Monoclonal Gammopathies Of Undetermined Significance

By: Dr. Chirag Parmar

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

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..

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.

Stepwise Progression

What are plasma cells??

What are plasma cells??

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.

What is M-protein?

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

Diagnostic Criteria And Classification Of MGUS

Diagnostic Criteria And Classification Of MGUS

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.

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.

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.

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.

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.

Thal/IMIDs

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.

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.

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.

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.

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.

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.

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.

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.

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

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.

Thank You