Haematological Malignancies - Multiple myeloma Flashcards
What is multiple myeloma?
The disease of plasma cells
- genetic changes occur during the terminal differentiation of B lymphocytes into plasma cells
- expansion of clone of malignant immature B cells (myeloma cells)
- produce monoclonal protein, detected in blood and urine
- myeloma cells accumulate in bone marrow and blood
What is the clinical presentation of MM?
Anaemia
Bone disease (over expression of receptor for nuclear factor kB ligand (RANKL) by bone marrow stroma
RANKL activates osteoclasts which resorb bone
Lytic lesions - bone pain +/- fracture
What criteria is used for the diagnosis of MM?
CRAB
- hyperCalcaemia
- Renal insufficiency
- Anaemia
- Bone lesions
What considerations are taken before therapy
- Stage - no treatment required for smouldering/asymptomatic unless increased risk of cytogenetics
- symptomatic disease
- Approach to therapy based on whether a pt is a transplantation cadidate
What considerations are taken before therapy
- Stage - no treatment required for smouldering/asymptomatic unless increased risk of cytogenetics
- symptomatic disease
- Approach to therapy based on whether a pt is a transplantation candidate (performance status, co-morbidities, frailty index)
renal impairment and age should not be used alone to determine suitability
What is the treatment for transplant eligible candidates?
- Induction - achievement of complete remission/partial prior to transplant
Bortezamib based regimens preferable - Stem cell harvesting
pre stem cell mobilising regime administered - high dose Melphalan (200mg/m2) and autologous stem cell transplantation
- post transplant consolidation
- ongoing tx - thalidomide/lenalidomide maintenance
What is the induction regimen for MM?
VTD - 28 day cycle
Days 1, 4, 8, and 11:
IV Bortezamib (Velcade) 1.3mg/m2 bolus/SC injection
Days 1-28:
Oral Thalidomide escalate to 200mg once daily at night
Days 1-4 and 8-11:
Oral Dexamethasone 40mg once daily at night
What is the aim of tx for non eligible transplant candidates
control disease
long progression free survival and overall survival
maintain QoL
What is the induction regime for non transplant
Lenalidomide continuously
Thalidomide OR Bortezamib and alkylating agent and corticosteroid
Give an example of a proteasome inhibitor
Bortezamib
How do proteasome inhibitors work
By inhibiting the ubiquitin-proteasome pathway which cancer cells use to breakdown incompatible transcription factors
cancer cells have high levels of proteasome activity therefore inhibition of this pathway leads to
accumulation of incompatible proteins
this leads to apoptosis
What are the side effects of Bortezamib
Peripheral neuropathy GI disturbances Hypotension Bone marrow suppression Tumour lysis syndrome CYP450 inhibitor - drug interactions
What is the moa of thalidomide
immunomodulatory activity
inhibition of angiogenesis
antiproliferative effects
What are the side effects of thalidomide
Teratogenic - PPP VTE Peripheral neuropathy Constipation Somnolence - drowsy Rashes Tremor leg swelling arrhythmias thyroid dysfunction
What are the second gen immunomodulatory agents?
Lenalidomide
in combo with dexamethasone as 2nd line
first line for transplant ineligible pts
- reduced incidence of constipation, neuropathy and somnolence
side effects = teratogen, myelosuppression, thrombotic events
What are the third gen immunomodulatory agents?
Pomalidamide
effective when myeloma cells resistant to thalidomide and lenalidomide
well tolerated
What are the standard supportive therapies?
Bisphosphonates
- IV Zolendronic acid
all pts require tx with chemotherapy
inhibits bone resorption by suppressing osteoclast activity
fewer lytic bone lesions and fewer skeletal events
VTE prophylaxis
Risk assessmnet in pts receiving idomides
aspirin, warfarin, LMWH (tinzaparin)
GI protection on days taking dex
Allopurinol (1st cycle bc of tumour lysis syndrome)
Infections (antiviral prophylaxis for all, PCP prophylaxis for pts requiring high dose steroids)
What is the treatment for relapse? (ineligible to Bortezamib and Thalidomide)
Lenalidomide
Pomalidamide
Pabinostat - histone deactylase inhibitor which promotes cell cycle arrest and apoptosis of tumour cells via multiple pathways
What is the treatment for relapse? (ineligible to Bortezamib and Thalidomide)
- Lenalidomide (2nd)
- Pomalidamide (3rd)
- Pabinostat - histone deactylase inhibitor which promotes cell cycle arrest and apoptosis of tumour cells via multiple pathways
- Ixazomib - oral proteasome inhibitor
- Cartilzomib - irreversible proteasome inhibitor
- Dararutumab - monoclonal antibody binds to CD38 leads to tumour cell death by immune mediated actions and apoptosis
- 2nd autologous transplant is considered depending on good performance status
What challenges are faced in the tx of MM?
- Autologous stem cell transplantation prolongs survival but NOT curative
- with relapse therapy no standard tx
- supportive care is an important aspect of tx
what is the molecular biology of MM
microenvironment consists of clonal myeloma cells
extracellular matrix proteins
bone marrow stromal cells
osteoblasts and osteoclats
increased secretion of cytokines IL-6, insulin like GF1, vascular endothelial GF, TNF-a
confer protection against apoptic stimuli
What are the phases of myeloma
- MGUS - asymptomatic, low levels of plasma cells
- Smouldering MM - no anaemia/bone lesions, normal calcium and kidney function
- Active MM - Anaemia, bone lesions, increased calcium, abnormal kidney function (presence of plasma cells and some monoclonal antibodies)
What are the different types and subtypes of MM?
myeloma cells produce immunoglobulin of homogenous structures
different types:
- Bence Jones Myeloma
- Non secretory myeloma
different subtypes:
- IgG with K or Y chains most common
- IgM, IgD IgE are rare
