Myeloma and Other Plasma Cell Dyscrasias

Question 1

Development of B cells?

Answer 1

Derived in bone marrow, from pluripotent haematopoietic stem cells

Question 2

Functions of B cells?

Answer 2

Part of adaptive immune system

2 roles:
• Ab production
• Act as APCs

Question 3

What is are immunoglobulins?

Answer 3

Abs produced by B cells and plasma cells; each Ab recognises a specific antigen

Question 4

Structure of Ig?

Answer 4

Proteins made of:
• 2 heavy chains (μ, α, δ, γ, ε)
AND
• 2 light chains (κ or λ)

Question 5

Production and development of B cells?

Answer 5

Initial production and development in the bone marrow

Under the control/influence of the micro-environment

Variable element of the Ig is generated early in development, from the V-D-J region recombination; 1000s of combinations can be produced

Self-reactive cells are removed

Immature B cells, withe Ig on their surface, exit bone marrow, ready to meet their target

Question 6

Journey of B cells in the periphery?

Answer 6

Travel to the follicle germinal centre of the lymph node and identify the Ig, improving the fit of the Ab via somatic mutation OR are deleted

May return to the marrow as a plasma cells or circulate as a memory cell

Question 7

Function of plasma cells?

Answer 7

Factory cell that pumps out Abs

Question 8

Structure of plasma cell?

Answer 8

Eccentric ‘clock-face nucleus’ on H&E

Question 9

Clonal populations in health vs disease?

Answer 9

Health - polyclonal; the increase in Ig is produced by many different plasma cell clones, allowing reactivity to infection, autoimmunity, malignancy (host reaction to malignant clone), liver disease

Cancer - monoclonal; the increase in Ig is all derived from clonal expansion of a single B-cell and they have identical structures and specificity; they are AKA PARAPROTEIN

Question 10

What are paraproteins?

Answer 10

Markers of underlying clonal B-cell disorder

Question 11

How to detect Igs?

Answer 11

Serum electrophoresis - used to DETECT abnormal protein bands; proteins move at differing rates, determined by their size and charge

Serum immunofixation - used to CLASSIFY abnormal protein band

Can then QUANTIFY the amount of abnormal protein

Question 12

Bands on serum electrophoresis?

Answer 12

From anode to cathode:

Albumin - closes to anode as it is the most -vely charged molecule

Alpha-1 - mainly alpha-1 antitrypsin

Alpha-2

Beta

Gamma - contains various Ig (IgG, IgA, IgM, IgD, IgE)

Question 13

What are Bence-Jones protein (BPJ)?

Answer 13

Ig light chains detected by urine electrophoresis:
• Kappa light chains (monomeric)
• Lambda light chains (dimeric)

NOTE - the free light chain production by normal plasma cell is 0.5 g/day; an excess can leak into the urine, as BPJ

Question 14

Causes of paraproteinaemia?

Answer 14

1. MGUS (most common)
2. Myeloma
3. Amyloidosis
4. Lymphoma
5. Asymptomatic myeloma
6. Solitary or extramedullary plasmacytoma
7. Chronic lymphocytic leukaemia
8. Waldenström’s macroglobulinaemia

Question 15

Define myeloma?

Answer 15

Plasma cell malignancy

Question 16

How does myeloma affect the body?

Answer 16

Direct tumour cell effects:
• Bone lesions (pepper-pot skull, fractures)
• Increased Ca2+
• Bone pain
• Replace normal bone marrow, leading to marrow failure

Paraprotein mediated effects:
• Renal failure
• Immune suppressions
• Hyperviscosity
• Amyloid

Question 17

How is myeloma classified?

Answer 17

By type of Ab produced:
• IgG (majority)
• Bence Jones (free light chains) myeloma 
• IgA
• Etc

Question 18

Explain myeloma lytic bone disease

Answer 18

Myeloma cells flourish and produce IL-6, which:
• Suppresses osteoblasts
• Activates osteoclasts - leading to increased Ca2+ release

Question 19

Consequences of hypercalcaemia?

Answer 19

Stones

Bones

Abdominal groans

Psychiatric moans

Thirst, dehydration and renal impairment

Question 20

Effect of myeloma on the kidneys?

Answer 20

30% have renal impairment at diagnosis:
• Tubular cell damage by light chains
• Light chain deposition leads to cast nephropathy
• Sepsis
• Hypercalcaemia and dehydration
• Drugs, e.g: NSAIDs
• Amyloid
• Hyperuricaemia 

NOTE - free light chains are small enough to filter into tubules

Question 21

Most common cause of renal failure in patient with myeloma?

