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YEAR 5: Haematology > Haem: Multiple Myeloma > Flashcards

Haem: Multiple Myeloma Flashcards

1
Q

List some key features of multiple myeloma.

A
  • Cancer of monoclonal plasma cells
  • Abundance of monoclonal immunoglobulin
  • Osteolytic bone lesions
  • Anaemia
  • Infections (due to deficient polyclonal response)
  • Kidney failure (due to hypercalcaemia)
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2
Q

What is the pre-malignant condition for multiple myeloma?

A

Monoclonal gammopathy of uncertain significance (MGUS)

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3
Q

How common is multiple myeloma compared to other haematological malignancies?

A

2nd most common after B cell lymphoma

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4
Q

What are the main mechanisms that drive plasma cell development?

A
  • Class switch recombination
  • Transcriptional control
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5
Q

What is another term of activated B cells?

A

Centroblasts

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6
Q

Outline the process by which B cells become plasma cells.

A
  • 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
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7
Q

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

A
  • 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)

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8
Q

Outline the pathogenesis of multiple myeloma.

A
  • Errors occur in the genome of normal plasma cells (possible due to infection/inflammation)
  • 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

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9
Q

What are the main clinical features of multiple myeloma?

A
  • Calcium (high)
  • Renal failure
  • Anaemia
  • Bone lesions (pain, pathological fractures)
  • Monoclonal paraprotein

NOTE: patients with MGUS have no clinical features - there are some arbitary cut-offs for MGUS/multiple myeloma based on monoclonal serum protein, bone marrow plasma cells and annual risk of progression to multiple myeloma

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10
Q

What is the median survival for patients with multiple myeloma?

A

3-4 years

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11
Q

Describe the histological appearance of mature plasmacytic cells.

A
  • Nucleus is pushed to one side of the cell
  • Clumped chromatin
  • Large cytoplasm (low nuclear-to-cytoplasmic ratio)
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12
Q

Describe the histological appearance of immature plasmablastic cells.

A
  • Prominent nucleoli
  • Reticular chromatin
  • Less abundant cytoplasm

NOTE: the presence of these cells is associated with a poor prognosis

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13
Q

Which antigens do myeloma cells test positive for on immunohistochemistry?

A
  • CD138
  • CD38
  • CD56/CD58
  • Monotypic cytoplasmic immunoglobulin
  • Light chain restriction
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14
Q

Which antigens do myeloma cells test negative for on immunohistochemistry?

A
  • CD19
  • CD20 (unlike B cell lymphomas and CLL)
  • Surface immunoglobulin
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15
Q

How does multiple myeloma lead to lytic bone disease?

A

The myeloma cells release osteoclast activating factors and osteoblast inhibiting factors

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16
Q

How can multiple myeloma lead to paralysis?

A

Pathological fracture of a vertebra can lead to spinal cord compression.

17
Q

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

A
  • 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
18
Q

Outline the mechanisms by which multiple myeloma causes kidney injury.

A
  • 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
  • Case nephropathy
19
Q

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

A
  • Classical cytostatic drugs (e.g. melphalan)
  • Steroids (very cytotoxic to lymphocytes)
  • Immunomodulators (IMIDs e.g. thalidomide)
  • Proteasome inhibitors
20
Q

What is melphalan?

A
  • 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
21
Q

Outline the process of autologous stem cell transplantation.

A
  • Patients receive induction treatment for 6 months to reduce the burden of myeloma
  • Stem cells from the bone marrow are harvested
  • Patients receive a single shot of high-dose melphalan to kill myeloma cells (also toxic to bone marrow)
  • Patient is reinfused with own stem cells to rescue blood cell formation
  • Within 24 hours, stem cells find their way to the bone marrow
22
Q

Describe the physiological role of proteasomes.

A
  • 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 the into amino acids (a process called ER-associated degradation (ERAD))
  • Inhibition of proteasomes leads to an accumultation of misolded proteins in myeloma cells leading to cell death

NOTE: proteasome inhibitors only work in multiple myeloma and not other cancers

23
Q

List some examples of proteasome inhibitors.

A
  • Bortezomib
  • Carflizomib
24
Q

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

A

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

25
Q

Give an example of a monoclonal antibody used to treat multiple myeloma.

A

Daratumumab - anti-CD38 antibody, binds to cell surface of plasma cells causing complement activation and cell lysis/death

YEAR 5: Haematology (18 decks)

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