Myeloma and Paraproteins

Question 1

Features of antibodies

Answer 1

An antibody is an immunoglobulin
Produced by B cells, mostly plasma cells
Can be either soluble or membrane-bound
Primary role is to recognise and bind pathogens
This may directly impede the biological process or direct other components of the immune system by “tagging” the antigen

Question 2

Basic structure of an antibody/immunoglobulin

Answer 2

Y shaped
2 heavy chains and 2 light chains
2 variable domains but everything else constant

Question 3

What is the Fc portion of an antibody defined by?

Answer 3

Heavy chains

Question 4

Types of heavy chain

Answer 4

Gamma - IgG
most prevalent antibody subclass, 75% of total

Alpha - IgA
mucous membrane immunity

Mu - IgM
initial phase of antibody production, exists as pentamer - highest molecular weight

Delta - IgD

Epsilon - IgE
parasite immune responses, hypersensitivity

Question 5

Types and features of light chains

Answer 5

Kappa or lambda

Random selection for each cell
Each cell will only make 1 type of light chain with 1 specificity
Free light chains also found in the blood flow at low levels - difficult to measure

Question 6

Function of the Fab and Fc regions of immunoglobulins

Answer 6

Fab region - variable, defines target binding

Fc region - constant, defines subclass

Question 7

Total levels of IgG, IgA and IgM, normally

Answer 7

IgG - 6-15g/L
IgA - 1-4.5g/L
IgM - 0.5-2g/L

Question 8

What is a paraprotein?

Answer 8

Monoclonal immunoglobulin present in blood or urine

Question 9

If a paraprotein is present, what does this tell us?

Answer 9

That there is monoclonal proliferation of a B lymphocyte/plasma cell somewhere in the body

Question 10

What does serum protein electrophoresis do?

Answer 10

Separates proteins based on size and charge and forms a characteristic pattern of bands of different widths and intensities based on proteins present
Assesses antibody diversity and identifies paraprotein

Question 11

What does total immunoglobulin levels measurement do?

Answer 11

Measures Ig subclasses by heavy chain/Fc section

Question 12

What does immunofixation do?

Answer 12

Identifies what class of paraprotein is present

Question 13

What does measurement of light chains do?

Answer 13

Assesses imbalance/excess of light chains in urine/serum

Question 14

What disease are IgM associated with?

Answer 14

Lymphoma

Maturing B lymphocytes make IgM antibody at the start of the immune response

Question 15

What disease are IgG and IgA paraproteins associated with?

Answer 15

Myeloma

Mature plasma cells generate these types of immunoglobulin after isotope switching

Question 16

What paraproteins are associated with myeloma?

Answer 16

IgG

IgA

Question 17

What is myeloma?

Answer 17

Neoplastic disorder of plasma cells resulting (usually) in excessive production of a single type of immunoglobulin (paraprotein)

Question 18

Incidence of myeloma

Answer 18

Peaks in 7th decade

Ethnicity - commoner in black population than in white

Question 19

What are clinical manifestations of myeloma a result of?

Answer 19

Direct effect of plasma cells or effect of paraprotein

Question 20

Clinical features of myeloma

Answer 20

Bone disease

• lytic bone lesions
• pathological fractures
• cord compression
• hypercalcaemia

Bone marrow failure, especially anaemia (thrombocytopenia and neutropenia)

Infections

Question 21

Effect of paraprotein on kidneys

Answer 21

Causes renal failure - cast nephropathy

Immunoglobulin deposition and blockage of renal tubules

Question 22

Effect of paraprotein on blood viscosity

Answer 22

Hyperviscosity - syndrome caused by increased viscosity in blood, impaired microcirculation and hypoperfusion
Commonest clinical feature is bleeding - retinal, oral, nasal or cutaneous
Can also cause cardiac failure, pulmonary congestion, confusion and renal failure

Question 23

Effect of paraprotein on immunoglobulin

Answer 23

Hypogammaglobulinaemia
Impaired production of normal immunoglobulin
Tendency for infection

Question 24

Features of amyloidosis

Answer 24

Group of diseases characterised by deposition of fibrillary protein
Morphological appearances and physical structure are similar but biochemical or protein composition can vary
When caused by a paraprotein or light chains = AL amyloid
- nephrotic syndrome
- cardiac failure
- carpal tunnel syndrome
- autonomic neuropathy
- cutaneous infiltration

Question 25

How common are paraproteins?

Answer 25

3-4% of the population > 75 years of age will have paraproteins, vast majority have nothing wrong with them
This is termed monoclonal gammopathy of uncertain significance (MGUS)

Question 26

How is myeloma diagnosed?

Answer 26

By finding excess plasma cells in the bone marrow

Must comprise > 10% of total bone marrow cell population

Question 27

Types of paraprotein in myeloma

Answer 27

IgG - 55%
IgA - 21%
Light chain only - 22%
Other e.g. IgD, non-secretory - 2%

Question 28

What is staging of myeloma based on?

Answer 28

Albumin and beta-2 microglobulin

Question 29

Treatment of myeloma

Answer 29

Chemotherapy - proteasome inhibitors, IMiDs, monoclonal antibodies (trial)
Bisphosphonate therapy - zoledronic acid
Radiotherapy
Steroids
Surgery - pinning of long bones, decompression of spinal cord
Autologous stem cell transplantation

Question 30

What disease are IgM paraproteins associated with?

Answer 30

Low grade lymphomas

Question 31

Clinical presentation of IgM low-grade lymphomas

Answer 31

Bone marrow failure (anaemia, thrombocytopenia) 
Lymphadenopathy 
Hepatosplenomegaly 
B symptoms 
Paraprotein-related symptoms 
Bone disease very rare