Monoclonal gammopathies of undetermined significance
-
Upload
drchirag-parmar -
Category
Health & Medicine
-
view
377 -
download
1
Transcript of Monoclonal gammopathies of undetermined significance
![Page 1: Monoclonal gammopathies of undetermined significance](https://reader033.fdocuments.in/reader033/viewer/2022052514/587b563c1a28abff1a8b6e1b/html5/thumbnails/1.jpg)
Monoclonal Gammopathies Of Undetermined Significance
By: Dr. Chirag Parmar
![Page 2: Monoclonal gammopathies of undetermined significance](https://reader033.fdocuments.in/reader033/viewer/2022052514/587b563c1a28abff1a8b6e1b/html5/thumbnails/2.jpg)
Since Antiquity
• Plasma cell dyscrasias have been with us since Antiquity.
• Archeologists have been able to tell us of individuals that suffered MM in Ancient Egypt, medieval Europe and pre-Columbus America
![Page 3: Monoclonal gammopathies of undetermined significance](https://reader033.fdocuments.in/reader033/viewer/2022052514/587b563c1a28abff1a8b6e1b/html5/thumbnails/3.jpg)
Introduction
• The real incidence of monoclonal gammopathy is unknown; however, it increases with age, with most cases being identified in the 7th or 8th decade of life.
• The presence of a monoclonal protein is indicative of an underlying clonal plasma cell or B cell disorder.
• These disorders encompass a spectrum of disease entities ranging from clinically benign monoclonal gammopathy of undetermined significance (MGUS) to clinically significant diseases such as multiple myeloma and plasma cell leukemia..
![Page 4: Monoclonal gammopathies of undetermined significance](https://reader033.fdocuments.in/reader033/viewer/2022052514/587b563c1a28abff1a8b6e1b/html5/thumbnails/4.jpg)
Definition
Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic, pre-malignant clonal plasma cell proliferative disorder.
MGUS is defined by the presence of: • serum M protein <3 g/dl, • bone marrow plasma cells <10%,• and absence of end organ damage that can be
attributed to the plasma cell proliferative disorder (CRAB)• HyperCalcemia, • Renal failure• Anemia.• Lytic Bone Lesions.
![Page 5: Monoclonal gammopathies of undetermined significance](https://reader033.fdocuments.in/reader033/viewer/2022052514/587b563c1a28abff1a8b6e1b/html5/thumbnails/5.jpg)
Stepwise Progression
![Page 6: Monoclonal gammopathies of undetermined significance](https://reader033.fdocuments.in/reader033/viewer/2022052514/587b563c1a28abff1a8b6e1b/html5/thumbnails/6.jpg)
What are plasma cells??
![Page 7: Monoclonal gammopathies of undetermined significance](https://reader033.fdocuments.in/reader033/viewer/2022052514/587b563c1a28abff1a8b6e1b/html5/thumbnails/7.jpg)
What are plasma cells??
![Page 8: Monoclonal gammopathies of undetermined significance](https://reader033.fdocuments.in/reader033/viewer/2022052514/587b563c1a28abff1a8b6e1b/html5/thumbnails/8.jpg)
What is M-protein?
• Immunoglobulins consist of two heavy polypeptide chains of the same class and subclass and two light polypeptide chains of the same type.
• A monoclonal increase in immunoglobulins results from a clonal process such as MGUS or MM, and a polyclonal increase in immunoglobulins is caused by a reactive or inflammatory process.
• The monoclonal immunoglobulin secreted by clonal plasma cells in MGUS, SMM, MM, and related monoclonal gammopathies is referred to as a monoclonal protein or M protein.
![Page 9: Monoclonal gammopathies of undetermined significance](https://reader033.fdocuments.in/reader033/viewer/2022052514/587b563c1a28abff1a8b6e1b/html5/thumbnails/9.jpg)
What is M-protein?
