Myeloma and Paraproteins Flashcards
Describe the basic immunoglobulin structure?
- Y shaped
- 2 heavy chains
- 2 light chains
What are the 2 regions of an immunoglobulin?
- Variable domains, also called Fab region
- Formed from heavy and light chain
- Defines target binding
- Fc portion
- Formed from only heavy chain
- Defines subclass of antibody
What is the variable domain also called?
Fab region
What is the variable domain formed from?
- Formed from heavy and light chain
What does the variable domain define?
- Defines target binding
What is the Fc portion formed from?
- Formed from only heavy chain
What does the Fc portion define?
- Defines subclass of antibody
What are the 5 types of heavy chains?
- Gamma IgG
- Most prevalent subclass (75%)
- Alpha IgA
- Mucous membrane immunity
- Mu IgM
- Initial phase of antibody production
- Exists as pentamer
- Delta IgD
- Epsilon IgE
- Parasite immune responses, hypersensitivity
What is the most prevalent subclass of heavy chain?
- Gamma IgG
- Most prevalent subclass (75%)
What is each of the 5 heavy chains for?
- Gamma IgG
- Most prevalent subclass (75%)
- Alpha IgA
- Mucous membrane immunity
- Mu IgM
- Initial phase of antibody production
- Exists as pentamer
- Delta IgD
- Epsilon IgE
- Parasite immune responses, hypersensitivity
Which heavy chain exists as a pentamer?
- Mu IgM
- Initial phase of antibody production
- Exists as pentamer
What are the 2 types of light chain?
- Kappa
- Lamba
How is the light chain of a Ig selected?
Which light chain cell has is selected randomly, with each cell only making 1 type of light chain with 1 specificity
What are the normal levels of:
- IgG
- IgA
- IgM
- IgD
- IgE
- IgG
- 6-15g/L
- IgA
- 1-4.5g/L
- IgM
- 0.5-2g/L
- IgD and IgE only present in small levels
What is a paraprotein?
Paraprotein = monoclonal immunoglobulin present in blood or urine
What does the presence of a paraprotein tell us?
If present, tells us there is monoclonal proliferation of a B lymphocyte/plasma cell somewhere in body
What investigation detects paraproteins?
This can be detected by serum protein electrophoresis:
- Separates protein based on size and charge
- Forms characteristic pattern of bands of different widths and intensities based on what proteins present
- Gamma region is for immunoglobulins
What is protein electrophoresis?
- Separates protein based on size and charge
- Forms characteristic pattern of bands of different widths and intensities based on what proteins present
- Gamma region is for immunoglobulins
What region on protein electrophoresis is for immunoglobulins?
Gamma region
What are investigation options to investigate paraproteins?
- 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 (such as IgG or IgM)
- Light chains
- Assesses imbalance/excess of light chains in urine or serum
What does total immunoglobulin levels tell us?
- Measures Ig subclasses by heavy chain/Fc section
What does electrophoresis tell us?
- Assesses antibody diversity, identifies paraprotein
What does immunofixation tell us?
- Identifies what class of paraprotein is present (such as IgG or IgM)
What does light chains investigation tell us?
- Assesses imbalance/excess of light chains in urine or serum
What are: IgM, IgG and IgA paraproteins associated with?
- IgM paraproteins associated with lymphoma
- Maturing B cells make IgM antibody at start of immune response
- IgG, IgA paraproteins associated with myeloma
- Mature plasma cells generate these types of Ig after isotype switching
What is myeloma?
Neoplastic disorder of plasma cells, resulting in excessive production of single type of immunoglobulin (paraprotein)
Describe the epidemiology of myeloma?
(age, ethnicity)
- Peaks in 7th decade
- Ethnicity – commoner in black people than white
Describe the clinical features of myeloma?
- Bone disease
- Lytic bone lesions
- Pathological fractures
- Cord compression
- Hypercalcaemia
- Bone marrow failure
- Especially anaemia
- Infections
- For presentation remember CARB
- Hypercalcaemia, renal failure, anaemia, bone disease
What are symptoms/signs of bone disease?
