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PATHOLOGY > Plasma cell myeloma > Flashcards

Plasma cell myeloma Flashcards

1
Q

Definition of multiple myeloma

A

malignancy of terminally differentiated plasma cells - Ig secreting B cells

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2
Q

Histology of plasma cells

A

Blue cytoplasm
pale area - golgi apparatus

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3
Q

Summarise features of myeloma plasma cells

A

home and infiltrate in bone marrow

can form bone expansile or soft tissue tumours - plasmacytomas

produce serum monoclonal IgG or IgA- paraprotein or M spike

make excess monoclonal (K/Lambda) serum free light chains

Bence jones protein - urine monoclonal free light chains

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4
Q

Summarise B cell development in the context of myeloma

A

Normal counterpart for myeloma cells is - terminally differentiated long-lived plasma cells in bone marrow
ie have been through whole path of B cell development:

been mature B Cell -> lymphoid organ -> if receptor recognise epitope either become:
1. short lived plasma cells produce IgM counterpart for lymphoma
2. go through germinal centre
* 3. Somatic hypermutation - increases affinity of Ab to epitope
* class switch recombination form IgM -> IgG or IgA
3. then either memory cell or long lived plasma cell

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5
Q

epidemiology of myeloma

A

Older age
>men
>black
prevalence increasing - 2nd most common haematological malignancy

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6
Q

Aetiology of myeloma

A

Unknown
RF
* obesity
* age
* genetics - suggested by FHx, ethnicity

Always preceded by monoclonal gammopathy of uncertain significance

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7
Q

Summarise monoclonal gammopathy of uncertain significance

A

Presence of monoclonal Ig in blood or urine
Commonly find in elderly - risk increases with age
Bone marrow plasma clonal cells <10%
No sx or organ damage
progresses to multiple myeloma -1% risk of progression/yr
Higher risk of osteoporosis, thrombosis, bacterial infection etc

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8
Q

MGUS risk stratification and mx

A

Mayo criteria
RF
1. non-IgG M spike
2. M spike >15g/L
3. abnormal serum fre light chain ration (kappa and lambda)

more RF = more risk of progression

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9
Q

What is smouldering myeloma

A

both:
1. serum monoclonal protein (IgG or IgA) >= 30g, or urine >=500mg/24hr and/or clonal bone marrow plasma cells 10-60%
2. absence of myeloma defining events or amyloidosis

*no sx *

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10
Q

Risk stratification for smouldering myeloma

A

IMWG model

No evidence that beneficial to rx high risk disease

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11
Q

Clinical spectrum of myeloma

A

Clonal cells get more mutations with time -> malignancy

Microenv in immune system - immune system in equilibrium with plasma cells in bone marrow - if lost - then the plasma cells escape - get sx disease

Cycle of remission and relapse - until run out of treatment options - when become refractrory - proliferative disease

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12
Q

Pathogenesis of multiple myeloma

A

primary - can see at MGUS
either have hyperdiploidy or rearrangement of the locus of the heavy Ig gene - bring genes close to powerful enhancer

secondary - additional genetic event contribute to progression and refractory to rx later

clonal cells** interact with microenvironment -**>
1. All of the sx and organ damage either due to this or the high level of Hb in blood
1. Stimulate osteoclasts to destroy bones - get hyperca, fractures, bone pain
1. Osteoblasts support the growth and proliferation of plasma cells

suppress bone marrow cells -> anaemia, immunocompromised

**Myeloma paralyses immune system - **and escapes immunological control - this process happens in relapse

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13
Q

Diagnostic criteria for multiple myeloma

A

> =10% plasma cells in marrow/plasmacytoma and at least 1 CRAB feature

bone disease - pain/lytic lesion/fracture

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14
Q

What is myeloma defining events

A

bone marrow plasma cells >=60%
involved:uninvolved FLC ratio >100
1 focal lesion in MRI >5mm

*Don’t have CRAB or other sx
In next few mo - they will devlelop the disease
So consider them the asx myeloma *

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15
Q

Bone disease in multiple myeloma

A

Involves the prox skeleton
Skull, spine, ribs, pelvis
Can cause fractures - lesions are always osteolytic
Can cause osteopenia
High ca
Pathological fractures

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16
Q

Ix for bone disease in multiple myeloma

A

Whole body CT scan low dose
CT/FDG-PET

Whole body diffusion weighted MRI - bone marrow cellularity, active/residual vs treated disease

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17
Q

Bone disease and emergencies in myeloma

A

cord compression

hypercalcaemia

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18
Q

cord compression in myeloma

A

Fracture/soft tissue -> spinal canal -> paralysing from that level down, back pain

dx in 24hrs - MRI
Ig and free light chanin studies +/- biopsy

dexamethasone
radiotherapy
neurosurgery - rarely
stablise unstable spine
MDT

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19
Q

Hypercalcaemia and myeloma

A

present: drowsy, constipation, fatigue, muscle weakness, AKI

Mx
1. fluids
2. steroids
3. zolendronic acid

20
Q

definition of myeloma kidney disease

A

serum creatinine >177umol (>2mg/dL) or eGFR <40

acute kidney injury as result of myeloma

common

21
Q

Pathophysiology of myeloma kidney disease

A
  1. Light chains - pass glomerulus in filtrate
  2. In prox tubules - cell detect the light chains - capture - endocytose and reabsorb
  3. When levels increase - cells go into stress - most light chains not resorbed
  4. Bind to uromodulin - form casts - block the passage in renal tubules

hyperca, loop diuretics, infection, dehydration and nephrotoxics also contribute

22
Q

effect of myeloma kidney disease on Px

A

Kidney disease have a major impact on outcome - early death, prolonged stay, lethal injections

nephrotoxic/renally excreted myeloma drugs - zoledronic acid, lenalidomide

Has to be mx as medical emergency - try to redyuce the free light chains - stop kidnye injury - and hope kiudneys recover

