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Haematology > Myeloma & Paraproteins > Flashcards

Myeloma & Paraproteins Flashcards

1
Q

Describe the basic structure of an antibody? [3]

A

Y shaped with 2 heavy and 2 light chains

“Trunk” = FC portion (constant & defines subclass)

“Branches” = FAB portion (variable & defines antigen binding)

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2
Q

What’s the most common antibody?

A

IgG - 75% of total

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3
Q

What is a paraprotein?

A

A monoclonal Ab in blood or urine (i.e. lots of the same Ab) indicating monoclonal proliferation of a B-cell type

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4
Q

How can we test antibody levels? [1]

How do we assess for antibody diversity & paraproteins? [2]

A

Total Immunoglobulin levels
Serum Protein Electrophoresis
(Separates the proteins incl antibodies by size/charge)

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5
Q 
How do we determine which class of paraprotein is present? [1]
Light chains aren't detected in electrophoresis but can cause myeloma, how do we test for them? [1]
A

Immunofixation

Serum light Chain Assay

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6
Q

What if we find a paraprotein in someone with no illness?

A

Diagnose with MGUS

Monoclonal Gammopathy of Uncertain Significance

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7
Q

How do we diagnose a myeloma? [4]

A

Urine/serum electrophoresis for paraproteins, light chain assay, blood will show hypogammaglobulinemia
Then we must find Excess Plasma Cells in the marrow (>10% of total marrow cell pop)

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8
Q

How do we stage myeloma? [2]

A

Based on Albumin & Beta2 Microglobulin levels

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9
Q

What is a myeloma? [2]

Epidemiology [2]

A

A neoplasm of plasma cells –> Excessive production of a single immunoglobulin

Peaks in the 7th decade
And is commonest amongst black people

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10
Q

Presentations of myeloma can occur through Plasma cells or the paraprotein. What are the myeloma-related symptoms? CRABBI
Radiological findings in myeloma

A
  • Calcium
  • Renal failure
  • Anaemia
  • Bone
  • Bleeding
  • Infections

X-ray spine for cord compression and pepper pot skull - whole body MRI

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11
Q

Paraprotein related symptoms in myeloma [4]

A

Renal failure - cast nephropathy
Hyperviscosity syndrome
Hypogammaglobulinaemia –> Infection susceptibility
Amyloidosis

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12
Q

How can we treat Myeloma? [7]

A 
Chemo
RT
Bisphosphonate
Steroids
Surgery
Autologous Stem Cell Transplant
Bortezomib + Dexamethasone
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13
Q

Why use bisphosphonates in myeloma?

A

Treat the bone disease, very like osteoporosis

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14
Q

What is surgery used for in myeloma?

A

Removal of single lesions and decompressing the spinal cord if causing paralysis/weakness

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15
Q

How does an autologous stem cell transplant work?

A

ITs not the transplant that treats you, its the chemo:

1) Shrink myeloma as much as possible
2) Harvest healthy stem cells
3) Hardcore chemo destroys myeloma & normal marrow
4) Stem cell transplant (prevents you dying from the marrow damage of chemo)

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16
Q

Which immunoglobulins are present in myeloma?

What immunoglobulins are present in lymphoma?

A

IgA & IgG

IgM paraproteins can be found instead in lymphoma or Waldenstroms macroglobulinemia

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17
Q

Acute myeloid leukemia
Presents with the triad of bone marrow failure [3]
What is a hematological emergency presentation of a sub-type of leukemia? [2]
What will blood count show? [2]
How to confirm dx [5]

A

Triad of bone marrow failure:

  1. Anemia
  2. Thrombocytopenic bleeding
  3. Infection secondary to neutropenia - bacterial, fungal

Acute promyelocytic leukemia can present with DIC

Blood count: neutropenia ~ leukocytosis ( whilst white cell counts may be very high, functioning neutrophil levels may be low leading to frequent infections etc)

