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JAMA Oncology Sep 2021POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome is a rare plasma cell disorder characterized by demyelinating... (Review)
Review
IMPORTANCE
POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome is a rare plasma cell disorder characterized by demyelinating peripheral neuropathy and clonal plasma cell proliferation. Clinical manifestations are believed to be associated with a surge of inflammatory and angiogenic mediators, including interleukins and vascular endothelial growth factor (VEGF), elicited by clonal and polyclonal plasma cells. The clinical manifestations of POEMS syndrome can be debilitating; therefore, early diagnosis is essential. This review discusses several aspects of POEMS syndrome and includes the most recently published findings, with a special emphasis on diagnosis and treatment strategies.
OBSERVATIONS
POEMS syndrome may be underdiagnosed because of its rarity, and it can be mistaken for chronic inflammatory demyelinating polyneuropathy; this misdiagnosis may lead to delayed therapy and progressive worsening of symptoms, especially neuropathy. Therefore, in addition to measurement of the VEGF level, patients with a monoclonal protein detected in blood and/or urine and neuropathy should be evaluated for POEMS syndrome with use of imaging to assess whether sclerotic bone lesions, effusions, and organomegaly are present. Clinical trials are scant, and treatment is largely based on small case series in which plasma cell-directed therapies, borrowed from the myeloma armamentarium, were used. High-dose melphalan and autologous hematopoietic cell transplantation may be offered to eligible patients. Lenalidomide and dexamethasone can be prescribed for patients who are ineligible for transplants. The main goals of therapy are to attain complete hematologic and VEGF responses and to reduce symptoms, although it may take up to 3 years for neurologic deficits to be ameliorated.
CONCLUSIONS AND RELEVANCE
POEMS syndrome should be considered in the differential diagnosis for patients who have peripheral neuropathy and paraproteinemia among other multisystem manifestations. The syndrome can be debilitating if not recognized early in its course; thus, appropriate diagnosis and treatment are important for optimal clinical outcomes.
Topics: Humans; Lenalidomide; Monoclonal Gammopathy of Undetermined Significance; POEMS Syndrome; Paraproteinemias; Vascular Endothelial Growth Factor A
PubMed: 34081097
DOI: 10.1001/jamaoncol.2021.0586 -
Clinical Lymphoma, Myeloma & Leukemia May 2023Monoclonal Gammopathy of Undetermined Significance (MGUS) is an asymptomatic premalignant plasma cell dyscrasia with a predominate rise of the IgG immunoglobulin... (Review)
Review
Monoclonal Gammopathy of Undetermined Significance (MGUS) is an asymptomatic premalignant plasma cell dyscrasia with a predominate rise of the IgG immunoglobulin fraction without end-organ damage, often diagnosed incidentally. Despite its progression into various subsequent forms of hematological malignancies, MGUS remains underdiagnosed. A literature search was conducted using the Medline, Cochrane, Embase, and Google Scholar databases, including articles published until December 2022. Keywords used encompassed "Monoclonal Gammopathy of Undetermined Significance," "Plasma Cell dyscrasia," "Monoclonal gammopathy of renal significance," and "IgM Monoclonal gammopathy of Undetermined Significance," This study aimed to conduct a critical review to update knowledge regarding the pathophysiology, risk factors, clinical features, diagnostic protocols, complications, and current and novel treatments for MGUS. We recommend a multidisciplinary approach to manage MGUS due to the complexity of the illness's etiology, diagnosis, and therapy. This comprehensive review also highlights future prospects, such as developing screening protocols for at-risk populations, prevention of disease progression by early diagnosis through genome-wide association studies, and management using Daratumumab and NSAIDs.
