Myeloma and paraprotein

Question 1

Myeloma pathogenesis

Answer 1

Plasma cells move back into the bone marrow commonly

Question 2

What is a paraprotein?

Answer 2

A paraprotein is an abnormal protein that is produced by plasma cells in the bone marrow.

They are made from monoclonal proliferation and all subsequent antibodies derived this way trace back to a unique parent cell (b-cell/plasma cell) somewhere in the body.

So basically myeloma is characterised by paraproteins which are populations of abnormal antibodies (paraproteins - produced by plasma cells) that have udnergone monoclonal proliferation so that there are lots of identical copies in the body.

Question 3

Which cells produce immunoglobulins?

Answer 3

B-cells, mostly plasma cells specifically

The majority of immunoglobulin is bound to the B-cell surface but a significant proportion is released into the ECF of the blood and this is what can be measured.

Question 4

What is the primary role of immunoglobulins?

Answer 4

Primary role is to recognise and bind pathogens to fight infection

They may directly impede the biological process or direct other components of the immune system by “tagging” the antigen

Question 5

Describe the structure of an antibody/immunoglobulin

Answer 5

Basic Y-shaped structure

• 2 heavy chains - Fc region - constant (the same in each antibody) - determines subclass
• 2 light chains - Fab region - variable (this bit changes) this part determines antigen binding and varies massively

Question 6

What are the 5 types of heavy chain (these determine the 5 subclasses of immunoglobulins)?

Answer 6

• Gamma – IgG - most prevalent antibody subclass (75% of total)
• Alpha – IgA - mucous membrane immunity so commonly found in the gut
• Mu – IgM - initial phase of antibody production, exists as a pentamer (highest weight)
• Delta – IgD - present in smaller quantities
• Epsilon - IgE - present in smaller quantities - parasite immune responses - determines allergic hypersensitivity/atopic responses

Question 7

Light chains can be 1 of 2 things?

Answer 7

Kappa or lambda

This is randomly selected by the B cell but should be about 50/50 in total

Question 8

So if you have a sample full of immunoglobulins that all look relatively the same, how can you tell if there’s something wrong/abnormal going on?

Answer 8

• You can identify the subclass by the Fc portion and measure the quantity of each subtype = total immunoglobulin levels test
• Now have lots of different antibodies – different sizes and shape - you can use lab tests to determine between them
• You can also have populations of antibody that are identical in their Fc and Fab region => paraprotein

Question 9

Which lab test can be used to assess antibody diveristy and identify paraproteins?

Answer 9

Serum protein electropheresis - separates protein based on their size and charge

Forms a characteristic pattern of bands of different widths and intensities based on proteins present. See image - unique population of immunoglobulins is present in large quanitity and has been identified

Question 10

Which test can be used to identify what class of paraprotein is present? i.e IgG or IgM

Answer 10

Immunofixation

Question 11

If you have a massive imbalance or excess of one antibody over another somwhere in the body what can you test?

Answer 11

Light chain test to see if there is imbalance/excess of light chains in the urin or serum - however this test isn’t really done anymore

Question 12

IgM paraproteins are commonly seen in which disease?

Answer 12

Lymphoma

• Maturing B-cells make IgM antibodies at the start of the immune response

Question 13

IgG and IgA paraproteins are seen in which disease?

Answer 13

Myeloma

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

Question 14

What is Myeloma?

Answer 14

• A neoplastic disorder of plasma cells
• Usually results in excessive production of a single type of immunoglobulin (paraprotein)
• Peaks in 70s
• Clinical manifestations may result from direct effect of plasma cells, or effect of paraprotein

Question 15

Clinical features of Myeloma

Answer 15

• Bone disease - widespread due to clonal proliferation in bone marrow.
  
  • ​Lytic bone disease
  • Pathological fractures
  • Cord compression
  • Back pain
  • Hypercalcaemia - release of Ca2+ as a result of damaged bone due to lytic bone disease
• Bone marrow failure - growth of plasma cells into bone marrow esp. anaemia
• Infection due to bone marrow failure (lower WCC) or through effect of paraprotein drowning out normal immunoglobulins

Question 16

What is the acronym used to remember the features of Myeloma?

Answer 16

CRAB

• Hypercalcaemia
• Renal failure
• Anaemia
• Bone disease

Question 17

What effects can paraproteins have on the body? (4)

Answer 17

• Renal failure – cast nephropathy - Immunoglobulin deposition and blockage of renal tubules
• Hyperviscosity – pretty rare but more common with IgM due to higher weight - increased viscosity in blood, impaired microcirculation and hypoperfusion
• Hypogammaglobulinaemia - Impaired production of normal Immunoglobulin and tendency to infection
• Amyloidosis

Question 18

What is Amyloidosis?

Answer 18

• A group of diseases characterised by deposition of fibrillar protein.
• When caused by a paraprotein or light chain = Amyloid light-chain (AL) amyloidosis
• Can cause:
  
  • Nephrotic syndrome
  • Cardiac failure (LVH)
  • Autonomic neuropathy
  • Carpal tunnel syndrome
  • Cutaneous infiltration

Question 19

How is myeloma diagnosed?

Answer 19

Myeloma is diagnosed by finding excess plasma cells in the bone marrow. Plasma cells must comprise > 10% of total bone marrow cell population.

Remember though that the levels of paraproteins go up as a normal variant as you age, so you can find them in healthy patients. This is known as monoclonal gammopathy of uncertain significance (MGUS).

• Monoclonal gammopathy = paraprotein
• Uncertain significance = not doing anything harmful

Paraproteins are produced by these abnormal plasma cells. So, if you have 9% you have MGUS and if you have 11% you have myeloma.

Question 20

How is Myeloma treated?

Answer 20

• Chemotherapy - Proteasome inhibitors (carfilzomib, bortezomib), IMiDs (lenalidomide, pomalidomide), monoclonal antibodies
• Bisphosphonate therapy – strengthen bone – inhibit osteoclasts - zoledronic acid
• Radiotherapy – effective for localised pain control
• Steroids – myeloma is v sensitive to steroids
• Surgery - Pinning of long bones (pathological fracture); decompression of spinal cord
• Autologous stem cell transplant – younger patients

Question 21

IgM paraproteins

Answer 21

IgM myeloma is so rare it is said to not exist!

IgM paraproteins are associated with low-grade lymphomas (various types)

Question 22

Which types of paraprotein are most common?

Answer 22

IgG paraprotein 55%

IgA paraprotein 21%

Light chain only 22%