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Clinical Applications/ Clinical Applications/ Monoclonal gammopathies/ Monoclonal Gammopathies of Clinical Significance

Monoclonal Gammopathies of Clinical Significance (MGCS)

Clinicians have become increasingly aware of MGCS and their effects on patients and their quality of life

Examples of situations where clinicians need to be aware of the effects and the clinical relevance of monoclonal gammopathies of undetermined significance are described below by Dr Maximilian Steinhardt, a specialist in internal medicine, hematology, and oncology at Würzburg University Hospital, focusing on Multiple Myeloma and amyloidosis. To hear more of the interview* with Dr Steinhardt, please visit here: https://info.bindingsite.com/de-de/flc.spe.hcp.ger

_{*interview is in German}

"Therefore, the next step when there is a suspicion of a monoclonal-protein related disorder, is that serum immunofixation should be performed [alongside SPE]. Because it is more sensitive than urine testing and because it detects free light chains, testing using a serum free light chain assay should also be performed. Free light chains are part of the antibody, but they are poorly detected by immunofixation. Changes in the values of sFLC are important in the diagnostic processes because they are very sensitive for the presence of a paraprotein. Therefore, they should be assessed in any case and not be left aside."

- Dr Steinhardt

“Many patients come to us to understand the cause of the paraprotein found in their blood samples. Paraproteins are antibodies that are measured in the blood or urine, and are found in abnormally high amounts. In these patients, further testing did not lead to a diagnosis of myeloma. However, these patients still have significant problems due to the elevated antibodies, even though the link is sometimes unclear. I see a lot of these patients in my outpatient clinic, and I have noticed that many of these paraprotein-related disorders, where there is elevated antibody and free light chain levels, are first of all, underdiagnosed, and when they are diagnosed, it is often too late.”

- Dr Steinhardt

“To stay with the patients for a moment, and to round off the subject, patients do often have unexplained symptoms which have a significant effect on their quality of life, for example polyneuropathy, gastrointestinal complaints, skin problems, but the cause of the problem is often unexplained. When paraproteins are the cause of these problems, these patients can really be helped and that naturally gives the patients a lot of relief. When the affected organ is a vital organ, then there is another dimension to the case, for instance in the case of deterioration of the kidney, which can be progressive, or heart failure, which can rapidly progress. In these cases, there is a clear correlation between identification [of the monoclonal protein] and not just quality of life but also directly with patient survival, which makes it even more important to recognise the paraprotein-associated diseases in a timely manner."

- Dr Steinhardt

1/3

Use this interactive diagram to learn more about different monoclonal gammopathies of clinical significance:

Monoclonal Gammopathy of Ocular Significance (MGOS)

Deposition of monoclonal proteins can cause visual impairments, and these impairments may cause patients to visit ophthalmologists. Therefore, it is important that ophthalmologists are aware of the potential for monoclonal proteins to cause these symptoms.

A common MGOS is paraproteinemic keratopathy. In paraproteinemic keratopathy, deposition of monoclonal proteins causes opacity of the cornea.³ It must be differentiated from hereditary, infectious, metabolic or drug-induced corneal diseases⁴ to help ensure correct patient management.

Why is sFLC is important in monoclonal gammopathy of ocular significance?

It is important to identify the monoclonal gammopathy as the underlying cause so that suitable treatment can be given. For instance, a keratinoplasty performed on a person with paraproteinemic keratopathy will not last if the cornea clouds over again due to further monoclonal protein deposition. In patients with MGUS causing the ocular symptoms, the monoclonal protein level may be very small and could be below the analytical sensitivity of SPE, sIFE, UPE and uIFE. Therefore, sFLC may be able to detect the monoclonal protein where other methods cannot.

To learn more, please download this white paper: COMING SOON

Effects of monoclonal gammopathy on the immune system

Patients with MGUS have reduced amounts of functional immunoglobulins and increased rates of infection.^5-7This is due to the effect of the underlying clone on the bone marrow microenvironment, and a reduction in the production of polyclonal immunoglobulins.⁸ The monoclonal immunoglobulins that are produced are not capable of mounting an immune response in the same way as polyclonal immunoglobulins.

