Monoclonal gammopathy of undetermined significance (MGUS) is usually asymptomatic and is often detected incidentally during routine laboratory tests. It is a plasma cell lymphoproliferative disorder with the potential of progressing to a malignancy or multiple myelomas (MM) [1]. It commonly occurs in individuals above the age of 50 and a higher incidence has been reported amongst Africans from America as well as from Africa [2] [3]. Other risk factors of MGUS include older age [1], family history, male sex [4], immunosuppression, and a history of pesticide exposure [5].

Although MGUS itself is asymptomatic, patients typically have clinical symptoms and signs of other disorders like osteoporosis, venous thrombosis [6], peripheral neuropathy, vasculitis, hemolytic anemia, skin rashes, gout or hypercalcemia.

Rajkumar et al [7] have described three clinical types MGUS with their own individual stages of progressing from a premalignant stage to an intermediate stage to a malignant stage. These are:

• Non-immunoglobulin (Ig)M MGUS (IgG, IgA, or IgD MGUS): This is the commonest subtype of MGUS. It can progress to either an asymptomatic form of MM or to symptomatic MM. Rarely, it can progress to AL amyloidosis, or light chain deposit disease, or another lymphoproliferative disorder.
• IgM MGUS: IgM MGUS can progress to either asymptomatic Waldenström macroglobulinemia or to symptomatic Waldenström macroglobulinemia and rarely to lymphoma or AL amyloidosis or IgM MM [8] [9].
• Light chain MGUS: this is a precursor to a light chain MM and almost 20% of new MM cases are of this type [10]. Idiopathic Bence Jones proteinuria represents the equivalent of symptomatic MM or asymptomatic Waldenström macroglobulinemia with light chain monoclonal gammopathies.

• Asymptomatic

  Monoclonal gammopathy of undetermined significance (MGUS) is usually asymptomatic and is often detected incidentally during routine laboratory tests. [symptoma.com]

  It is not known whether MM is always preceded by a premalignant asymptomatic MGUS stage. [ncbi.nlm.nih.gov]

  Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic disorder associated with an increased risk of developing multiple myeloma and related plasma cell proliferative malignancies. [bestpractice.bmj.com]

• Hodgkin Lymphoma

  ＊Nodular lymphocyte predominant Hodgkin lymphoma ＊Classical Hodgkin lymphoma Nodular sclerosis Lymphocyte-rich classical Hodgkin lymphoma Mixed cellularity classical Hodgkin lymphoma Lymphocyte-depleted classical Hodgkin lymphoma HISTIOCYTIC AND DENDRIC [med.osaka-cu.ac.jp]

  At a median follow-up of 65 months (range, 12 to 239 months), 64 MGUS cases (5.8%) evolved to multiple myeloma (MM) (n = 43), extramedullary plasmacytoma (n = 1), primary amyloidosis (n = 1), Waldenström’s macroglobulinemia (n = 12), non-Hodgkin’s lymphoma [doi.org]

  BACKGROUND AND AIM: Chronic hepatitis C (CHC) has been associated with lymphoproliferative disorders (LPD) such as mixed cryoglobulinemia syndrome (MCS), monoclonal gammopathy of undetermined significance (MGUS), and B-cell non-Hodgkin lymphoma (B-NHL [ncbi.nlm.nih.gov]

  […] disorders of plasma cell leukemia, light chain deposition disease in patients with IgG- or IgA-type MGUS; Monoclonal gammopathy of undetermined significance (MGUS), plasma cell dyscrasias, venous thromboembolism or lymphoproliferative disorders, such as non-Hodgkin [hematologyandoncology.net]

• Recurrent Infection

  Characterised by the association of a thymoma, hypogammaglobulinaemia, and B-cell and T-cell dysfunction, Good's syndrome (GS) is a rare cause of adult immunodeficiency leading to recurrent infections, and autoimmune manifestations related to the thymoma [ncbi.nlm.nih.gov]

  Importantly, M-protein-associated kidney diseases have a high recurrence rate after kidney transplantation. [doi.org]

• Lymphadenopathy

  Patients with constitutional symptoms including fever, night sweats, and unintentional weight loss, in the presence of lymphadenopathy and/or hepatosplenomegaly suggest lymphoma. [cancertherapyadvisor.com]

  Generalized lymphadenopathy Lambda restriction of plasma cells in bone marrow aspirate M protein of 5 g/l M protein of 15 g/l Back to top [pathologyoutlines.com]

  85 In Schnitzler syndrome there is deposition of para-protein (IgM-κ is most common) at the dermoepidermal junction and in capillary walls which probably contributes to development of chronic urticaria, intermittent fever, arthralgia, bone pain, and lymphadenopathy [doi.org]