Confirm dx:
Peripheral blood film - Auer rods and myeloblasts
Bone marrow aspirate/trephine
Cytogenetics/karyotyping from leukemic blasts
Immunophenotyping
CSF exam if symptomatic

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18
Q

Acute myeloid leukemia
What will bone marrow biopsy microscopy show [1]
Targeted molecular genetics are used for acquired gene mutations - name 3

A

≥ 20% myeloblasts in the bone marrow confirm the diagnosis
Targeted molecular genetics for associated acquired gene mutations
FLT3, NPM1, IDH1+2

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19
Q

AML Tx:

A
  1. General supportive therapy with blood products, keep plt>10
  2. Induce complete remission <5% blasts in bone marrow, normalising FBC, then consolidation
  3. Allogeneic stem cell transplant for poor prognosis
  4. Intensive chemo in 3-4 blocks each lasting 1w: cytosine and danorubicin

Specific treatments include:
CD33 - Mylotarg
Midostaurin for FLT3 mutations

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20
Q

AML

Anti-leukemic chemotherapy [2]
Chemo-free therapy: 2 drugs, 1 indication
Targeted treatment: 2 eg of targeted antibiotics, 1 eg of targeted mutations in AML

A

Anti-leukemic chemotherapy
Induction: Daunorubicin and cytosine arabinoside
Consolidation: High dose cytosine arabinoside

All-trans retinoic acid (ATRA) and arsenic trioxide (ATO)
Indication: low risk acute promyelocytic leukemia
APML may present as DIC, ATRA is continued as maintenance therapy

Targeted abs:
Gemtuzumab Ozogamicin anti-CD33 + Mylotarg (Calicheamicin)
Midostaurin for FLT3 mutations in AML

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21
Q

Hyperviscosity syndrome in multiple myeloma [2]

Manifests in [4]

A

impaired microcirculation > hypoperfusion
Bleeding e.g. retinal, oral, nasal or cutaneous
Sometimes HF, confusion or renal failure

22
Q

Amyloidosis manifestations… [5]

Tx

A 
Nephrotic syndrome
Cardiac failure LVH
CTS nodules
Raccoon eyes - cutaneous infiltration
Autonomic neuropathy - dizziness
Tx: chemotherapy
23
Q

Features of bone disease in MM [4]

Treatment [6]

A 
Lytic lesions, path fractures, cord compression &amp; hypercalcaemia
Tx:
Chemotherapy
Bisphosphonate therapy - zolendronic acid
Steroids
Radiotherapy
Surgery
Autologous stem cell transplant
24
Q

Rationale for tx in MM
Give 4 drugs used in chemotherapy
Function of zolendronic acid
Function of radiotherapy
What special ingredient is used in autologous stem cell transplant after harvesting

A

Chemotherapy
○ Proteasome inhibitors
○ IMiDs (immunomodulatory drugs)
○ Monoclonal abs
○ Thalidomide
Bisphosphonate therapy - zoledronic acid
○ Inhibit bone breakdown and increased BMD

Radiotherapy
○ for localised pain control

Autologous stem cell transplant
○ Autologous stem cell harvest first
Mustard gas - oral form used to kill off all lymphocytes and plasma cells

25
Q

CML
Presentation [5]
FBC features [3] and microscopy [2]

A
  1. Anemia
  2. Splenomegaly
  3. Hypermetabolic - weight loss
  4. Hyperleukostasis, tumor lysis syndrome
  5. Gout

Patients usually present in 50s.
* Anemic
* WBC high - High neutrophil level
* Platelets high

Bone marrow/blood: heterogenous blood film, Philadelphia chromosome

26
Q

CML
Leukemogenic process [4]
Treatment:
Tyrosine kinase inhibitors are first line treatment. What is the rationale for their use? [1]
Give 3 examples of TKI
When is allogeneic transplantation indicated?
Risks of TKI [2]

