Myeloma

Question 1

What are antibodies?

Are they soluble?

Answer 1

• Produced by B cells, mostly plasma cells
• Primary role is to recognise and bind to pathogens
• Either soluble or membrane bound

Question 2

What is the basic structure of antibodies?

Answer 2

• Basic structure - Y –shaped
• 2 heavy chains
• 2 light chains

Question 3

What are the variable domains of antibodies?

Answer 3

• There are variable domains
• Everything else remains constant

Question 4

What are the types of heavy chain of antibodies?

Answer 4

• 5 types of heavy chain
  
  • Gamma – IgG
  • Alpha – IgA
  • Mu – IgM
  • Delta – IgD
  • Epsilon - IgE

Question 5

What are the characteristics of each heavy chain?

Answer 5

• IgM
  
  • Initial phase of antibody production
  • Exists as a pentamer – highest molecular weight
• IgG
  
  • Most prevalent antibody subclass (75% of total)
• IgA
  
  • Mucous membrane immunity
• IgE
  
  • Parasite immune responses, hypersensitivity

Question 6

What are the light chains?

Answer 6

• Kappa or lambda
  
  • Random selection for each cell
  • But, each cell will only make 1 type of light chain with 1 specificity
  • Free light chains are also found in the blood at low levels – difficult to measure

Question 7

What is the FAB vs FC region of antibody?

Answer 7

• FAB region: variable, defines target binding
• FC region: constant, defines subclass

Question 8

What are the rough levels of the different types of immunoglobulin?

Answer 8

• IgG : 6-15g/l
• IgA : 1-4.5g/l
• IgM : 0.5-2.0g/l

Question 9

What is a paraprotein?

Answer 9

• monoclonal immunoglobulin present in blood or urine
• If present, it tells us that there is monoclonal proliferation of a B lymphocyte / plasma cell somewhere in the body

Question 10

What use is serum protein electropheresis?

Answer 10

• Separates protein based on size and charge
• Forms a characteristic pattern of bands of different widths and intensities based on proteins presenta

Question 11

What does total immunoglobin levels measure?

What does electrophoresis measure?

What does immunofixation tell us?

What will light chains tell us?

Answer 11

• Total immunoglobulin levels
  
  • Measures Ig subclasses by heavy chain/ Fc section
• Electrophoresis
  
  • Assesses antibody diversity, identifies paraprotein
• Immunofixation
  
  • Identifies what class of paraprotein is present (i.e. IgG, IgM)
• Light chains
  
  • Assesses imbalance/ excess of light chains in urine / serum

Question 12

Which diseases present with IgM paraproteins?

Answer 12

= Lymphoma

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

Question 13

Which diseases present with IgG, IgA paraproteins?

Answer 13

= Myeloma

• Mature plasma cells generate these types of immunoglobulin after isotype switching

Question 14

What is myeloma?

Answer 14

• Neoplastic disorder of plasma cells, resulting (usually) in excessive production of a single type of immunoglobulin (paraprotein)
• Peaks in 7th decade
• Ethnicity – commoner in black population than white

Question 15

What are the features of myeloma?

Answer 15

• Bone disease
  
  • lytic bone lesions
  • pathological fractures
  • cord compression
  • hypercalcaemia
• Bone marrow failure esp. anaemia
• Infections

Question 16

What are the effects of IgG and IgA paraproteins in Myeloma?

Answer 16

• Renal failure (cast nephropathy)
• Hyperviscosity
• Hypogammaglobulinaemia
• Amyloidosis

Question 17

Effects of IgG and IgA paraproteins in Myeloma

Explain the reason for renal failure:

Answer 17

• Immunoglobulin deposition and blockage of renal tubules

Question 18

Effects of IgG and IgA paraproteins in Myeloma

Reason for hyperviscosity?

Answer 18

• Syndrome caused by increased viscosity in blood, impaired microciculartion and hypoperfusion
• Commonest clinical feature is bleeding – retinal, oral, nasal, cutaneous
• Can also cause cardiac failure, pulmonary congestion, confusion, renal failure

Question 19

Effects of IgG and IgA paraproteins in Myeloma

Reason for the Hypogammaglobulinaemia?

Answer 19

• Impaired production of normal Immunoglobulin
• Tendency to infection

Question 20

Effects of IgG and IgA paraproteins in Myeloma

Reason for the amyloidosis?

Answer 20

• Group of diseases characterised by deposition of fibrillar protein
• Morphological appearances, physical structure are similar
• Biochemical or protein composition can vary
• When caused by a paraprotein or light chains – AL amyloid
  
  • Nephrotic syndrome
  • Cardiac failure (LVH)
  • Carpal tunnel syndrome
  • Autonomic neuropathy
  • Cutaneous infiltration

Question 21

How do we make a diagnosis of myeloma?

Answer 21

• Paraproteins are common
  
  • 3-4% of population over age of 75
  • The vast majority have nothing wrong with them
  • This is termed monoclonal gammopathy of uncertain significance (MGUS)
• Myeloma is diagnosed by finding excess plasma cells in the bone marrow
• Must comprise > 10% of total bone marrow cell population

Question 22

Which types of paraprotein are present in myeloma?

How do we stage myeloma?

Answer 22

Type of paraprotein

• IgG 55%
• IgA 21%
• Light chain only 22%
• Other (IgD, non-secretory) 2%

Stage

• Based on albumin & beta-2 microglobulin

Question 23

What are the treatment options for myeloma?

Answer 23

• Chemotherapy
  
  • Proteasome inhibitors, IMiDs, monoclonal antibodies
• Bisphosphonate therapy
  
  • Zoledronic acid
• Radiotherapy
• Steroids
• Surgery
  
  • Pinning of long bones; decompression of spinal cord
• Autologous stem cell transplant

Question 24

What about IgM paraproteins??

Answer 24

IgM paraprotein Myeloma doesn’t exist

• IgM paraproteins are associated with low-grade lymphomas (various types)
• Clinical presentation
  
  • Bone marrow failure (anaemia, thrombocytopenia)
  • Lymphadenopathy
  • Hepatosplenomegaly
  • B symptoms
  • Paraprotein-related symptoms can occur
  • Bone disease is very rare