• Congestive Heart Failure

  Risk factors included immobilization for longer than 48 hours, surgery in the past 3 months, current hospitalization at the time of VTE occurrence, oral contraceptive use, and congestive heart failure. [hematologyandoncology.net]

  If the M-protein and the proportion of plasma cells in the bone marrow are consistent with MGUS but there is a nephrotic syndrome, congestive heart failure, peripheral neuropathy, orthostatic hypotension, massive hepatomegaly or any combination of these [doi.org]

• Dyspnea

  Fifty nine year-old man was admitted because of dyspnea for several months. Echocardiography revealed diastolic dysfunction showing restrictive physiology with elevated left ventricular filling pressure. [ncbi.nlm.nih.gov]

  Presenting symptoms related to anemia such as fatigue, generalized weakness and dyspnea, bone or back pain, are suggestive of multiple myeloma. [cancertherapyadvisor.com]

• Heart Disease

  The increased risk of dying in individuals with monoclonal gammopathy of undetermined significance is caused by malignant progression and heart disease. [Manuscript] III. [openarchive.ki.se]

  Your recognised location is United States (US) More: Guidance Coronary heart disease Source: Finnish Medical Society Duodecim This article is freely available only to users in the UK. [evidence.nhs.uk]

  However, because of the relatively low annual risk of progression, one needs to take into consideration other competing causes of death such as heart disease and unrelated malignancies. [ufrgs.br]

• Osteoporosis

  KEYWORDS: Aging; Fractures; Monoclonal gammopathy of undetermined significance; Osteoporosis [ncbi.nlm.nih.gov]

  Although MGUS itself is asymptomatic, patients typically have clinical symptoms and signs of other disorders like osteoporosis, venous thrombosis, peripheral neuropathy, vasculitis, hemolytic anemia, skin rashes, gout or hypercalcemia. [symptoma.com]

  However, if evaluation shows evidence of significant loss of bone density ( osteopenia or osteoporosis ), doctors may recommend treatment with bisphosphonates. [merckmanuals.com]

  Osteoporosis MGUS patients have an increased risk of osteoporosis and fractures (axial >distal). 47, 52 – 56 Conversely, the prevalence of MGUS is 3.6% in patients with osteoporosis, compared to 2% in patients without osteoporosis. 57 The prevalence of [doi.org]

• Osteopenia

  However, if evaluation shows evidence of significant loss of bone density ( osteopenia or osteoporosis ), doctors may recommend treatment with bisphosphonates. [merckmanuals.com]

  Individuals with MGUS also have an increased risk of osteoporosis and osteopenia associated with an increased likelihood of developing fractures especially in the vertebral column, peripheral neuropathy and thromboembolic events. [ncbi.nlm.nih.gov]

  However, recent studies suggest that MGUS patients with associated bone loss (osteopenia or osteoporosis) may benefit from treatment with intravenous bisphosphonates but less frequently than the monthly treatments usually required to treat patients with [msdmanuals.com]

• Purpura

  A 79-year-old Japanese male who had been suffering from renal insufficiency of unknown causes visited us with reddish papules and purpura on both forearms of a month's duration. [ncbi.nlm.nih.gov]

  Many patients (39) in whom the monoclonal protein disappeared underwent treatment for myeloma or lymphoma or for unrelated disorders, such as idiopathic thrombocytopenic purpura or vasculitis. [doi.org]

• Hematuria

  Laboratory workup displayed increased serum creatinine, proteinuria, and mild microscopic hematuria. [ncbi.nlm.nih.gov]

  Two years prior to the current presentation, he developed intermittent microscopic hematuria and was examined by abdominal ultrasound and urinary cytology. [elynsgroup.com]

  In conclusion, collaborative follow-ups by both a hematologist and a nephrologist are necessary for MGUS patients with renal involvement such as proteinuria, hematuria, or renal insufficiency, not only for early detection of disease progression but also [karger.com]

  Renal involvement is nearly constant and usually manifests with high-grade proteinuria, hematuria, hypertension, and renal insufficiency. Extrarenal manifestations, particularly cardiac and hepatic, are not uncommon, but are rarely symptomatic. [doi.org]

• Peripheral Neuropathy

  Peripheral neuropathy associated with IgA MGUS is uncommon, and there are limited reports. [ncbi.nlm.nih.gov]

  Miki Suzuki, Peripheral neuropathy in the elderly, Peripheral Nerve Disorders, 10.1016/B978-0-444-52902-2.00046-1, (803-813), (2013). [doi.org]

