Myeloma & Paraproteins Flashcards
Describe the basic structure of an antibody? [3]
Y shaped with 2 heavy and 2 light chains
“Trunk” = FC portion (constant & defines subclass)
“Branches” = FAB portion (variable & defines antigen binding)
What’s the most common antibody?
IgG - 75% of total
What is a paraprotein?
A monoclonal Ab in blood or urine (i.e. lots of the same Ab) indicating monoclonal proliferation of a B-cell type
How can we test antibody levels? [1]
How do we assess for antibody diversity & paraproteins? [2]
Total Immunoglobulin levels
Serum Protein Electrophoresis
(Separates the proteins incl antibodies by size/charge)
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]
Immunofixation
Serum light Chain Assay
What if we find a paraprotein in someone with no illness?
Diagnose with MGUS
Monoclonal Gammopathy of Uncertain Significance
How do we diagnose a myeloma? [4]
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)
How do we stage myeloma? [2]
Based on Albumin & Beta2 Microglobulin levels
What is a myeloma? [2]
Epidemiology [2]
A neoplasm of plasma cells –> Excessive production of a single immunoglobulin
Peaks in the 7th decade
And is commonest amongst black people
Presentations of myeloma can occur through Plasma cells or the paraprotein. What are the myeloma-related symptoms? CRABBI
Radiological findings in myeloma
- Calcium
- Renal failure
- Anaemia
- Bone
- Bleeding
- Infections
X-ray spine for cord compression and pepper pot skull - whole body MRI
Paraprotein related symptoms in myeloma [4]
Renal failure - cast nephropathy
Hyperviscosity syndrome
Hypogammaglobulinaemia –> Infection susceptibility
Amyloidosis
How can we treat Myeloma? [7]
Chemo RT Bisphosphonate Steroids Surgery Autologous Stem Cell Transplant Bortezomib + Dexamethasone
Why use bisphosphonates in myeloma?
Treat the bone disease, very like osteoporosis
What is surgery used for in myeloma?
Removal of single lesions and decompressing the spinal cord if causing paralysis/weakness
How does an autologous stem cell transplant work?
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)
Which immunoglobulins are present in myeloma?
What immunoglobulins are present in lymphoma?
IgA & IgG
IgM paraproteins can be found instead in lymphoma or Waldenstroms macroglobulinemia
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]
Triad of bone marrow failure:
- Anemia
- Thrombocytopenic bleeding
- 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
Acute myeloid leukemia
What will bone marrow biopsy microscopy show [1]
Targeted molecular genetics are used for acquired gene mutations - name 3
≥ 20% myeloblasts in the bone marrow confirm the diagnosis
Targeted molecular genetics for associated acquired gene mutations
FLT3, NPM1, IDH1+2
AML Tx:
- General supportive therapy with blood products, keep plt>10
- Induce complete remission <5% blasts in bone marrow, normalising FBC, then consolidation
- Allogeneic stem cell transplant for poor prognosis
- Intensive chemo in 3-4 blocks each lasting 1w: cytosine and danorubicin
Specific treatments include:
CD33 - Mylotarg
Midostaurin for FLT3 mutations
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
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
Hyperviscosity syndrome in multiple myeloma [2]
Manifests in [4]
impaired microcirculation > hypoperfusion
Bleeding e.g. retinal, oral, nasal or cutaneous
Sometimes HF, confusion or renal failure
Amyloidosis manifestations… [5]
Tx
Nephrotic syndrome Cardiac failure LVH CTS nodules Raccoon eyes - cutaneous infiltration Autonomic neuropathy - dizziness Tx: chemotherapy
Features of bone disease in MM [4]
Treatment [6]
Lytic lesions, path fractures, cord compression & hypercalcaemia Tx: Chemotherapy Bisphosphonate therapy - zolendronic acid Steroids Radiotherapy Surgery Autologous stem cell transplant
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
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
CML
Presentation [5]
FBC features [3] and microscopy [2]
- Anemia
- Splenomegaly
- Hypermetabolic - weight loss
- Hyperleukostasis, tumor lysis syndrome
- Gout
Patients usually present in 50s.
* Anemic
* WBC high - High neutrophil level
* Platelets high
Bone marrow/blood: heterogenous blood film, Philadelphia chromosome
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
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
Myeloproliferative neoplasms
Name 3 that are covered
Polycythemia vera
Essential thrombocytothemia
Idiopathic myelofibrosis
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
Polycythemia vera
Progression [2]
Lab features [3]
Treatment [3]
- Bone marrow failure from development of secondary myelofibrosis (fibrotic bone marrow)
- Transforms to AML- development of additional mutations
Lab: - Raised hemoglobin concentration and hematocrit but blood vol normal
- Tendency for raised WCC and platelets
- Raised uric acid
Tx: - Take blood to keep hematocrit down plus aspirin
- Hydroxycarbamide
- Ruxolitinib - JAK2 inhibitor indicated in HC failures
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.
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.
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
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
Myelofibrosis
What other cytoreductive therapies are there? [4]
prednisolone; danazol; thalidomide; lenalidomide
Essential thrombocytopenia
* Complications
- Complications
- Transformation to an acute leukaemia: occurs when blasts are >20%.
- Thrombosis.
- Haemorrhage.
- Microvascular symptoms: Erythromelalgia, Migraine.
Essential thrombocytopenia
Treatment
- High risk: HC
- Second line: anagrelide
- Low risk: only consider cytoreduction if symptomatic
Recurrent clots - long term warfarin
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
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
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.
What is Amyloid light chain amyloidosis associated with?
AL amyloidosis is associated with myeloma, Waldenstrom’s macroglobinaemia and lymphoma.
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.
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.
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.
What is poor prognosis in myeloma?
Raised B2 microglobulin
Low albumin
50% of Waldenstrom’s macroglobulinaemia patients have which deletion?
Chromosome 6q
How is WMG diagnosed?
IgM paraproteinaemia >30g
Raised RF
FBC with flow cytometry
Serum protein electrophoresis
How is Waldenstrom’s macroglobulinaemia differentiated from multiple myeloma clinically?
No bone lesions/pain
What is the treatment of Waldenstrom’s macroglobulinaemia?
Rituximab based chemo
with dex, cyc, fludarabine
Why do WMG patients receiving rituximab need IgM monitoring?
Risk of IgM flare which leads to hyperviscosity
