Haematology 12: Myeloma And Amyloid, Monocloncal Gammopathy Flashcards
What is monoclonal gammopathy of uncertain significance (MGUS) ?
- 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
Which mutation can trigger transformation of MGUS to multiple myeloma ?
K-RAS
What are the clinical features of Multiple myeloma ?
Calcium - elevated
Renal impairment
Anaemia
Bone lesions
Monoclonal paraprotein (gammaglobulins) Bence jones protein in urine (immunoglobulin light chains)
What are some of the characteristic features of Multiple myeloma on histology ?
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
List 3 characteristic finding of multiple myeloma on Immunohistochemistry ?
CD138
CD38
light chain restricted Ig
What is fanconi syndrome ?
Renal tubule acidosis with light chain Chrystal depositions
What are the 4 main types of treatment for multiple myeloma ?
Cytostatic drug - Melphalan
Steroids
Immuno modulators- Thalidomide
Proteasome inhibitors
List the 3 features required to diagnose Multiple myeloma ?
- Clonal plasma cells on bone marrow biopsy
- Paraprotein in blood or urine
- Evidence of end-organ damage - CRAB
List the 3 features that are required to diagnose Smouldering myeloma ?
- 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)
List 3 features required to diagnose MGUS ?
- Serum paraprotein < 30g/l
- Clonal plasma cells < 10 % on bone marrow biopsy
- No signs of end organ damage (CRAB)
List 3 features of waldenstrom macroglobinaemia ?
- Low grade NHL (lymphoplasmacytoid)
- Monoclonal IgM
- Hyperviscosity symptoms (visual problems, CCF, weakness, confusion)
list some key features of myeloma plasma cells
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
define multiple myeloma
cancer of transformed plasma cells, terminally differentiated B cells, that secrete immunoglobulins and are effector cells of the specific humoural response
describe B cell development
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)
RF for myeloma
obesity
age
genetics
always preceded by a premalignany condition = MGUS
what is MGUS
most common (known) premalignant condition incidence increases with age average risk of progression 1% annually IgG or IgA MGUS --> myeloma IgM --> lymphoma
diagnostic criteria for MGUS
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
RF for MGUS progression
non-IgM spike
M spike > 15g/L
abnormal serum free light chain (FLC) ratio
what is smouldering myeloma
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
describe the clinical spectrum of myeloma and related plasma cell disorders
MGUS smouldering myeloma symptomatic myeloma relapsing-remitting refractory plasma cell leukaemia
describe the pathogenesis of MM
primary events - hyperdiploidy, IGH rearrangements
secondary events -
KRAS, NRAS…
how do myeloma cells interact with the bone marrow microenvironment
bone destruction
angiogenesis
anaemia
immunosuppression and infection
diagnostic criteria for MM
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
presentation of bone disease in myeloma patients
proximal skeleton back, chest wall, pelvic pain ostrolytic lesions, never osteoblastic osteopenia pathological fractures hypercalcaemia
what bone imaging can we do in myeloma
plain XR films
whole body CT
CT/FDG-TER
whole body diffusion weighted MRI
what bone disease emergencies to we get in MM
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
define myeloma kidney disease
serum creatinine >177 umol/l
OR
eGFR <40ml/min
AKI as a result of myeloma
what are the causes of myeloma kidney disease
cast nephropathy cause by high serum free light chain (FLC) levels and BJP
hypercalcaemia, loop diuretics, infection, dehydration, nephrotoxics
what medication is the cornerstone of myeloma kidney disease treatment
bortezomib
why do we get infections in myeloma
humoral and cellular immunodeficiency myeloid, T and NK impairment immunoparesis: low serum normal Igs chemo impairs the immune response myeloma immune evasion
how can we diagnose myeloma
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)
describe the myeloma plasma cell phenotype
CD319 (SLAM7) ++ CD56 ++ cytoplasmic Ig +++ CD38 +++ CD138 +++ BCMA ++
how is myeloma staged
ISS
international staging system
how can myeloma result in AL amyloidosis
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%
clinical presentation of AL amyloidosis
kidney, heart, liver, neuropathy - nephrotic syndrome - proteinuria and peripeheral oedema unexplained HF - raised NT-proBNP sensory neuropathy abnormal LFTs macroglossia
what is MGRS
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
what therapies are used in myeloma treatment
melphalan
cyclophosphamide - in combination with steroids
dexamethasone + pred - induces apoptosis in myeloma cells
which immunomodulatory drugs can be used in myeloma
lenalidomide
promalidomide
how can proteasome inhibitors treat myeloma
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
treatment algorithm for transplant eligible MM pt
induction - PI + iMiD + Dex
+ autologous SC transplant
+ consolidation x2
+ maintenance low dose lenalidomide
treatment algorithm for transplant-ineligible patients
lenalidomide + dex or bortezomib -cyclophosphamide - dex or daratumumab - bartezomib - cyclophosphamide - pred
new MM treatments
CAR-T cell therapy, BiTE and immunoconjugates
