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Immunology > Immunoproliferative Disorders: Monoclonal Gammopathies > Flashcards

Immunoproliferative Disorders: Monoclonal Gammopathies Flashcards

1
Q

Gammopathy

A

disorder of gamma globulins (antibodies)

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2
Q

what do monoclonal gammopathies result from

A

a single clone of plasma cells producing high levels of a single class and type of antibody, referred to as monoclonal protein, M protein or Paraprotein

ONLY plasma cells

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3
Q

2 e.gs of monoclonal gammopathies

A

multiple myeloma

Waldenstrom primary macroglobulinaemia

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4
Q

Polyclonal gammopathy

A

secondary disease with increased levels of 2 or more antibodies, produced by several clones of plasma cells

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5
Q

what are immunoglobulins synthesised and secreted by in bone marrow and lymph nodes

A

plasma cells

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6
Q

what are plasma cells the final stage of maturation of

A

B lymphocytes

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7
Q

what are immunogloublins made of

A

2 identical heavy chains and 2 identical light chains

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8
Q

What happens to the excess light chains which enter the kidneys and pass through the glomerulus and into the proximal tubule

A

they are reabsorbed and degraded into smaller peptides which are then recycled because of their low molecular weight

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9
Q

what are light chain levels seen in urine in monoclonal gammopathies like and why

A

high as the capacity of the proximal tubule can be overwhelmed

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10
Q

why is the amount of plasma cells produced regulated by homeostasis

A

so that the required amount of antibody to deal with an infection is produced

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11
Q

what allows plasma cells to overcome growth restraints

A

Chromosome abnormalities

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12
Q

some subdivisions of Monoclonal gammopathies

A

Monoclonal gammopathy of undetermined significance (MGUS)

myeloma (AKA multiple myeloma)

Waldenstrom primary macroglobulinaemia

Light-chain disease

Heavy-chain disease

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13
Q

what are tumours derived from mature naïve B cells are found in

A

lymph node follicles (forming follicular centre cell lymphoma)

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14
Q

where are plasma cell tumours (myelomas) found

A

bone marrow

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15
Q

what is the commonest subtype of monoclonal gammopathy

A

Monoclonal gammopathy of undetermined significance (MGUS)

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16
Q

where are less than 10% plasma cells in MGUS

A

in the bone marrow

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17
Q

what does MGUS incidence increase with

A

age (1% in >50s, 10% in>80s)

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18
Q

what do 1% of MGUS tranform into

A

the malignant form of MG (multiple myeloma)

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19
Q

what is multiple myeloma the cancer of

A

bone marrow

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20
Q

what do multiple myeloma patients have in their bones

A

lytic bone lesions

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21
Q

where is there a monoclonal immunoglobulin build up in multiple myeloma

A

serum and/or urine

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22
Q

clinical features of multiple myeloma

A

bone pain

anaemia

infections (defects in humoral not cell immunity)

renal failure

proteinuria in 50% of patients excreting abnormal amounts of Bence Jones proteins (light chains)

hyperviscosity syndrome

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23
Q

3 lab features of multiple myeloma

A

electrophoresis of serum or urine shows a monoclonal protein in 90% of patients

increased serum calcium

low haemoglobin

raised mean cell volume (MCV)

increased erythrocyte sedimentation rate

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24
Q

multiple myeloma incidence

A

Incidence is ~5-7 per 100,000

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25
Q

what ages is MM very rare in

A

<40 years

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26
Q

what is MM thought to possibly result from excess production of

A

interleukin (IL) -6

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27
Q

antibody produced in multiple myeloma

A

Paraprotein or M protein

28
Q

2 most common protein types secreted in MM

A

IgG (60%)

IgA (>20%)

29
Q

nonsecretory myeloma

A

myeloma where cancer cells either don’t make or don’t release antibodies

30
Q

what do all secretory myelomas produce excess of

A

free light chains

31
Q

if levels of free light chains are too high in MM what can result

A

Proteinuria

32
Q

what can the presenting symptom of MM be

A

renal failure

33
Q

what is immunoglobulin in light chain myeloma like

A

Immune paresis - suppression of normal immunoglobulin production by a malignant plasma clone

34
Q

what is bone breakdown due to in MM

A

breakdown of the homeostatic control of bone remodelling by osteoclasts and osteoblasts

35
Q

what do osteoclasts do in MM as they’re upregulated

A

dissolve bone

36
Q

what causes the osteolytic lesions

A

plasma cells proliferating in bone, forming areas which are replaced by a circular clone of plasma cells

37
Q

how does MM appear on X-rays

A

decreased bone density with a lot of “punched out” holes in the bone

no white rim of bone

38
Q

plasmacytoma

A

early, isolated form of multiple myeloma (one lesion found)

39
Q

what do plasma cells release in MM which acts as Osteoclast activating factor and may be responsible for the lytic lesions and osteoporosis

A

IL-6

40
Q

MM diagnostics criteria

A

Paraprotein in serum and/or urine

> 20% abnormal plasma cells in bone marrow or monoclonality of plasma cells (>12% with one light chain type)

