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Haematology > Haematology 11 - Plasma cell myeloma and Monoclonal Gammopathy of Uncertain Significance > Flashcards

Haematology 11 - Plasma cell myeloma and Monoclonal Gammopathy of Uncertain Significance Flashcards

1
Q

What immunoglobin is produced by myeloma cells?

A

One single type (eith IgG or IgA) which is known as paraprotein or M spike

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2
Q

What are Bence Jones proteins?

A

Urine monoclonal free light chains

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3
Q

What is Waldenstrom’s-Lymphoplacytic lymphoma?

A

A lymphoplasmocytic lymphoma with IgM paraprotein that causes visual disturbances

and mucous lesions???

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4
Q

What is the name of the premalignant condition that ALWAYS precedes myeloma?

A

Monoclonal gammaopathy of uncertain significance (MGUS)

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5
Q

What is the difference between a pre-myeloma MGUS and pre-lymphoma MGUS?

A

Pre-myeloma: IgG/A-producing B cells
Pre-lymphoma: IgM-producing B cells

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6
Q

What are the two most significant risk factors for myeloma?

A

Obesity
Black > causasians/ asians

age is another risk factor

  • chronic infection/ inflammation can increase the risk e.g. rheumatoid arthritis, viral (HHV8/HIV): immune system is more active whereby there is more active proliferation and differentiation of B cells, creating more of a chance for error.
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7
Q

What are the diagnostic criteria for MGUS?

A

Serum M-protein (i.e. paraprotein) <30g/L
BM clonal plasma cells <10%
Asymptomatic: no lytic lesions, no organ/tissue impairment, no clincal manifestation

no evidence of other B cell proliferation

**less severe version of multiple myeloma

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8
Q

What are the risk factor for progession of MGUS into multiple myeloma?

A
  1. non-IgG paraprotein (i.e. IgG is GOOD, G for Good!!)
  2. M spike (IgG/IgA paraprotein) >15
  3. abnromal serum free light chain ratio

average risk of progression to Multiple myeloma is 1%, so most people will not go on to develop multiple myeloma

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9
Q

What is smouldering myeloma?

A

Serum M-protein >30g/L
BM clonal plasma cells >10%
Asymptomatic- no signs of end organ damage

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10
Q

What is the clinical spectrum of multiple myeloma diseases?

A

Essentially MGUS is the least severe version

Then you have smouldering myeloma which is a more severe version but doesn’t have any organ damage

Then you have multiple myeloma

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11
Q

Diagnostic criteria of multiple myeloma

A

remember the values!!!

calcium: >2.75
creatinine: >177
anaemia: <100

**if it doesn’t meet the above criteria then you have smouldering myeloma**

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12
Q

Epidemiology of multiple myeloma

Risk factors for multiple myeloma

A
  • 2nd most common haemato;ogical malignancy
  • mostly affects older people- median age is 67 years old
  • men>women
  • black>caucasians and asians

___

RF: obesity

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13
Q

What % of plasma cells is there in symptomatic multiple myeloma?

A

>10%

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14
Q

What are the clinical effects of myeloma due to?

A
  1. BM microenvironment interaction
  2. Circulating paraprotein
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15
Q

What is the most notable interaction of myeloma cells with the bone marrow micro-environment?

A

Produce RANK ligand which stimulates osteoclasts to cause bone resorption

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16
Q

What is the incidence of IgM myeloma?

A

Very rare (<1% of myelomas)

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17
Q

What does CRAB stand for in myeloma diagnosis?

A

Calcium (hypercalcaemia, >2.75)

  • this is because of stimulation of osteoclasts which release calcium from the bone

Renal (creatinine >177/ eGFR <40)

Anaemia

  • this is because of infiltration of plasma cells into the bone marrow

Bone disease (see lytic lesions)

  • bone pain caused by infiltration of bone by plasma cells
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18
Q

What is the most common and 2nd most common cytogenetic abnormality in myeloma?