- Lytic bone lesions
- Pathological fractures
- Cord compression
- Hypercalcaemia
What pneumonic should be remembered for the presentation of myeloma?
- For presentation remember CARB
- Hypercalcaemia, renal failure, anaemia, bone disease
Describe the clinical features of myeloma due to the paraproteins?
- Renal failure
- Immunoglobulin deposition and blockage or renal tubules
- Hyperviscocity
- Syndromes caused by increased viscosity in blood, impaired microcirculation and hypoperfusion
- Commonest feature is bleeding – retinal, oral, nasal, cutaneous
- Can also cause cardiac failure
- Hypogammaglobulinaemia
- Impaired production of normal immunoglobulin
- Tendency to infection
- Amyloidosis
- Group of diseases characterised by deposition of fibrillary protein
- Called AL amyloid when caused by paraprotein or light chains
- Symptoms (depends on where amyloid forms) – nephrotic syndrome, cardiac failure (LVH), carpal tunnel syndrome, autonomic neuropathy, cutaneous infiltration
What is amyloidosis?
- Group of diseases characterised by deposition of fibrillary protein
- Called AL amyloid when caused by paraprotein or light chains
Describe clinical features of amyloidosis?
- Symptoms (depends on where amyloid forms) – nephrotic syndrome, cardiac failure (LVH), carpal tunnel syndrome, autonomic neuropathy, cutaneous infiltration
What is amyloidosis called when caused by paraproteins or light chains?
- Called AL amyloid when caused by paraprotein or light chains
What is hypogammaglobulinaemia?
- Impaired production of normal immunoglobulin
What is a complication of hypogammaglobulinaemia?
- Tendency to infection
Do paraproteins always indicate pathology?
Some of population (3-4% of over 75s) have paraproteins, there is nothing wrong with them and is termed monoclonal gammopathy of uncertain significance (MGUS)
What does MGUS stand for?
Monoclonal gammapathy of uncertain significance
How is myeloma diagnosed?
- Diagnosed by finding excess plasma cells in the bone marrow
- Must comprise >10% of total bone marrow cell population
What % of total bone marrow cell population must be plasma cells to be myeloma?
- Diagnosed by finding excess plasma cells in the bone marrow
- Must comprise >10% of total bone marrow cell population
What are the most common kinds of paraproteins responsible for myeloma?
- IgG 55%
- IgA 21%
- Light chain only 22%
- Often not detected with electrophoresis as looks for heavy and light chains
- Other (IgD, non-secretory) 2%
What is staging of myeloma based on?
- Based on albumin and beta-2 microglobulin
Describe the treatment for myeloma?
- Chemotherapy
- Proteasome inhibitors
- Drugs – Carfilzomib, Bortezomib
- IMiDs
- Drugs – Lenalidomide, Pomalidomide
- Monoclonal antibodies
- Proteasome inhibitors
- Bisphosphonate therapy
- Drug – Zoledronic acid
- Effect – prevents bone breakdown
- Radiotherapy
- For localised symptom control
- Steroids
- Surgery
- Pinning of long bones
- Decompression of spinal cord
- Autologous stem cell transplant
What chemotherapy drugs are used for myeloma?
- Proteasome inhibitors
- Drugs – Carfilzomib, Bortezomib
- IMiDs
- Drugs – Lenalidomide, Pomalidomide
- Monoclonal antibodies
For biphosphonate therapy:
- drug
- effect
- Drug – Zoledronic acid
- Effect – prevents bone breakdown
What is IgM myeloma?
Remember IgM myeloma does not exist
What are IgM paraproteins associated with?
Associated with low-grade lymphomas
Describe the presentation of IgM paraproteins?
- Bone marrow failure
- Anaemia, thrombocytopenia
- Lymphadenopathy
- Hepatosplenomegaly
- B symptoms
- Paraprotein related symptoms can occur
- Bone disease very rare
