Immunoproliferative Disorders: Monoclonal Gammopathies Flashcards
Gammopathy
disorder of gamma globulins (antibodies)
what do monoclonal gammopathies result from
a single clone of plasma cells producing high levels of a single class and type of antibody, referred to as monoclonal protein, M protein or Paraprotein
ONLY plasma cells
2 e.gs of monoclonal gammopathies
multiple myeloma
Waldenstrom primary macroglobulinaemia
Polyclonal gammopathy
secondary disease with increased levels of 2 or more antibodies, produced by several clones of plasma cells
what are immunoglobulins synthesised and secreted by in bone marrow and lymph nodes
plasma cells
what are plasma cells the final stage of maturation of
B lymphocytes
what are immunogloublins made of
2 identical heavy chains and 2 identical light chains
What happens to the excess light chains which enter the kidneys and pass through the glomerulus and into the proximal tubule
they are reabsorbed and degraded into smaller peptides which are then recycled because of their low molecular weight
what are light chain levels seen in urine in monoclonal gammopathies like and why
high as the capacity of the proximal tubule can be overwhelmed
why is the amount of plasma cells produced regulated by homeostasis
so that the required amount of antibody to deal with an infection is produced
what allows plasma cells to overcome growth restraints
Chromosome abnormalities
some subdivisions of Monoclonal gammopathies
Monoclonal gammopathy of undetermined significance (MGUS)
myeloma (AKA multiple myeloma)
Waldenstrom primary macroglobulinaemia
Light-chain disease
Heavy-chain disease
what are tumours derived from mature naïve B cells are found in
lymph node follicles (forming follicular centre cell lymphoma)
where are plasma cell tumours (myelomas) found
bone marrow
what is the commonest subtype of monoclonal gammopathy
Monoclonal gammopathy of undetermined significance (MGUS)
where are less than 10% plasma cells in MGUS
in the bone marrow
what does MGUS incidence increase with
age (1% in >50s, 10% in>80s)
what do 1% of MGUS tranform into
the malignant form of MG (multiple myeloma)
what is multiple myeloma the cancer of
bone marrow
what do multiple myeloma patients have in their bones
lytic bone lesions
where is there a monoclonal immunoglobulin build up in multiple myeloma
serum and/or urine
clinical features of multiple myeloma
bone pain
anaemia
infections (defects in humoral not cell immunity)
renal failure
proteinuria in 50% of patients excreting abnormal amounts of Bence Jones proteins (light chains)
hyperviscosity syndrome
3 lab features of multiple myeloma
electrophoresis of serum or urine shows a monoclonal protein in 90% of patients
increased serum calcium
low haemoglobin
raised mean cell volume (MCV)
increased erythrocyte sedimentation rate
multiple myeloma incidence
Incidence is ~5-7 per 100,000
what ages is MM very rare in
<40 years
what is MM thought to possibly result from excess production of
interleukin (IL) -6
antibody produced in multiple myeloma
Paraprotein or M protein
2 most common protein types secreted in MM
IgG (60%)
IgA (>20%)
nonsecretory myeloma
myeloma where cancer cells either don’t make or don’t release antibodies
what do all secretory myelomas produce excess of
free light chains
if levels of free light chains are too high in MM what can result
Proteinuria
what can the presenting symptom of MM be
renal failure
what is immunoglobulin in light chain myeloma like
Immune paresis - suppression of normal immunoglobulin production by a malignant plasma clone
what is bone breakdown due to in MM
breakdown of the homeostatic control of bone remodelling by osteoclasts and osteoblasts
what do osteoclasts do in MM as they’re upregulated
dissolve bone
what causes the osteolytic lesions
plasma cells proliferating in bone, forming areas which are replaced by a circular clone of plasma cells
how does MM appear on X-rays
decreased bone density with a lot of “punched out” holes in the bone
no white rim of bone
plasmacytoma
early, isolated form of multiple myeloma (one lesion found)
what do plasma cells release in MM which acts as Osteoclast activating factor and may be responsible for the lytic lesions and osteoporosis
IL-6
MM diagnostics criteria
Paraprotein in serum and/or urine
> 20% abnormal plasma cells in bone marrow or monoclonality of plasma cells (>12% with one light chain type)
Osteolytic bone lesions
2 clinical findings of MM due to decreased production of normal blood cells due to infiltration of bone marrow
Anaemia-fatigue, lethargy, dyspnoea (shortness of breath)
