Multiple myeloma Flashcards
What is multiple myeloma (MM)
Disease of plasma cell (originating from B lymphocytes)
Causes genetic changes so B lymphocytes don’t differentiate into plasma cells instead into myeloid cells which do no produce functional antibodies but they produce monoclonal proteins which can be detected in the blood and urine which cause organ and tissue impairment
-neoplastic plasma cells accumulate in the bone marrow and blood
resulting in suppression of normal B cell production
- Myeloma cells accumulate in the bone marrow and blood
- accumulation of monoclonal proteins in renal tubules can cause renal impairment
- MM is incurable and associated with older people
What is the molecular biology of MM
- Large production of myeloma cells leads to MM microenvironment
- this microenvironment resists drug intervention therapy and protects the myeloma cells
What does the MM microenvironment consist of
- Clonal myeloma cells
- Extracellular matrix proteins
- Bone marrow stromal cells (BMSC)
- Osteoblasts and Osteoclasts
What is increased secretion of cytokines associated with in MM
-associated with MM micro environment
it is:
- interleukin-6
- vascular endothelial growth factor
- Tumour necrosis factor- alpha (TNF-alpha)
What is secretion of monoclonal protein in MM
- Myeloma cells produce immunoglobulin of homogenous structure
- different types and subtypes of myeloma - IgG - most common but does not produce any monoclonal antibodies
What are the phases of Meyloma and when do you initiate treatment with the phases
Non-symptomatic phase - do not treat at this point:
- MGUS
- Smoldering MM
No anaemia or bone lesions and normal cellular and kidney function
Symptomatic phase - treatment initiation:
-Active MM
Anaemia, bone lesions, high calcium or abnormal kidney function
What are the clinical presentation/symptoms of MM
- anaemia - fatigue
- hypercalcaemia - due to unopposed osteolysis
- Bone disease - bone pain +/- fracture - caused by lytic lesions
- pain
- frequent infections due to suppression of bone marrow function and absence of functioning antibodies
- reduces urination - associated with AKI
What causes bone disease in MM
- over expression of RANKL (receptor activation for nuclear factor kB ligand) by bone marrow stroma
- RANKL activates osteoclasts which resorb bone
- Lytic lesions - results in bone pain +/- fracture
What’s the criteria for diagnosis of symptomatic MM
C - hyperCalcaemia
R - renal insufficiency
A - anaemia
B - bone lesions
What is the staging of MM
Cytogentics is important
High risk cytogenes involved n prognosis and staging of the patient
revised international staging system focuses more on tumour markers
What is a tumour marker associated with MM
beta-2 microglobulin
Normal cells have it but in MM the beta-2 micro globulin is much higher
What are the initial therapy considerations of MM
Stage of disease
- no treatment required for smouldering/asymptomatic disease unless high cytogenes
Symptomatic disease
-treatment of complication may be required e.g managing infection, anaemia, kidney
-whether the patient is a transplant candidate or not - takes into consideration: performance status, co-morbodities and fratility index
What are the treatment outline for TRANSPLANT ELIGIBLE patients in MM
Induction:
-achievement of complete or partial remission prior to transplant
-Regimen: VTD 28 day cycle BORTEZOMIB THALIDOMIDE DEXAMETHASONE -the regimen is complicated because they have to take different medications on different days
Stem cell harvesting:
-pre stem-cell mobilising regime administered
- high dose melphaln - destroys existing diseases bone marrow then
- autologous stem cell transplantation (ASCT) - have their stem cells infused back into their body so they can recover
Post transplant consolidation:
-improves response rates
Ongoing treatment: thalidomide/lenalidomide maintenance
What are the treatment outline for NON -ELIGIBLE TRANSPLANT patients in MM
Aim:
- control disease
- maintain QOL
- long progression free survival and overall survival
Induction regimen:
-treatment chose according to co-morbidities and performance status
- lenalidomide continuously
- thalidomide or Bortezonib + alkylating agent + corticosteroid
What are immunomodolatory agents and their MOA
Proteasome inhibitors e.g
-Bortezomib - 1st line treatment
Thalidomide & Lenalidomide (not proteasome inhibitors)
MOA:
-ubiquitin-proteasome pathway degrades the majority of regulating protein
- disruption of protease activity results in rapid accumulation of incompatible regulatory proteins
- this induces the apoptotic cascade
cancer cells have a higher level of proteasome activity hence why is is targeted
What is an example of Proteasome inhibitors and its MOA and side-effect
Bortezomib
- it is a reversible PI
-has multiple MOA
such as
-directly induces apoptosis
-inhibits NF-kB pathway
-reduces IL-6 production and signalling
Side-effects:
- peripheral neuropathy - dose limiting
- hypotension
- tumour lysis syndrome
- GI disturbances
- rare: pulmonary, cardiotoxic effects and liver effects
it is metabolised by liver enzyme and is a weak inhibitor of CYP450 isoenzymes
What is thalidomide MOA in MM and its side-effects
MOA:
-activates t-cell and natural killer cells (immunomodulatory activity)
- inhibition of angiogenesis
- anti-proliferation effects
side-effects:
- TERATOGENIC
- peripheral neuropathy
- venous thromboembolism
- constipation
- drowsiness
What is a 2nd/3rd gen immunomodulatory agent and it’s side effects
Lenalidomide
causes less neuropathy
Side-effects
- TERATOGENIC presumed
- myleosuppression
- thrombotic events
What supportive therapy are there for MM
Bisphosphonate therapy:
- for all patients requiring treatment with chemotherapy
- suppressed osteoclast activity thereby inhibiting bone resorption
- so fewer lytic lesions and fewer skeletal events
- it exhibits specific cytotoxicity against myeloma cells
- Alendronic acid is commonly prescribed but avoid if creatinine clearance is <35ml/min
VTE prophylaxis:
-risk assessment in patients receiving thalidomide/lenalidomide
GI protection w/ dexamethasone
Allopurinol (1st cycle) - tumour lysis syndrome
Infections:
- anti virals
- PCP prophylaxis
What are the counselling requirement for Alendronic acid
Take first thing in the morning before you eat anything and stay sitting or standing for 30 mins
side-effects include:
- dizziness
- headache
- GI disturbances
- joint swelling
Why is a medication reminder chart used in MM
-patients take different medication on different days and time so it is useful in reminding the patient on what to take and when
What is the treatment relapse options for MM
- Lenalidomide
- Pomalidomide
- Pabinostat
What are the challenged when treating MM
- autologous stem cell transplantation prolongs survival but is not curative
- relapse therapy - no standard treatment
- supportive care is an important aspect of the treatment
What are the counselling requirement for MM treatment
Thalidomide
- causes drowsiness so take at night
- teratogenic so pregnancy prevention and safe handling
Dexamethasone - causes nightmares so take during the day
Adherence and compliance importance - think HOLISTIC
Key side effects: neuropathic pain (both thalidomide and bortezomib) discuss symptoms to report and impact on activities of daily living (e.g.his gardening)
