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Myeloma and other plasma cell dyscrasias Flashcards

1
Q

Where are B cells developed from?

A

Bone marrow from pluripotent haematopoietic stem cell

Part of adaptive immune system

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2
Q

What is the dual function of B cells?

A

Antibody production

Acts as antigen presenting cells

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3
Q

What are immunoglobulins?

A

Antibodies produced by B cells and plasma cells
Proteins made up of 2 heavy and 2 light chains
Each antibody recognizes a SPECIFIC antigen

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4
Q

Describe the different shapes of immunoglobulins

A

Monomer; IgD, IgE, IgG
Dimer; IgA
Pentamer; IgM

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5
Q

What generates the variable region of Ig?

A

V-D-J region recombination early in development

Self reactive cells removed

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6
Q

Describe the development of B cells within the bone marrow

A

Stem cells
Common lymphoid progenitor
Pro B cells
Pre B cells

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7
Q

Where will B cells travel to once they reach the circulation?

A

Follicle germinal centre of the lymph node

Identify antigens and improves the fit by somatic mutation or deletion

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8
Q

How can B cells return to the circulation once they have passed through the germinal center?

A

Plasma cells; production antibodies

Memory B cell

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9
Q

What is a plasma cell?

A

Production of antibodies

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10
Q

Describe the appearance of a plasma cell?

A

Eccentric clock face nucleus on H+E
Open chromatin; synthesising mRNA
Plentiful blud cytoplasm laden with protein
Pale perinuclear area; golgi apparatus

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11
Q

What does a polyclonal increase in Ig suggest?

A 
Produced by many different plasma cells 
Reactive; 
Infection 
Autoimmune
Malignancy; reaction of host to malignant clone
Liver dx
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12
Q

What does a monoclonal rie in Ig suggest?

A

All derived from clonal expansion of single B-cell

Identical antibody structure and specificity

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13
Q

What is a monoclonal immunoglobulin?

A

Paraprotein

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14
Q

What is a monoclonal Ig an maker of?

A

Underlying clonal B cell disorder

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15
Q

How can immunoglobulins be detected?

A

Electrophoresis

The separated proteins appear as distinct bands or zones

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16
Q

What determines how far proteins move on electrophoresis?

A

Size

Charge

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17
Q

What will electrophoresis detect?

A

ABNORMAL protein bands

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18
Q

What is the purpose of serum immunofixation?

A

Classify abnormal protein band

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19
Q

What is a bence jones protein?

A

Immunoglobulin light chain

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20
Q

How are bence jones proteins identified?

A

Urine electrophoresis

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21
Q

How much free light chain is produced by normal plasma cells?

A

0.5g/ day

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22
Q

What are the different light chains?

A

Kappa - monomer

Lambda - dimeric

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23
Q

What can cause an increase in light chain immunoglobulin production?

A

Polyclonal increase; infection

Monoclonal increased; multiple myeloma

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24
Q

What are the commonest causes for paraproteinaemia?

