Multiple Myeloma Flashcards
What is multiple myeloma?
cancer of plasma cells in the bone marrow (rare outside of marrow)
- disease is often patchy throughout marrow
- effects pelvis, spine, rib cage, skull, shoulders and hips
What are plasma cells?
mature B cells that produce antibodies - usually <5% in your bone marrow and throughout lymphoid tissue
What is the most frequent feature of multiple myeloma?
bone disease - substantially impairs quality of life and is a major cause of morbidity and mortality
any evidence of bone disease is an indication to start treatment
What is produced in multiple myeloma?
produce an immunoglobulin molecule (either intact immunoglobulin, or just light chain or both) in excess = myeloma protein, M-protein, paraprotein
- paraprotein is a treatment marker and need to look at levels to determine how they are responding to treatment
- it is monoclonal NOT polyclonal (single antibody = monoclonal paraprotein)
What is the epidemiology of myeloma?
10,000-15,000 its in UK
median age = 65-70 (<2% in less than 40)
higher incidence in afro-carribbean
vast majority of cases preceded by silent, asymptomatic precursor condition, MGUS (monoclonal gammopathy of undetermined significant)
How does multiple myeloma present?
CRABI
- hypercalcaemia
- renal impairment
- anaemia
- bone pain and destruction (fractures, cord compression)
- infection
Unlucky to have all of them at presentation
What are the diagnostic criteria for multiple myeloma?
M protein in serum >30g/L (high M protein)
and/or bone marrow plasma cells >10% (Excess plasma cells)
related organ damage (end organ damage, CRABI=hypercalcaemia, renal insufficiency, anaemia, bone lesions, infections)
asymptomatic multiple myeloma - no organ damage
What is MGUS?
monoclonal gammopathy of uncertain significance
benign = does not cause symptoms or damage
pre-malignant forerunner of myeloma = tiny clone of plasma cells
characteristic features:
- monoclonal protein <30g/L
- bone marrow clonal cells <10%
- no evidence of end organ damage
90% + don’t develop myeloma but 90% of myeloma have an MGUS stage
What is the difference between lytic lesions and sclerotic lesions?
Lytic lesions: spots where bone tissue has been destroyed- can take biopsies of them to help with diagnosis - myeloma is lytic because it doesn’t allow new bone formation
Sclerotic lesion: unusual hardening or thickening of bone (malignant or benign)
How does renal failure occur in multiple myeloma?
light chain deposition in renal tubules leading to cast nephropathy “myeloma” kidney
- excess of immunoglobulins can precipitate in the renal tubules and cause damage and they can also cause inflammation which is toxic to the kidney
- hypercalcaemia damages the kidneys
- increased risk of infections which can affect kidneys (disease itself and the treatments for it)
- dehydration can further aggravate the kidneys
- certain drugs aggravate it
- uric acid
- amyloid
- acute tubular necrosis can occur
What is a less common complication of multiple myeloma?
cord compression or pathological fractures
- hyper viscosity = confusion, headache, visual disturbance, bleeding, ischemic events (angina)
- amyloid= nephrotic syndrome, sensorimotor and atomic neuropathy, soft tissue involvement and cardiac involvement
What is plasmacytoma?
localized deposit of plasma cells
can be bony or in soft tissue
may be associated with a small monoclonal paraprotein
How do you treat plasmacytoma?
treat with radiotherapy
Unfortunately possibility of recurrence or multiple myeloma at a later date (usually years)- risk is greater for bone c/w soft tissue
How is multiple myeloma diagnosed?
production of a single immunoglobulin in excess - the M protein or paraprotein
- 15% just produce light chain only (kappa or lambda)
- 99% produce an M proteins
ask for immunoglobin/serum free light chain electrophoresis/measurements = detects abnormal excess of M protein
Other than diagnosis by M protein/light chains what other investigations help with the diagnosis?
Bone marrow biopsy Skeletal survey = X-ray central skeleton (chest, spine, skull, long bones) FBC Blood chemistry including calcium B2 microglobulin
How is disease response determined?
monoclonal protein spikes are monitored to show disease response
When carrying out the investigations what are you looking for?
anaemia
renal impairment - raised creatinine
total protein is often raised
hypercalcaemia - not always
other normal immunoglobulins are suppressed = immunoparaesis
albumin is often low in advanced stage myeloma
What is the staging system for myeloma?
