Haem: Multiple Myeloma

Question 1

Another name for immunoglobulin

Answer 1

M spike

Paraprotein

Question 2

Epidemiology of Multiple Myeloma

Answer 2

Black

Male

Older (eg. 67)

Question 3

List some key features of multiple myeloma.

Answer 3

• Cancer of monoclonal plasma cells
• Abundance of monoclonal immunoglobulin
• Osteolytic bone lesions
• Anaemia
• Infections (due to deficient polyclonal response)
• Kidney failure (due to hypercalcaemia)

Question 4

What is the pre-malignant condition for multiple myeloma?

Answer 4

Monoclonal gammopathy of uncertain significance (MGUS)

Question 5

What is MGUS

Answer 5

Monoclonal Gammopathy of uncertain significance

Precedes Multiple Myeloma

• Serum M <30g/L
• Bone marrow clonal plasma cells <10%
• No lytic lesions
• No myeloma organ or tissue impairment
• No evidence of B-cell proliferative disorder

Question 6

Which Ig indicates myeloma? Which indicates lymphoma?

Answer 6

IgA or G = Myeloma

IgM = Lymphoma

Question 7

How common is multiple myeloma compared to other haematological malignancies?

Answer 7

2nd most common after B cell lymphoma

Question 8

Risk stratification for MGUS

Answer 8

Mayo criteria

Based on 3 risk factors

1. Isotype of immunoglobulin - IgG lower risk
2. M-spike >15g/L
3. Abnormal serum free light chain ratio

Question 9

What is smouldering myeloma

Answer 9

Both:

1. Serum monoclonal protein (IgG or A) >30g/L
   OR urinary ~500mg per 24h
   OR bone plasma 10-60%
2. Absence of myeloma defining events or amyloidosis

(no CRAB)

Spectrum

in between MGUS and Myeloma

Question 10

What are the 2 main primary mechanisms that drive myeloma development?

Answer 10

• Hyperdiploidy
• IGH rearrangements (heavy chain gene translocations)

Question 11

What is another term of activated B cells?

Answer 11

Centroblasts

Question 12

Outline the process by which B cells become plasma cells.

Answer 12

• Centroblasts mature in lymph nodes where they are stimulated by antigens and turn into memory B cells or immature plasmablasts
• Various transcription factors regulate the conversion of plasmablasts into plasma cells

Question 13

Which components of the cell ultrastructure are particularly developed in plasma cells?

Answer 13

• Endoplasmic reticulum and golgi body
• This is where immunoglobulins are assembled, folded and modified before secretion

NOTE: plasma cells are the most secretory cells in the body (10,000 immunoglobulin per second)

Question 14

Outline the pathogenesis of multiple myeloma.

Answer 14

• Errors occur in the genome of normal plasma cells (possible due to infection/inflammation)
  most common - Hyperdiploid karyotype (extra chromosomes), IGH translocations
• This leads to a limited monoclonal accumulation of plasma cells (MGUS)
• This is still harmless (5% of people >75 will have MGUS)
• 1% of people with MGUS per year will acquire more mutations that transform these pre-malignant cells into multiple myeloma cells
• This will trigger a cascade of events in the tumour microenvironment including increased angiogenesis and increased bone resorption

NOTE: it is difficult to develop targeted therapies for multiple myeloma because a lot of different mutations can cause it

Question 15

What is CRAB?

Answer 15

Hypercalcaemia (>2.75 mmol/L)

Renal failure (creatinine >177μmol/L or eGFR <40ml/min)

Anaemia (Hb <100g/L or drop by 20g/L)

Bone lesions (One or more bone lytic lesions in imaging

Question 16

What is a myeloma defining event

Answer 16

• Bone marrow plasma cells ≥60%
• Involved : uninvolved FLC ratio >100
• > 1 focal lesion in MRI (>5mm)

Question 17

What is the diagnostic criteria for multiple myeloma?

Answer 17

≥10% plasma cells in bone marrow + ≥1 CRAB or myeloma defining event

Question 18

What is the median survival for patients with multiple myeloma?

Answer 18

3-4 years

Question 19

Describe the histological appearance of mature plasmacytic cells.

Answer 19

• Nucleus is pushed to one side of the cell
• Clumped chromatin
• Large cytoplasm (low nuclear-to-cytoplasmic ratio)

Question 20

Describe the histological appearance of immature plasmablastic cells.

Answer 20

• Prominent nucleoli
• Reticular chromatin
• Less abundant cytoplasm

Question 21

What is the presence of immature plasmablastic cells associated with?

Answer 21

The presence of these cells is associated with a poor prognosis

Question 22

Which antigens do myeloma cells test positive for on immunohistochemistry?

Answer 22

CD138 - commonly used diagnostic marker

CD38 - can be targeted by monoclonal antibodies

Question 23

Which antigens do myeloma cells test negative for on immunohistochemistry?

