ReviewMonoclonal gammopathy: The good, the bad and the ugly
Introduction
Monoclonal gammopathy is a condition in which a monoclonal immunoglobulin or its fragment is produced by clonal proliferation of cells in the B lymphocyte lineage. The spectrum of hematologic conditions capable of producing a monoclonal gammopathy includes monoclonal gammopathy of undetermined significance (MGUS), multiple myeloma (MM), plasmacytoma, Waldenström macroglobulinemia (WM), chronic lymphocytic lymphoma (CLL), and other low grade lymphomas. [1] Of these, MGUS is the most common occurring in 3% of the population older than 50 years. It is defined by 3 criteria: < 3 g/dL of monoclonal (M) protein, < 10% plasma cells in the bone marrow, and no evidence of end organ damage. While it is a known precursor of malignant hematological disorders, such MM, immunoglobulin light chain (AL) amyloidosis, and WM, patients generally progress to these disorders at an average rate of ~ 1% per year.[2] As a result, most patients never develop a plasma cell malignancy and because of this MGUS has gained a relatively benign reputation. Unfortunately, this is not entirely accurate.
In the seminal paper titled “Monoclonal gammopathy of undetermined significance. Natural history in 241 cases”, Dr. Robert Kyle was very astute and careful in choosing the title.[3] The term was controversial because terms such as essential, idiopathic, asymptomatic and even benign were being used at the time to describe monoclonal gammopathy (MG) which occurred without MM or lymphoma. The importance of “undetermined significance” was validated by studies showing a constant percentage of patients progressed at a rate that never plateaus.[2] More recently, it has been recognized that nearly all cases with MM are preceded by a period of MGUS.[4] Replacing the terms with more “benign” connotations with “undetermined significance” was one of the most important contributions to this field.
In addition to the risk of malignant transformation, MG has been a wide variety of disorders that are not related to direct invasive or destructive properties of the clone.[5], [6] In fact, in patients with AL amyloidosis, one of the most lethal disorders, only 8% of patients meet criteria for MM proving that small clones are not only capable of producing disease but can also be quite dangerous.[7], [8] MG is most often detected as an incidental finding in patient's serum. The diagnosis of MG has increased in recent years, undoubtedly related to the increased screening of patients with common disorders such as anemia and renal impairment and the increased sensitivity of modern assays. As a result, there is an increasing recognition of the clinical significance in its own right and its association with a number of clinical entities, in which the monoclonal protein and not the clonal mass is implicated as a causative factor. Some causative associations certainly exist; however, given the relatively high prevalence of MGUS in the general population, many reported disease associations are possibly coincidental.[9] Therefore, careful consideration of this entity in each individual clinical scenario is required. In addition, since by definition MGUS cannot have end organ damage, it should not be used in the context where a pathologic condition is attributed to the monoclonal gammopathy.
In this review, we tried to summarize some of the more common disorders associated with MG. The conditions selected generally have a higher degree of certainly for a causative relationship between the condition and the MG and not just associative. Thus, to adhere to the definition, once end organ damage occurs, the term MGUS is no longer appropriate to describe the monoclonal gammopathy. These monoclonal gammopathies are clinically significant and as such should be properly denoted.
Section snippets
Impact of MGUS on survival independent of MM development
Population-based studies have demonstrated a reduced survival in patients with MGUS as compared to matched controls secondary to both malignant and non-malignant causes, implicating MGUS as a possible independent determinant of mortality.[10] A large population based cohort study of 17,398 patients tested for MGUS conducted at Mayo Clinic identified 605 cases of MGUS. In addition to previously reported associations of MGUS, it also found increased rates of osteoporosis, vertebral and hip
Nephropathies
Renal impairment is a diagnostic component of MM which is associated with a higher early mortality and reduced overall survival if present at diagnosis in MM.[13], [14], [15] Cast nephropathy, acute tubular necrosis resulting from hypercalcemia or nonsteroidal anti-inflammatory drugs, AL amyloidosis, monoclonal immunoglobulin deposition disease of the Randall type (MIDD), and light chain proximal tubulopathy (with or without Fanconi syndrome) have all been described with MM as causes of renal
Dermopathies
