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HaemPath > Plasma cell myeloma > Flashcards

Plasma cell myeloma Flashcards

1
Q
  1. List some key features of multiple myeloma.
A

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)

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

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

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

IgG and IgA MGUS – myeloma

IgM – lymphoma

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

2nd most common after B cell lymphoma

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

Class switch recombination

Transcriptional control

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6
Q
  1. What is another term for activated B cells?
A

Centroblasts

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7
Q
  1. 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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8
Q
  1. 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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9
Q
  1. Outline the pathogenesis of multiple myeloma.
A

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

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

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

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

Smouldering myeloma

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

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12
Q
  1. Describe the progression of multiple myeloma?
A

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

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13
Q
  1. How does multiple myeloma interact with bone?
A

Bone destruction – fractures
Anaemia
Immunosuppression and infection
Angiogenesis

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14
Q
  1. What is the diagnostic criteria for multiple myeloma?
A

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

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15
Q
  1. 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
  1. How can multiple myeloma lead to paralysis?
A

Pathological fracture of a vertebra can lead to spinal cord compression

17
Q
  1. 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
  1. 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
Cast nephropathy

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

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

20
Q
  1. What are the complications of MM?
A

Hypercalcaemia
Cord compression
Renal disease

21
Q
  1. Which conditions are associated with toxic monoclonal immunoglobulins?
A

AL amyloidosis

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

22
Q
  1. What is AL amyloidosis?
A

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

23
Q
  1. How does amyloidosis present?
A

Neuropathy
Unexplained heart failure
Macroglossia
Abnormal LFTs

24
Q
  1. 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, lenalidomide)
Proteasome inhibitors

25
Q
  1. 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

26
Q
  1. How does lenalidomide work?
A

Block CRBN which drives transcription factor production

27
Q
  1. 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 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

28
Q
  1. List some examples of proteasome inhibitors.
A

Bortezomib

Carfilzomib

29
Q
  1. 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

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

Daratumumab and Isatuximab – CD38 inhibitors

HaemPath (8 decks)

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