A

Translocation of ch9 and 22 resulting in truncated ch22 + BCR-ABL gene segment
This is the Ph chromosome whose transcription results in increased amounts of ABL
Treatment:
- Tyrosine kinase inhibitors prevent phosphorylation of BCR-ABL eg Imatinib, busitinib, ponatinib
- Allogenic transplantation only in TKI failures

Risks of TKI

  • Cardiovascular risk
  • Reactivation of Hep B
27
Q 
Myelodysplastic syndromes
Define [1]
Presents with [2]
Progression [2]
Tx [2]
A

Acquired clonal disorders of bone marrow
Presents with Macrocytic anemia, pancytopenia
Pre-leukemic so progresses to bone marrow failure and AML > death
Tx: supportive and stem cell transplantation for few young patients

28
Q

Myeloproliferative neoplasms

Name 3 that are covered

A

Polycythemia vera
Essential thrombocytothemia
Idiopathic myelofibrosis

29
Q 
Myeloproliferative neoplasms: 
Polycythemia vera
Mutation in 95% is...
Presentation: 3 symptoms, 5 findings
RF [2]
A 
JAK2V617F mutation
Presentation:
Headaches, itch, plethoric facies
Vascular occlusion, TIA, stroke, thrombosis
Splenomegaly
RF: Stroke, arterial/venous thromboses
30
Q

Polycythemia vera
Progression [2]
Lab features [3]
Treatment [3]

A
  1. Bone marrow failure from development of secondary myelofibrosis (fibrotic bone marrow)
  2. Transforms to AML- development of additional mutations
    Lab:
  3. Raised hemoglobin concentration and hematocrit but blood vol normal
  4. Tendency for raised WCC and platelets
  5. Raised uric acid
    Tx:
  6. Take blood to keep hematocrit down plus aspirin
  7. Hydroxycarbamide
  8. Ruxolitinib - JAK2 inhibitor indicated in HC failures
31
Q

Essential thrombocytothemia
Mutation in 25%…
Lab findings [2]
Presentation [4]

A

CALR mutation 25%
Predominant features- raised platelet count, giant platelets
Presentations
- Arterial, venous thromboses, digital ischemia
- Gout
- Headache
- Mild splenomegaly
- Haemorrhage: bleeding normally associated with very high platelet counts >1500.

32
Q

Idiopathic myelofibrosis
Pathogenesis [2]
Which mutation are most often involved [1]

A

Mutation resulting in JAK2 receptor being autophosphorylated so erythropoiesis is independent of EPO
50% are JAK2 mutations
Hyperplasia of abnormal megakaryocytes causing Platelet derived growth fator to stimulate FIBROBLASTS
Haematopoiesis develops in liver and spleen leading to organomegaly.

33
Q

Idiopathic myelofibrosis
Symptoms [2]
Signs [1]
Blood film appearance [2]

A

50-60s
Weight loss, extreme tiredness
Cytopenic symptoms, gout
Signs: splenomegaly
Blood film: leukoerythroblastic blood film, tear drop poikilocyte
Dry tap on bone marrow biopsy - unobtainable

34
Q

Idiopathic myelofibrosis treatment [6]

A
  • Supportive care or watchful waiting for low risk patients.
  • EPO if anaemic and no spenomegaly, supportive transfusions.
  • Allopurinol for hyperuricemia
  • Cytoreductive therapy with hydroxycarbamide
  • JAK2 inhibitors for high risk patients
  • Allogeneic stem cell transplant for high risk patients
35
Q

Myelofibrosis

What other cytoreductive therapies are there? [4]

A

prednisolone; danazol; thalidomide; lenalidomide

36
Q

Essential thrombocytopenia
* Complications

A
  • Complications
  • Transformation to an acute leukaemia: occurs when blasts are >20%.
  • Thrombosis.
  • Haemorrhage.
  • Microvascular symptoms: Erythromelalgia, Migraine.
37
Q

Essential thrombocytopenia
Treatment

A
  • High risk: HC
  • Second line: anagrelide
  • Low risk: only consider cytoreduction if symptomatic

