Plasma Cell Myeloma and Amyloid and MGUS Flashcards
What are the key features of myeloma (6)
Monoclonal PCs. Anaemia. Paraprotein. Infections. Kidney failure. Osteolytic lesions.
What is multiple myeloma
It is a cancer of transformed plasma cells, terminally differentiated B cells that secrete Ig and are the effector cells of the specific humoural immune response.
What causes transformation of B cells into myeloma cells
Transformation results from a range of numeric and structural genetic aberrations that accumulate from a pre-malignant condition (MGUS) to terminal progression.
What are the two major complications of MM
Bone disease.
Renal failure.
How common is MM
It is the second most common haematopoietic malignancy (after the B cell lymphomas)
How many people are affected by MM in the UK
> 4000 people every year are affected.
What is the median survival for MM
4-7 years
It is debilitating and incurable
What are plasma cells
Plasma cells are the terminally differentiated efffector cells of the specific humoural immune response
How are mature plasma cells formed (4)
Encountering antigen drives a virgin B cell to generate a low-affinity plasma cell or stimulates its migration to a germinal centre. In the germinal centre, affinity maturation occurs and is mediated through two processes: somatic hypermutation and antigen selection. Subsequently, class switch recombination occurs, leading to the development of immunoglobulin (Ig) isotypes. Once this process is complete, the plasmablast leaves the germinal centre and migrates to the bone marrow where it becomes a long-lived plasma cell that produces antibody.
What cell in the body secretes the most proteins
Plasma cells secrete more proteins than any other cell (up to 10,000lg molecules/second)
What is the pathogenesis of MM
Genetic instability leads to monoclonal gammopathy of undetermined significance (MGUS).
1%/year of these transform to MM due to genetic alterations and changes in the bone marrow microenvironment
What genetic instability occurs to generate MGUS (2)
Translocations at 14q32 (50%)
Deletion of chromosome 13 (50%)
What genetic defects need to occur for MGUS to transform to MM (3)
N-RAS, K-RAS (30%)
p16 Methylation (40%)
Secondary translocations?
What changes occur in the bone marrow microenvironment to contribute to malignancy change of MGUS to MM (2)
Increased bone resorption
Increased angiogenesis
What karyotype suggests better prognosis in MM
55-60% of patients have a hyperdiploid karyotype, which gives a better prognosis than those with non-hyperdiploid disease.
What is the evolution of MM
Post-germinal centre B cell –> MGUS –> smouldering myeloma –> myeloma –> plasma cell leukaemia
What are the symptoms of MM (6)
Back pain. Fatigue Acute renal failure Pneumonia Paralysis - cord compression Abnormality on routine lab test
What is the pneumonic to remember the clinical signs of MM
CRAB
What does CRAB stand for
Calcium elevated
Renal impairment
Anaemia
Bone lesions
(and monoclonal proteins)
What is the median age at diagnosis of MM
65-70 years
What is the medial survival for MM patients
3-4 years (6-10 years in patients fit for intensive treatment)
What proportion of blood cancers does MM constitute
15%
What is the incidence of MM
5/100,000/year
What groups of people are at increased risk of MM (4)
Farmers, laxative takers, cosmetologists, radiologists.
Exposure to what increases MM risk (4)
Asbestos, petrolium products, pesticides, rubber/wood products
What condition may predispose to MM
Chronic infection/inflammatory conditions
What is the cell morphology of mature myeloma cells (4)
Clumped chromatin
Low nuclear-cytoplasmic ratio.
Abundant cytoplasm.
Rare nucleoli.
What are MM positive for in immunophenotypeing (4)
CD38
CD138
CD56/58
Monotypic cytopasmic Ig
What do MM cells lack (immunophenotyping) (3)
CD19
CD20
Surface Ig
What does myeloma bone disease consist of (5)
80-90% of patients with myeloma have lytic lesions (or low bone density)
20% have pathological fractures at diagnosis, up to 60% at some point.
Spinal cord compression (paralysis)
Hypercalcaemia (renal failure)
Bone pain (mobility, independence, quality of life)
What are some osteoclast activating factors (4)
RANK-L
TNFalpha
IL-6
IL-3
What are some osteoblast inhibiting factors (4)
Dkk-1
HGF
Sclerostin
sFRP3
What is the best imaging to detect myeloma bone disease
MRI
High sensitivity for marrow infiltration
Response monitoring possible
Expensive and limited availability
What is the more realistic imaging used for MM
CT
Detects very small lesions
Good for radiotherapy planning
Higher radiation dose
What would the ideal imaging technique for MM detection
PET
Detects active disease
High costs, limited availability
How does MM cause kidney injury (3)
Inflammatory mediations are activated in the proximal tubule epithelium.
This leads to proximal tubule necrosis.
Fanconi syndrome (renal tubule acidosis) with crystal deposition (FLC)
What are the treatment options available for MM (4)
Steroids
Classical Cytostatic drugs (melphalan)
Proteasome inhibitors
IMIDs (thalidomide, lenalidomide, pomalidomide)
How does melphalan work
Nitrogen mustart-type alkylating agent
Adds alkyl group to DNA (guanine) –> crosslinkes G/blocks DNA replication.
How is melphalan used for MM (3)
Stem ell collection from the blood and storage
High-side melphalan to kill myeloma cells
Re-infusion of stem cells to rescue blood formation
How do proteasome inhibitors work
Proteins are folded within the cell by the ER.
Misfolded proteins can cause cell stress, so they are recycled by proteasomes.
Inhibition of proteasomes cause fatal ER strass and intracellular amino acid starvation.
How does thalidomide work in MM
The small molecule drug binds to the protein CRBN, which activates the enzymatic activity of the CRBN E3 ubiquitin ligase complex.
The transcription factors IKZF1 and IKZF3 are modified with ubiquitin molecules, targeting then for proteolysis.
This alters the function of the T cells and B cells, with a toxic outcome for MM cells.
