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Year 5 path SW > Haematology 12: Myeloma And Amyloid, Monocloncal Gammopathy > Flashcards

Haematology 12: Myeloma And Amyloid, Monocloncal Gammopathy Flashcards

1
Q

What is monoclonal gammopathy of uncertain significance (MGUS) ?

A
  • IgG/IgA < 30G/L
  • <10% clonal plasma cells
  • No symptoms (CRAB)
  • Genetic errors occur in plasma cell due to infection, inflammation or chromosomal instability.
  • This causes monoclonal accumulation of the plasma cells
  • This is considered harmless but pre-malignant
  • If further mutation, can become multiple myeloma
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2
Q

Which mutation can trigger transformation of MGUS to multiple myeloma ?

A

K-RAS

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3
Q

What are the clinical features of Multiple myeloma ?

A

Calcium - elevated
Renal impairment
Anaemia
Bone lesions

Monoclonal paraprotein (gammaglobulins) 
Bence jones protein in urine (immunoglobulin light chains)
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4
Q

What are some of the characteristic features of Multiple myeloma on histology ?

A

Overcrowding of plasma cells in bone marrow

Plasmacytic cells: Nucleus on one side (eccentric nucleus), dense chromatin, low nuclear to cytoplasmic ratio

Plasmablastic cells: prominent nucleoli, reticular chromatin, less cytoplasm than mature cells

Red cell rouleaux

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5
Q

List 3 characteristic finding of multiple myeloma on Immunohistochemistry ?

A

CD138
CD38
light chain restricted Ig

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6
Q

What is fanconi syndrome ?

A

Renal tubule acidosis with light chain Chrystal depositions

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7
Q

What are the 4 main types of treatment for multiple myeloma ?

A

Cytostatic drug - Melphalan
Steroids
Immuno modulators- Thalidomide
Proteasome inhibitors

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8
Q

List the 3 features required to diagnose Multiple myeloma ?

A
  • Clonal plasma cells on bone marrow biopsy
  • Paraprotein in blood or urine
  • Evidence of end-organ damage - CRAB
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9
Q

List the 3 features that are required to diagnose Smouldering myeloma ?

A
  • Serum paraprotein > 30 g/L
  • Clonal plasma cell > 10 % on bone marrow biopsy
  • No evidence of end organ damage (CRAB)

(This is basically asymptomatic MM)

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10
Q

List 3 features required to diagnose MGUS ?

A
  • Serum paraprotein < 30g/l
  • Clonal plasma cells < 10 % on bone marrow biopsy
  • No signs of end organ damage (CRAB)
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11
Q

List 3 features of waldenstrom macroglobinaemia ?

A
  • Low grade NHL (lymphoplasmacytoid)
  • Monoclonal IgM
  • Hyperviscosity symptoms (visual problems, CCF, weakness, confusion)
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12
Q

list some key features of myeloma plasma cells

A

infiltrate bone marrow
can form expansile or soft tissue tumours - plasmacytomas
produce a serym monoclonal IgG or IgA - paraprotein or M spike
produce excess of monoclonal kappa or lambda free light chains
BJ protein in urine - urine monoclonal free light chains

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13
Q

define multiple myeloma

A

cancer of transformed plasma cells, terminally differentiated B cells, that secrete immunoglobulins and are effector cells of the specific humoural response

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14
Q

describe B cell development

A

common lymphoid progenitor … mature B cell (bone marrow)

mature B cell… short lived plasma cell (marginal zone)

mature B cell … memory cell/ long lived plasma cell (germinal centre)

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15
Q

RF for myeloma

A

obesity
age
genetics

always preceded by a premalignany condition = MGUS

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16
Q

what is MGUS

A 
most common (known) premalignant condition 
incidence increases with age 
average risk of progression 1% annually 
IgG or IgA MGUS --> myeloma
IgM --> lymphoma
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17
Q

diagnostic criteria for MGUS

A

serum M (monoclonal) protein <30g/l
bone marrow clonal plasma cells <10%
no lytic bone lesions
no myeloma-related organ or tissue impairment
no evidence of other B-cell proliferative disorder

