Multiple Myeloma

Question 1

B-cell development

Answer 1

Blood stem cell -> lymphoid stem cell -> B Lymphocyte -> plasma cell

Question 2

What B cells are present in the BM?

Answer 2

Plasma cell and pro/pre B cell

Question 3

What B cell is present in the germinal centre?

Answer 3

Activated B cell

Question 4

Define MGUS

Answer 4

Monoclonal gammopathy of undetermined significance

Question 5

Spectrum of plasma cell dyscrasias

Answer 5

Post GC B cell -> MGUS -> smouldering MM -> plasma cell leukaemia

Question 6

What are the primary genetic events in the spectrum of plasma cell dyscrasias?

Answer 6

IGH translocations
Hyperdiploidy

Question 7

What are the secondary genetic events in the spectrum of plasma cell dyscrasias?

Answer 7

Copy number abnormalities
DNA hypomethylation
Acquired mutations

Question 8

MGUS criteria for diagnosis

Answer 8

<30g/L serum M protein
<10% clonal plasma cells
No related organ and tissue impairment
No treatment - monitor

Question 9

Smouldering myeloma criteria for diagnosis

Answer 9

> 30g/L serumM protein
10% clonal plasma cells
No related organ and tissue impairment
No treatment - monitor

Question 10

Symptomatic myeloma tests

Answer 10

> 30g/L M protein in the serum or urine
10% clonal plasma cells
Related organ and tissue impairment
More than one focal lesion on MRI
Treatment required

Question 11

Clinical manifestations of MM

Answer 11

Calcium elevation
Renal insufficiency
Anaemia
Bone lesions

Question 12

Pathogenesis of MM (genetic involvement)

Answer 12

Normal cell -> (inflammation or infection by translocations 14q32 (50%) deletion of chromosome 13 (50%))

MGUS -> N-RAS, K-RAS (30%) p16 methylation (40%) secondary translocations => myeloma

Question 13

Two pathways involved in early Pathogenesis of MM and MGUS

Answer 13

Hyperdiploid
~57%
Trisomy of chromosomes odd chromosomes from 3-21(except 13)

Diploid
~43%
Reciprocal translocations involving Ig heavy chain gene (IgH) on chromosome 14 and an oncogene

Question 14

5 main translocation partner chromosomes

Answer 14

t(4;14) MMSET and FGFR3
t(6;14) CYCLIN D3
t(11;14) CYCLIN D1
t(14;16) MAF
t(14;20), MAFB

Question 15

The majority of secondary translocations acquired in MM involve the Myc gene on ______________.

Answer 15

Chromosome 8

Question 16

What are deletions responsible for in MM?
(Pre deletion)

Answer 16

Tumour suppressors
Negative cell cycle regulators
NFkB pathway regulators

Question 17

What are gains responsible for in MM?

Answer 17

Oncogenes and NFkB pathway activation

Question 18

BM SC promote

Answer 18

Growth and survival of MM cells & protect against drug induced apoptosis

Question 19

MM cells secrete IL6 to….

Answer 19

Stimulate osteoclast & bone resorption to stimulate tumour growth; inhibit osteoblasts

Question 20

What factors do MM cells secrete to evade the immune system?

Answer 20

IL-10
TGFB

Question 21

What factors does MM secrete to evade the immune system?

Answer 21

IL-10
TGFB

Question 22

VEGF promotes ____________

Answer 22

Angiogenesis

Question 23

Treatment of MM is aimed at

Answer 23

Disease control
Relieving symptoms
Extending and improving the quality of patients lives

Question 24

IMIDs

Answer 24

Immunomodulatory agents
Thalidomide
Approved for treatment of MM in 2006

Bind to CRBN -> cell cycle arrest & induction of apoptosis in MM cells

Inhibits production of TNFalpha, IL-6(proinflam) &VEGF
=> decreased inflammation, bone destruction and angiogenesis

Question 25

New classes of therapies for MM

Answer 25

HDAC inhibitors (panobinostat)
Immunotherapy - MAb
CAR-T cell therapy

Question 26

Multiple myeloma revised international staging system

Answer 26

Stage 1 -> Standard risk chromosomal abnormalities
Normal LDH
Stage 2 -> Not stage 1 or 3
Stage 3 -> High risk chromosomal abnormalities (del(17p)
High LDH