Most effective rx - bortezomib

23
Q

Why does myeloma predispose to infection

A

immunoparesis - low serum normal Igs
myeloid, T cells and NK cell impairment
chemo impairs immune response
myeloma immune invasion

Susceptable to gram +ve first - then -ve and viruses

24
Q

Myeloma and covid

A

High mortality
RF - age, high risk disease, progressive/active disease, renal failure, non-white patients

reduced response to vaccination

25
Q

diagnostic work up for myeloma

A

FISH - on individual plasma cells

MRD = minimal residual disease

26
Q

Staging of myeloma

A

uses
1. b2-microglobulin
2. albumin
3. LDH
4. FISH high risk mutations
5. Iq chr

27
Q

Pathophysiology of amyloidosis and myeloma

A

free light chains misfold -> amyloid fibrils
amyloidogenic potential of light chains is more important than amount

amyloid fibrils stain congo red, are solid, non-branching, randomly arranged in diameter of 7-12nm

Lambda light chain in 60%
1. IGLV6-57 in kidney
2. IGLV1-44 in cardiac

28
Q

Features of amyloidosis

A

nephrotic syndrome - proteinuria, peripheral oedema

unexplained HF - determines Px - high NT-proBNP, abnormal echo and cardiac MRI

sensory neuropathy

abnormal LFTs

macroglossia

29
Q

Definition of monoclonal gammopathy of renal significance

A

no symptomatic myeloma - have premalignant condition

produce Ig or light chain that interacts with nephron -> kidney disease

Have to treat with myeloma treatment

30
Q

Pathology of monoclonal gammopathy of renal significance

A
31
Q

Myeloma treatment

A

Plasma cells not responsive to conventional cytotoxics

Now have immunotherapies
= much better outcomes for patients

CAR-T cell therapy

Melphalan - still use

Cyclo - use as oral drug. Has immunomodulatory effect

Steroids - plasma cells are sensitive to steroids

32
Q

Melphalan as myeloma therapy

A

alkylator

nitrogen mustard derivitive
high dose still used in autogolous SCT

33
Q

Cyclophosphide for myeloma

A

alkylator

used in combination with steroids and others
immunomodulation and microenvironment

oral

34
Q

Cyclophosphide for myeloma

A

alkylator

used in combination with steroids and others
immunomodulation and microenvironment

oral

35
Q

Steroids for myeloma

A

dexamethasone and prednisolone
induce apoptosis
strong synergy - part of combination regiemes

36
Q

Thalidamide for myeloma

A

Interfere with angiogenesis

Replaced chemo
And used in relapse

Developed similar immunomodulatory drugs:

Lenalidaomuide and pomalidomide - better effects and lower toxicity profile

37
Q

Cereblon E3 ligase modulators (CELMoDs)

A

Iberdomide
Main mech of action of these drugs and thalidomide act on CRBN
Work as a glue - stick the substrate of protein -> alter transcritption factors-> upstreal of IR4 whihc is important for transcription for plasma cells

38
Q

Proteosome inhibitors in myeloma - mechanism

A

Plasma cells produce a lot of protein
To be able to do this - have proteosome - so we block this - > ER stress -> apoptosis

Also involved in NF-kB pathway

Have become v important drugs

39
Q

Specific proteasome inhibitors in myeloma

A

Bortezomin - for first line/relapse, IV or SC, neuropathy is main SE

Carflizomib - more potent, for relapse, IV, SE - thrombocytopenia, cardiotoxicity

ixazomib - relapse in combination, oral,

40
Q

Immunotherapy for multiple myeloma

A

Daratumumab targets CD38 - strongly expressed in normal and malignant cells
Not specific for plasma cells
Attack the cells
Has lots of mechanism

used in combination with other drug

41
Q

Immunotherapy for multiple myeloma

A

Daratumumab targets CD38 - strongly expressed in normal and malignant cells
Not specific for plasma cells
Attack the cells
Has lots of mechanism

used in combination with other drug

42
Q

Holistic approach for myeloma

A
43
Q

Treatment algorithm for myeloma

A

Younger patients (<70yrs), fir 0 may be eligible for transplant - fit enough to have high dose of drugs and deal with se
Induction - 4 cycles - will get most patients into a complete response
Maintenance - low intensity therapy for a very long time.

For older more sensitive patients - use lower doses

44
Q

Importance of maintenance therappy for myeloma

A

Low dose lenalidomide long term for maintenance improves outcome - survival benefit

45
Q

Belantamab mafodotin for myeloma

A

Anti-BMCA ab conjugate
Targets BMCA (specific for plasma cells)
Endocytosed
Release toxin -> kill plasma cells
60% response rate in refractory myeloma

46
Q

CAR-T cells for myeloma

A

CAR-T cells also target BCMA
- Ide-cel
- Cilta-cel (better outcome)

SE of CAR-T cell
- Cytokine release syndrome
- Neurotoxicity
- Prolonged cytopenia and infection

47
Q

BiTE Ab for myeloma

A

Bispecific ab
Recognise CD3 and the other part recognise the molecule in the target cell - BCMA and FcRL5
Bispecific brings together T cell and tumour cell

One has EDA approbal - can produce 60% respons

Other bispecifics are coming into play

PATHOLOGY (94 decks)

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