A 
MGUS (monoclonal gammopathy of unknown significance) (56%)
Myeloma (18%)
Amyloidosis (10%) 
Lymphoma (5%) 
Asymptomatic myeloma (4%) 
Solitary or extramedullary plasmacytoma (3%) 
Chronic lymphocytic leukaemia (2%) 
Waldenstrom's macroglobulinemia (2%)
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25
What is myeloma?
A plasma cell malignancy
26
How does myeloma occur?
``` Normal plasma cells Genetic "hit" MGUS (benign/ premalignant) Genetic "hit" Asymptomatic myeloma (malignant but no organ damage) Genetic "hit" Myelom (overtly malignant) ```
27
How will myeloma affect the body?
Direct tumour cell effects | Paraprotein mediated effects
28
What are the direct tumour cell effects of myeloma?
Bone lesions Increased calcium Bone pain Replace normal bone marrow (marrow failure)
29
What are the paraprotein mediated effects of myeloma?
Renal failure Immunosuppression Hyperviscosity Amyloid
30
How is myeloma classified?
On the type of monoclonal protein they produce Majority (60%) produce IgG Then IgA Then free light chains (bence jones myeloma)
31
What is the characteristic skull x-ray appearance in myeloma?
Multiple "punched out" lytic lesions in skull
32
What are the bony abnormalities seen in multiple myeloma?
Lytic skull lesions | Wedge compression fracture of thoracic vertebrae
33
Which cytokines are upregulated in multiple myeloma?
IL-6 | TGF beta
34
What is the pathogenesis of myeloma lytic bone disease?
Myeloma cells increased IL-6 This activated osteoclasts and suppressed osteoblasts Increased calcium
35
What are the symptoms of hypercalcaemia?
``` Stones Bones Abdominal groans Psychiatric moans Thirst Dehydration Renal impairment ```
36
What is the commonest consequence of myeloma on organ damage?
KIDNEY | 30% will have renal impairment at diagnosis
37
What are the different types of renal damage that myeloma can cause?
``` Tubular cell damage via light chains Light chain deposition - cast nephropathy Sepsis Hypercalcaemia and dehydration Drugs; NSAIDs Hyperuricemia Amyloid ```
38
What is the half life of free light chains?
2-6 hours Can filter through the glomerular pores Proximal tubules will attempt to reabsorb these proteins but if overwhelmed the protein will pass into the thick ascending loop of henle where it will combine with tamm horsfall proteins to produce insoluble casts
39
What are the casts made from in cast nephropathy?
Free immunoglobulin light chains and Tamm Horsfall protein
40
Where will casts form in cast nephropathy?
Thick ascending loop of henle
41
Is cast nephropathy reversible?
Can be with prompt treatment Hydration STOP nephrotoxic drugs Switch off light chain production via steroids/ chemo
42
What is the treatment of myeloma?
Corticosteroids; dexa or pred Alkylating agents; cyclophosphamide Novel agents; thalidomide, bortezomib and lenalidomide
43
What is the gold standard treatment for myeloma in fit patient?
High dose chemo | Autologous stem cell transplant
44
How is response monitored in myeloma treatment?
Paraprotein (monoclonal immunoglobulin) levels
45
What is autologous haematopoietic stem cell transplant?
Administer pre-treatment to release blood stem cells from bone marrow into blood stream Collect blood stem cells Freeze Administer chemo to remove or partially remove immune system Return thawed stem cells by infusion via vein
46
What CD marker is present on B cells?
CD 20
47
What CD marker is present on plasma cells?
CD 38
48
What antibody can be used to target plasma cells in myeloma?
Daratumumab - targets CD38 surface receptor
49
What is the symptom control management in multiple myeloma?
Opiate analgesia (avoid NSAIDs) Local radiotherapy Bisphosphonates (corrects hypercalcaemia and bone pain) Vertebroplasty (inject sterile cement into fractured bone to stabilise)
50
What is MGUS?
Paraprotein <30 g/l Bone marrow plasma cells <10% NO evidence of myeloma end organ damage
51
What are the signs of myeloma end organ damage?
``` Raised calcium Reduced renal function Reduced Hb Lytic lesions Increase in infection ```
52
Can MGUS progress to myeloma?
Yes - risk is 1% per year
53
What is AL amyloidosis?
Small plasma cell clone mutation in light chain; altered structure
54
What will AL amyloidosis precipitate as?
Insoluble beta pleated sheet
55
What are the consequences of AL amyloidosis?
Accumulation in tissues = organ damage Multisystem Poor prognosis if cardiac amyloid
56
What is the treatment of AL amyloidosis?
Chemo similar to myeloma to switch off light chain supply
57
What organ damage will occur in AL amyloidosis?
``` Kidney; nephrotic syndrome Heart; cardiomyopathy Liver; organomegaly - deranged LFTs Neuropathy; autonomic, peripheral GI; malabsorption ```
58
How is amyloid diagnosed?
Organ biopsy Congo red stain with apple green birefringence under polarised light Rectal or fat biopsy if high clinical suspicion
59
How is amyloid staged?
SAP scan Echo/ cardiac MRI Nephrotic range proteinura
60
What is a SAP scan?
Amyloid labelled scintigraphy to monitor disease burden and response Localises rapidly and specifically to amyloid deposits in proportion to quantity of amyloid present
61
What is waldenstrom's macroglobulinaemia?
IgM paraprotein Lymphoplasmacytoid neoplasm Clonal disorder of cells intermediate between a lymphocyte and plasma cell
62
What is the characteristic sign of waldenstrom's macroglobulinemia?
IgM paraprptein
63
What are the tumour effects of waldenstrom's macroglobulinemia?
Lymphadenopathy Splenomegaly Marrow failure
64
What are the paraprotein effects of waldenstrom's macroglobulinemia?
Hyperviscosity | Neuropathy
65
What is the structure of an IgM antibody?
Pentamer | 900 KDa
66
What is hyperviscosity syndrome?
``` Fatigue Visual disturbance Confusion Coma Bleeding Cardiac failure ```
67
What is the treatment of waldenstrom's macroglobulinemia?
``` Chemo Plasmapheresis (removes paraprotein from circulation) ```
68
What is a bence jones protein?
Free Ig light chain of kappa or lamba type filtered by the kidney
69
How is myeloma diagnosed?
Monoclonal protein band in serum of urine electrophoresis Increased plasma cells on marrow biopsy Evidence of end-organ damage from myeloma; hypercalcaemia, renal insufficiency, anaemia Bone lesions; skeletal survey after diagnosis detected bone diseae +/- Tc-99m MIBI and PET
70
What can be seen on the blood film in multiple myeloma?
Rouleaux formation

Haematology (31 decks)

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