Clinical Workshop- MYELOMA Haematology Flashcards
What is the referral guideline for myeloma and when what symptoms are seen?
2 weeks
Symptoms: bone pain anaemia raised ESR and plasma viscosity x-rays suggestive of myeloma showing lytic lesions
If someone comes in with 3 month back pain, signs of anaemia, what would you ask?
nature of pain what makes pain worse neurological symptoms? history of infections? blood tests? imaging?
What kind of neulogical symptoms could arise?
over 50% patients with myeloma have myeloma affecting the spine
space for the spinal cord behind the vertebral body is small and limited
any size tumour can put pressure on spinal corde or nerve roots coming out- this is emergency
so we need to know it problem passing urine, or opening their bowel, if they have any numbness or pain in the body, or pain or numbness in the legs or arms
What is myeloma?
malignancy of plasma cells, which are important to make antibodies- need for immune response
so in myeloma you keep getting many infections
What are constitutional symptoms?
symptoms affecting different systems of the body
What is the incidence of Monoclonal Gammopathy of Undetermined Significance (MGUS)?
1% of population over 50
increase by 1% every decade
3% of people in 80s
What happens in Monoclonal Gammopathy of Undetermined Significance (MGUS)?
small clone of plasma cells produce paraprotein (monoclonal M protein)
What should be the value of monoclonal M protein and Plasma cells?
MGUS:
the M protein is never greater than 30g/l
a bone marrow investigation will show a small clone of plasma cells in the bone marrow, but it will never be greater than 10%
What is relation between MGUS and myeloma?
closely linked
if you have MGUS, might get lymphoma and myeloma
a risk score can be made with chance of getting lymphoma or myeloma in next 20 years but it is not accurate
What can myeloma be?
symptomatic or asymptomatic depending on organ and tissue impairment
How do you differentiate between MGUS and myeloma?
MGUS: M protein levels less than 30g/l clonal plasma cells less than 10% no evidence of B cell proliferative disease no related organ or tissue impairment
MYELOMA:
M protein (paraprotein) levels more than 30g/l
AND/OR
clonal plasma cells in bone marrow are more than 10%
AND
no related organ or tissue impairment
OR
M protein in serum and urine AND
biopsy proven plasmacytoma (a tumour purely made up of plasma cells) AND
myeloma related end organ impairment
(SYMPTOMATIC)
What end organ impairments can you have?
C Hypercalcaemia
R Renal impairment
A Anaemia
B Bone lesions
What emergencies are associated with myeloma?
hyper viscosity hypercalcaemia infection pathological fractures spinal cord compression renal failure
Why do you get hyperviscosity in myeloma?
plasma cells producing high levels of paraprotien in the blood (80g protein)
What problems does hyperviscosity lead to?
breathing trouble, headaches, visual disturbance, neurological disturbance, vascular problems e.g. MI
Why do you get hypercalcaemia in myeloma?
myeloma causes bone damage
calcium leaks from blood
calcium levels go up
What are the symptoms of hypercalcaemia?
abdominal pain
confusion
hard to open bowel
constipation
In myeloma, where are lytic lesions common?
skull
spine
pelvis
long bones
it is common here because they are areas of active bone marrow
Why is myeloma always found in the bone marrow?
bc plasma cells after proliferating and maturing settle down in the bone marrow
What are used to diagnose bone disease from myeloma?
used to be X ray
now low Dose CT, PET, MRI
bc X ray insensitive and dont pick up 30-40% of people with bone disease
What is seen in a normal spine X ray?
posterior spine
the spine = symmetrical
two little eyes on either side of the vertebrae which arethe pedicles
the spinous process should be central
the transverse process should be visible on either side
the vertebral body should be fairly uniform with a crisp outline
lateral view−the height of the vertebral body should be nicely maintained
pedicles, transverse processes, and spinous processes should be fairly visible
What is seen in a lateral view of a spine xray of someone who has bone disease?
= hard to see X ray bc all bones are osteopenic (similar pic to person with osteoporosis)
= bone density is LESS THAN NORMAL
= lots of the lower vertebrae are of normal height, but as you go higher there is a vertebra with high bone density and low height= BC compression fracture of vertebrae
- there is sclerosis (replacement of bone with connective tissue) and break down of the bone
What is seen in the skull of a patient with bone disease?
‘pepper-pot skull’= where the patient has got multiple lytic lesions within the skull
most patients are asymptomatic from this as there is no pressure put on the skull on a day to day bases
the only time you will pickup myeloma in the skull will be when one of the plasmacytomas in the skull is pressing on nerve roots
there are patients with unilateral deafness, 6thnerve palsies, and other isolated cranial nerve palsies
What happens if the lesion if very large in a bone?
comprises cortex of the bone
patient can have fracture with very simple activity (like changing car gears, taking out the bins)
sometimes can pick this up before acc fracture and put pins in bone (prophylactic) to prevent the fracture occuring
Why is MRI useful?
