Pain and myeloma Flashcards
How do the morphology of normal plasma cells differ from neoplastic plasma cells?
normal: mononucleated
neoplastic: multi-nucleated, with many granules present (which would contain high amounts of light chain paraprotein)
What is MGUS?
= monoclonal gammopathy of unknown source
All myeloma patients have MGUS
But not all MGUS will be myeloma
MGUS is not itself defined as a malignancy
leads to increased infectious risk, osteoporosis.
Why is myeloma a complex illness?
- heterogenous disease
- broad clinical spectrum
- includes progression through multiple clinical stages
- Can present at any age: most commonly around 70yo, but 25% of patients are <60yo
- most myelomas contain multiple neoplastic plasma cell clones
- Dominant clone will determine (initial) treatment response
- But more resistant secondary clones may appear at later stage (reduced efficiency of treatment response over time)
What are the main clinical stages through which myeloma progresses?
- Premalignant MGUS
- Smouldering (asymptomatic) myeloma: light chains present in blood/urine but no end organ damage is present
- Symptomatic myeloma
- Relapsed and refractory myeloma (almost a certainty relapse)
- Plasma cell leukaemia (end stage disease when neoplastic plasma tumour cells leave BM and enter blood stream)
What is a plasma cell
terminally differentiated B lymphoid cell
matured in BM and LNs
plasma cels produce high affinity Ab with diverse Ag specificities
(one Ag type per cell clone)
What is the pathogenesis of myeloma?
clonal expansion of Ig-secreting plasma cells
BM-sited disease which produces lytic lesions in bone, anaemia and BM failure
- Plasma cells secrete monoclonal protein
- most commonly IgG (60%) or IgA (20-25%) or light chains only (15-20%)
Are the Ig produced by neoplastic plasma cells functional?
No
- they are essentially junk forms of normal Ig secreted by normal tissue
- light chain only means incomplete Ig structure
Note: IgM secreting tumours are more common in lymphoma
Is amyloidosis common in all types of myeloma?
Can occur in any type or even in MGUS
But it is more common in lambda than kappa light chain restricted myeloma
What is the epidemiology of multiple myeloma?
blood cancers: 5th most common cancer in UK
2x as common in African Americans
most commonly Dx in >70yo
What are the main tests used to Dx myeloma?
INITIAL
Lab tests: FBCs, U&Es, LFTs
Serum/urine protein electrophoresis: M-protein in serum and M-protein fragments in urine (Bence-Jones)
Can also use liquid chromatography to detect M-protein in serum
beta2 microglobulin
FURTHER
BM aspirate: immunophenotyping (flow cytometry), conventional cytogenetics, FISH, gene profiling
Imaging: X-ray/skeletal survey, CT, MRI and PET-TMG
What is beta-2-microglobulin and how is it used to investigate myeloma?
B2-microglobulin = part of MHC protein
In advanced stage myeloma, this is likely to be elevated
What are the main genetic abnormalities associated with myeloma?
risk loci on chromosome 1, chromosome 14 (heavy chain genes reside here), 17p deletions
Looking for DNA translocations into these key sites
How can burden/progression of myeloma affect lab tests?
high burden of disease is associated with seeing abnormalities relating to end organ damage e.g. renal failure
Anaemia can precede myeloma Dx by >2yr
Anaemia can also itself elevate ESR (FYI)
What are the IMWG criteria for myeloma? What does is distinguish?
IMWG = international myeloma working group
Dx criteria
Distinguishes MGUS, vs. smouldering myeloma vs. myeloma
What are the IMWG criteria for Dx of MGUS?
Either
1) IgG/A/M MGUS
serum M-protein >3g/dL AND clonal BM plasma cells <10% AND no myeloma defining events
OR
2) Light chain MGUS
Abnormal sFLC ration AND increased level of appropriate light chain AND no Ig heavy chain on immunofixation AND clonal BM plasma cells <10% AND urinary M-protein <500mg/24hr AND no myeloma defining events
What are the IMWG criteria for Dx of smouldering MGUS?