International staging system
stage 1: beta2-M <3.5mg/L, serum albumin >35g/L = median survival - 62 months
stage 2: neither stage 1 or 3 = median survival - 44 months
stage 3: beta2-M >5.5 mg/L= median survival 29 months
replaced curie-salmon staging
What monitoring is necessary?
every time they come into clinic- monitor their M protein, FBC, biochem
M protein acts as a tumor marker measurable in g/L
Repeat X-rays/MRI if concerned about bone pain
What does it mean by multistep disease?
relapses and plateau phases - each relapse more difficult to treat = after treatment quiet periods can last for months or years
May even leave bone marrow and invade elsewhere
BUT still very heterogenous disease
What is the biology of myeloma?
cells of origin is unclear- tumor of mature plasma cells
Genetic chaos even at the earliest stages- chr show numeric and structural abnormalities
biology changes with time and tumor becomes more drug resistant
What are the various genes involved in myeloma?
cyclin D1, myeov - 15%
FGFR3, MMSET - 15%
c-maf - 5%
Cyclin D3 - 3%
mafB - 2%
promiscuous range of partner chromosomes involved - 20%
t(4;14)- often IgA - lack of bone disease, do very badly
t(11;14) - often CD20+, lymphoplasmacytoid, small paraprotein - do better
What stimulates and inhibits osteoclasts?
stimulated by osteoprotegrin ligand (OPGL) = RANKL = TRANCE stimulates osteoclasts
Osteoprotegrin (OPG) inhibits osteoclasts
Myeloma plasma cells up regulate OPGL and down regulate expression of OPG by stroll cells = increased bone resorption
What are the treatment options for myeloma?
supportive management - pain, anaemia,, infections, radiotherapy, orthopedics, anticoagulation
- induction therapy - unsuitable for a transplant
- induction therapy - prior to PBSCT (peripheral blood stem cell transplant)
- autologous PBSCT
- allogeneic transplantaion
- maintenance
- relapse
- bone disease
- renal impairment
How is emergency renal failure treated?
aim to salvage renal failure and avoid dialysis dependence
- aggressive hydration - really important for reversing renal damage
- avoid nephrotoxic drugs
- treat myeloma (dexmathasone initially)
- experimental = remove light chains - plasmapheresis, dialysis with wide pore membrane
10% of myelomas are dialysis dependent
How is hypercalcaemia >3 treated?
IV fluid replacement - ideal 3L/24 hours
then pamidronate and zoledronate IV (bisphosphonates)
usually works - if not dexamethasone
What is done if there is cord compression?
an emergency - MRI scan
- spinal surgeons needed if instability
- radiotherapy if stable
Hyper viscosity = high levels of paraprotein - need to remove protein by plasma exchange
What is done if an infection arises?
Normally bacterial - encapsulated strep pneumonia, ahem influenza, E.coli etc
10% die within a couple of months
Usually not neutropenic but still immunosuppressed
IV antibiotics promptly
Prophylaxis to reduce infection risk
What is done to treat the pain?
paracetamol, co-proxamol (codeine/paracetamol), strong opiates (fentanyl patches, MST, oramorph, tramadol)
How is anaemia treated?
erythropoietin injections is recommended but NHS can’t afford them so most places give blood transfusions
Why is radiotherapy used in the treatment?
useful to relive bony pain but takes a few weeks to have an effect
How is the bone disease treated?
analgesia
radiotherapy to defined areas
chemotherapy = interferes with mitosis usually impairing DNA polymerization and effects all dividing cells
orthopedic surgery for fractures and potential fracture sites
physiotherapy
all patients should be on bisphosphonates - reduces risk of fractures
What are the side effects of chemotherapy?
myelosuppresion, hair loss, mucositis, sub fertility, fatigue
Is it beneficial to treat asymptomatic patients?
do not benefit from early interventions
What is the likelihood of thrombotic complications?
background risk of 5-10% (central venous catheters, immobility)
10-15% with thalidomide + dec and lenalidomide + dec
15-20% with MPT and >30% with thalidomide and anthracycline
risk is higher in first year
Tx
- high dose warfarin is effective + aspirin
What different induction treatments are there if the patient is unsuitable for transplant?
melphalan + prednisolone
melphalan + prednisolone + thalidomide
cyclophosphamide + thalidomide + dexamethasone
VMP - bortexomib + melphalan + prednisolone
thalidomide + dexamethasone
lenalidomide + dexamethasone
cyclophosphamide weekly
combination therapy is supported
What are some other expensive anti-myeloma drugs?
ixazomib = oral once weekly - protease inhibitor carflizomob = IV - protease inhibitor pomalidomide = immunomodulatory drugs monoclonal antibodies - daratumumab - anti-CD38 - elotuzumab - anti cs1 HDAC inhibitor - panobinostat
