Plasma Cell Myeloma and Amyloid and MGUS

Question 1

What are the key features of myeloma (6)

Answer 1

Monoclonal PCs. 
Anaemia. 
Paraprotein. 
Infections. 
Kidney failure. 
Osteolytic lesions.

Question 2

What is multiple myeloma

Answer 2

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.

Question 3

What causes transformation of B cells into myeloma cells

Answer 3

Transformation results from a range of numeric and structural genetic aberrations that accumulate from a pre-malignant condition (MGUS) to terminal progression.

Question 4

What are the two major complications of MM

Answer 4

Bone disease.

Renal failure.

Question 5

How common is MM

Answer 5

It is the second most common haematopoietic malignancy (after the B cell lymphomas)

Question 6

How many people are affected by MM in the UK

Answer 6

> 4000 people every year are affected.

Question 7

What is the median survival for MM

Answer 7

4-7 years

It is debilitating and incurable

Question 8

What are plasma cells

Answer 8

Plasma cells are the terminally differentiated efffector cells of the specific humoural immune response

Question 9

How are mature plasma cells formed (4)

Answer 9

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.

Question 10

What cell in the body secretes the most proteins

Answer 10

Plasma cells secrete more proteins than any other cell (up to 10,000lg molecules/second)

Question 11

What is the pathogenesis of MM

Answer 11

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

Question 12

What genetic instability occurs to generate MGUS (2)

Answer 12

Translocations at 14q32 (50%)

Deletion of chromosome 13 (50%)

Question 13

What genetic defects need to occur for MGUS to transform to MM (3)

Answer 13

N-RAS, K-RAS (30%)
p16 Methylation (40%)
Secondary translocations?

Question 14

What changes occur in the bone marrow microenvironment to contribute to malignancy change of MGUS to MM (2)

Answer 14

Increased bone resorption

Increased angiogenesis

Question 15

What karyotype suggests better prognosis in MM

Answer 15

55-60% of patients have a hyperdiploid karyotype, which gives a better prognosis than those with non-hyperdiploid disease.

Question 16

What is the evolution of MM

Answer 16

Post-germinal centre B cell –> MGUS –> smouldering myeloma –> myeloma –> plasma cell leukaemia

Question 17

What are the symptoms of MM (6)

Answer 17

Back pain. 
Fatigue 
Acute renal failure 
Pneumonia 
Paralysis - cord compression 
Abnormality on routine lab test

Question 18

What is the pneumonic to remember the clinical signs of MM

Answer 18

CRAB

Question 19

What does CRAB stand for

Answer 19

Calcium elevated
Renal impairment
Anaemia
Bone lesions

(and monoclonal proteins)

Question 20

What is the median age at diagnosis of MM

Answer 20

65-70 years

Question 21

What is the medial survival for MM patients

Answer 21

3-4 years (6-10 years in patients fit for intensive treatment)

Question 22

What proportion of blood cancers does MM constitute

Answer 22

15%

Question 23

What is the incidence of MM

Answer 23

5/100,000/year

Question 24

What groups of people are at increased risk of MM (4)

Answer 24

Farmers, laxative takers, cosmetologists, radiologists.

Question 25

Exposure to what increases MM risk (4)

Answer 25

Asbestos, petrolium products, pesticides, rubber/wood products

Question 26

What condition may predispose to MM

Answer 26

Chronic infection/inflammatory conditions

Question 27

What is the cell morphology of mature myeloma cells (4)

Answer 27

Clumped chromatin Low nuclear-cytoplasmic ratio. Abundant cytoplasm. Rare nucleoli.

Question 28

What are MM positive for in immunophenotypeing (4)

Answer 28

CD38 CD138 CD56/58 Monotypic cytopasmic Ig

Question 29

What do MM cells lack (immunophenotyping) (3)

Answer 29

CD19 CD20 Surface Ig

Question 30

What does myeloma bone disease consist of (5)

Answer 30

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)

Question 31

What are some osteoclast activating factors (4)

Answer 31

RANK-L TNFalpha IL-6 IL-3

Question 32

What are some osteoblast inhibiting factors (4)

Answer 32

Dkk-1 HGF Sclerostin sFRP3

Question 33

What is the best imaging to detect myeloma bone disease

Answer 33

MRI High sensitivity for marrow infiltration Response monitoring possible Expensive and limited availability

Question 34

What is the more realistic imaging used for MM

Answer 34

CT Detects very small lesions Good for radiotherapy planning Higher radiation dose

Question 35

What would the ideal imaging technique for MM detection

Answer 35

PET Detects active disease High costs, limited availability

Question 36

How does MM cause kidney injury (3)

Answer 36

Inflammatory mediations are activated in the proximal tubule epithelium. This leads to proximal tubule necrosis. Fanconi syndrome (renal tubule acidosis) with crystal deposition (FLC)

Question 37

What are the treatment options available for MM (4)

Answer 37

Steroids Classical Cytostatic drugs (melphalan) Proteasome inhibitors IMIDs (thalidomide, lenalidomide, pomalidomide)

Question 38

How does melphalan work

Answer 38

Nitrogen mustart-type alkylating agent | Adds alkyl group to DNA (guanine) --> crosslinkes G/blocks DNA replication.

Question 39

How is melphalan used for MM (3)

Answer 39

Stem ell collection from the blood and storage High-side melphalan to kill myeloma cells Re-infusion of stem cells to rescue blood formation

Question 40

How do proteasome inhibitors work

Answer 40

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.

Question 41

How does thalidomide work in MM

Answer 41

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.