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
