Plasma Cell Disorders Flashcards
What are the rates of progression from smouldering myeloma to symptomatic myeloma and what are the risk factors for progression?
o 10% per year for the first 5 years following diagnosis, 3% per year over the next 5 years then 1% thereafter.
o Higher risk with t(4;14), del(17p) and gain 1q.
o Both plasma cells ≥10% and paraprotein ≥30g/L
o >95% of plasma cells in BM with an abnormal immunophenotype
o Abnormal serum free light chain ratio
o Immunosuppression of uninvolved immunoglobulins.
o High plasma cell Ki67/ proliferation rate
Rates are lower with light chain only multiple myeloma
What are the diagnostic criteria for non-IgM MGUS?
Serum monoclonal antibody (non-IgM) <30g/L
Clonal plasma cells <10% in the BM
Absence of symptoms or end organ damage
What is the definition of smouldering multiple myeloma
Serum monoclonal antibody ≥30g/L OR Clonal plasma cells 10-60% AND Absence of myeloma defining events or amyloidosis
List the myeloma defining events (as per the IMWG)
1) End organ damage that can be attributed to the underlying plasma cell disorder
- CRAB criteria
2) Clonal bone marrow population ≥60%
3) Involved: uninvolved SFLC ratio ≥100 (involved FLC must be ≥100mg/L)
4) >1 focal lesion on MRI imaging that is at least 5mm in size
What is the definition of light chain MGUS?
- Elevated involved SFLC
- Abnormal SFLC ratio
- No immunoglobulin heavy chain on immunofixation
- Malignant plasma cells <10% in BM
- Absence of end organ damage
- Urinary monoclonal protein <500mg/ 24hrs
What is the difference between solitary plasmacytoma and solitary plasmacytoma with minimal bone marrow involvement?
- Solitary plasmacytoma: no clonal plasma cells in the BM
- Solitary plasmacytoma with minimal bone marrow involvement: <10% clonal plasma cells in the BM
The presence of non-CRAB myeloma defining events is associated with what % progression to symptomatic disease?
80%
As per the IMWG what should the minimum FISH panel include?
- The high risk markers: t(4;14), t(14;16), del(17p)
- More comprehensive panel includes t(11;14), del 13, ploidy category, chromosome 1 abnormalities
List the primary molecular cytogenetic subgroups of multiple myeloma
- Hyperdiploid
- Non-hyperdiploid
o CCND translocations
t(11;14), t(6;14)
o NSD2/ MMSET translocation
t(4;14)
o MAF translocation
t(14;16)
t(14;20)
- Unclassified
List the poor risk cytogenetic markers in MM
- t(4;14) (adverse risk may be overcome in the bortezomib era)
- t(14;16)
- t(14;20)
- Gain 1q.
- del17(p)
List the poor prognostic factors in MM
Clinical
- Age
- ECOG
Lab
- Elevated B2M (>5.5)
- Elevated LDH
- Serum albumin <35
- Renal impairment
- High plasma cell Ki67
- Circulating plasma cells
Molecular
- Presence of high risk cytogenetic markers
(particularly t(4;14), t(14;16), t(14;20), gain 1q, del 17(p))
What is the definition of a CR and sCR in myeloma?
- Negative immunofixation of urine and serum
- Disappearance of any soft tissue plasmacytomas
- <5% BM plasma cells
sCR as above plus
- Normal SFLC ratio
- Absence of clonal plasma cells on flow cytometry
What is the definition of a VGPR in myeloma?
- Serum and urine M band detectable on immunofixation but not electrophoresis
- ≥90% reduction in paraprotein plus urine M protein <100mg per 24hrs
What are some of the goals of MRD assessment?
- Provide objective methodology to establish a deeper remission status
- Refine outcome prediction
- Inform post-remission treatment
- Identify impending relapse and enable early intervention
- Serve as a surrogate end point to accelerate drug testing and approval.
What is the definition of “MRD negative” as per the most recent IMWG recommendations?