In this population, it is important to consider infection risk, and prophylactic vaccination.

To learn more, please download this white paper: COMING SOON

Effect of monoclonal proteins on the heart and circulatory system

Monoclonal proteins may affect the heart through direct deposition, as in AL amyloidosis,⁹ or through an increase in thrombotic events. Patients with MGUS develop higher rates of thrombosis than people without MGUS^6,7,10-15 and this is linked to an increased rate of myocardial infarction.¹⁶ It is important to monitor cardiac function and be aware of the potential of thrombotic events in patients with MGUS, especially in patients with IgM MGUS.¹⁵

Identification of monoclonal protein as a cause of cardiac amyloidosis

In some patients with MGUS, the monoclonal free light chain produced might have the propensity of forming amyloid fibrils. These may deposit in the heart, leading to severe disease and mortality. This condition is called cardiac amyloidosis. Not all patients with cardiac amyloidosis have a monoclonal gammopathy but 98% of cases of cardiac amyloidosis are due to deposits of either free light chains or transthyretin (ATTR amyloidosis).¹⁷ It is important to distinguish which type of protein is causing the deposits in order that the correct treatment is given, as the underlying disease require different treatments.

As the confirmatory steps in the diagnostic pathway are invasive or expensive, a simple, front-line test to rule out a monoclonal gammopathy when AL amyloidosis is a potential cause of cardiac amyloidosis is desired. Guidelines recommend the use of a panel of tests including sFLC, serum protein electrophoresis (SPE), serum immunofixation (sIFE), urine protein electrophoresis (UPE) and urine immunofixation (uIFE) in this frontline testing.^17,18

To learn more, please download this white paper: COMING SOON

Monoclonal Gammopathy of Renal Significance (MGRS)

Patients who develop a monoclonal gammopathy of renal significance are at greater risk of progression to Multiple Myeloma.¹⁹

Why are serum free light chains (sFLC) important in monoclonal gammopathy of renal significance?

In monitoring, sFLC levels may reflect treatment response.

The amount of monoclonal protein produced may be low, therefore, if the monoclonal protein is a free light chain, it may be below the analytical sensitivity of SPE and sIFE. Depending on renal function, UPE and uIFE may not detect the monoclonal protein either, therefore sFLC may be able to detect the monoclonal protein where other methods cannot.

Examples of diseases in the MGRS category include AL amyloidosis, light chain deposition disease, type I and II cryoglobulinemic glomerulonephritis, C3 glomerulopathy with monoclonal gammopathy.

To learn more, please download this white paper:

Download MGRS Significance Whitepaper

Monoclonal Gammopathy of Dermatological Significance (MGDS)

Patients with MGUS are at greater risk of developing a number of skin conditions.¹¹ When MGCS affects the skin, it can lead to urticaria, plaques, ulcers, or acrocyanosis.

Why is sFLC is important in monoclonal gammopathy of dermatological significance?

In order to identify that a monoclonal gammopathy is the cause the skin symptoms, the monoclonal protein must be identified. In patients with MGUS and skin symptoms, the monoclonal protein level may be very small. It may be below the analytical sensitivity of SPE, sIFE, UPE and uIFE may not detect the monoclonal protein either, therefore sFLC may be able to detect the monoclonal protein where other methods cannot.

To learn more, please download this white paper: COMING SOON

Monoclonal Gammopathy of Skeletal Significance (MGSS)

Patients with MGUS are already at risk of increased fractures, even if there is no progression to multiple myeloma, due to reduced bone strength and impaired bone microarchitecture caused by the effects of the underlying monoclonal gammopathy.^6,7,10,20-26

Why is sFLC is important in monoclonal gammopathy of skeletal significance?

It is important to test for sFLC to rule out monoclonal gammopathies. Patients may present to emergency care departments with fractures. In patients with unexplained fractures, particularly in populations at higher risk of monoclonal gammopathies, including sFLC testing within the panel of monoclonal gammopathy tests is important, and recommended by guidelines.^27-29

To learn more, please download this white paper: COMING SOON

Monoclonal Gammopathy of Neurological Significance (MGNS)

Patients with MGUS are at increased risk of peripheral neuropathy, chronic inflammatory demyelinating neuropathy, and autonomic neuropathy, diabetic sensorimotor polyneuropathy.^{5,7,11,26,30-33} Patients with MGUS and peripheral neuropathy are at increased risk of fractures compared to patients with MGUS alone.²⁵

Why is sFLC is important in monoclonal gammopathy of neurological significance?