All of the below:
- serum M-protein >= 3g/dL OR
- urinary M-protein >= 500mg/24h
- clonal BM plasma cells 10-60%
- no myeloma defining events or amyloidosis
What are the IMWG criteria for Dx of Multiple Myeloma?
- clonal BM plasma cells >10% OR
- Biopsy proven body or extramedullary plasmacytoma
AND - 1 or more myeloma defining features
What are the myeloma defining features as defined as CRAB?
C: hypercalcaemia
R: renal insufficiency/failure
A: anaemia
B: bony lytic lesions and pain
What are the myeloma defining features as defined as SLiM?
These are only referred to in the absence of CRAB criteria
S: ≥60% clonal BM plasma cells; Li: serum free Light chain ratio involved:uninvolved ≥100;
M: >1 focal lesion (≥5 mm each) detected by MRI studies
When would smouldering myeloma be treated?
Updated IMWG criteria
- high risk smouldering myeloma with 70-80% chance of disease progression in 2 yr
SLiM criteria must be met
Ratio of abnormal : normal light chain. If > 100 then treat
What is the pattern or remission and relapse associated with myeloma?
asymptomatic (smouldering)
symptomatic
relapsing
refractory
How does relapse and remission correlate with therapy line in myeloma?
Duration of remission reduces with each line of therapy
Myeloma becomes progressively more resistant to therapy
As remaining clones are more and more treatment resistant
Given the high relapse rate, how is Rx for myeloma approached?
first line therapy is most important and targeted
As this can greatly inform general prognosis
How can pain present in myeloma?
- Pain caused by disease (bone pain, nerve pain, spinal cord compression)
- Pain caused by treatment (peripheral neuropathy)
How is bone disease in myeloma managed?
imaging, ID of bone disease cause
Rx:
pain control, radiotherapy/cheo with steroids, surgery, bisphosphonates
What is the role of imaging in myeloma Mx?
Dx: asymptomatic myeloma
important for evaluation of spinal disease
important in monitoring: non-secretory, oligo-secretory and extra-medullary disease
Why may surgery in myeloma be indicated?
high risk of pathological fracture (reduced bone strength, lytic lesions)
e.g. pin insertion or cement to stabilise spinal column
this can also help as part of pain control
Why is imaging particularly important in non-secretory myeloma?
non-secretory = no secreted paraprotein or light chain fragments, so won’t be able to detect these in serum/urine
other Ix such as imaging become more important for Dx
What are the NICE guideline re: imaging in myeloma?
- offer imagine to all patients - with suspected myeloma
- whole body MRI is first line iii available (most centres don’t have access to this however)
- whole-body low dose CT (shows bone only as no contrast) can be used as an alternative
- skeletal survey to be used as third line (or if MRI/CT are unsuitable)
- Isotope bone scans are not used
For imagine in myeloma, where are CT/MRI directed? How accurate is CT in this?
sites where BM is active
so central-axial locations of skeleton
cellularity burden must be 40-50% in order to be picked up by CT
What are the common sites for bone involvement in multiple myeloma?
- skull
- spine
- pelvis
- long bones
What is osteopenia?
Marked reduction in bone strength
Cortical thinning can be observed on X ray
preceding stage before full osteoporosis
often leads to wedge shaped vertebral fractures
How is osteoporosis distinguished from myeloma driven bone disease?
Similar: osteopenia and cortical thinning on X ray
Difference: osteoporosis does not have abnormal BM activity
What are the main questions to ask in history when assessing bone pain in myeloma?
quality of the pain
site of pain
associated Sx
What is the aetiology of bone pain in myeloma-driven bone disease?