Skin manifestations of MG have been well described (Table 1). Interestingly, majority actually involve small clones. The most recognized of these conditions is cryoglobulinemia. Cryoglobulins are classified into 3 types based on the composition of the immunoglobulins.[49] Type I consist of only monoclonal immunoglobulins. Type II and III are mixed where a monoclonal IgM (II) or polyclonal immunoglobulins (III) bind polyclonal IgG in a rheumatoid factor fashion. Of the three types of
Neuropathy
Neuropathy (peripheral and central) is a well-recognized complication of monoclonal gammopathy. Studies suggest up to 10% of patients with peripheral neuropathy have symptomatic neuropathy at the time of diagnosis.[70] In MM, the prevalence can be as high as 20% at diagnosis and increases to 75% after treatment due to neurotoxic chemotherapies.[71], [72] It is important to remember that first: neuropathy is not equally distributed across the different heavy chains. Nearly half of the patients
Autoimmune disorders
Given the abnormal production of immunoglobulin in MGUS it is possible that this immunoglobulin can interact with self-antigen and manifest clinically in a variety of ways. The monoclonal immunoglobulin produced by the B-cell clone can stimulate an autoimmune antibody that interacts with self-antigen. This has been recently been reported to contribute to the development of an insulin related autoimmune syndrome, which occurs when the monoclonal immunoglobulin binds to human insulin. This
Ocular manifestations
In a small number of patients, the underlying monoclonal gammopathy can be associated with ocular injury. Awareness of this relationship is important to ensure that patients are screened for the presence of a monoclonal protein. In cases of severe ocular involvement, treatment of the ophthalmological injury and the monoclonal gammopathy may be warranted. Also, physicians following patients with MGUS should be aware of the possibility of development of associated ocular disease, so as to
Immunodeficiency
Infection is a major contributor to morbidity and is the leading cause of death in multiple myeloma.[85], [86] This is often related to treatment of the disease but also to disease related immunodeficiency. MM-related immunodeficiency involves B-cell dysfunction, such as hypogammaglobulinemia, as well as T-cell, dendritic cell, and NK-cell abnormalities.[87] Given that plasma cell dysfunction may be present at the MGUS stage, it is feasible that this condition may also impair immune function.
Thromboembolism
Venous thromboembolism is a common complication occurring in patients with cancer and is the second leading cause of death in cancer patients on chemotherapy.[91] Although, more commonly associated with solid cancers, a higher incidence of VTE also occurs in hematological malignancies.[92] MM has a VTE rate of almost 10%, contributed to by a number of factors, including elevated plasma viscosity, high levels of circulating immunoglobulin and the procoagulant activity of the monoclonal protein.
AL amyloidosis
The most recognized multi-systemic disease associated with monoclonal gammopathy is AL amyloidosis. It is the first disease where cytotoxic agents are routinely used despite the fact that majority of the patients do not meet criteria for MM.[7] While 40% of patients have > 10% bone marrow plasma cells, only 8% meet criteria of symptomatic MM. AL amyloidosis can also be the result of CLL and low-grade lymphomas especially lymphoplasmacytic lymphoma-producing WM.[21], [22] Interestingly, a
Conclusion
In conclusion, MG may be associated with a wide variety of conditions in different organ systems. In most, causality can be demonstrated in a number of these pathological relationships. Increased cognizance and appreciation of this clinical-pathological entity and associated treatment options may improve patient outcomes, particularly in relation to organ-threatening diseases such as MGRS. Similarly, perhaps recognition of the association between MG and the phenomena described in other organ
Conflict of interest
Neither author has any financial or personal conflict of interest to declare.
Acknowledgements
This work was funded by the generous donations of Mr. and Mrs. Ted Kirshenbaum, as well as Dr. Gary Kohler and Anne Drennan.
References (115)
Monoclonal gammopathy of undetermined significance. Natural history in 241 cases
Am J Med
(1978)- et al.
A monoclonal gammopathy precedes multiple myeloma in most patients
Blood
(2009) - et al.
Neuropathies associated with monoclonal gammopathies
Neuromuscul Disord
(1996) - et al.
Dangerous small B-cell clones
Blood
(2006) - et al.
Disease associations with monoclonal gammopathy of undetermined significance: a population-based study of 17,398 patients
Mayo Clin Proc
(2009) - et al.
Arterial and venous thrombosis in monoclonal gammopathy of undetermined significance and multiple myeloma: a population-based study
Blood
(2010) - et al.
Monoclonal gammopathy of renal significance: when MGUS is no longer undetermined or insignificant
Blood
(2012) - et al.
Light chain deposition disease with renal involvement: clinical characteristics and prognostic factors
Am J Kidney Dis
(2003) - et al.
Long-term follow-up and response to chemotherapy in patients with light-chain deposition disease
Am J Kidney Dis
(1992) - et al.