In patients with unexplained neurological symptoms, particularly peripheral neuropathy, it is important to rule out monoclonal gammopathy as a cause. When there is a suspicion of monoclonal gammopathy, guidelines recommend testing with sFLC assays, so that sFLCs can be detected, even if their levels are too low to be detected by SPE.^27-29

To learn more, please download this white paper: COMING SOON

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What is a Monoclonal Gammopathy of Clinical Significance?

MGCS are monoclonal gammopathies that do not meet the clinical definition of an active malignancy but where the monoclonal protein or the plasma cell clone itself causes organ damage in a manner unrelated to the tumour burden.¹

It is important to monitor patients with MGUS to detect the development of MGCS early. This allows for timely treatment, effective symptom management, and an improved quality of life for the patients.

The clinical significance of Monoclonal Gammopathy of Undetermined Significance (MGUS) is not limited to progression to Multiple Myeloma, AL amyloidosis or another active malignancy such as Waldenström’s Macroglobulinemia.

Life expectancy is reduced, even in patients who do not progress to an active malignancy.

Some of this reduction in life expectancy is due to monoclonal gammopathies of clinical significance.

Learn more about MGUS

Graph showing relative survival compared to age and sex matched controls

^{Figure 1 – Life expectancy in patients with MGUS in comparison to people without MGUS. Adapted from Kristinsson et al. 2009²}

In monoclonal gammopathies of clinical significance, recognising that the monoclonal protein is the cause of the patient’s symptoms is of utmost importance. Since the amount of monoclonal protein produced by the underlying tumour may be small, all of the guideline-recommended tests for the identification of monoclonal protein should be used. As some patients have tumours that only secrete monoclonal free light chains, sFLC testing should be included in the assessment for possible monoclonal gammopathies.

Monoclonal protein levels may change over time, so it is important to monitor the patient’s monoclonal protein. sFLC testing should also be included in this step, to monitor sFLC levels. sFLC measurements provide additional information and may detect rises in monoclonal protein production earlier than other methods.

