Haem: Multiple Myeloma + Amyloidosis

Question 1

Define Multiple Myeloma

Answer 1

Neoplasia of terminally differentiated Ig secreting plasma B cells of the bone marrow.

Question 2

Outline the key concequence of having clonal proliferation of malignant plasma cells in multiple myeloma

Answer 2

Neoplastic plasma cells produce in excess monoclonal immunoglobulins (called: paraproteins or M-spike) - these are commonly IgG (can also be IgA).

These paraproteins are often produced by light chains - therefore there is an excess of light chains. However, a pathognomic feature is that there is NO balance of light chains - therefore there is excess of either kappa or lambda light chains.

This results in increased:
- serum paraprotein levels
- serum light chain levels (predominantly one type)
- Bence Jone Proteins in urine (free light chains in urine)

Question 3

Outline the aetiology of Multiple Myeloma

Answer 3

Often caused by genetic errors in plasma cell develoment. Divided in two: primary events and secondary events.

Primary events: predispose to disease - hence increase risk of developing MGUS (pre-malignant condition).
- Hyperdiploidy OR
- IgH rearrangements in Chr 14 (high risk translocation = t(4;14) - places a proto-oncogene after a very active IgH promoter

Secondary events: causes the transformation of premalignant conditions into MM. Occurs due to increased proliferation of cells = higher risk of point mutations.
- del 17p (removes tumour suppressor gene)

Question 4

Risk factors for the development of multiple myeloma

Answer 4

• Age (increases with age)
• Genetics (increased risk in African and African Carribean descent)
• Obesity

Question 5

Outline the stages of development for Multiple Myeloma

Answer 5

1. MGUS (monoclonal gammopathy of uncertain significance)
2. Smouldering Multiple Myeloma
3. Multiple Myeloma

MM is always preceded by MGUS (the commonest premalignant condition)!

Question 6

Define MGUS
(including: serum paraprotein levels, bone marrow cellularity and clinical features)

Answer 6

Premalignant condition to multiple myeloma - incidence increases with age.

M-Spike/Paraprotein levels: < 30g/L
Bone marrow: < 10% clonal plasma cells
Symptoms: Asymptomatic - but at increased risk of osteoporosis, thrombosis and bacterial infections compared to general pop

Question 7

Outline the risk of progression of MGUS to MM

Answer 7

Low risk of progression (although all of MM arises from MGUS, not all of MGUS results in MM).

Risk of progression increases with increased risk factors (Mayo criteria) - but maximum of 27% risk progression

Question 8

Define Smouldering MM
(including: serum paraprotein levels, bone marrow cellularity and clinical features)

Answer 8

Intermediate premalignant condition between MGUS and MM.

M-Spike/Paraprotein levels: > 30g/L
Bone marrow: 10-60% clonal plasma cells
Symptoms: Asymptomatic

Question 9

Outline the risk of progression of Smouldering MM to MM

Answer 9

Higher risk of progressio to MM compared to MGUS.

(With >2 risk factors = 46% risk of progression).

Question 10

Explain how myeloma cells interact with the bone marrow microenviroment to cause the clinical features seen in MM

Answer 10

• Myeloma cells over-activate osteoclasts in bone causing excess bone resorption = bone disease (of axial skeleton as it is these bones that still have red bone marrow) + hypercalcaemia
• Myeloma cell proliferation impacts the function of normal plasma cells and bone marrow function = increased risk of infection + anaemia
• Myeloma cell clone proliferation causes excess serum free light chains which must be excreted = myeloma kidney disease
• Myeloma cells release VEGF = result in angiogenesis

Question 11

Outline the clinical features seen in a patient with Multiple myeloma

Answer 11

CRAB:
* Calcium elevated: thirst, moans, groans, stones, bone pain
* Renal failure
* Anaemia
* Bones: bone pain, osteoporosis, osteolytic lesions, (never osteoblastic - hence never see osteosclerosis in MM), pathological fractures, cord compression

Question 12

Investigations and results for multiple myeloma
(bloods, serum electrophoresis, urine mcs, blood film, ct pet)

Answer 12

Bloods: high calcium, anaemia + very high ESR +
Serum electrophoresis: high serum paraprotein + high serum free light chains (of 1 type)
Urine MC&S: Bence-Jones protein
Blood film: Rouleaux (stacking)
CT-PET or Diffusion Weighted MRI: allows identification of bone marrow cellularity and disease severity!

Question 13

Diagnostic Criteria for MM

Answer 13

greater or equal 10% plasma cells in BM
+
greater or equal 1 CRAB or Myeloma Defining Events

Question 14

What are Myeloma Defining Events

Answer 14

• Bone marrow plasma cells >60%
• Abnormal:Normal FLC ratio >100
• > 1 Focal lesion on MRI

Question 15

Compare the defining parameters of MGUS, Smouldering MM and MM

Answer 15

Question 16

What medical emergencies can occur in patients with Multiple Myeloma

Answer 16

Spinal Cord Compression
* progressive leg weakness, sensory numbness, inability to walk,
* Diagnosis and treatment ideally in 24hrs!
* Diagnosis: whole spine MRI (identification of compression
* Treatment: Dexmethasone + Radiotherapy +/- neurosurgery

Hypercalcaemia - severe = >3.5mmol/L
* results in severe dehydration, renal disease, cardiac dysfunction
* Treatment: fluids + steroids + Biphosphonate

Myeloma Kidney Injury

Question 17

What are important complications that can arise from multiple myeloma

Answer 17

Myeloma Kidney Disease
Recurrent infections

Question 18

Aetiology and Pathophysiology of Myeloma kidney disease

Answer 18

Aetiology: increased levels of serum free light chain

Pathophysiology
- serum free light chains are normally reabsorbed by tubular cells - however due to being produced in excess, the increased endocytosis results in tubular cell apoptosis.
- this results in a lot of serum free light chains being left in the filtrate. These then bind to THP causing a jelly-like precipitate which can cause blockage of nephron tubules.
- Resulting in renal failure (oedema!!)

Question 19

Why is Myeloma Kidney Disease considered a medical emergency in myeloma patients

Answer 19

If not treated it results in chronic renal failure which is associated with a worse prognosis.

Question 20

Why do patients with multiple myeloma have increased risk of infections

Answer 20

Due to immunoparesis (normal plasma cells no longer function normally as a result of myeloma cells) and bone marrow suppression.

Patients are, in early disease, at risk of gram positive infections and then all kinds of infections and reactivation of dormant diseases (e.g. Herpes Zoster).

Question 21

Treatment of Multiple Myeloma

Answer 21

• Supportive measures to treat CRAB (e.g. biphosphonates)
• First line = Bortezemib + Dexmethasone (aim to achieve remission)
• Once remission is achieved =autologous stem cell transplant for young patients oR anti-CD38 for older
• Following transplant = consolidation chemotherapy

Question 22

Explain AL Amyloidosis

Answer 22

AL Amyloidosis can occur at any point from MGUS to MM.

It is caused by mis-folded light chains (commonly lambda chains - which have a higher amyloidogenic potential) forming amyloid proteins which deposit in various organs causing proteins.

The amyloidogenic potential of light chains is more important than their amount in risk of causing AL amyloidosis.

Question 23

Concequences of AL Amyloidosis

Answer 23

• Nephrotic Syndrome –> protienuria + peripheral oedema
• Heart failure –> amyloid deposits on cardiomyocytes causes hypertrophy
• Sensory neuropathy
• Macroglossia

Question 24

Diagnosis of AL Amyloidosis

Answer 24

Biopsy of affected organ using congo-red stain - allows identificaiton of amyloid deposits!