Osteolytic bone lesions

41
Q

2 clinical findings of MM due to decreased production of normal blood cells due to infiltration of bone marrow

A

Anaemia-fatigue, lethargy, dyspnoea (shortness of breath)

Thrombocytopenia-increased bleeding

Leukopenia-increased infection rate

42
Q

2 clinical findings of MM due to the bone lesions:

A

Bone pain, fractures, vertebral collapse

Hypercalcaemia (lots of calcium from bone loss)

Osteoporosis

43
Q

what do high concentrations of Ig in serum in MM cause, which can cause platelet abnormalities

A

serum hyperviscosity (increased thickness from increased protein concentration)

44
Q

what can you see from a complete blood count for MM diagnosis

A

Anaemia
Thrombocytopenia
Increased erythrocyte sedimentation rate (ESR)

45
Q

what is seen in Peripheral blood films if its MM

A

Rouleaux formation (red cells stacking)

Sometimes low numbers of neoplastic plasma cells

46
Q

what cells are seen abnormal and larger in MM bone marrow biopsies

A

plasma cells

47
Q

Why do MM patients have very high serum Ig levels, but decreased values of other immunoglobulins

A

Plasma cells are involved in the production of Ab and MM is due to uncontrolled proliferation of plasma cells

48
Q

how are Immunoglobulin concentrations measured for MM diagnosis

A

turbidimetry (how cloudy)

nephelometry (detection of light energy scattered or reflected toward detector)

radial immunodiffusion (circular ring formation on agar) - usually IgD as not much of it

49
Q

why do all patients with suspected multiple myeloma require a 24-hour urinalysis by protein electrophoresis

A

to determine the presence of Bence Jones proteinuria and kappa or lambda light chains.

50
Q

what is serum analysis for the myeloma protein performed by to diagnose MM

A

serum protein electrophoresis and immunofixation electrophoresis

51
Q

serum protein electrophoresis process

A

A small amount of serum is loaded at one end of the agarose gel.

An electric current is applied to the buffer (ph 8.6), and the current moves through the gel.

As the current moves through the gel, it brings negatively charged proteins with it. Albumin moves the quickest towards the anode, then alpha-1 globulins, then alpha-2 globulins, beta globulins and finally the gamma globulins. The movement of each molecule depends upon charge, size, and shape

The current is then switched off, and the gels are fixed and stained to make the proteins visible.

The gels are then analysed by passing light through. The amount of light that is absorbed by the protein bands appears as peaks on the trace.

52
Q

what do serum protein electrophoresis patterns produced by tumour cells in MM show

A

a sharp peak

53
Q

Immunofixation electrophoresis

A

is serum protein electrophoresis of serum (6 replicates)

Incubation of antiserum to IgG, IgA, IgM, kappa light chains, lambda light chains/lane (6th lane is control)

The reaction of antiserum to the Ig in the patient’s serum forms an immunoprecipitation reaction, fixes it in gel

Gels rinsed to remove unprecipitated proteins

Gels are stained to visualise precipitated proteins

54
Q

what are the immunofixation electrophoresis results in myeloma

A

sharp dark bands in either IgG or IgA heavy chains and 1 light chain (kappa or lambda)

55
Q

what are the immunofixation electrophoresis results in macroglobulinemia

A

strong band in IgM lane and 1 of light chains.

56
Q

what biochemical markers show as increased in MM

A

urea,
creatinine (shows kidney dysfunction)
uric acid
Calcium

57
Q

2 serum levels that can be used to stage a patient with MM

A

C-reactive protein and Beta 2 microglobulin

58
Q

whats the standard MM treatment which has poor complete remission rates (5%)

A

melphalan (chemo) and prednisone

59
Q

what completes remission rates of 40% and an overall survival 5 years (MM treatment)

A

Intensive chemotherapy and stem cell transplantation

60
Q

what does radiation therapy aim to do in MM treatment

A

reduce tumour cell growth in areas with bone pain.

61
Q

why is plasmapharesis done to treat MM

A

to remove Ig and try to reduce the rate of renal failure

62
Q

3 NICE treatment approvals for MM since 2021

A

April 2021: carfilzomib (Kyprolis) with dexamethasone and lenalidomide (Revlimid) for previously treated multiple myeloma in adults

April 2022: daratumumab (Darzalex) for relapsed and refractory multiple myeloma in adults

February 2023: Ixazomib (Stivarga) with lenalidomide and dexamethasone for relapsed or refractory multiple myeloma.

63
Q

Daratumumab

A

anti-cancer monoclonal antibody medication. It binds to CD38, which is overexpressed in multiple myeloma cells

results in tumour cell death by immune-mediated actions and apoptosis.

64
Q

Elotuzumab

A

first monoclonal antibody approved to treat multiple myeloma.

targets SLAMF7 protein and therefore activates natural killer cells

It is given intravenously

65
Q

immune paresis in MM treatments

A

Red cell transfusion
Antibiotics
Bisphosphonates

Immunology (13 decks)

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