Paraprotienemia classifiction MGUS, smouldering and overt myeloma

1. By /Marwa Mahmoud Khalifa
Alexandria University

2. Monoclonal gammopathy of
undetermined significance
(MGUS(

3. WHAT’S MGUS??
MGUS describes premalignant
disorder characterized by
 Limited monoclonal plasma cell
proliferation
 Stable monoclonal paraprotien in
serum or less commonly in urine
 Absence of clinicopathological
evidence of MM,WM,AL or LPDs.

4. INCIDENCE

5. EPIDEMIOLOGY
 Age. The risk of increases with age. The
highest incidence is among adults age 85
and older.
 Race. Blacks are more likely to
experience this condition than are
whites.
 Sex. more common in men than it is in
women.
 Family history.

6. PATHOPHYSIOLOGY
Pathologically, the lesion in MGUS is in fact
very similar to that in multiple myeloma.
There is a predominance of clonal plasma
cells in the bone marrow with an
abnormal immunophenotype (CD38+
CD56+ CD19−) mixed in with cells of a
normal phenotype (CD38+ CD56−
CD19+); in MGUS, on average more than
3% of the clonal plasma cells have the
normal phenotype, whereas in multiple
myeloma, less than 3% of the cells have
the normal phenotype

7. Pathogenesis
Approximately 50% of patients with MGUS and SMM have
primary translocations in the clonal plasma cells
involving the immunoglobulin heavy chain (IgH)
locus on chromosome 14q32 (IgH translocated
MGUS/SMM
The most common partner chromosome loci and genes
dysregulated in these translocations are: [cyclin D1
gene]), [cyclin D3 gene])
Deletion of chromosome 13, a major prognostic factor
in multiple myeloma, is seen in up to 50% of patients
with MGUS by interphase fluorescent in situ
hybridization; hence, the presence of this abnormality
cannot be used to differentiate MGUS from multiple
myeloma

8. It is felt that these translocations are important
pathogenetically in initiating and sustaining
clonal proliferation.
The precipitating event for these translocations
may be related to infection or immune
dysregulation, and likely occurs during IgH
switch recombination or somatic hypermutation
The pathogenesis in 40%–50% of MGUS and
SMM with no evidence of IgH translocations
(IgH non-translocated MGUS/SMM) is unclear.

9. Pathogenesis and progression of monoclonal gammopathies.
Rajkumar S V Hematology 2005;2005:340-345
©2005 by American Society of Hematology

10. CLINICAL FEATURES
 Asymptomatic
 No abnormal physical findings
 Incidental discovery : ESR /↑
globlin↑
 Neuropathy may be ass attributed
to monoclonal gammopathy
 Thrombotic events

11. INVESTIGATIONS
exclude CRAB
 FBC: no anemia or other cytopenia
 Chemistry : RFT, s Ca++↔
 Serum protein electrophoresis:IgG 70%,IgM 15%,
IgA12%,biclonal 3%,LC<1%
 Immunoglobulin quantitation :immunoparesis
 SFLC:~30% have abn ĸ:λ ratio
 Urine electrophoresis:
 Skeletal survey:normal
 Serum β2 microglobulin:normal
 BMA or trephine biopsy:indicated if abn
FBC,RFT,sCa, SFLC,sk survey,non IgG
paraprotein,paraprotein>15g/L

12. DIAGNOSIS
All 4 criteria must be met :
1. Serum monoclonal protein <3g/dL
2. BM plasma cells <10%
3. No evidence of other B cell LPDs
4. No myeloma related end organ or
tissue impairment ie CRAB

13. DIFFERENTIAL DIAGNOSIS
 MM,WM,AL
 Bone pains ,anemia, renal
impairment ??myeloma
 IgM with lymphadenopathy or
splenomegaly ??WM

14. NATURAL HISTORY

15. RISK FACTORS FOR PROGRESSION
 Paraprotein level >1.5g/dL
 Paraprotein type IgM>IgA>IgG
 Abn SFLC ratio
 BM plasma cells >5%
 Circulating plasma cells by IF
 Others: immunoparesis, urinary
paraprotein ,BM angiogenesis

16. Risk of progression to myeloma or related disorder in 1148 patients with monoclonal
gammopathy of undetermined significance (MGUS).
Rajkumar S V Hematology 2005;2005:340-345
©2005 by American Society of Hematology

17. Risk of progression of monoclonal gammopathy of undetermined significance (MGUS) to
multiple myeloma based on the serum free light chain ratio.
Rajkumar S V Hematology 2005;2005:340-345
©2005 by American Society of Hematology

18. RISK STRATIFICATION
1. Assess patient for each of three
risk factors
 Abnormal serum free light chain ratio
(SFLC)
 Serum M protein ≥ 1.5 g/dL
 M protein not of IgG subtype

19. 2. Sum the number of risk factors
to determine risk category and
prognosis

20. MANAGEMENT
 NO treatment
 Follow up every 6m then annually
(FBC, renal function ,serum Ca+
+ ,serum Igs, paraprotein
quantitation ,SFLC)

21. Smouldering multiple myeloma
(asymptomatic myeloma(

22. IDENTIFICATION
 Paraprotein > 3gm/dl
and / or
 Plasma cells in BM >10%
Without clinical evidence of complications
associated with MM (CRAB(

23. INCIDENCE
Accounts for about 15% o all new
cases of myeloma

24. PATHOGENESIS
 Almost all have either translocation
involving IgH (50%) or
hyperdiploidy(40%)
 Angiogenesis is greater than MGUS
but less than in MM

25. CLINICAL & LABORATORY
FEATURES
 Absence of signs & symptoms
 FBC : Hb >10 gm/dL
 S. creat <130 micromol /L ,normal
s Ca++
 β2 microglobulin :normal / minimal rise
 BMA: >10% plasma cells
 BM cytogenetics
 Skeletal radiology :normal

26. DIAGNOSTIC CRITERIA
 Paraprotein > 3gm/dl and / or
plasma cells in BM >10%
 No evidence of other B cell LPD
 No myeloma related end organ or
tissue impairment

27. DIFFERENTIAL DIANOSIS
1. MGUS
2. MM
3. WM
4. AL

28. RISK FACTORS FOR EARLY
PROGRESSION
Shorter time ass with:
 Serum paraprotein >3g/dL
 IgA protein type
 Urinary BenceJones proteinuria>50mg/d
 BM plasmacytosis>25%
 Suppression of uninvolved Ig
 SFLC<0.125 or >8
 Abn MRI

29. RISK STRATIFICATION
 A scoring system has been developed
using 2 parameters
1. Quantity of paraprotein <3 vs.>3 g/dL
2. Type of paraprotein IgG vs.IgA
 Another scoring system using 3
parameters
1. BM plasmacytosis>10%
2. Serum M protein>3g/dL
3. SFLC ratio <0.125 or >8

30. MANAGEMENT
 Chemotherapy is not indicated
 No benefit for therapy before
symptomatic disease
 Follow up every 3-4 months
 Clinical trials early treatment with
bisphosphonate, thalidomide and
lenalidomide ??? Delay progression