Recurrent clots - long term warfarin

38
Q

Myelodysplasia

A
  • Heterogeneous group of clonal disorders.
  • Characterised by ineffective haematopoiesis and, as a consequence, cytopaenia
  • May be primary or secondary to previous exposure to alkylating agents.
  • 30% progress to AML
39
Q

Myelodysplasia Treatments [5]

A
  • Iron chelation if more than 20–30 red cell transfusions.
  • Erythopoietin replacement if low erythropoietin level. An adequate iron store is necessary for erythropoietin replacement to be effective.
  • Immunosuppression with ciclosporin and anti-thymocyte globulin (ATG) if erythropoietin levels are adequate.
  • Hypomethylating agents such as azacitidine or decitabine
  • Lenalidomide is effective in reducing red blood cell transfusion requirements in patients with a 5q deletion cytogenetic abnormality.
  • Allogeneic BMT
40
Q

Amyloidosis

Defintion
Name three types of amyloidosis

A
  • amyloidosis is a term which describes the extracellular deposition of an insoluble fibrillar protein termed amyloid
  • Localised amyloidosis affects skin
  • AL amyloidosis is a clonal plasma cell disorder with deposition of the fibrous protein, resulting in organ dysfunction, particularly of the kidneys, heart, liver and peripheral nervous system.
41
Q

What is Amyloid light chain amyloidosis associated with?

A

AL amyloidosis is associated with myeloma, Waldenstrom’s macroglobinaemia and lymphoma.

42
Q

Amyloidosis manifestations

Kidney, heart, liver, nerves, endocrine, skin

A

■ Renal failure (most common) including nephrotic syndrome (% see Chapter 6, Amyloidosis, p. 577).
■ Cardiac failure leading to shortness of breath, peripheral oedema, hepatosplenomegaly.
■ Liver dysfunction.
■ Sensory and autonomic neuropathies.
■ Hypothyroidism.
■ Susceptibility to bleeding with bruising around the eyes, termed ‘racoon-eyes’ (due to amyloid depos-
ition in blood vessels and reduced activity of thrombin and factor V as a result of amyloid binding).
■ Macroglossia that may lead to dysphagia and obstructive sleep apnoea.
■ Carpal tunnel syndrome.

43
Q

Amyloidosis investigations

A
  • FBC.
  • U&E.
  • LFT.
  • 24-hour urine collection for proteinuria.
    Myeloma screen:
    ◆ serum and urine electrophoresis;
    ◆ skeletal survey.
  • Bone marrow biopsy with Congo red stain for presence of amyloid fibrils.
  • Echocardiogram.
  • SAP (serum amyloid P component) scanning:
    ◆ Involves injecting radiolabelled SAP into the patient to detect amyloid deposits in the body without the need for an invasive biopsy.
44
Q

Amyloidosis management

A
  • Excision or laser removal of localised amyloidosis lesions.
  • Treating underlying inflammatory disorder or infection in AA amyloidosis to reduce serum amyloid
    A protein production.
  • Treating underlying myeloma in AL amyloidosis, usually with bortezomib-based chemotherapy.
  • Management of secondary organ dysfunction, e.g. nephrotic syndrome, cardiac failure.
45
Q

What is poor prognosis in myeloma?

A

Raised B2 microglobulin

Low albumin

46
Q

50% of Waldenstrom’s macroglobulinaemia patients have which deletion?

A

Chromosome 6q

47
Q

How is WMG diagnosed?

A

IgM paraproteinaemia >30g
Raised RF
FBC with flow cytometry
Serum protein electrophoresis

48
Q

How is Waldenstrom’s macroglobulinaemia differentiated from multiple myeloma clinically?

A

No bone lesions/pain

49
Q

What is the treatment of Waldenstrom’s macroglobulinaemia?

A

Rituximab based chemo

with dex, cyc, fludarabine

50
Q

Why do WMG patients receiving rituximab need IgM monitoring?

A

Risk of IgM flare which leads to hyperviscosity

Haematology (11 decks)

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