Absence of clonal plasma cells by flow cytometry or sequencing based techniques with a minimum sensitivity of 10^5
What is the benefit and what are some of the drawbacks in using multichannel flow cytometry for MRD assessment?
o Simultaneous identification and characterization of single PCs based on multiple parameters
o Evaluation of at least 8 markers in a single tube can readily identify aberrant phenotypes at MRD levels if sufficient cell numbers are evaluated (e.g. ≥5x 10^6).
o More colours= more power to resolve populations but more complex, more skill required in interpreting results.
o Spectral overlap requires compensation
What are the markers used in MM MRD assessment and how does the expression of these markers differ between malignant and non-malignant plasma cells?
- CD38, CD138, CD19, CD27, CD45, CD56, CD81, CD117
(lambda and kappa can also be used to assess for light chain restriction) - Normal plasma cells: CD19+, CD27++, CD45+ (generally), CD56-, CD81+, CD117-
- Malignant plasma cells CD19-, CD27- (or weak), CD45-, CD56+, CD81- (or weak). CD117+
What is amyloidosis?
Disease characterised by tissue deposition of a protein that is able to form an insoluble beta-pleated sheet structure.
This tissue deposition ultimately interferes with normal organ function.
What are the ways in which amyloidosis can be subtyped?
1) Immunohistochemistry using antibodies to SAA, TTR, and kappa and lambda FLC.
o Can be reliable in a significant percentage of cases
o Problems not infrequently encountered
- False negative/weak staining for κ and λ light chains
- False-positive or background staining of light chains in non-AL amyloid
- False-positive staining for TTR in AL amyloid.
2) Direct immunofluorescence
o More reliable but less available.
3) High-performance liquid chromatography and mass spectrometry with laser capture microdissection
- Sensitive even in samples with small amounts of amyloid.
- Can identify whether some subtypes are acquired or inherited.
4) Genetic screening
o Particularly important in ATTR for differentiating between senile and inherited ATTR.
5) Bone scintigraphy using technetium-labelled radiotracers (Tc-99m)
o High diagnostic accuracy in cardiac ATTR.
o AL amyloid can give a positive (but generally weaker) result
What are some of the poor prognostic markers in AL amyloid?
o Cardiac involvement (increased BNP, troponin) o Multiple organs involved o High serum uric acid level o Plasma cell burden >10% o High serum free light chain ratio o High B2M
What is Castlemans Disease?
· Polyclonal lymphoproliferative disorders driven by a proinflammatory hypercytokinaemia.
· Characterised by lymphoid tissue hyperplasia that can occur at any site of the lymphoid chain.
List the immunophenotypic features of plasmablastic lymphoma
o Plasma cell immunophenotype: CD20, PAX5 negative, CD38, CD138, IRF4/MUM1 positive with cytoplasmic light chain restriction.
o Can also display aberrant phenotypes seen in plasma cell dyscrasias: CD45 neg in majority, CD56 pos in 25%
o EMA, CD30 and EBER-ISH are commonly positive with a very high Ki67
o BCL2 and BCL6 negative
o CMYC rearranged in ~50%.
What immunophenotypic features distinguish between plasmablastic lymphoma and ALK positive large B cell lymphoma?
Both are positive for plasma cell markers (CD38, CD138, IRF4/ MUM1) and negative for B-cell markers (CD20, CD79a and PAX5) with light chain restriction
PBL: CD30 and EBERISH positive
ALK: CD30 and EBERISH negative. ALK pos.
What is electrophoresis?
Separation of charged particles in a buffered medium under the influence of an electrical field
What is immunofixation
- Separation of proteins by electrophoresis on gel
- Fixation and immunoprecipitation by specific antisera on individual migration tracks (precipitated antibody-antigen complex trapped within the gel matrix.)
- Precipitated proteins visualised by staining and compared with the corresponding abnormal bands on the original electrophoretic strip.
Electrophoresis: abnormal band detected in the gamma globulin region
Immunofixation: identifies the first band as IgG kappa
What can interfere with serum protein electrophoresis/ immunofixation?
- High levels of fibrinogen (can run in the same place as an IgM band)
- Heparin exposure
- Haemolysis
- Hypertransferrinaemia
- Therapeutic monoclonal antibodies for myeloma
How are serum free light chains measured?
- Antibody based immunochemical method.
- Antibodies that only detect epitopes that are exposed on free light chains but hidden on intact light chains are used.
- Uncertainty of measurement 20% for both kappa and lambda
