Detailed presentation about MGUS- Plasma cell dyscrasias:Other

1. Monoclonal Gammopathies Of
Undetermined Significance
By: Dr. Chirag Parmar

2. 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

3. 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..

4. 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.

5. Stepwise Progression

6. What are plasma cells??

7. What are plasma cells??

8. 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.

9. What is M-protein?

10. 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

11. Diagnostic Criteria And Classification Of MGUS

12. Diagnostic Criteria And Classification Of MGUS

13. 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.

14. 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.

15. 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.

16. 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.

17. 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.

18. Thal/IMIDs

19. 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.

20. 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.

21. 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.

22. 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.

23. 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.

24. 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.

25. 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.

26. 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
multiple
myeloma, 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.

27. 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

28. 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.

29. Thank You