Topics: Humans; Monoclonal Gammopathy of Undetermined Significance; Genome-Wide Association Study; Paraproteinemias; Risk Factors; Neoplasms, Plasma Cell; Multiple Myeloma; Disease Progression
PubMed: 36966041
DOI: 10.1016/j.clml.2023.02.004 -
American Journal of Kidney Diseases :... Dec 2019Dysproteinemic kidney diseases occur when B- or plasma cell clones produce pathogenic monoclonal immunoglobulins or light chains that cause kidney damage. The clinical... (Review)
Review
Dysproteinemic kidney diseases occur when B- or plasma cell clones produce pathogenic monoclonal immunoglobulins or light chains that cause kidney damage. The clinical presentation of these disorders ranges from sub-nephrotic-range proteinuria or microscopic hematuria with preserved kidney function to severe nephrotic syndrome to severe acute kidney injury or rapidly progressive glomerulonephritis. These monoclonal immunoglobulins can cause a variety of histologic patterns of injury, including cast nephropathy, glomerular and tubular deposition diseases, amyloidosis, and inflammatory glomerulonephritis. The underlying clonal disorder may meet criteria for overt multiple myeloma or systemic lymphoma. In recent years, there has been increased recognition and study of dysproteinemic kidney diseases that occur in the setting of smaller clonal plasma and B-cell populations, which are classified as monoclonal gammopathies of renal significance. Regardless of clonal cell burden, the goal of treatment is to achieve a hematologic response (ie, improvement or resolution of the monoclonal protein) by eradicating the underlying clone. Organ-specific responses are dependent on achieving hematologic response. Without appropriate treatment, many of these disorders are associated with high rates of progressive kidney disease and end-stage kidney disease. In this installment of AJKD's Core Curriculum in Nephrology, we review the pathogenesis, diagnosis, and treatment of dysproteinemic kidney diseases.
Topics: Amyloidosis; Antineoplastic Agents; Biopsy, Needle; Clinical Competence; Curriculum; Education, Medical, Graduate; Female; Humans; Immunohistochemistry; Immunosuppressive Agents; Male; Multiple Myeloma; Nephrology; Nephrotic Syndrome; Paraproteinemias; Risk Assessment; Treatment Outcome
PubMed: 31331759
DOI: 10.1053/j.ajkd.2019.04.029 -
Critical Reviews in Oncology/hematology Mar 2023Monoclonal gammopathy of renal significance (MGRS) is a hemato-nephrological term referring to a heterogeneous group of kidney disorders characterized by direct or... (Review)
Review
Monoclonal gammopathy of renal significance (MGRS) is a hemato-nephrological term referring to a heterogeneous group of kidney disorders characterized by direct or indirect kidney injury caused by a monoclonal immunoglobulin (MIg) produced by a B cell or plasma cell clone that does not meet current hematologic criteria for therapy. MGRS-associated kidney diseases are diverse and can result in the development of end stage kidney disease (ESKD). The diagnosis is typically made by nephrologists through a kidney biopsy. Many distinct pathologies have been identified and they are classified based on the site or composition of the deposited Mig, or according to histological and ultrastructural findings. Therapy is directed towards the identified underlying clonal population and treatment decisions should be coordinated between hematologists and nephrologists in a multidisciplinary fashion, depend on the type of MGRS, the degree of kidney function impairment and the risk of progression to ESKD.
Topics: Humans; Kidney; Paraproteinemias; Monoclonal Gammopathy of Undetermined Significance; Kidney Diseases; Kidney Failure, Chronic
PubMed: 36736510
DOI: 10.1016/j.critrevonc.2023.103926 -
Journal of the American Society of... Jul 2018Monoclonal gammopathies are characterized by the overproduction of monoclonal Ig (MIg) detectable in the serum or urine resulting from a clonal proliferation of plasma... (Review)
Review
Monoclonal gammopathies are characterized by the overproduction of monoclonal Ig (MIg) detectable in the serum or urine resulting from a clonal proliferation of plasma cells or B lymphocytes. The underlying hematologic conditions range from malignant neoplasms of plasma cells or B lymphocytes, including multiple myeloma and B-cell lymphoproliferative disorders, to nonmalignant small clonal proliferations. The term MGUS implies presence of an MIg in the setting of a "benign" hematologic condition without renal or other end organ damage. The term MGRS was recently introduced to indicate monoclonal gammopathy with MIg-associated renal disease in the absence of hematologic malignancy. Most MIg-associated renal diseases result from the direct deposition of nephrotoxic MIg or its light- or heavy-chain fragments in various renal tissue compartments. Immunofluorescence microscopy is essential to identify the offending MIg and define its tissue distribution. Mass spectrometry is helpful in difficult cases. Conditions caused by direct tissue deposition of MIg include common disorders, such as cast nephropathy, amyloidosis, and MIg deposition diseases, as well as uncommon disorders, such as immunotactoid glomerulopathy, proliferative GN with MIg deposits, light-chain proximal tubulopathy, and the rare entities of crystal-storing histiocytosis and crystalglobulinemia. Indirect mechanisms of MIg-induced renal disease can cause C3 glomerulopathy or thrombotic microangiopathy without tissue MIg deposits. Treatment of MIg-associated renal disease is aimed at eliminating the clonal plasma cell or B-cell population as appropriate. Both the renal and the underlying hematologic disorders influence the management and prognosis of MIg-associated renal diseases.