![Page 10: Monoclonal gammopathies of undetermined significance](https://reader033.fdocuments.in/reader033/viewer/2022052514/587b563c1a28abff1a8b6e1b/html5/thumbnails/10.jpg)
Risk Factors
•A-bomb•Radiation (e.g. sun exposure, radiologists & nuclear power plant workers)•Pesticides? (evidence not compelling)•Benzene? (evidence not compelling)•Risk modified by gender & race
Insult
![Page 11: Monoclonal gammopathies of undetermined significance](https://reader033.fdocuments.in/reader033/viewer/2022052514/587b563c1a28abff1a8b6e1b/html5/thumbnails/11.jpg)
Diagnostic Criteria And Classification Of MGUS
![Page 12: Monoclonal gammopathies of undetermined significance](https://reader033.fdocuments.in/reader033/viewer/2022052514/587b563c1a28abff1a8b6e1b/html5/thumbnails/12.jpg)
Diagnostic Criteria And Classification Of MGUS
![Page 13: Monoclonal gammopathies of undetermined significance](https://reader033.fdocuments.in/reader033/viewer/2022052514/587b563c1a28abff1a8b6e1b/html5/thumbnails/13.jpg)
Pathophysiology
• MM is almost always preceded by the asymptomatic premalignant MGUS stage.
• A Study of 77,469 healthy individual by National Cancer Institute and the Mayo Clinic was done. In which 71 Individuals who developed multiple myeloma during the course of study, they all had MGUS 6 years before.
• The events responsible for malignant transformation of MGUS to MM or a related plasma cell proliferative disorder are unknown.
• Genetic changes, bone marrow angiogenesis, various cytokines related to MM bone disease and infectious agents may play a role in the progression of MGUS to MM or a related disorder.
![Page 14: Monoclonal gammopathies of undetermined significance](https://reader033.fdocuments.in/reader033/viewer/2022052514/587b563c1a28abff1a8b6e1b/html5/thumbnails/14.jpg)
Initiation of Clone
• The precise sequence of events that leads to the initiation of the MGUS clone are not known.
• However, antigenic stimulation and/or immunosuppression are thought to be predisposing factors.
• Toll-like receptors (TLRs) are normally expressed by B lymphocytes, and are essential for these cells to recognize infectious agents.
• The aberrant expression of TLRs by plasma cells may be an initiating event that causes these cells to respond abnormally to TLR-specific ligands resulting in increased MM cell proliferation, survival, and resistance to apoptosis, mediated in part by autocrine interleukin-6 production.
• Immunosuppression may also contribute to the initiation of monoclonal gammopathies inhibiting tumor surveillance.
![Page 15: Monoclonal gammopathies of undetermined significance](https://reader033.fdocuments.in/reader033/viewer/2022052514/587b563c1a28abff1a8b6e1b/html5/thumbnails/15.jpg)
Cytogenetic Changes
• Almost all patients with MM have either IgH translocations involving chromosome 14q32 or trisomies.
• These cytogenetic changes referred to as “primary cytogenetic abnormalities” are also present in 50 % of patients with MGUS.
• These translocations lead to the dysregulation of oncogenes such as CCND1 (cyclin D1) (11q13), FGFR3/WHSC1 (fibroblastic growth factor receptor 3/Wolf-Hirschhorn syndrome candidate; 4p16.3), CCND3(cyclin D3; 6p21), MAF (16q23), and MAFB (20q11).
• The dysregulation of these oncogenes is thought to be critical for the initiation of the MGUS clone rather than progression of MGUS to MM.
![Page 16: Monoclonal gammopathies of undetermined significance](https://reader033.fdocuments.in/reader033/viewer/2022052514/587b563c1a28abff1a8b6e1b/html5/thumbnails/16.jpg)
Angiogenesis
• Bone marrow angiogenesis is increased in MM and has prognostic value.• Bone marrow angiogenesis increases progressively from the pre-
malignant MGUS stage to advanced MM. • Using a chick embryo chorioallantoic membrane angiogenesis assay,
Vacca et al. reported that 76% of MM bone marrow samples had increased angiogenic potential compared with 20% of MGUS samples.
• Their findings suggest that increased angiogenesis may play a role in progression of MGUS to MM.
