assay is recommended in all newly diagnosed patients with plasma cell dyscrasias. Bone marrow aspiration and/or biopsy along with demonstration of clonality of plasma cells are necessary. Serum β2-microglobulin, albumin, and lactate dehydrogenase are necessary for prognostic purposes. Standard metaphase cytogenetics and fluorescent in situ hybridization for 17p, t(4;14), and t(14;16) are recommended. The skeletal survey remains the standard method for imaging screening, but magnetic resonance imaging frequently provides valuable diagnostic and prognostic information. Most of these tests are repeated during follow-up or at relapse.
The optimal treatment for the monoclonal gammopathies of renal significance is not known, but there is consensus among experts that treatment should be specific for the underlying clone. The majority ...of patients with proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) do not have an identifiable clone, and prior studies have found poor renal outcomes for patients with PGNMID treated with a variety of regimens. Here we present a retrospective case series of 19 patients with PGNMID with a more uniform, clone-directed approach. A circulating paraprotein was detected in 37% of patients, and the overall clone detection rate was 32%. Treatment was directed at the underlying clone or, for patients without a detectable clone, empirically prescribed to target the hypothesized underlying clone. Of the 16 patients who underwent treatment, the overall renal response rate was 88%, and 38% of patients experienced complete renal response (proteinuria reduction to under 0.5 gm/24 hours) with initial treatment. All patients were End Stage Renal Disease-free at last follow-up (median 693 days after diagnosis), and treatment was well tolerated. Thus, a clone-directed approach may lead to novel, targeted treatment strategies that could significantly improve outcomes for patients with PGNMID.
To better define the clinical-pathologic spectrum and prognosis of monoclonal immunoglobulin deposition disease (MIDD), this study reports the largest series.
Characteristics of 64 MIDD patients who ...were seen at Mayo Clinic are provided.
Of 64 patients with MIDD, 51 had light chain deposition disease, 7 had heavy chain deposition disease, and 6 had light and heavy chain deposition disease. The mean age at diagnosis was 56 years, and 23 patients (36%) were ≤50 years of age. Clinical evidence of dysproteinemia was present in 62 patients (97%), including multiple myeloma in 38 (59%). M-spike was detected on serum protein electrophoresis in 47 (73%). Serum free light chain ratio was abnormal in all 51 patients tested. Presentation included renal insufficiency, proteinuria, hematuria, and hypertension. Nodular mesangial sclerosis was seen in 39 patients (61%). During a median of 25 months of follow-up (range, 1-140) in 56 patients, 32 (57%) had stable/improved renal function, 2 (4%) had worsening renal function, and 22 (39%) progressed to ESRD. The mean renal and patient survivals were 64 and 90 months, respectively. The disease recurred in three of four patients who received a kidney transplant.
Patients with MIDD generally present at a younger age than those with light chain amyloidosis or light chain cast nephropathy. Serum free light chain ratio is abnormal in all MIDD patients, whereas only three-quarters have abnormal serum protein electrophoresis. The prognosis for MIDD is improving compared with historical controls, likely reflecting earlier detection and improved therapies.
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