Topics: Amyloidosis; Humans; Immunoglobulin Heavy Chains; Immunoglobulin Light Chains; Kidney Diseases; Kidney Glomerulus; Kidney Tubules; Laser Capture Microdissection; Mass Spectrometry; Paraproteinemias; Terminology as Topic
PubMed: 29703839
DOI: 10.1681/ASN.2017121319 -
Blood Oct 2018Monoclonal gammopathy is a common condition, particularly in the elderly. It can indicate symptomatic multiple myeloma or another overt malignant lymphoid disorder... (Review)
Review
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.
Topics: Animals; Autoantibodies; B-Lymphocytes; Cytokines; Humans; Immunoglobulins; Paraproteinemias
PubMed: 30012636
DOI: 10.1182/blood-2018-04-839480 -
Continuum (Minneapolis, Minn.) Oct 2023Coexistence of polyneuropathy and gammopathy is a common but potentially challenging situation in clinical practice. This article reviews the clinical,... (Review)
Review
OBJECTIVE
Coexistence of polyneuropathy and gammopathy is a common but potentially challenging situation in clinical practice. This article reviews the clinical, electrophysiologic, and hematologic phenotypes of the paraproteinemic neuropathies and the diagnostic and treatment strategies for each.
LATEST DEVELOPMENTS
Advances in our understanding of the underlying pathophysiology of various paraproteinemic neuropathies and their corresponding phenotypes have identified potential new therapeutic targets. Therapeutic strategies to diminish anti-myelin-associated glycoprotein (MAG) IgM antibodies have shown partial and inconsistent efficacy; however, antigen-specific immune therapy is being investigated as a novel treatment to remove the presumably pathogenic anti-MAG antibody. Advances in genetic and cell signaling studies have resulted in the approval of Bruton tyrosine kinase inhibitors for Waldenström macroglobulinemia. Monoclonal antibodies are being investigated for the treatment of light chain amyloidosis.
ESSENTIAL POINTS
Early recognition and treatment of underlying plasma cell disorders improves clinical outcomes in patients with paraproteinemic neuropathy. Despite significant progress, our knowledge regarding underlying mechanisms for paraproteinemic neuropathy is still limited. Clinicians' awareness of clinical phenotypes, electrophysiologic hallmarks, and hematologic findings of the different paraproteinemic neuropathies is crucial to promptly identify and treat patients and to avert misdiagnosis. Multidisciplinary collaboration among specialists, including neurologists and hematologists, is paramount for the optimal treatment of these patients with overlapping conditions.
Topics: Humans; Peripheral Nervous System Diseases; Paraproteinemias; Polyneuropathies; Myelin-Associated Glycoprotein; Autoantibodies
PubMed: 37851040
DOI: 10.1212/CON.0000000000001294 -
Neurological Sciences : Official... Nov 2021Paraproteinemia is associated with different peripheral neuropathies. The major causes of neuropathy correlated with paraproteinemia are the deposition of immunoglobulin... (Review)
Review
Paraproteinemia is associated with different peripheral neuropathies. The major causes of neuropathy correlated with paraproteinemia are the deposition of immunoglobulin in the myelin, represented by anti-myelin-associated glycoprotein (MAG) neuropathy; deposition of immunoglobulin or its fragment in the interstitium, represented by immunoglobulin light chain amyloidosis (AL amyloidosis); and paraneoplastic mechanisms that cannot be solely attributed to the deposition of immunoglobulin or its fragment, represented by polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin change (POEMS) syndrome. Patients with anti-MAG neuropathy and POEMS syndrome present with slowing of nerve conduction parameters. This characteristic fulfills the electrodiagnostic criteria for chronic inflammatory demyelinating polyneuropathy (CIDP) defined by the European Academy of Neurology and Peripheral Nerve Society (EAN/PNS). Although direct damage caused by the deposition of amyloid can induce axonal damage in AL amyloidosis, some patients with this condition have features fulfilling the EAN/PNS electrodiagnostic criteria for CIDP. Conventional immunotherapies for CIDP, such as steroids, intravenous immunoglobulin, and plasma exchange, offer no or only minimal-to-modest benefit. Although rituximab can reduce the level of circulating autoantibodies, it may only be effective in some patients with anti-MAG neuropathy. Drugs including melphalan, thalidomide, lenalidomide, and bortezomib for POEMS syndrome and those including melphalan, thalidomide, lenalidomide, pomalidomide, bortezomib, ixazomib, and daratumumab for AL amyloidosis are considered. Since there will be more therapeutic options in the future, thereby enabling appropriate treatments for individual neuropathies, there is an increasing need for early diagnosis.