References

Dispenzieri A. Monoclonal gammopathies of clinical significance. Hematology Am Soc Hematol Educ Program 2020; 2020:380-388
Kristinsson SY, et al. Patterns of survival and causes of death following a diagnosis of monoclonal gammopathy of undetermined significance: a population-based study. Haematologica 2009; 94:1714-1720
Wasielica-Poslednik J, et al. [Hematological diagnosis in the corneal consultation]. Ophthalmologe 2018; 115:765-768
Lisch W, et al. The Hematologic Definition of Monoclonal Gammopathy of Undetermined Significance in Relation to Paraproteinemic Keratopathy (An American Ophthalmological Society Thesis). Trans Am Ophthalmol Soc 2016; 114:T7
Bird J, et al. UK Myeloma Forum (UKMF) and Nordic Myeloma Study Group (NMSG): guidelines for the investigation of newly detected M-proteins and the management of monoclonal gammopathy of undetermined significance (MGUS). Br J Haematol 2009; 147:22-42
Stern S, et al. Investigation and management of the monoclonal gammopathy of undetermined significance: A British Society for Haematology Good Practice Paper. Br J Haematol 2023; 202:734-744
Caers J, et al. Diagnosis and follow-up of monoclonal gammopathies of undetermined significance; information for referring physicians. Ann Med 2013; 45:413-422
Tete SM, et al. Monoclonal paraprotein influences baseline B-cell repertoire diversity and perturbates influenza vaccination-induced B-cell response. Exp Hematol 2015;
Wechalekar AD, et al. AL Amyloidosis for Cardiologists: Awareness, Diagnosis, and Future Prospects: JACC: CardioOncology State-of-the-Art Review. JACC CardioOncol 2022; 4:427-441
Madan S & Greipp PR. The incidental monoclonal protein: current approach to management of monoclonal gammopathy of undetermined significance (MGUS). Blood Rev 2009; 23:257-265
Fermand JP, et al. Monoclonal gammopathy of clinical significance: a novel concept with therapeutic implications. Blood 2018; 132:1478-1485
Srkalovic G, et al. Monoclonal gammopathy of undetermined significance and Multiple Myeloma are associated with an increased incidence of venothromboembolic disease. Cancer 2004; 101:558-566
Kristinsson SY, et al. Arterial and venous thrombosis in monoclonal gammopathy of undetermined significance and multiple myeloma: a population-based study. Blood 2010; 115:4991-4998
Gregersen H, et al. Monoclonal gammopathy of undetermined significance and risk of venous thromboembolism. Eur J Haematol 2011; 86:129-134
Rögnvaldsson S, et al. Monoclonal gammopathy of undetermined significance and the risk of thrombotic events: Results from iStopMM, a prospective population-based screening study. Br J Haematol 2024;
El-Khoury H, et al. Prevalence of monoclonal gammopathies and clinical outcomes in a high-risk US population screened by mass spectrometry: a multicentre cohort study. Lancet Haematol 2022; 9:e340-e349
Garcia-Pavia P, et al. Diagnosis and treatment of cardiac amyloidosis. A position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur J Heart Fail 2021; 23:512-526
Stern LK & Kittleson MM. Updates in Cardiac Amyloidosis Diagnosis and Treatment. Curr Oncol Rep 2021; 23:47
Steiner N, et al. Monoclonal gammopathy of renal significance (MGRS) increases the risk for progression to multiple myeloma: an observational study of 2935 MGUS patients. Oncotarget 2018; 9:2344-2356
Melton LJ, 3rd, et al. Fracture risk in monoclonal gammopathy of undetermined significance. J Bone Miner Res 2004; 19:25-30
Gregersen H, et al. Fracture risk in patients with monoclonal gammopathy of undetermined significance. Br J Haematol 2006; 135:62-7
Berenson JR & Yellin O. Monoclonal gammopathy of undetermined significance: why identification of these patients and assessment of their skeletons is important. Clin Lymphoma Myeloma 2009; 9:311-315
Kristinsson SY, et al. Monoclonal gammopathy of undetermined significance and risk of skeletal fractures: a population-based study. Blood 2010; 116:2651-2655
Veronese N, et al. Monoclonal gammopathy of undetermined significance and bone health outcomes: a systematic review and exploratory meta-analysis. Journal of Bone and Mineral Metabolism 2018; 36:128-132
Rögnvaldsson S, et al. Untangling fracture risk in monoclonal gammopathy of undetermined significance: A population-based cohort study. European Journal of Haematology 2021; 107:137-144
Bida JP, et al. Disease associations with monoclonal gammopathy of undetermined significance: a population-based study of 17,398 patients. Mayo Clin Proc 2009; 84:685-693
Dispenzieri A, et al. International Myeloma Working Group guidelines for serum-free light chain analysis in Multiple Myeloma and related disorders. Leukemia 2009; 23:215-224
NICE. Myeloma: diagnosis and management [NG35]. NICE Guidelines 2016;
Keren DF, et al. Laboratory Detection and Initial Diagnosis of Monoclonal Gammopathies: Guideline From the College of American Pathologists in Collaboration With the American Association for Clinical Chemistry and the American Society for Clinical Pathology. Arch Pathol Lab Med 2021; 146:575-590
Ramchandren S & Lewis RA. An update on monoclonal gammopathy and neuropathy. Curr Neurol Neurosci Rep 2012; 12:102-110
Abraham A, et al. High frequency of MGUS in DSP. Muscle Nerve 2018; 57:1018-1021
Matà S, et al. Polyneuropathy and monoclonal gammopathy of undetermined significance (MGUS); update of a clinical experience. J Neurol Sci 2021; 423:117335
Zis P, et al. Prevalence of Peripheral Neuropathy (PN) Among Patients with Asymptomatic Monoclonal Gammopathies: A Clinical & Electrophysiological Study. Blood 2023; 142:529-529

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Monoclonal Gammopathy of Undetermined Significance (MGUS)

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