Answer 21

Cast nephropathy

If the proximal tubules are overwhelmed by large amounts of light chain, or damaged in some other way, then light chains can pass through into the loop of Henle

In the thick ascending limb of the loop of Henle, Tamm-Horsfall protein is produced and this can combine with free light chains, to produce insoluble casts that block the nephron

Question 22

Treatment of cast nephropathy?

Answer 22

Damage may be reversible with prompt treatment

Aim is to switch off light chain production with steroids / chemotherapy

Question 23

Median age of myeloma diagnosis?

Answer 23

65 years old

Question 24

Treatment of myeloma?

Answer 24

Corticosteroids (dexamethasone or prednisolone)

Alkylating agents, e.g: cyclophosphamide, melphalan

‘Novel agents’ like thalidomide, bortezomib and lenalidomide

High dose chemo/autologous stem cell transplant, in fit patients

Question 25

How is treatment response monitored?

Answer 25

Use paraprotein level

Question 26

Symptom control in myeloma?

Answer 26

Opiate analgesia (avoid NSAIDs, to prevent renal failure) Local radiotherapy - good for pain relief or spinal cord compression Bisphosphonates - corrects hypercalcaemia and bone pain Vertebroplasty – inject sterile cement into fractured bone to stabilise

Question 27

What is MGUS?

Answer 27

Monoclonal Gammopathy of Uncertain Significance Presence of a small clone of plasma cells, which produce paraprotein; the cells are normal and are not proliferating It is likely a step in the direction of myeloma but, as it occurs in older age groups mainly, most patients will die of other causes before that ever happens

Question 28

Features of MGUS?

Answer 28

Paraprotein <30g/l Bone marrow plasma cells <10% ``` No evidence of myeloma end organ damage: • Normal calcium • Normal renal function • Normal Hb • No lytic lesions • No increase in infections ```

Question 29

Occurrence of MGUS?

Answer 29

Far more common in older age groups (elderly population) 2x more common in Black people

Question 30

Risk of progression to myeloma?

Answer 30

Remains low (~1% per year)

Question 31

What is AL amyloidosis (amyloid light chain amyloidosis)?

Answer 31

Rare disorder where there is a small plasma cell clone that has a mutation in the light chain (altered structure) It precipitates in tissues as an insoluble beta-pleated sheet NOTE - the protein is different from SAA (serum amyloid A) amyloidosis (chronic inflammation) and familial amyloidosis

Question 32

PC of AL amyloidosis?

Answer 32

Often present late with organ damage; it is a slowly progressive, multi-system disease

Question 33

Prognosis of AL amyloidosis?

Answer 33

Poor prognosis, esp. if cardiac amyloid

Question 34

Organ damage in AL amyloidosis?

Answer 34

Kidney: • Nephrotic syndrome Heart: • Cardiomyopathy Liver: • Organomegaly deranged LFT’s Neuropathy: • Autonomic • Peripheral GI tract: • Malabsorption

Question 35

Diagnosis and staging of AL amyloidosis?

Answer 35

Organ biopsy confirming AL amyloid deposition: • Congo red stain • Apple-green birefringence under polarised light NOTE - rectal or fat biopsy may be done if high clinical suspicion, as this is less invasive Evidence of deposition in other organs: • SAP scan • Echocardiogram • Heavy proteinuria

Question 36

What is Waldenstrom’s Macroglobulinaemia?

Answer 36

Lymphoplasmacytoid neoplasm - a clonal disorder where the cells are intermediate between a lymphocyte and plasma cell; produce a CLASSIC IgM PARAPROTEIN

Question 37

Effects of Waldenstrom’s Macroglobulinaemia?

Answer 37

Tumour effects: • Lymphadenopathy • Splenomegaly • Marrow failure Paraprotein effects: • Hyperviscosity • Neuropathy

Question 38

Structure of the IgM paraprotein in Waldenstrom’s Macroglobulinaemia?

Answer 38

Pentameric (very large)

Question 39

PC of Waldenstrom’s Macroglobulinaemia?

Answer 39

Hyperviscosity syndrome: • Fatigue, visual disturbance, confusion, coma • Bleeding • Cardiac failure B symptoms: • Fever • Night sweats (drenching) • Weight loss

Question 40

Treatment of Waldenstrom’s Macroglobulinaemia?

Answer 40

Chemotherapy Plasmapharesis (removes patient plasma rich in IgM paraprotein and replace with donor plasma)