A
  1. Hyperdiploid karyotype: with extra copies of chromosome
  2. IgH gene rearrangement: chromosomal translocation of chromosome 14q32- locus for IgH gene

note these also occur in MGUS and smouldering myeloma. further secondary events causes progression into multiple myeloma e.g. (but not limited to):

  • Commonly mutations of NRAS and KRAS
  • Other translocations e.g. of Myc
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19
Q

What are the 3 2014 Myeloma Defining Events

A

BM plasma cells >60%
involved:uninvolved FLC ratio >100
>1 focal lesion on MRI

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20
Q

Which part of the skeleton is affected by myeloma?

A

Proximal skeleton (spine, ribs, pelvis, femur, skull, knees)

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21
Q

Where are myeloma patients most likely to feel pain?

A

Back, chest wall, pelvis

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22
Q

What % of myeloma patients present with bone disease?

A

80%

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23
Q

What scan is necessary to detect bone lesions in myeloma?

A

Whole body CT is first line (X ray is obsolete for this use)

PET scan can also be used - (often used in combination with CT/MRI)

Gold-standard = whole body diffusion-weighted MRI as this shows active vs treated disease

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24
Q

What are the 3 most likely emergency presentations of myeloma?

A

Cord compression- due to soft tissue mass or pathological fracture of vertebrae

Hypercalcaemia

renal failure

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25
Q

What tests should be done to diagnose myeloma?

A

First:
Serum protein electrophoreis- very sensitive screening monitoring: 24 hour bence jones protein
Serum free light chains

Next:
Bone marrow aspirate- demonstrate infiltration by malignant plasma cells

biopsy for immunohistochemistry: CD138

FISH (for prognostic)

Flow cytometry immunophenotyping: important after treatment to detect small amounts of residual disease if present

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26
Q

What is the best way to treat cord compression in myeloma?

A

Dexamethosone
Radiotherapy

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27
Q

What type of nephropathy does myeloma cause?

A

Cast nephropathy

28
Q

What causes kidney disease in multiple myeloma?

A

unable to filter overproduced serum free light chains = accumulation as casts = inflammation and fibrosis of proximal tubule

They cause proximal tubule injury and myeloma cast nephropathy

29
Q

How should myeloma kidney disease be treated in an emergency?

A

hydration

Bortezomib-based therapy is the cornerstone of myeloma kidney disease treatment - once the patients can become independent from dialysis their outcomes improve dramatically

30
Q

How does myeloma affect immunity?

A

Serum levels of normal Igs reduced: immunoparesis- low normal serum immunoglobulins

BM micro-environment interference also impairs myeloid, T and NK cells

Chemo also impairs immune response

myeloma immune evasion

**basically increased predisposition to infections

31
Q

What is tested for in BM biopsy in suspected myeloma?

A

Immunohistochemistry for CD138 - specific for myeloma cells in BM

32
Q

What test can detect cytogenetic abnormalities of prognostic significance in myeloma?

33
Q

What are the 3 parameters in the international staging system for myeloma?

A

Serum beta2 microglobulin

Cytogenetic risk

LDH

34
Q

How does AL amyloidosis link to myeloma?

A

Misfolded FLCs aggregate into amyloid fibrils in target organs

Amyloidosis can occur in background of MGUS/myeloma

35
Q

How does amyloidosis affect the kidney?

A

Nephrotic syndrome

i.e. NOT CAST NEPHROPATHY

36
Q

Give 5 features of the clinical presentation of AL amyloidodis and common target organs

A

common target organs: kidney, heart(myocardium), liver, neuropathy

Nephrotic syndrome

  • proteinuria (not bence jones protein), oedema

Unexplained heart failure: determinant of prognosis:

  • cardiac amyloidossis has very poor prognosis

Sensory neuropathy
Abnormal liver function tests
Macroglossia

erectile dysfunction

37
Q

What is MGRS?

A

Monoclonal gammaopathy of Renal significance

38
Q

How is MGRS defined?

