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Path - Haem > Plasma cell myeloma > Flashcards

Plasma cell myeloma Flashcards

1
Q

what is multiple myeloma?

A

we have been learning in haem about blood malignancies, and these are mainly of blasts (right at beginning of the chain)

multiple myeloma is blood malignancy affecting plasma B cells (right at end of the differentiation chain - even after b cells themselves as plasma cells make antibodies)

Multiple myeloma (MM) is a hematologic neoplastic disease in which uncontrolled proliferation of clonal plasma cells’ leads to end-organ damage

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2
Q

what are the features of multiple myeloma on ivx?

A

Physical:
may form bone expansile or soft tissue tumours: plasmacytomas

Bloods:
- produce serum monoclonal immunoglobulins IgG or IgA:
paraprotein or M-spike
- excess monoclonal (κ or λ) serum free light chains

Urine:
Bence Jones protein: urine monoclonal free light chains

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3
Q

what is the epidemiology of MM?

A

2nd most common blood cancer

Median age 67 years
Incidence increases with age
Only 1% of patients are younger than 40 years

Men > women
Black > Caucasian and Asians

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4
Q

what is Waldenstrom’s - Lymphoplasmacytic lymphoma?

A

a cancer of 2 types of B cells;

plasma cells and lympho-plasmacy-toid cells.

is similar to NHL clinically - indolent. it is not multiplee myeloma but can predispose to MM.

aetiology: genetic mutations

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5
Q

myeloma is always preceded by a which premalignant condition?

A

Monoclonal Gammopathy of Uncertain Significance (MGUS)

average risk for progression : 1% annually

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6
Q

IgG or IgA MGUS -> _____ ?

IgM -> ____ ?

A

IgG or IgA MGUS -> myeloma

IgM -> lymphoma

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7
Q

what is the Diagnostic criteria for MGUS (WHO)?

A

Serum M-protein (monoclonal immunoglobulins) <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

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8
Q

how is the risk of MGUS progression to MM determined on an individual basis?

A

Mayo criteria:

Non-IgG M-spike (so IgA spike)
M-spike >15g/L
Abnormal serum free light chain (FLC) ratio

above are the 3 risk factors, the more the gr8 your risk of progression 3 = 27% risk.

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9
Q

what is the intermediate condition between MGUS and MM?

what are its diagnostic criteria

A

smouldering myeloma

diagnostics: above MGUS criteria but below MM criteria:
≥10% Plasma cells
+/-
M-spike ≥30g/L

no organ damage or symptoms

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10
Q

which events are involved in the pathogenesis of multiple myeloma ? which are more common

A

primary & secondary genetic events
primary happens first then secondary occur after primary

Primary events:

  1. Hyperdiploidy - MOST common
  2. IgH rearrangement

Secondary events:
Gene abberations eg
KRAS, NRAS
t(8;14) IGH/MYC

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11
Q

what is the role of primary & secondary genetic events in disease progression in Myeloma?

A

Having primary events is generally only associated with early stage disease (MGUS)

as secondary geneetic abberations are added, the disease progresses on to SM –> MM and at the worst of the spectrum is relpase.

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12
Q

what is the association between genes and outcome in MM?

A

Increased genetic heterogeneity is linked to poor prognosis

because treatment has a bottleneck effect driving clonal selection

heterogeneity means that is is hard to devleop targetted therapy in MM

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13
Q

what is the diagnostic criteria for MM?

A

≥10% plasma cells in bone marrow or plasmacytoma + ≥1 CRAB or MDE

Myeloma defining events:
Bone marrow plasma cells ≥60%
Involved : uninvolved FLC ratio >100
> 1 focal lesion in MRI (>5mm)

C: Hypercalcaemia
	calcium >2.75mmol/L 
R: Renal disease
	creatinine >177μmol/L or eGFR <40ml/min
A: Anaemia
	Hb <100g/L or drop by 20g/L
B: Bone disease
	One or more bone lytic lesions in imaging
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14
Q

what is the normal plasma cell response to infection (in terms of gammopathy)?