Kidney diseases associated with monoclonal immunoglobulin M-secreting B-cell lymphoproliferative disorders: a case series of 35 patients
Am J Kidney Dis
(2015)
How I treat monoclonal gammopathy of renal significance (MGRS)
Blood
Diagnosis of monoclonal gammopathy of renal significance
Kidney Int
Paraffin immunofluorescence in the renal pathology laboratory: more than a salvage technique
Mod Pathol
Recurrent goodpasture's disease secondary to a monoclonal IgA1-kappa antibody autoreactive with the alpha1/alpha2 chains of type IV collagen
Am J Kidney Dis
Acquired Fanconi syndrome is an indolent disorder in the absence of overt multiple myeloma
Blood
Long-term outcome of kidney transplantation in patients with fibrillary glomerulonephritis or monoclonal gammopathy with fibrillary deposits
Kidney Int
Long-term outcome of renal transplantation in light-chain deposition disease
Am J Kidney Dis
Recurrent membranoproliferative glomerulonephritis after kidney transplantation
Kidney Int
Cyclophosphamide, bortezomib, and dexamethasone therapy in AL amyloidosis is associated with high clonal response rates and prolonged progression-free survival
Blood
Cyclophosphamide-bortezomib-dexamethasone (CyBorD) produces rapid and complete hematologic response in patients with AL amyloidosis
Blood
Renal response after high-dose melphalan and stem cell transplantation is a favorable marker in patients with primary systemic amyloidosis
Am J Kidney Dis
High dose chemotherapy in light chain or light and heavy chain deposition disease
Kidney Int
A staging system for renal outcome and early markers of renal response to chemotherapy in AL amyloidosis
Blood
Reversal of dialysis-dependent renal failure in light-chain deposition disease by autologous peripheral blood stem cell transplantation
Am J Kidney Dis
Cryoglobulinemia
Blood Rev
The cryoglobulinaemias
Lancet
Schnitzler syndrome: beyond the case reports: review and follow-up of 94 patients with an emphasis on prognosis and treatment
Semin Arthritis Rheum
The role of infliximab in the treatment of superficial granulomatous pyoderma of the head and neck
J Am Acad Dermatol
Pathogenesis and treatment of xanthomatosis associated with monoclonal gammopathy
Blood
Complete response to thalidomide and dexamethasone in a patient with necrobiotic xanthogranuloma associated with monoclonal gammopathy: a case report and review of the literature
Clin Lymphoma Myeloma Leuk
Scleromyxedema: a multicenter study of characteristics, comorbidities, course, and therapy in 30 patients
J Am Acad Dermatol
Treatment of recalcitrant scleromyxedema with thalidomide in 3 patients
J Am Acad Dermatol
Prevalence, specificity and functionality of anti-ganglioside antibodies in neuropathy associated with IgM monoclonal gammopathy
J Neuroimmunol
Paraproteinemic keratopathy: the expanding diversity of clinical and pathologic manifestations
Ophthalmology
Uveal effusion associated with an IgM lambda subtype monoclonal gammopathy
Arch Soc Esp Oftalmol
Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy
J Thromb Haemost
How I treat the acquired von Willebrand syndrome
Blood
Diagnostic workup of patients with acquired von Willebrand syndrome: a retrospective single-centre cohort study
J Thromb Haemost
Treatment of acquired von Willebrand syndrome in patients with monoclonal gammopathy of uncertain significance: comparison of three different therapeutic approaches
Blood
Prevalence of monoclonal gammopathy of undetermined significance
N Engl J Med
A long-term study of prognosis in monoclonal gammopathy of undetermined significance
N Engl J Med
Cancer risk in patients with monoclonal gammopathy of undetermined significance
Am J Hematol
Primary systemic amyloidosis: clinical and laboratory features in 474 cases
Semin Hematol
Patterns of survival and causes of death following a diagnosis of monoclonal gammopathy of undetermined significance: a population-based study
Haematologica
Monoclonal gammopathy of undetermined significance and risk of infections: a population-based study
Haematologica
Impact of age and serum creatinine value on outcome after autologous blood stem cell transplantation for patients with multiple myeloma
Bone Marrow Transplant
Long-term outcome of patients with multiple [corrected] myeloma-related advanced renal failure following auto-SCT
Bone Marrow Transplant
Renal failure in multiple myeloma: presenting features and predictors of outcome in 94 patients from a single institution
Arch Intern Med
Clinical outcome of immunoglobulin light chain amyloidosis affecting the kidney
Nephrol Dial Transplant
Nephrotoxic potential of Bence Jones proteins
N Engl J Med
Cited by (52)
Liver in Systemic Disease
2023, MacSween's Pathology of the Liver, Eighth EditionParaproteins
2019, Onco-Nephrology