Haem: Multiple Myeloma Pt.1

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