A
  1. One or more kidney lesions caused by mechanisms related to the produced monoclonal immunoglobulin (Ig)
  2. The underlying B cell clone does not cause tumor complications or meet current hematological criteria for immediate specific therapy

Work up is similar to myeloma and most patinets will require myeloma type treatment

39
Q

Recall 6 options for myeloma therapy

A
  1. Alkylators (eg cyclophosphamide + Melphalan)
  2. Steroids (eg dex + pred)
  3. immunemodulators: Thalidomide, Lenalidomide
  4. Cereblon-binding drugs
  5. Proteosome inhibitors- Bortezomib + Carfilzomib
  6. Anti-CD38 (daratumumab)- monoclonal AB
40
Q

Which monoclonal antibody is used in myeloma treatment?

A

Anti-CD38 (daratumumab)

41
Q

What are the first investigations to be done in suspected myeloma?

A

Serum protein electrophoresis - this is for IgG/IgA
Serum free light chains- this is for the light chains

42
Q

4 main complications of multiple myeloma

A
  • Osteolytic bone lesions: fracture risk
    • ​spinal chord compression
  • Anaemia
  • Kidney failure
  • recurrent Infections
43
Q

prognosis of myeloma

A

INCURABLE disease

44
Q

comorbidities associated to MGUS compared to general population

A
  • osteoporosis, thrombosis and bacterial infection
45
Q

what is plasmacytoma:

A

soft tissue tumour caused by multipel myeloma plasma cells

46
Q

how does hypercalcaemia present and how can it be treated:

47
Q

common infections in myeloma

A

chest infections especially gram negative

fungal infections uncommon but can occur in later stages especially after prolonged use of steroids.

Main problem is viral infections especially herpes zoster reactivation- shingles is very common

48
Q

treatment for transplant eligible patients and ineligible patients

A

NB: only autologous stem cell transplant is licensed- not allogeniec.

49
Q

Mechanisms by which Multiple Myeloma and 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
50
Q

Main markers presented by B cells vs plasma cells

A

B Cells:

CD19, CD20, surface Ig

Plasma Cells

CD138, CD38

51
Q

what determines the severity in amyloidossi associated to mylemoma/MGUS

A

severity of disease does not equate to amount of light chains but type of misfolding

amyloidogenic potential of light chains is more important than their amount

52
Q

how can you test for amyloid deposites in bone marrow

A
  • congo red staining and under polarised light
    • stains as pinky/reddish on Congo red
    • green apple colour in polarised light
53
Q

which light chian is amyloidosis commonly associated to in myeloma/MGUS

A

lambda light chain

54
Q

summarise the investiations done for multiple myeloma

55
Q

what percentage of plasma cells do you see the bone marrow in multiple myeloma?

56
Q

WHat staging system is used for MM?

A

durie salmon

57
Q

Treatment if MM

58
Q

M spike in MGUS vs SM vs MM

A

MGUS: <30

SM: >30

MM: >30

59
Q

Bone marrow clonal plasma cells MGUS vs SM vs MM

A

MGUS: <10%

SM: >10%

MM: any clonal plasma cell population; automatically diagnostic of <60% plasma cells

60
Q

CRAB features in MGUS vs SM vs MM

A

ONLY PRESENT IN MM

61
Q

Organ damage in MGUS vs SM vs MM

A

ONLY IN MM

hypogammaglobuulinaemia

occult bone disease

hypervisoccity

cytopenia

62
Q

MGUS vs SM vs MM : which one needs treatment?

63
Q

Summary of MGUS vs SM vs MM

64
Q

what is another name of waldernstrom’s macroglobulinaemia?

A

Lymphoplasmacytoid Lymphoma - LPL

65
Q

Who gets waldenstrom’s macroglobulinaemia?

A

elderly men typically

66
Q

presentation of waldenstrom’s

A

Low-grade NHL; lymphoplasmacytoid cells producing monoclonal serum IgM infiltrate the LNs/BM

Weight loss, fatigue, hyperviscosity syndrome (visual problems, confusion, CCF, muscle weakness)

Treatment: plasmapheresis for hyperviscosity; rituximab / bendamustine or ibrutinib for active disease

Haematology (16 decks)

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