Plasma cell myeloma

Question 1

1. List some key features of multiple myeloma.

Answer 1

Cancer of monoclonal plasma cells
Abundance of monoclonal immunoglobulin IgG/IgA
- Produce excess kappa or lambda light chains in serum
- Bence jones protein – light chain in urine
Osteolytic bone lesions
Anaemia
Infections (due to deficient polyclonal response)
Kidney failure (due to hypercalcaemia)

Question 2

2. What is the pre-malignant condition for multiple myeloma?

Answer 2

Monoclonal gammopathy of uncertain significance (MGUS)
- Abnormal serum immunoglobulin <30g/L produced in bone marrow and clonal expansion in bone marrow <10% BUT no lytic bone lesions

Question 3

3. Which immune profile in MGUS predisposes to which malignancies?

Answer 3

IgG and IgA MGUS – myeloma

IgM – lymphoma

Question 4

4. How common is multiple myeloma compared to other haematological malignancies?

Answer 4

2nd most common after B cell lymphoma

Question 5

5. What are the main mechanisms that drive plasma cell development?

Answer 5

Class switch recombination

Transcriptional control

Question 6

6. What is another term for activated B cells?

Answer 6

Centroblasts

Question 7

7. Outline the process by which B cells become plasma cells.

Answer 7

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 8

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

Answer 8

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 9

9. Outline the pathogenesis of multiple myeloma.

Answer 9

Errors occur in the genome of normal plasma cells
Primary – hypodiploidy in odd number chromosome OR translocation fo Chr14q32 which codes for heavy chain

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 10

10. What are the risk factors for multiple myeloma development from MGUS?

Answer 10

Non-IgG M-spike (monoclonal spike)
M-spike <15g/L
Abnormal serum free light chain ratio

Question 11

11. What is another pre-malignant disease for multiple myeloma? How is it different to MGUS?

Answer 11

Smouldering myeloma

Serum Ig >30g/L and clonal expansion in bone marrow 10-60% but still no symptoms

Question 12

12. Describe the progression of multiple myeloma?

Answer 12

MGUS, smouldering myeloma, symptomatic myeloma, remitting relapse, refractory, plasma cell leukaemia

Question 13

13. How does multiple myeloma interact with bone?

Answer 13

Bone destruction – fractures
Anaemia
Immunosuppression and infection
Angiogenesis

Question 14

14. What is the diagnostic criteria for multiple myeloma?

Answer 14

Calcium (high) >2.75
Renal failure raised creatinine and reduced eGFR
Anaemia
Bone lesions (pain, pathological fractures)
Monoclonal paraprotein
NOTE: patients with MGUS have no clinical features – there are some arbitrary cut-offs for MGUS/multiple myeloma based on monoclonal serum protein, bone marrow plasma cells and annual risk of progression to multiple myeloma

Question 15

15. How does multiple myeloma lead to lytic bone disease?

Answer 15

The myeloma cells release osteoclast activating factors and osteoblast inhibiting factors

Question 16

16. How can multiple myeloma lead to paralysis?

Answer 16

Pathological fracture of a vertebra can lead to spinal cord compression

Question 17

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

Answer 17

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 18

18. Outline the mechanisms by which multiple myeloma causes kidney injury.

Answer 18

Immunoglobulin light chains activate inflammatory mediators in the proximal tubule epithelium
Proximal tubule necrosis
Fanconi syndrome (renal tubule acidosis with failure of reabsorption in the proximal tubule) with light chain crystal deposition
Cast nephropathy

Question 19

19. What investigations would you do in someone with suspected MM?

Answer 19

Ig studies – serum protein electrophoresis, serum free light chain, 24h Bence Jones
Bone marrow aspirate and biopsy – stain for CD138
FISH
Flow cytometry diagnosis

Question 20

20. What are the complications of MM?

Answer 20

Hypercalcaemia
Cord compression
Renal disease

Question 21

21. Which conditions are associated with toxic monoclonal immunoglobulins?

Answer 21

AL amyloidosis

Monoclonal gammopathy of renal significance (MGRS) – nephrotixic light chains causing kidney disease

Question 22

22. What is AL amyloidosis?

Answer 22

Mis-folding of free light chains accumulate in amyloid fibrils in target organs. Stained with congo red stain. Common targets kidneys, heart, liver and neuropathy

Question 23

23. How does amyloidosis present?

Answer 23

Neuropathy
Unexplained heart failure
Macroglossia
Abnormal LFTs

Question 24

24. What are the four main domains of treatment of multiple myeloma?

Answer 24

Classical cytostatic drugs (e.g. melphalan)
Steroids (very cytotoxic to lymphocytes)
Immunomodulators (IMIDs e.g. thalidomide, lenalidomide)
Proteasome inhibitors

Question 25

25. What is melphalan?

Answer 25

An alkylating agent that acts as a cytostatic drug Very effective when given as part of high-dose chemotherapy with an autologous stem cell transplant Related compounds include cyclophosphamide

Question 26

26. How does lenalidomide work?

Answer 26

Block CRBN which drives transcription factor production

Question 27

27. Describe the physiological role of proteasomes.

Answer 27

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 them into amino acids (a process called ER-associated degradation (ERAD)) Inhibition of proteasomes leads to an accumulation of misfolded proteins in myeloma cells leading to cell death NOTE: proteasome inhibitors only work in multiple myeloma and not other cancers

Question 28

28. List some examples of proteasome inhibitors.

Answer 28

Bortezomib | Carfilzomib

Question 29

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

Answer 29

Thalidomide – targets the turnover of transcription factors which are essential for myeloma cell survival

Question 30

30. Which biological therapies have been approved for multiple myeloma?

Answer 30

Daratumumab and Isatuximab – CD38 inhibitors