A

polyclonal gammaopathy - so it makes loads of antibodies - alpha, beta AND gamma globulins ; IgG, IgA1, IgA2 etc

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15
Q

what are the 2 histological subtypes of MM?

A

Mature Plasmacytic Cells

Immature Plasmablastic Cells -

  • Less abundant cytoplasm
  • poorer prognosis
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16
Q

On immunoHISTOchemistry, what would you find for MM?

*yes so it is staining histology

A

§ CD138 mainly!!
§ CD38
§ CD56 - very important differentiator
note: so not your typical B cell antigens
§ Monotypic cytoplasmic immunoglobulin
§ Light chain restriction (either kappa or lambda positive)

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17
Q

80-90% of MM patients have what?

A

lytic bone lesions + bone PAIN

less present with fractures though

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18
Q

which imaging modalities are used in MM?

A

○ MRI
§ High sensitivity for bone marrow infiltration
§ Rx Response monitoring

○ CT Scans
§ Better at detecting very small lytic lesions
§ Good for radiotherapy planning
§ low dose used radiation dose

○ PET Scans
§ Detects active disease
§ Often combined with MRI

19
Q

patient presents with drowsiness, constipation, fatigue, muscle weakness, AKI.

what is happening and rx?

A

hypercalcaemia

rx: Fluids, steroids, zolendronic acid

20
Q

list the emergencies in MM?

A

CORD COMPRESSION - must treat within 24hrs!!

Hypercalcaemia

Kidney disease - as associated w poor outcome:
  - renal calculi, amyloidosis, pyelonephritis, casts
  - renal tubular acidosis -> fanconi syndrome
#Save the kidneys
21
Q

how is cord compression managed in MM?

A

MRI scan
Ig and FLC studies +/- biopsy

Dexamethasone
Radiotherapy

22
Q

high serum free light chains (FLC) levels and Bence Jone proteinuria results in?

A

cast nephorpathy:

the formation of plugs (urinary casts) in the kidney tubules from free immunoglobulin light chains leading to kidney failure (envisage a pipe blocked up with a ball)

23
Q

what is the diagnostic work up for MM?

A

Immunoglobulin studies:
Serum protein electrophoresis
Serum free light chain levels
24h Bence Jones protein

Bone marrow aspirate and biopsy:
IHC for CD138!! CD56

FISH analysis:
looks for translocations

Flow cytometry immunophenotyping
for diagnosis and resdiaul diseasee monitoring

24
Q

how do we identify AL amyloid?

A

Amyloid fibrils stain with Congo Red, are solid, non-branching and randomly arranged with a diameter of 7 – 12 nm

25
Q

what is AL amyloidosis and how dose it present?

A

Misfolded free light chains aggregate into amyloid fibrils in target organs.

Presentation:
Nephrotic syndrome (70%)
-Proteinuria (not BJP!), peripheral oedema

Unexplained heart failure  determinant of prognosis
-Raised NT-proBNP

Abnormal echocardiography and cardiac MRI
Sensory neuropathy
Abnormal liver function tests
Macroglossia

26
Q

what are the components of myeloma therapy?

A

Cyclophosphamide

  • used wheen trnasplant ineligible
  • Immunomodulation and microenvironment

Dexamethasone and Prednisolone
- Induce apoptosis in myeloma cells

Thalidomide derivatives - Immunomodulatory drugs (IMiD)
- Lenalidomide

Proteosome inhibitors - rememberr MM spews out proteins
- Bortezomib

Mumabs - anti CD38s

Autologous Stem Cell Transplantation

-> despite these, MM is still incurable!

27
Q

in MM who can get Autologous Stem Cell Transplantation?

what is the rx before then?
what is the rx after transplant?

A

Fit and typically <65 years old

  1. Induction: PI + IMiD + Dex
    + Daratumumab in high-risk
  2. Autologous Stem Cell Transplantation
  3. Maintenance for 2 years:
    Low dose Lenalidomide
28
Q

apart from MM and the emergencies, what other notable conditions are caused by toxic monoclonal immunoglobulins and free light chains?

A

Monoclonal Gammopathy of Renal Significance (MGRS) and AL amyloidosis

29
Q

what is the structure and nomenclature for antibodies?