![Page 17: Monoclonal gammopathies of undetermined significance](https://reader033.fdocuments.in/reader033/viewer/2022052514/587b563c1a28abff1a8b6e1b/html5/thumbnails/17.jpg)
Cytokines
• There is overexpression of CD126 (IL-6 receptor a-chain) in MGUS compared to normal plasma cells. IL-6 is a major growth factor for plasma cells and may therefore play a role in the clonal proliferation of plasma cells in MGUS.
• Another cytokine that is of importance is IL-1b. IL-1b is produced by plasma cells in all patients with MM, but is undetectable in most patients with MGUS.
• IL-1b has strong osteoclast-activating factor activity, increases the expression of adhesion molecules, and induces paracrine IL-6 production.
• This activity parallels the development of osteolytic bone lesions, homing of MM cells to bone marrow, and IL-6–induced cell growth.
![Page 18: Monoclonal gammopathies of undetermined significance](https://reader033.fdocuments.in/reader033/viewer/2022052514/587b563c1a28abff1a8b6e1b/html5/thumbnails/18.jpg)
Thal/IMIDs
![Page 19: Monoclonal gammopathies of undetermined significance](https://reader033.fdocuments.in/reader033/viewer/2022052514/587b563c1a28abff1a8b6e1b/html5/thumbnails/19.jpg)
Clinical Features
• Disease of old age.• 2 folds higher risk in male than female.• Asymptomatic condition. Typically detected as an incidental finding during the
work-up of suspected MM or WM.• Thus, MGUS is usually detected during the work-up of unexplained:
• weakness or fatigue, • increased erythrocyte sedimentation rate, • anemia, unexplained back pain,• osteoporosis, • osteolytic lesions or fractures, • hypercalcemia, proteinuria, • renal insufficiency, or recurrent infections.
![Page 20: Monoclonal gammopathies of undetermined significance](https://reader033.fdocuments.in/reader033/viewer/2022052514/587b563c1a28abff1a8b6e1b/html5/thumbnails/20.jpg)
Clinical Features
• MGUS is also detected during work-up of patients with symptoms suggestive of amyloidosis such as:• unexplained peripheral neuropathy, • carpal tunnel syndrome, • Refractory congestive heart failure, • nephrotic syndrome, orthostatic hypotension, • malabsorption, weight loss, • paresthesias, numbness, • increased bruising, bleeding, and steatorrhea.
![Page 21: Monoclonal gammopathies of undetermined significance](https://reader033.fdocuments.in/reader033/viewer/2022052514/587b563c1a28abff1a8b6e1b/html5/thumbnails/21.jpg)
Management
• At the time of initial diagnosis:• A complete blood count (CBC), • serum calcium, • serum creatinine, • Radiographic survey of the skeleton.
• Bone marrow aspiration and biopsy should also be done in indicated cases.• Once the diagnosis is made, the CBC, serum calcium, creatinine, and serum protein
electrophoresis must be repeated in 6 months.• If stable, then in patients with low-risk MGUS, an assessment of the M protein level is
needed only if symptoms worrisome for progression develop.• In all other patients with MGUS, annual follow-up of the M protein is recommended
lifelong.
![Page 22: Monoclonal gammopathies of undetermined significance](https://reader033.fdocuments.in/reader033/viewer/2022052514/587b563c1a28abff1a8b6e1b/html5/thumbnails/22.jpg)
Detection of M-protein
1. Electrophoresis and Immunofixation
• detected using agarose gel or capillary electrophoresis of the serum and urine.
• An M-protein is usually visible as narrow spike or peak in the β or ϒ region.
• A suspected M protein on electrophoresis must be confirmed on immunofixation.
• It also determines the immunoglobulin heavy-chain class and its light chain type.
![Page 23: Monoclonal gammopathies of undetermined significance](https://reader033.fdocuments.in/reader033/viewer/2022052514/587b563c1a28abff1a8b6e1b/html5/thumbnails/23.jpg)
Detection of M-protein
2. Quantitative Immunoglobulins• Another assay that aids in monitoring is quantitation of
immunoglobulins performed with a rate nephelometer. • It can accurately measure polymers of IgA, and aggregates of IgG.• However, levels of IgM obtained by nephelometry may be 1,000 to
2,000 mg/dl higher than those expected on the basis of the serum protein electrophoretic tracing.