- tumour volume
- lytic lesions
- pathological fractures
- nerve root compression
- spinal cord compression
What is the pathogenesis of bone pain in myeloma-driven bone disease?
myeloma produced inflammatory cytokines, stimulation of local stromal cells and osteoclasts. These can also sensitise nerves and potentiate them in the long term
pain from sensory and sympathetic neurones in bone medulla
BM contains rich plexus of nerves
What is the pathophysiology of dysregulated bone remodelling in myeloma?
myeloma and stromal cells have symbiotic relationship for survival
myeloma increases RANKL expression and reduced OPG
This disproportionately drives osteoclast activity and bone reabsorption
What is RANK-L?
= receptor activator of NF-kB
member of the TNF family
Binds RANK (on osteoclasts) and also OPG
controls apoptosis and osteoclast activity
What is Denusomab? How does it rank against traditional Rx in myeloma?
Denusomab = anti-RANK-L MAb
RANKL good target as it always plays a critical role in tumour-induced bone disease
Bisphosphonates (BP) also effective in these patients, but osteonecrosis is key adverse effect
Studies show similar clinical effects between BPs and Denusomab
However, denusomab is more expensive so not currently used as much as BPs
BPs: -onate ending medications
What are the treatment goals in myeloma?
induce remission (if possible) prevent immunosuppression prevent haematological abnormalities (anaemia, thrombocytopenia) prevent end organ damage prevent fractures maintain function, QoL Control Sx
What Rx are used for analgesia in myeloma?
Syngeristic effect of opiate and non-opiate medications
- Gabapentin (Ca2+ mechanism)
- Opiates/fentanyl (opioid)
- Benzodiazepines (GABA)
What does the Kaplan-Meier curve show for survival in MM?
improved survival rates year on year
Deeper the response of treatment (assessed using immunophenotyping), the better the overall outcome
(hence the need for a strong first line therapy for good overall prognosis)
What are the 3 types of response following chemotherapy?
Partial response: 50% reduction in M-protein
Moderate response: 90% reduction in M-protein
Complete response: 100% reduction in M-protein
CR is best outcome and prognosis (significantly better than MR)
What are proteasome inhibitors and how are they effective in MM?
Proteosomal-i: Bortezomib, ixazomib
Work by inhibiting proteasome-mediated clearance of excess paraprotein in neoplastic plasma cells
This causes these dysfunctional proteins to accumulate in the cytosol of these cells and eventually mediates death
How is self-stem cell transplant used in treatment for MM?
Used as a rescue treatment
following ‘SALVAGE CHEMO’
where very high doses of chemo are used to kill all the tumour cells
But this will inherently kill all of the cells present, so stem cells needed to keep patient alive (without this step, patient would not survive)
Are allogenic transplants ever used in the treatment for MM?
Allogenic = stem cells/organ from a donor
Only ever considered if patient with MM is with v. high risk disease
e.g. severe genetic abnormalities
What are the current Rx used in INDUCTION for MM?
INDUCTION
- Velcade/bortezomib, thalidomide, DMSO (VTD)
- cyclophosphamide, Velcade/bortezomib, DMSO (CVD)
- trial based
What are the current Rx used in CONSOLIDATION for MM?
High dose melphalan
with peripheral stem cell transplant
risk of encephalopathy (Schuh et al 1999)
(HDM with PBSCT)
What are the main Rx steps in INTENSIVE treatment plan for MM?
- induction
- consolidation
- relapse
- maintenance
- novel drugs
What are the main Rx steps in NON-INTENSIVE treatment plan for MM?
- assessment of frailty
- doublet vs. triplet therapy
- induction
- relapse
(same drugs, but more gentle approach. Stem cell therapy not generally indicated)
What are the current Rx used in RELAPSE treatment for MM?
- velcade
- proteosomal inhibitors
- thalidomide derivatives
- HDAC inhibitor
- novel agents
What are the current Rx used in MAINTENANCE for MM?
- thalidomide
- velcade
- lenalidomide
(+ novel drugs)
What is the general approach for treating non-transplant eligible patients?
- Stage the malignancy
- Stage the age (assess how frail patient is and how much Rx they can take and what pace)
N.B. median age for MM Dx is MM
What kind of orthopaedic input may aid Rx for MM?