A

gamma globulins - antibodies
heavy chains : GAMED
light chain: kappa, lambda

30
Q

what is the reason for the term ‘M spike’ of serum electrophoresis?

A

monoclonal spike eg monoclonal gammopathy

31
Q

what is the reason for the term ‘M spike’ of serum electrophoresis?

what does it signify?

A

monoclonal spike eg monoclonal gammopathy

signifies:
excess gamma globulins which can be any of:
heavy chain - GAMED
light chain - kappa, lambda

S Protein elctrophoresis cannot tell these apart! only immunofixation can

32
Q

which infections are MM sufferers at risk of and why?

A

Bacterial infections eg pneumonia

Proliferation of the 1 antibody = crowding out = reduced immunity (humoral)

defence against viruses fine - T cells

33
Q

what is the mechanism of bone resorption in MM?

A

Osteoprotegrin is an osteoclast inhibitor

it is inhibited in MM = increased osteoclastic bone resorption

Osteoblasts are inhibited as myeloma cells secrete an inhibitor (DKK1)

34
Q

Above we have discussed treatment options to. control myeloma. What are symptomatic rx for MM?

A

painkillers –

radiotherapy – to relieve bone pain or help healing after a bone is surgically repaired

bisphosphonate – to help prevent bone damage and reduce the levels of calcium in your blood

blood transfusions or erythropoietin medication – treat anaemia

surgery – to repair or strengthen damaged bones, or treat compression of the spinal cord

dialysis – may be required if you develop kidney failure. to remove M proteins

plasma exchange – replace (plasma), if you have thick blood - hyper viscosity syndrome (too much M proteins)

NHS - says chemo is part of main treatment regime with steroids etc

35
Q

what are the sx of hyper viscosity syndrome?

A

headahce
fatigue
SOB

spontaneous bleeding from mucous membranes,
visual disturbances due to retinopathy,

neurologic symptoms ranging from headache and vertigo to seizures and coma

36
Q

what are the neurological sx of MM?

A

Cord compression due to lytic lesions

those caused by hypercalcaemia -> hyporeflexia, muscle weakness

37
Q

how is renal function impacted by MM?

A

Glomerular function is normal
urine dip normal

Tubular function destroyed

38
Q

List some Emerging treatments in myeloma.

what are they used for?

A

They are immunotherapies, often used for resistant and refractory disease / relapse :

CAR T-cell therapy, BiTE and immunoconjugates (Belantamab mafodotin)

are still in the works - have been shown to improve survival but are still not Curative.

39
Q

what is Belantamab mafodotinand what is. its mechanism of action?

A

It is an Anti-BCMA toxin conjugate - immunoconjugate used in MM

The drug is attached to an antibody which then binds to the Myeloma plasma cell

it is endocytosied and caused Myeloma cell lysis

40
Q

what is CAR T-cell therapy?

A

Chimeric antigen receptor (CAR) T-cell therapy targeting BCMA (B-cell maturation antigen)

T cells) are taken from patient’s blood or tumor tissue, expanded and/or modified ex vivo and then reinfused back to the patient.

can be engineered to express a new T-cell receptor (TCR)or a chimeric antigen receptor (CAR)

CAR T cells can induce powerful immune responses against the cells expressing the target BCMA

41
Q

why is BCMA (B-cell maturation antigen) chosen as target for CAR-T cells?

A

Moreover, malignant plasma cells usually express higher BCMA levels than normal plasma cells - even though its found on both.

CAR T cells can induce powerful immune responses against the cells expressing the target BCMA

42
Q

what is BiTE therapy in myeloma?

A

“bispecific T cell engager”.
BiTEs are antibodies with two arms.

One arm of the drug attaches to a specific protein on the tumor cell. So connects tumour and T cell.
The other arm of the BiTE activates T cells = expansion and cytokine release = kill MM cells.

43
Q

we know about the CRAB of MM, but how does it usually present?

A

Not every myeloma case has a full house of symtoms and lab results some have mainly:

1 Hypercalcaemia and lytic bone lesions
or
2) renal failure and excess free light chains

Path - Haem (13 decks)

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