HIS Case 2: Multiple Myeloma

Question 1

Describe the B-cell compartment including plasma cells of adaptive immune system

Answer 1

See lecture

Question 2

Describe the pathological features of plasma cell myeloma, with an emphasis on the immunological aspects of plasma cell myeloma

Answer 2

Blood test:

1. ↓ Hb / Anaemia
2. Normal MCV
3. Leukocyte count / Platelet count normal

Peripheral blood smear:

1. ***Rouleaux formation (>=4 RBC clump together due to ↑ globulin production —> e.g. Plasma cell myeloma)
2. NO abnormal leukocytes

Biochemistry:

1. ↓ Albumin
2. ↑ Total globulin
3. Urea, Creatinine, Ca normal
4. LDH normal

Physical examination:

1. Low back pain, Multiple rib pain
2. Tiredness, ↓ exercise tolerance
3. Weight loss

Radiograph:
1. Multiple lytic lesions in ribs / lumbar spines

Serum immunoglobulin assays:
1. ↑ IgG, ↓ IgA, ↓ IgM —> Monoclonal band —> 40% of Paraprotein —> Monoclonal IgG kappa

• **Urine protein electrophoresis + ***Immunofixation
• Monoclonal free kappa paraprotein

β2 microglobulin ↑ —> Prognosis

Question 3

Describe the major potential complications of plasma cell myeloma

Answer 3

Neoplastic proliferation of **plasma cells producing a **monoclonal Ig

Features:
1. Proliferate in BM —> extensive skeletal destruction with Osteolytic lesions (severe bone loss) / Osteopenia

2. Osteolytic bone lesions (Hallmark of MM)
   - osteoclast activation (by RANKL)
   - osteoblast suppression
   —> Fracture
   —> Hypercalcaemia
3. ↑ Total serum protein concentration
4. Presence of ***monoclonal protein in urine / serum
5. ***Hypercalcaemia
6. Acute renal failure
   - Light chain cast nephropathy
   - Hypercalcaemia
   - Ig Light Chain Amyloidosis (AL Amyloidosis)
7. Anaemia
   - Anaemia of chronic disease (Normal MCV)
   - Erythropoietin insufficiency due to kidney damage
   - Dilution of blood by large M protein
8. Infections
   - impaired lymphocyte function
   - suppressed normal plasma cell function
9. Bleeding tendency
   - Acquired VW syndrome by M protein

Question 4

Investigations for Multiple myeloma

Answer 4

1. CBC with manual blood film review + differential count (D/C)
2. Diagnostic BM aspiration, Trephine biopsy
3. CXR
4. LFT, RFT
5. Serum electrolytes (K, PO4)
6. LDH, urate levels

其他:

1. Clotting profile, d-dimer, fibrinogen (Leukaemia)
2. **Serum protein electrophoresis + **Immunofixation, ***Serum immunoglobulin assay, ESR, β2 microglobulin, Whole body PET-CT (Lymphoma)

Diagnostic:
BM examination:
1. Morphology on PB/BM —> PB smear, BM aspiration, Trephine biopsy
2. Cytochemistry —> Myeloperoxidase, Sudan Black B
3. Immunophenotype —> Flow cytometry + Immunohistochemistry
4. Cytogenetics —> Karyotyping + FISH
5. Molecular genetics —> PCR

Pre-treatment investigations:

1. ECG, transthoracic echocardiogram
2. Lung function
3. Hepatitis B, C serology
4. HIV serology
5. G6PD assay
6. HLA-typing of patients, siblings for allogeneic HSCT

Question 5

Latest treatment options for plasma cell myeloma

Answer 5

1. Bortezomib + Thalidomide + Dexamethasone for 4-6 cycles
   - Induction + Consolidation + Maintenance
2. Autologous BM transplantation

Question 6

Thalidomide, Bortezomib, Dexamethasone

Answer 6

Thalidomide
MOA:
- Disrupt microenvironment of BM
- Immunomodulatory
- Anti-inflammatory
- Anti-neoplastic effects due to suppression of TNFα

SE:

• Teratogenic
• Constipation
• Thrombosis
• Sleepiness

Bortezomib
MOA:
- Proteasome inhibitor
—> prevent degradation of ubiquitinated proteins
—> affect cell signalling cascade
—> cell cycle arrest
—> cell death

SE:

• Thrombocytopenia
• Peripheral neuropathy
• N+V

Dexamethasone:

• Herpes prophylaxis
• DM control
• ***HBV status (reactivation) —> Entecavir

Question 7

Method of monitoring of patients with plasma cell myeloma

Answer 7

1. ***Serum protein electrophoresis
2. 24 hour ***urine protein electrophoresis
3. Serum ***free light chain assay
4. ***Immunofixation
5. Periodic BM aspirate / biopsy
6. PET-CT

Question 8

Prognosis of plasma cell myeloma and impact on patients and their families

Answer 8

Median overall survival:

• Stage 1: 62 months
• Stage 2: 44 months
• Stage 3: 29 months

4 factors:

1. Staging (International Staging System ISS: based on **β2 microglobulin + **Albumin level)
2. Patient factors
3. Disease biology
4. Response to therapy

Question 9

Socioeconomic impacts of cost of treatment of plasma cell myeloma both for patients and society

Answer 9

• Financial loss
• Morbidity
• Reduced QOL
• Premature death

Direct medical costs
- costs of treatment

Indirect costs

• time
• lost productivity

Question 10

Ethical issues related to current funding model of expensive new drugs for plasma cell myeloma and other targeted therapies

Answer 10

Apply Samaritan funds through Medical social worker

LO omitted

Question 11

Ethical issues related to availability of treatment to different patients with plasma cell myeloma

Answer 11

LO omitted

Question 12

Protein electrophoresis

Answer 12

Blood proteins:

1. Albumin
2. Globulin
   - α1: α1-antitrypsin, α1-acid glycoprotein
   - α2: Haptoglobin, Ceruloplasmin, α2-macroglobulin, α2-antiplasmin
   - β: Transferrin, LDL, Complement
   - γ: Immunoglobulin (M protein i.e. Ig fragments usually appear in this band)