18
Q

RF for MGUS progression

A

non-IgM spike
M spike > 15g/L
abnormal serum free light chain (FLC) ratio

19
Q

what is smouldering myeloma

A

serum monoclonal protein (IgG or IgA) >/= 30g/L or urinary monoclonal protein >/=500mg per 24 hrs and/or clonal bone marrow plasma cells 10-60%

abesence of myeloma deficing events or amyloidosis

20
Q

describe the clinical spectrum of myeloma and related plasma cell disorders

A 
MGUS
smouldering myeloma
symptomatic myeloma
relapsing-remitting 
refractory 
plasma cell leukaemia
21
Q

describe the pathogenesis of MM

A

primary events - hyperdiploidy, IGH rearrangements

secondary events -
KRAS, NRAS…

22
Q

how do myeloma cells interact with the bone marrow microenvironment

A

bone destruction
angiogenesis
anaemia
immunosuppression and infection

23
Q

diagnostic criteria for MM

A

C - hypercalcaemia - Ca >2.75 mmol/L

R - renal disease - creatinine > 177 umol/L or eGFR <40 ml/min

A - anaemia - Hb <100g/L or drop by 20g/L

B - bone disease - two or more bone lytic lesionso

24
Q

presentation of bone disease in myeloma patients

A 
proximal skeleton 
back, chest wall, pelvic pain 
ostrolytic lesions, never osteoblastic 
osteopenia
pathological fractures
hypercalcaemia
25
Q

what bone imaging can we do in myeloma

A

plain XR films
whole body CT
CT/FDG-TER
whole body diffusion weighted MRI

26
Q

what bone disease emergencies to we get in MM

A

cord compression - diagnose and treat within 24 hrs, MRI, dexamethasone, radiotherapty, stabilise unstable spine

hypercalcaemia - dowsiness, constipation, fatigue, muscle weakness, AKI
Give fluids, steroids, zolendronic acid

27
Q

define myeloma kidney disease

A

serum creatinine >177 umol/l
OR
eGFR <40ml/min

AKI as a result of myeloma

28
Q

what are the causes of myeloma kidney disease

A

cast nephropathy cause by high serum free light chain (FLC) levels and BJP

hypercalcaemia, loop diuretics, infection, dehydration, nephrotoxics

29
Q

what medication is the cornerstone of myeloma kidney disease treatment

A

bortezomib

30
Q

why do we get infections in myeloma

A 
humoral and cellular immunodeficiency 
myeloid, T and NK impairment 
immunoparesis: low serum normal Igs
chemo impairs the immune response 
myeloma immune evasion
31
Q

how can we diagnose myeloma

A

immunoglobulin studies:

  • serum protein electrophoresis
  • serum free light chain levels
  • 24hr BJP

BM aspirate and biopsy:
- IHC fod CD138

FISH analysis

Flow cytometry immunophenotyping:
- MRD (detection of minimal residue disease)

32
Q

describe the myeloma plasma cell phenotype

A 
CD319 (SLAM7) ++
CD56 ++
cytoplasmic Ig +++
CD38 +++
CD138 +++
BCMA ++
33
Q

how is myeloma staged

A

ISS

international staging system

34
Q

how can myeloma result in AL amyloidosis

A

MGUS or myeloma in the background
misfolded free light chains aggregate into amyloid fibrils in target organs
amyloid potential of light chains is more important than the amount
amyloid fibrils stain with congo red
lambda light chain involvement in 60%

35
Q

clinical presentation of AL amyloidosis

A 
kidney, heart, liver, neuropathy 
- nephrotic syndrome - proteinuria and peripeheral oedema
unexplained HF - raised NT-proBNP 
sensory neuropathy 
abnormal LFTs
macroglossia
36
Q

what is MGRS

A

monoclonal gamaopathy of renal significance

any B cell clonal lymphoproliferation where there are

  • one or more kidney lesions caused by raised Ig AND
  • the underlying B cell clone does no cause tumour complications or meet the haem criteria for specific therapy
37
Q

what therapies are used in myeloma treatment

A

melphalan
cyclophosphamide - in combination with steroids
dexamethasone + pred - induces apoptosis in myeloma cells

38
Q

which immunomodulatory drugs can be used in myeloma

A

lenalidomide

promalidomide

39
Q

how can proteasome inhibitors treat myeloma

A

myeloma cells are protein production factories
proteasome is crucial in removing misfolded proteins

accumulation of misfolded proteins - ER stress and unfolded protein response - apoptosis

eg bortezomib, carflizombib, ixazomib

40
Q

treatment algorithm for transplant eligible MM pt

A

induction - PI + iMiD + Dex
+ autologous SC transplant
+ consolidation x2
+ maintenance low dose lenalidomide

41
Q

treatment algorithm for transplant-ineligible patients

A 
lenalidomide + dex 
or 
bortezomib -cyclophosphamide - dex
or 
daratumumab - bartezomib - cyclophosphamide - pred
42
Q

new MM treatments

A

CAR-T cell therapy, BiTE and immunoconjugates

Year 5 path SW (106 decks)

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