  Original language English (US) Title of host publication Contemporary Issues in Peripheral Neuropathy Publisher Nova Science Publishers, Inc. [nebraska.pure.elsevier.com]

• Tingling

  However, the monoclonal antibody can bind to nerves and lead to numbness, tingling, and weakness. People with this disorder also are more likely to have bone loss and fractures. [merckmanuals.com]

  Symmetrical paresthesia, tingling and numbness of the hands and feet in a socks and gloves pattern are the common presentation features. [nebraska.pure.elsevier.com]

  Rarely, some people have numbness or tingling in their hands and feet, or problems with their balance. MGUS is often found during a blood test carried out for some other reason. [bloodwise.org.uk]

• Paresthesia

  A 75-year-old man complained of paresthesiae in both feet and unsteady gait for 6 months. He had no weakness, but deep tendon reflexes were absent and vibratory sensation distally diminished in both legs. [ncbi.nlm.nih.gov]

  Symmetrical paresthesia, tingling and numbness of the hands and feet in a socks and gloves pattern are the common presentation features. [nebraska.pure.elsevier.com]

MGUS is usually diagnosed incidentally when patients are being evaluated with serum protein electrophoresis for clinical features of osteoporosis, or hypercalcemia or elevated erythrocyte sedimentation rate, venous thrombosis, etc. MGUS can be easily evaluated and monitored with blood tests and therefore its conversion to a malignancy can be easily observed [11]. A thorough workup for MGUS includes a complete blood count to detect anemia, thrombocytopenia, and leukopenia; renal function tests, serum uric acid levels, and lactate dehydrogenase levels [12]. The gold standard test for diagnosis of MGUS is serum and urine electrophoresis. Tests to determine prognosis include beta2 microglobulin, C-reactive protein, and serum free light chain assay. The progression of MGUS can be evaluated with quantitative immunoglobulin measurements.

Lytic bone lesions are usually noticed on a radiological skeletal survey and it should be performed for documentation as it can predict sites of pathological fractures. Bone marrow biopsy helps to detect abnormal cytogenetics [13] and is indicated in patients with IgA and IgM M-proteins but is not recommended in patients with IgG MGUS unless their serum M-protein level is > 1.5 g/dL or there is evidence of end-organ damage [14].

In the RAVE trial, which compared rituximab with cyclophosphamide for induction treatment of AAV, ANCA specificity was not useful predictor of complete remission at six months both in the entire cohort and in the two treatment groups [13]. [elynsgroup.com]

The M-protein levels in people with MGUS often remain stable for years—25 years in some people—and do not require treatment. [merckmanuals.com]

Conclusions : Exudative maculopathy unresponsive to conventional treatment may suggest an underlying hematologic condition. [iovs.arvojournals.org]

Indeed, multiple myeloma has perhaps seen more remarkable progress in treatment and patient outcomes than any other cancer during the last decade. [ncbi.nlm.nih.gov]

The treatment of MGRS-related kidney diseases should be tailored to the clone responsible. In the past, part of the reticence for withholding treatment was that alkylators were the only antiplasma cell therapies available. [doi.org]

KEYWORDS: DNA copy-number changes; DNA microarrays; monoclonal gammopathies; prognosis [ncbi.nlm.nih.gov]

The etiology of the prothrombotic state in myeloma has yet to be definitively characterized. [ncbi.nlm.nih.gov]

In a real life exhaustive study, the Martinique Cancer Registry proposes an epidemiological focus on MGUS in Martinique. [mona.uwi.edu]

Epidemiologic studies have established the prevalence of these conditions and the estimated risk of progression to symptomatic disease. [ncbi.nlm.nih.gov]

Thus we propose a possible pathophysiologic link between the gammopathy-associated factors and the generation of lymphedema with initial fibrogenesis aggravating pre-existing lipedema. [ncbi.nlm.nih.gov]

“Monoclonal gammopathy of undetermined significance and smoldering myeloma: new insights into pathophysiology and epidemiology”. Hematology Am Soc Hematol Educ Program.. vol. 2010. 2010. pp. 295-302. [cancertherapyadvisor.com]

More prevalent in African Americans than Caucasians (2 - 3 fold) ( Leukemia 2014;28:1537 ) More common in men than women (1.5:1) Non-IgM MGUS represents up to 85% of MGUS cases Pathophysiology Origin is clonal mature plasma cells residing in the bone [pathologyoutlines.com]

Etiologic Factors for MGUS and Prospects for Primary Prevention Recent observations offer important clues, indicating that genetic predisposition and potentially preventable environmental factors may play a key role in the development of MGUS. [doi.org]

This progression cannot be prevented. [merckmanuals.com]

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