Answer 23

• CD19
• CD20 (unlike B cell lymphomas and CLL)
• Surface immunoglobulin

Question 24

How does multiple myeloma lead to lytic bone disease?

Answer 24

The myeloma cells release osteoclast activating factors and osteoblast inhibiting factors

Question 25

How is bone imaging utilised in myeloma

Answer 25

* X-ray now obselete * Whole body CT * CT/PDG-PET * **Whole body diffusion weighted MRI** * Bone marrow cellularity * Active vs treated disease

Question 26

How can multiple myeloma lead to paralysis?

Answer 26

Pathological fracture of a vertebra can lead to spinal cord compression.

Question 27

Which imaging techniques are used to investigate multiple myeloma and what are their benefits?

Answer 27

* MRI - sensitive for bone marrow infiltration, expensive * CT - sensitive for very small lytic lesions, high radiation dose * PET scans - detects active disease, usually used with CT/MRI

Question 28

Outline the mechanisms by which multiple myeloma causes kidney injury.

Answer 28

**20-50% AKI** at diagnosis * Cast nephropathy - caused by high serum FLC, which is filtered and precipitates in tubules * Hypercalcaemia - nephrocalcinosis

Question 29

Normal amount of light chains in blood

Answer 29

20mg/dL

Question 30

Multiple Myeloma diagnostic workup

Answer 30

**Immunoglobulin studies** * Serum protein electrophoresis (M-spike) * Involved:Uninvolved FLC ratio serum assay * 24h urine Bence Jones protein **Bone Marrow aspirate/biopsy** * IHC for CD138 **FISH** * For high risk mutations **Flow** **Cytometry** * Diagnostic * Monitioring

Question 31

Staging of Multiple Myeloma

Answer 31

Question 32

How can myeloma cause AL amyloidosis

Answer 32

Light chains have the potential to misfold and deposit = Amyloid (because of variable regions in immunoglobulin, can occur in MGUS or Smouldering) Target organs: Kidneys, Heart others - GI, Skin, Liver, Spleen, Lymph

Question 33

Stain for amyloid

Answer 33

Congo Red Solid, non-branching and randomly arranged with diameter of 7-12nm

Question 34

Common presentations of amyloidosis

Answer 34

* Nephrotic (70%) * Proteinuria, Oedema * Unexplained HF - (10%) * Raised NT-pro-BNP * Abnormal Echo and cardiac MRI * Sensory Neuropathy * Abnormal LFTs (9%) * Macroglossia * Malabsorption plus GI symptoms

Question 35

What is MGRS

Answer 35

Monoclonal Gammopathy of Renal significance Any B cell lymphoproliferation where there are: 1. 1+ kidney lesions caused by mechanisms related to Ig produced and.. 2. Underlying B cell clone does not cause tumour complications or meet criteria for immediate specific therapy

Question 36

What is the ideal treatment for MM

Answer 36

Autologous stem cell transplant

Question 37

What are the four main types of drug treatment of multiple myeloma?

Answer 37

* Classical alkylator chemotherapy drugs (e.g. melphalan, cyclophosphamide) * Steroids (very cytotoxic to lymphocytes) * Immunomodulators (IMIDs e.g. thalidomide) * Proteasome inhibitors e.g. bortezomib

Question 38

Describe the physiological role of proteasomes.

Answer 38

* All proteins produced by a cell are folded in the endoplasmic reticulum * If this process goes wrong, misfolded proteins would accumulate in the ER * These misfolded proteins are insoluble and non-functional and lead to fatal ER stress and cell death * So, we have proteasomes in the cytoplasm which targets misfolded proteins and degrades the into amino acids (a process called ER-associated degradation (ERAD)) * Inhibition of proteasomes leads to an accumultation of misolded proteins in myeloma cells leading to cell death NOTE: proteasome inhibitors only work in multiple myeloma and _not_ other cancers

Question 39

List some examples of proteasome inhibitors.

Answer 39

* Bortezomib * Carflizomib

Question 40

Which old drug is used in the treatment of multiple myeloma?

Answer 40

Thalidomide - downregultes pro-survival cytokines and induces apoptosis

Question 41

Give an example of a monoclonal antibody used to treat multiple myeloma.

Answer 41

Daratumumab - anti-CD38 antibody, binds to cell surface of plasma cells causing complement activation and cell lysis/death

Question 42

Outline the 2 main treatment algorithms for MM

Answer 42

Question 43

Emerging medications for multiple myeloma

Answer 43

**Belantamab mafodotin** * Anti-BCMA (B cell maturation antigen) - highly specific for malignant plasma cells * Conjugated to toxic drug - will kill cell antibody binds to * 60% response rate in refractory MM **Anti-BCMA CAR T cells** Side effects * Cytokine release syndrome * Neurotoxicity * Infection and cytopenias