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review haem > Haem: Multiple Myeloma > Flashcards

Haem: Multiple Myeloma Flashcards

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

Precedes Multiple Myeloma

  • Serum M <30g/L
  • Bone marrow clonal plasma cells <10%
  • 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 MGUS

A

Mayo criteria

Based on 3 risk factors

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

What is smouldering myeloma

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 2 main primary mechanisms that drive myeloma development?

A
  • Hyperdiploidy
  • IGH rearrangements (heavy chain gene translocations)
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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), IGH translocations
  • 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 is CRAB?

A

Hypercalcaemia (>2.75 mmol/L)

Renal failure (creatinine >177μmol/L or eGFR <40ml/min)

Anaemia (Hb <100g/L or drop by 20g/L)

Bone lesions (One or more bone lytic lesions in imaging

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15
Q

What is a myeloma defining event

A
  • Bone marrow plasma cells ≥60%
  • Involved : uninvolved FLC ratio >100
  • > 1 focal lesion in MRI (>5mm)
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16
Q

What is the diagnostic criteria fo multiple myelome?

A

≥10% plasma cells in bone marrow + ≥1 CRAB or myeloma defining event

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17
Q

What is the median survival for patients with multiple myeloma?

A

3-4 years

18
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)
19
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

20
Q

Which antigens do myeloma cells test positive for on immunohistochemistry?

A

CD138

21
Q

Which antigens do myeloma cells test negative for on immunohistochemistry?

A
  • CD19
  • CD20 (unlike B cell lymphomas and CLL)
  • Surface immunoglobulin
22
Q

How does multiple myeloma lead to lytic bone disease?

A

The myeloma cells release osteoclast activating factors and osteoblast inhibiting factors

23
Q

How is bone imaging utilised in myeloma

A
  • X-ray now obselete
  • Whole body CT
  • CT/PDG-PET
  • Whole body diffusion weighted MRI
    • Bone marrow cellularity
    • Active vs treated disease
24
Q

How can multiple myeloma lead to paralysis?

A

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

25
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
26
Q

Outline the mechanisms by which multiple myeloma causes kidney injury.

A

20-50% AKI at diagnosis

  • Cast nephropathy - caused by high serum FLC, which is filtered and precipitates in tubules
  • Hypercalcaemia - nephrocalcinosis
27
Q

Normal amount of light chains in blood

A

20mg/dL

28
Q

Multiple Myeloma diagnostic workup

A

Immunoglobulin studies

  • Serum protein electrophoresis (M-spike)
  • Involved:Uninvolved FLC ratio serum assay
  • 24h urine Bence Jones protein

Bone Marrow aspirate/biopsy

  • IHC for CD138

FISH

  • For high risk mutations

Flow Cytometry

  • Diagnostic
  • Monitioring
29
Q

Staging of Multiple Myeloma

A
30
Q

How can myeloma cause AL amyloidosis

A

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

31
Q

Stain for amyloid

A

Congo Red

Solid, non-branching and randomly arranged with diameter of 7-12nm

32
Q

Common presentations of amyloidosis

A
  • Nephrotic (70%)
    • Proteinuria, Oedema
  • Unexplained HF - (10%)
    • Raised NT-pro-BNP
    • Abnormal Echo and cardiac MRI
  • Sensory Neuropathy
  • Abnormal LFTs (9%)
  • Macroglossia
  • Malabsorption plus GI symptoms
33
Q

What is MGRS

A

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 clone does not cause tumour complications or meet criteria for immediate specific therapy
34
Q

What is the ideal treatment for MM

A

Autologous stem cell transplant

35
Q

What are the four main types of drug treatment of multiple myeloma?

A
  • Classical alkylator chemotherapy drugs (e.g. melphalan, cyclophosphamide)
  • Steroids (very cytotoxic to lymphocytes)
  • Immunomodulators (IMIDs e.g. thalidomide)
  • Proteasome inhibitors e.g. bortezomib
36
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

37
Q

List some examples of proteasome inhibitors.

A
  • Bortezomib
  • Carflizomib
38
Q

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

A

Thalidomide - downregultes pro-survival cytokines and induces apoptosis

39
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

40
Q

Outline the 2 main treatment algorithms for MM

A
41
Q

Emerging medications for multiple myeloma

A

Belantamab mafodotin

  • Anti-BCMA (B cell maturation antigen) - highly specific for malignant plasma cells
  • Conjugated to toxic drug - will kill cell antibody binds to
  • 60% response rate in refractory MM

Anti-BCMA CAR T cells

Side effects

  • Cytokine release syndrome
  • Neurotoxicity
  • Infection and cytopenias

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