- stabilisation of pathological fracture
- Cord decompression
- Vertebroplasty
- Balloon Kyphoplasty
- Radiotherapy
Surgical procedures may be performed before onset of VCFs
What is balloon kyphoplasty?
Rx of vertebral compression fractures (VCFs)
inflation of balloon at affected vertebra creates void in body, which is then filled with bone cement, which stabilises the vertebrae
What is vertebroplasty?
injection of bone cement into the affected vertebra to stabilise unit
Kyphoplasty can correct the kyphotic angle of vertebra
Kyphoplasty is preferred but evidence is mixed for which is better
What is the general role of bisphosphonates in MM?
used to treat malignant hypercalcaemia and bone pain
mediates inhibition of osteoclastic bone resorption
MRC myeloma VI trial: reduction in vertebral and non-vertebral fractures
What is the mechanism of action for bisphosphonates?
Rapidly absorbed onto bone surface and taken up by osteoclasts
Remain in bone for years after use of BPs
2 types of BPs (with different MoA)
- Non-nitrogen containing
- Nitrogen-containing
How do non-nitrogen containing bisphosphonates work?
e.g. clodronate
metabolised by osteoclast and disrupt cell metabolism leading to apoptosis
How do nitrogen containing bisphosphonates work?
e.g. pamidronate (aminobisphosphonates)
induce apoptosis and inhibit osteoclast function by disrupting signalling cascades
What are the main features of osteonecrosis of the jaw (ONJ)?
- exposed bone in maxillofacial area
- no evidence of healing
- typically found in posterior lingual mandible (top jaw) and non-healing extraction socket (bottom jaw)
When is bony osteonecrosis (BON) suspected?
- no evidence of healing after 6 wks of appropriate evaluation or dental care
- no evidence for metastatic disease in jaw or osteoradionecrosis
What are the main causes of peripheral neuropathy in myeloma?
DISEASE RELATED
amyloid, cryoglobulin, nerve root compression, autoimmune, POEMS syndrome
CO-MORBIDITIES
DM, EtOH, weight loss and malnutrition
DRUG RELATED
thalidomide, proteasome inhibitors, platinum, immunomodulatory drugs
What is POEMS syndrome?
rare type of plasma cell disorder, complication of myeloma
P: polyneuropathy O: organomegaly E: endocrinopathy M: monoclonal protein S: skin changes
What is cryoglobulin?
Paraprotein can precipitate in the cold = cryoglobulin
If this happens at 4C not so much of an issue, issue is when the precipitation temperature is near 37C (body temp)
As this will cause damage from paraprotein precipitation
How is neuropathic pain managed in myeloma?
peripheral neuropathy associated more with newer Rx e.g. thalidomide and bortezomib/velcade
Ix: neurotoxicity assessment tool, neuro exam, EMG (nerve) studies, Ab studies, biopsy
Mx: dose reduction, pharmacological agent, massage, patient education
What Sx may indicate neuropathy?
neuropathy is altered sensation, does not have to be complete numbness
associated Sx: tinnitus, dizziness (autonomic neuropathy)
What is the incidence of neuropathic pain with MM? Why is this?
- 11-20% of newly Dx patients
- 83% in relapsed + refractory patients
- high incidence due to neurotoxic drugs
How does thalidomide work in MM Rx?
inhibits angiogenesis around plasma cell neoplasm
stimulates proliferation and function of cytotoxic T cells
What are the main presenting SENSORY Sx for drug-induced neuropathy?
hypoesthesia (loss of sensitivity) parasthesia (altered sensation, pins and needles) numbness hyperesthesia (heightened sensation) ataxia gait abnormalities neuropathic pain
What are the main presenting MOTOR Sx for drug-induced neuropathy?
weakness
tremor
What are the main presenting AUTONOMIC Sx for drug-induced neuropathy?
constipation
impotence
postural hypotension
bradycardia
What is the most common cause of HYPERCALCAEMIA in the UK in hospitalised patients?
hospital: metastatic malignancy
community: primary hyperparathyroidism
together these account 90%