![Page 24: Monoclonal gammopathies of undetermined significance](https://reader033.fdocuments.in/reader033/viewer/2022052514/587b563c1a28abff1a8b6e1b/html5/thumbnails/24.jpg)
Detection of M-protein
3. Serum Free Light Chain Assay
• It is an automated nephelometric assay that measures free kappa (k) and lambda (ʎ) light chains.
• The normal serum free-k level is 3.3 to 19.4 mg/L . • Normal free-ʎ level is 5.7 to 26.3 mg/L.• Normal ratio for FLC-k/l is 0.26 to 1.65.• Patients with a k/ʎ FLC ratio <0.26 are considered to have a monoclonal ʎ
free light chain.• And those with ratios >1.65 are defined as having a monoclonal k free light
chain.
![Page 25: Monoclonal gammopathies of undetermined significance](https://reader033.fdocuments.in/reader033/viewer/2022052514/587b563c1a28abff1a8b6e1b/html5/thumbnails/25.jpg)
Detection of M-protein
3. Serum Free Light Chain Assay• The serum FLC assay can be used in place of urine protein electrophoresis
and immunofixation in the initial screening algorithm for M proteins.• Urine studies can be eliminated by using the serum FLC assay in
combination with the SPEP and immunofixation. • Also used to predict prognosis in MGUS, SMM, AL, and solitary
plasmacytoma.• Also used to monitor oligo-secretory MM, nonsecretory MM, light chain
only form of MM, and AL amyloidosis.
![Page 26: Monoclonal gammopathies of undetermined significance](https://reader033.fdocuments.in/reader033/viewer/2022052514/587b563c1a28abff1a8b6e1b/html5/thumbnails/26.jpg)
Prognosis
• No findings at diagnosis of MGUS can reliably distinguish patients whose condition will remain stable indefinitely from those in whom MM or related malignancy develops.
• However, there are several known prognostic factors that assist in estimation of the risk of progression for appropriate counseling and management.
Non-IgM MGUS 1% per year risk of progression to multiplemyeloma, AL amyloidosis, or related disorder
IgM MGUS 1.5% per year risk of progression to Waldenström macroglobulinemia; rare patients can progress to IgM multiple myeloma
Light chain MGUS
Risk of progression to light chain myeloma and AL amyloidosis. Rate of progression not defined.
![Page 27: Monoclonal gammopathies of undetermined significance](https://reader033.fdocuments.in/reader033/viewer/2022052514/587b563c1a28abff1a8b6e1b/html5/thumbnails/27.jpg)
Prognostic Factors
1. Size of M Protein
• the risk of progression to MM or a related disorder 10 years after diagnosis of MGUS was 6% for patients with an initial M-protein level of 0.5 g/dl or less, 7% for 1 g/dl, 11% for 1.5 g/dl, 20% for 2 g/dl, 24% for 2.5 g/dl, and 34% for 3.0 g/dl.
2. Type of M Protein
• Patients with an IgM or IgA M protein have a higher risk of progression compared with those with an IgG M protein
![Page 28: Monoclonal gammopathies of undetermined significance](https://reader033.fdocuments.in/reader033/viewer/2022052514/587b563c1a28abff1a8b6e1b/html5/thumbnails/28.jpg)
Prognostic Factors
3. Bone Marrow Plasma Cells
• patients with MGUS who have 5% to 9% bone marrow plasma cells have a higher risk of progression compared with those with <5% bone marrow plasma cells.
4. Abnormal Serum-Free Light Chain Ratio
• An abnormal FLC ratio is an independent risk factor for progression of MGUS.
![Page 29: Monoclonal gammopathies of undetermined significance](https://reader033.fdocuments.in/reader033/viewer/2022052514/587b563c1a28abff1a8b6e1b/html5/thumbnails/29.jpg)
Thank You