Thrombocytopenia-increased bleeding
Leukopenia-increased infection rate
2 clinical findings of MM due to the bone lesions:
Bone pain, fractures, vertebral collapse
Hypercalcaemia (lots of calcium from bone loss)
Osteoporosis
what do high concentrations of Ig in serum in MM cause, which can cause platelet abnormalities
serum hyperviscosity (increased thickness from increased protein concentration)
what can you see from a complete blood count for MM diagnosis
Anaemia
Thrombocytopenia
Increased erythrocyte sedimentation rate (ESR)
what is seen in Peripheral blood films if its MM
Rouleaux formation (red cells stacking)
Sometimes low numbers of neoplastic plasma cells
what cells are seen abnormal and larger in MM bone marrow biopsies
plasma cells
Why do MM patients have very high serum Ig levels, but decreased values of other immunoglobulins
Plasma cells are involved in the production of Ab and MM is due to uncontrolled proliferation of plasma cells
how are Immunoglobulin concentrations measured for MM diagnosis
turbidimetry (how cloudy)
nephelometry (detection of light energy scattered or reflected toward detector)
radial immunodiffusion (circular ring formation on agar) - usually IgD as not much of it
why do all patients with suspected multiple myeloma require a 24-hour urinalysis by protein electrophoresis
to determine the presence of Bence Jones proteinuria and kappa or lambda light chains.
what is serum analysis for the myeloma protein performed by to diagnose MM
serum protein electrophoresis and immunofixation electrophoresis
serum protein electrophoresis process
A small amount of serum is loaded at one end of the agarose gel.
An electric current is applied to the buffer (ph 8.6), and the current moves through the gel.
As the current moves through the gel, it brings negatively charged proteins with it. Albumin moves the quickest towards the anode, then alpha-1 globulins, then alpha-2 globulins, beta globulins and finally the gamma globulins. The movement of each molecule depends upon charge, size, and shape
The current is then switched off, and the gels are fixed and stained to make the proteins visible.
The gels are then analysed by passing light through. The amount of light that is absorbed by the protein bands appears as peaks on the trace.
what do serum protein electrophoresis patterns produced by tumour cells in MM show
a sharp peak
Immunofixation electrophoresis
is serum protein electrophoresis of serum (6 replicates)
Incubation of antiserum to IgG, IgA, IgM, kappa light chains, lambda light chains/lane (6th lane is control)
The reaction of antiserum to the Ig in the patient’s serum forms an immunoprecipitation reaction, fixes it in gel
Gels rinsed to remove unprecipitated proteins
Gels are stained to visualise precipitated proteins
what are the immunofixation electrophoresis results in myeloma
sharp dark bands in either IgG or IgA heavy chains and 1 light chain (kappa or lambda)
what are the immunofixation electrophoresis results in macroglobulinemia
strong band in IgM lane and 1 of light chains.
what biochemical markers show as increased in MM
urea,
creatinine (shows kidney dysfunction)
uric acid
Calcium
2 serum levels that can be used to stage a patient with MM
C-reactive protein and Beta 2 microglobulin
whats the standard MM treatment which has poor complete remission rates (5%)
melphalan (chemo) and prednisone
what completes remission rates of 40% and an overall survival 5 years (MM treatment)
Intensive chemotherapy and stem cell transplantation
what does radiation therapy aim to do in MM treatment
reduce tumour cell growth in areas with bone pain.
why is plasmapharesis done to treat MM
to remove Ig and try to reduce the rate of renal failure
3 NICE treatment approvals for MM since 2021
April 2021: carfilzomib (Kyprolis) with dexamethasone and lenalidomide (Revlimid) for previously treated multiple myeloma in adults
April 2022: daratumumab (Darzalex) for relapsed and refractory multiple myeloma in adults
February 2023: Ixazomib (Stivarga) with lenalidomide and dexamethasone for relapsed or refractory multiple myeloma.
Daratumumab
anti-cancer monoclonal antibody medication. It binds to CD38, which is overexpressed in multiple myeloma cells
results in tumour cell death by immune-mediated actions and apoptosis.
Elotuzumab
first monoclonal antibody approved to treat multiple myeloma.
targets SLAMF7 protein and therefore activates natural killer cells
It is given intravenously
immune paresis in MM treatments
Red cell transfusion
Antibiotics
Bisphosphonates