Topics: Humans; Neural Conduction; POEMS Syndrome; Paraproteinemias; Peripheral Nerves; Polyradiculoneuropathy, Chronic Inflammatory Demyelinating
PubMed: 34529193
DOI: 10.1007/s10072-021-05583-7 -
Ugeskrift For Laeger Oct 2021Monoclonal gammopathies range from benign conditions to severe malignancies. A summary is given in this review. Overall, the prevalence is high; monoclonal gammopathies... (Review)
Review
Monoclonal gammopathies range from benign conditions to severe malignancies. A summary is given in this review. Overall, the prevalence is high; monoclonal gammopathies (MGUS) occur in > 3% of persons above 50 years of age. Approximately 400 new cases of multiple myeloma and 80 new cases of amyloid light-chain (AL) amyloidosis are diagnosed yearly in Denmark. MGUS is most often asymptomatic, but M-protein associated syndromes exist and should be considered when finding M-protein. Serum free light kappa and lambda chain analysis, CT, PET/CT and whole-body MRI have revolutionised diagnostics and monitoring of monoclonal gammopathies. New treatment modalities have improved outcome in multiple myeloma and AL amyloidosis.
Topics: Humans; Monoclonal Gammopathy of Undetermined Significance; Multiple Myeloma; Paraproteinemias; Positron Emission Tomography Computed Tomography
PubMed: 34709161
DOI: No ID Found -
Journal of Clinical Oncology : Official... Jun 2023The existence of patients with multiple myeloma (MM) and light-chain (AL) amyloidosis who present with a monoclonal gammopathy of undetermined significance (MGUS)-like...
PURPOSE
The existence of patients with multiple myeloma (MM) and light-chain (AL) amyloidosis who present with a monoclonal gammopathy of undetermined significance (MGUS)-like phenotype has been hypothesized, but methods to identify this subgroup are not standardized and its clinical significance is not properly validated.
PATIENTS AND METHODS
An algorithm to identify patients having MGUS-like phenotype was developed on the basis of the percentages of total bone marrow (BM) plasma cells (PC) and of clonal PC within the BM PC compartment, determined at diagnosis using flow cytometry in 548 patients with MGUS and 2,011 patients with active MM. The clinical significance of the algorithm was tested and validated in 488 patients with smoldering MM, 3,870 patients with active MM and 211 patients with AL amyloidosis.
RESULTS
Patients with smoldering MM with MGUS-like phenotype showed significantly lower rates of disease progression (4.5% and 0% at 2 years in two independent series). There were no statistically significant differences in time to progression between treatment versus observation in these patients. In active newly diagnosed MM, MGUS-like phenotype retained independent prognostic value in multivariate analyses of progression-free survival (PFS; hazard ratio [HR], 0.49; = .001) and overall survival (OS; HR, 0.56; = .039), together with International Staging System, lactate dehydrogenase, cytogenetic risk, transplant eligibility, and complete remission status. Transplant-eligible patients with active MM with MGUS-like phenotype showed PFS and OS rates at 5 years of 79% and 96%, respectively. In this subgroup, there were no differences in PFS and OS according to complete remission and measurable residual disease status. Application of the algorithm in two independent series of patients with AL predicted for different survival.
CONCLUSION
We developed an open-access algorithm for the identification of MGUS-like patients with distinct clinical outcomes. This phenotypic classification could become part of the diagnostic workup of MM and AL amyloidosis.
Topics: Humans; Monoclonal Gammopathy of Undetermined Significance; Clinical Relevance; Immunoglobulin Light-chain Amyloidosis; Disease Progression; Paraproteinemias; Multiple Myeloma; Phenotype
PubMed: 36930848
DOI: 10.1200/JCO.22.01916