MRIs are often used to look at the sternum and spine for people with myeloma
this is because MRIs can be used to look at changes in the cellular content of the bone marrow (cellular content increases during myeloma)
T1 images have reduced signal, and T2 & STIR images have an increased signal
Why do you get pain in bone disease?
due to how big the tumour is•due to lytic lesions in the bone•due to pathological fractures•due tonerve root compression•due to spinal cord compression
In myeloma, which 2 cells are really close together?
myeloma cells and bone marrow stromal cells
Why do the myeloma cells and bone marrow stromal cells need eachother?
myeloma cells need the bone marrow stromal cells to nourish them, and cytokines are constantly released between myeloma cells and stromal cells to keep the viability of the cells
What is RANK ligand involved in in normal bones?
in normal bone marrow, RANK ligand is involved in proliferation of osteoclasts which would lead to resorption of bone minerals −there isa protein called osteoprotegrin (OPG) normally keeps the regulation of the amount of RANK ligand in the bone marrow constant such that there are normal levels of osteoblast and osteoclasts
What does the protein osteoprotegrin (OPG) do?
osteoprotegrin (OPG) normally keeps the regulation of the amount of RANK ligand in the bone marrow constant such that there are normal levels of osteoblast and osteoclasts
What do myeloma cells do?
upregulate the RANK ligand
What do the stromal cells do?
downregulate osteoprotegrin
Overall what happens bc of myeloma?
myeloma cells= UPREGULATE RANK
stromal cells= DOWNREGULATE OSTEOROTEGRIN
overall= RANK PATHWAY UPREGULATED
=production of osteoclasts, and there is thus an imbalance between osteoclasts and osteoblasts
= SO NET BREAKDOWN OF BONES BC OSTEOCLASTS BREAK BONES
How do we treat myeloma?
target RANK ligand
RANK ligand inhibitors would directly down regulate the amountof activity of osteoclast and thus lead to a reduction in bone resorption−an example of this which is in phase III trials right now is denosumab
the current treatment is BISPHOSPHONATES
What is the advantage of denosumab over bisphosphonates (current treatment)?
denosumab has over bisphosphonates is that denosumab can be given to people with renal disease/failure whilst bisphosphonates cannot be given
What does bisphosphonate do?
inhibit osteoclastic resorption of bone, and have been shown to reduce the number of bony fractures and progression of bone disease
Where can bone marrow samples be taken from?
posterior iliac crest (most common- easy access)
anterior iliac crest (less common- not easy access)
sternum (least common- his is used least commonly because there is a possibility that the needle can slip and could damage structures close by like the lungs and nerve)
What are the 2 samples of bone marrow?
aspirate- using needle to get cells of bone marrow
trephine- take 1-2cm bone marrow core out of bone
During myeloma, looking down the slide of a bone marrow aspirate, what do you see in a normal cell?
eccentric nucleus ie the nucleus will not be in the centre
blue-ish cytoplasm
area of pallor next to the nucleus called the Hoff’s sign
the nucleus looks like a clock face
During myeloma, looking down the slide of a bone marrow aspirate, what do you see in an abnormalcell?
more than one nucleus
there will be inclusions in the cytoplasm or nucleus which contain Igs
a cell containing many many inclusiosn is called a Mott cell
Why do we do a blood test?
to see if patient has normal blood count
Why is blood count affected in myeloma?
blood count is affected, as myeloma cells take over a lot of space in the bone marrow, leading to significant reduction in the space available to produce normal blood cells (including platelets, Hb, and white cells)
Patients with myeloma usually present with what?
anaemia (of chronic disease)
normochromic normocytic anaemia
What happens to ESR in myeloma?
raised ESR
What is ESR?
the ESR is basically the rate at which the blood cells settle in a test tube•this will obviously depend on the plasma content of the blood•ie if there is a lot of protein in the plasma, the rate at which red cells will settle will be reduced
Other than in myeloma, where else can you see raised ESR?
In patients with inflammatory arthritis
What conditions can raise the ESR to over 100?
there are very few conditions that increase the ESR to over 100-tuberculosis, myeloma and rheumatoid conditions
What is the new staging system of myeloma called?
International prognostic index
What is the international prognostic index based on?
- beta 2microglobulin (which is part of the MHC II molecule) and is secreted by B cells and B cell tumors and is directly proportional to tumour volume
- serum albumin (patients with myeloma have low serum albumin)
- cytogenetics−there are particular cytogenetic abnormalities that confer a bad risk
= eg the tp53 mutation (patients with this have a very low prognosis)
= eg abnormalities affecting chromosome 14 at the heavy chain locus which also lead to a low prognosis
How do bisphosphonates work?
Bisphosphonates work by having a high affinity to bone, once absorbed into the circulation they are rapidly absorbed into bone and ingested by osteoclasts.
There are two different classes of osteoclast and they work in different ways:
Non-nitrogen containing (e.g. clondronate) are metabolised by the osteoclast and disrupt the cell metabolism leading to apoptosis Nitrogen containing (e.g. aminobisphosphonates, pamidronate and zoledronic acid) these induce apoptosis and inhibit osteoclastic function by disrupting signalling of regulatory proteins in the osteoclast.
A number of bisphosphonates are currently licensed for the treatment of myeloma in the UK:
Clondronate – orally (daily)
Pamidronate – IV (monthly)
Zolendronic acid (zometa) – IV (monthly)
IV bisphosphonates are far more potent than oral bisphosphonates.
Pamidronate is 10x more potent than clondronate
Zometa is 1,000x more potent than clodronate
