Haematological Malignancies - Multiple myeloma

Question 1

What is multiple myeloma?

Answer 1

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

Question 2

What is the clinical presentation of MM?

Answer 2

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

Question 3

What criteria is used for the diagnosis of MM?

Answer 3

CRAB

1. hyperCalcaemia
2. Renal insufficiency
3. Anaemia
4. Bone lesions

Question 4

What considerations are taken before therapy

Answer 4

1. Stage - no treatment required for smouldering/asymptomatic unless increased risk of cytogenetics
2. symptomatic disease
3. Approach to therapy based on whether a pt is a transplantation cadidate

Question 5

What considerations are taken before therapy

Answer 5

1. Stage - no treatment required for smouldering/asymptomatic unless increased risk of cytogenetics
2. symptomatic disease
3. 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

Question 6

What is the treatment for transplant eligible candidates?

Answer 6

1. Induction - achievement of complete remission/partial prior to transplant
   Bortezamib based regimens preferable
2. Stem cell harvesting
   pre stem cell mobilising regime administered
3. high dose Melphalan (200mg/m2) and autologous stem cell transplantation
4. post transplant consolidation
5. ongoing tx - thalidomide/lenalidomide maintenance

Question 7

What is the induction regimen for MM?

Answer 7

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

Question 8

What is the aim of tx for non eligible transplant candidates

Answer 8

control disease
long progression free survival and overall survival
maintain QoL

Question 9

What is the induction regime for non transplant

Answer 9

Lenalidomide continuously

Thalidomide OR Bortezamib and alkylating agent and corticosteroid

Question 10

Give an example of a proteasome inhibitor

Answer 10

Bortezamib

Question 11

How do proteasome inhibitors work

Answer 11

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

Question 12

What are the side effects of Bortezamib

Answer 12

Peripheral neuropathy
GI disturbances
Hypotension
Bone marrow suppression 
Tumour lysis syndrome
CYP450 inhibitor - drug interactions

Question 13

What is the moa of thalidomide

Answer 13

immunomodulatory activity
inhibition of angiogenesis
antiproliferative effects

Question 14

What are the side effects of thalidomide

Answer 14

Teratogenic - PPP
VTE 
Peripheral neuropathy
Constipation
Somnolence - drowsy
Rashes
Tremor
leg swelling 
arrhythmias 
thyroid dysfunction

Question 15

What are the second gen immunomodulatory agents?

Answer 15

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

Question 16

What are the third gen immunomodulatory agents?

Answer 16

Pomalidamide
effective when myeloma cells resistant to thalidomide and lenalidomide
well tolerated

Question 17

What are the standard supportive therapies?

Answer 17

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)

Question 18

What is the treatment for relapse? (ineligible to Bortezamib and Thalidomide)

Answer 18

Lenalidomide
Pomalidamide
Pabinostat - histone deactylase inhibitor which promotes cell cycle arrest and apoptosis of tumour cells via multiple pathways

Question 19

What is the treatment for relapse? (ineligible to Bortezamib and Thalidomide)

Answer 19

• 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

Question 20

What challenges are faced in the tx of MM?

Answer 20

• Autologous stem cell transplantation prolongs survival but NOT curative
• with relapse therapy no standard tx
• supportive care is an important aspect of tx

Question 21

what is the molecular biology of MM

Answer 21

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

Question 22

What are the phases of myeloma

Answer 22

1. MGUS - asymptomatic, low levels of plasma cells
2. Smouldering MM - no anaemia/bone lesions, normal calcium and kidney function
3. Active MM - Anaemia, bone lesions, increased calcium, abnormal kidney function (presence of plasma cells and some monoclonal antibodies)

Question 23

What are the different types and subtypes of MM?

Answer 23

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