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YEAR 5: Haematology SM > Haem: Multiple Myeloma > Flashcards

Haem: Multiple Myeloma Flashcards

(38 cards)

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1
Q

Another name for immunoglobulin

A

M spike

Paraprotein

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2
Q

Epidemiology of Multiple Myeloma

A

Black

Male

Older (eg. 67)

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3
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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4
Q

What is the pre-malignant condition for multiple myeloma?

A

Monoclonal gammopathy of uncertain significance (MGUS)

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5
Q

What is MGUS

A

Monoclonal Gammopathy of uncertain significance

Preceding Multiple Myeloma

Serum M <30g/L

Bone marrow cells <10%

Asymptomatic

No lytic lesions

No myeloma organ or tissue impairment

No evidence of B-cell proliferative disorder

IgA or G = Myeloma

IgM = Lymphoma

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6
Q

How common is multiple myeloma compared to other haematological malignancies?

A

2nd most common after B cell lymphoma

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7
Q

Risk stratification for Multiple myeloma

A

Mayo criteria

Based on 3 factors

  1. Isotype of immunoglobulin - IgG lower risk,
  2. M-spike >15g/L,
  3. Abnormal serum free light chain
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8
Q

What is smouldering syndrome

A

Both:

  1. Serum monoclonal protein (IgG or A) >30g/L or urinary ~500mg per 24h
    or bone plasma 10-60%
  2. Absence of myeloma defining events or amyloidosis

(no CRAB)

Spectrum

in between MGUS and Myeloma

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9
Q

What are the main mechanisms that drive plasma cell development?

A
  • Class switch recombination
  • Transcriptional control
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10
Q

What is another term of activated B cells?

A

Centroblasts

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11
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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12
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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13
Q

Outline the pathogenesis of multiple myeloma.

A
  • Errors occur in the genome of normal plasma cells (possible due to infection/inflammation)
  • *most common - Hyperdiploid karyotype** (extra chromosomes)
  • 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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14
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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15
Q

What is the median survival for patients with multiple myeloma?

A

3-4 years

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16
Q

Describe the histological appearance of mature plasmacytic cells.

Study These Flashcards
A
  • Nucleus is pushed to one side of the cell
  • Clumped chromatin
  • Large cytoplasm (low nuclear-to-cytoplasmic ratio)
17
Q

Describe the histological appearance of immature plasmablastic cells.

Study These Flashcards
A
  • Prominent nucleoli
  • Reticular chromatin
  • Less abundant cytoplasm

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

18
Q

Which antigens do myeloma cells test positive for on immunohistochemistry?

Study These Flashcards
A
  • CD138
  • CD38
  • CD56/CD58
  • Monotypic cytoplasmic immunoglobulin
  • Light chain restriction
19
Q

Which antigens do myeloma cells test negative for on immunohistochemistry?

Study These Flashcards
A
  • CD19
  • CD20 (unlike B cell lymphomas and CLL)
  • Surface immunoglobulin
20
Q

How does multiple myeloma lead to lytic bone disease?

Study These Flashcards
A

The myeloma cells release osteoclast activating factors and osteoblast inhibiting factors

Dont use Xrays so much - now more Cross secitonal - CT or PET

or diffuse weighted MRI - showing effect of treatment; bone marrow cellularity

(as lytic lesions will be there after therapy)

21
Q

How can multiple myeloma lead to paralysis?

Study These Flashcards
A

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

22
Q

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

Study These Flashcards
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
23
Q

Outline the mechanisms by which multiple myeloma causes kidney injury.

Study These Flashcards
A

20-50% AKI at diagnosis

  • 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 (light chains + uromodulin) - blocking renal tubules
24
Q

Normal amount of light chains in blood

25
Multiple Myeloma diagnostic workup
**Immunoglobulin studies** Serum free light chains - usually all needed (Serum electrophoresis) 24h Bence Jones usually not necessary **Bone Marow aspirate** CD138 **Flow** **Cytometry** Diagnosis
26
Staging of Multiple Myeloma
**International Staging System ISS** Based on *B*2 Serum microglobulin, & Albumin and **Revised ISS**
27
How can myeloma relate to AL amyloidosis
Light chains have the potential to misfold and deposit = Amyloid (because of variable regions in immunoglobulin, can occur in MGUS or Smouldering) Target organs: Kidneys, Heart others - GI, Skin, Liver, Spleen, Lymph
28
Stain for amyloid
Congo Red Solid, non-branching and randomly arranged with diameter of 7-12nm
29
Common presentations of amyloidosis
**Nephrotic (70%)** Proteinuria, Oedema **Unexplained HF** - (10%) Raised NT-pro-BNP Abnormal Echo and cardiac MRI **Sensory Neuopathy** **Abnormal LFTs (9%)** **Macroglossia**
30
What is MGRS
Monoclonal Gammopathy of Renal significance Any B cell lymphoproliferation where there are: 1. 1+ kidney lesions caused by mechanisms related to Ig produced and.. 2. Underlying B cell cone does not cause tumour complications or meet criteria for immediate specific therapy
31
What are the four main domains of treatment of multiple myeloma?
* Classical cytostatic drugs (e.g. melphalan) * Steroids (very cytotoxic to lymphocytes) * Immunomodulators (IMIDs e.g. thalidomide) * Proteasome inhibitors
32
What is melphalan?
* 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
33
Outline the process of autologous stem cell transplantation.
* 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
34
Describe the physiological role of proteasomes.
* 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
35
List some examples of proteasome inhibitors.
* Bortezomib * Carflizomib
36
Which old drug is used in the treatment of multiple myeloma?
Thalidomide - targets the turnover of transcription factors which are essential for myeloma cell survival
37
Give an example of a monoclonal antibody used to treat multiple myeloma.
Daratumumab - anti-CD38 antibody, binds to cell surface of plasma cells causing complement activation and cell lysis/death
38
Emerging medications for multiple myeloma
**Belantamab mafodotin** antibody targeting marker (BCMA) for plasma cells (normal and malignant) – v. specific (not as prevalent of CD38) Carries a toxin with it – will kill the cell it binds to 60% response rate as. Monotherapy **Car T cells** Isloating patient T cells and making them attack cancer side effects - cytokine release syndrome

YEAR 5: Haematology SM (19 decks)

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