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Myeloma & Paraproteins Flashcards

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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]

Study These Flashcards
A

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

22
Q

Amyloidosis manifestations… [5]

Tx

Study These Flashcards
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]

Study These Flashcards
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

Study These Flashcards
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
CML Presentation [5] FBC features [3] and microscopy [2]
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
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]
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
``` Myelodysplastic syndromes Define [1] Presents with [2] Progression [2] Tx [2] ```
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
Myeloproliferative neoplasms | Name 3 that are covered
Polycythemia vera Essential thrombocytothemia Idiopathic myelofibrosis
29
``` Myeloproliferative neoplasms: Polycythemia vera Mutation in 95% is... Presentation: 3 symptoms, 5 findings RF [2] ```
``` JAK2V617F mutation Presentation: Headaches, itch, plethoric facies Vascular occlusion, TIA, stroke, thrombosis Splenomegaly RF: Stroke, arterial/venous thromboses ```
30
Polycythemia vera Progression [2] Lab features [3] Treatment [3]
1. Bone marrow failure from development of secondary myelofibrosis (fibrotic bone marrow) 2. Transforms to AML- development of additional mutations Lab: 1. Raised hemoglobin concentration and hematocrit but blood vol normal 2. Tendency for raised WCC and platelets 3. Raised uric acid Tx: 1. Take blood to keep hematocrit down plus aspirin 2. Hydroxycarbamide 3. Ruxolitinib - JAK2 inhibitor indicated in HC failures
31
Essential thrombocytothemia Mutation in 25%... Lab findings [2] Presentation [4]
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
Idiopathic myelofibrosis Pathogenesis [2] Which mutation are most often involved [1]
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
Idiopathic myelofibrosis Symptoms [2] Signs [1] Blood film appearance [2]
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
Idiopathic myelofibrosis treatment [6]
* 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
# Myelofibrosis What other cytoreductive therapies are there? [4]
prednisolone; danazol; thalidomide; lenalidomide
36
Essential thrombocytopenia * Complications
* Complications * Transformation to an acute leukaemia: occurs when blasts are >20%. * Thrombosis. * Haemorrhage. * Microvascular symptoms: Erythromelalgia, Migraine.
37
Essential thrombocytopenia Treatment
* High risk: HC * Second line: anagrelide * Low risk: only consider cytoreduction if symptomatic Recurrent clots - long term warfarin
38
Myelodysplasia
* 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
Myelodysplasia Treatments [5]
* 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
# Amyloidosis Defintion Name three types of amyloidosis
* 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
What is Amyloid light chain amyloidosis associated with?
AL amyloidosis is associated with myeloma, Waldenstrom’s macroglobinaemia and lymphoma.
42
Amyloidosis manifestations | Kidney, heart, liver, nerves, endocrine, skin
■ 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
Amyloidosis investigations
* 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
Amyloidosis management
* 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
What is poor prognosis in myeloma?
Raised B2 microglobulin | Low albumin
46
50% of Waldenstrom's macroglobulinaemia patients have which deletion?
Chromosome 6q
47
How is WMG diagnosed?
IgM paraproteinaemia >30g Raised RF FBC with flow cytometry Serum protein electrophoresis
48
How is Waldenstrom's macroglobulinaemia differentiated from multiple myeloma clinically?
No bone lesions/pain
49
What is the treatment of Waldenstrom's macroglobulinaemia?
Rituximab based chemo with dex, cyc, fludarabine
50
Why do WMG patients receiving rituximab need IgM monitoring?
Risk of IgM flare which leads to hyperviscosity

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