Multiple Myeloma

Question 1

What is multiple myeloma?

Answer 1

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

Question 2

What are plasma cells?

Answer 2

mature B cells that produce antibodies - usually <5% in your bone marrow and throughout lymphoid tissue

Question 3

What is the most frequent feature of multiple myeloma?

Answer 3

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

Question 4

What is produced in multiple myeloma?

Answer 4

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)

Question 5

What is the epidemiology of myeloma?

Answer 5

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)

Question 6

How does multiple myeloma present?

Answer 6

CRABI

• hypercalcaemia
• renal impairment
• anaemia
• bone pain and destruction (fractures, cord compression)
• infection

Unlucky to have all of them at presentation

Question 7

What are the diagnostic criteria for multiple myeloma?

Answer 7

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

Question 8

What is MGUS?

Answer 8

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

Question 9

What is the difference between lytic lesions and sclerotic lesions?

Answer 9

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)

Question 10

How does renal failure occur in multiple myeloma?

Answer 10

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

Question 11

What is a less common complication of multiple myeloma?

Answer 11

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

Question 12

What is plasmacytoma?

Answer 12

localized deposit of plasma cells
can be bony or in soft tissue
may be associated with a small monoclonal paraprotein

Question 13

How do you treat plasmacytoma?

Answer 13

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

Question 14

How is multiple myeloma diagnosed?

Answer 14

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

Question 15

Other than diagnosis by M protein/light chains what other investigations help with the diagnosis?

Answer 15

Bone marrow biopsy
Skeletal survey = X-ray central skeleton (chest, spine, skull, long bones)
FBC
Blood chemistry including calcium 
B2 microglobulin

Question 16

How is disease response determined?

Answer 16

monoclonal protein spikes are monitored to show disease response

Question 17

When carrying out the investigations what are you looking for?

Answer 17

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

Question 18

What is the staging system for myeloma?

Answer 18

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

Question 19

What monitoring is necessary?

Answer 19

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

Question 20

What does it mean by multistep disease?

Answer 20

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

Question 21

What is the biology of myeloma?

Answer 21

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

Question 22

What are the various genes involved in myeloma?

Answer 22

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

Question 23

What stimulates and inhibits osteoclasts?

Answer 23

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

Question 24

What are the treatment options for myeloma?

Answer 24

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

Question 25

How is emergency renal failure treated?

Answer 25

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

Question 26

How is hypercalcaemia >3 treated?

Answer 26

IV fluid replacement - ideal 3L/24 hours
then pamidronate and zoledronate IV (bisphosphonates)
usually works - if not dexamethasone

Question 27

What is done if there is cord compression?

Answer 27

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

Question 28

What is done if an infection arises?

Answer 28

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

Question 29

What is done to treat the pain?

Answer 29

paracetamol, co-proxamol (codeine/paracetamol), strong opiates (fentanyl patches, MST, oramorph, tramadol)

Question 30

How is anaemia treated?

Answer 30

erythropoietin injections is recommended but NHS can’t afford them so most places give blood transfusions

Question 31

Why is radiotherapy used in the treatment?

Answer 31

useful to relive bony pain but takes a few weeks to have an effect

Question 32

How is the bone disease treated?

Answer 32

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

Question 33

What are the side effects of chemotherapy?

Answer 33

myelosuppresion, hair loss, mucositis, sub fertility, fatigue

Question 34

Is it beneficial to treat asymptomatic patients?

Answer 34

do not benefit from early interventions

Question 35

What is the likelihood of thrombotic complications?

Answer 35

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

Question 36

What different induction treatments are there if the patient is unsuitable for transplant?

Answer 36

melphalan + prednisolone
melphalan + prednisolone + thalidomide
cyclophosphamide + thalidomide + dexamethasone
VMP - bortexomib + melphalan + prednisolone
thalidomide + dexamethasone
lenalidomide + dexamethasone
cyclophosphamide weekly

combination therapy is supported

Question 37

What are some other expensive anti-myeloma drugs?

Answer 37

ixazomib = oral once weekly - protease inhibitor 
carflizomob = IV - protease inhibitor 
pomalidomide = immunomodulatory drugs 
monoclonal antibodies 
- daratumumab - anti-CD38
- elotuzumab - anti cs1 
HDAC inhibitor - panobinostat