Myeloma and Other Plasma Cell Dyscrasias Flashcards
What are B cells derived from?
Pluripotent haematopoietic stem cells in bone marrow
What is the role of B cells?
Part of adaptive immune system
Dual roles: antibody production, acting as APCs
What are Immunoglobulins?
Antibodies produced by B or plasma cells
Proteins made up of 2 heavy ((μ, α, δ, γ, ε) and 2 light chains (κ or λ)
Each Ab recognises a specific Ag
What is the structure of IgD, E and G?
Monomer
What is the structure of IgA?
Dimer
What is the structure of IgM?
Pentamer
What is the Ig variable element of B-cells generated from?
V-D-J region recombination early in development
Describe B cell development
Initial production/development in marrow
Under control/influence of microenvironment
Ig variable element generated
Self-reactive cells removed
Immature B cells with Ig on their surface exit bone marrow ready to meet target
From IgM Pro B cells, what is then produced?
IgM and IgD Pre B cells in marrow, then: IgM B cells, which produce IgM plasma cells IgA IgE IgG, which produce plasma cells
Describe B cells in the periphery
Travel to the follicle germinal centre of the LN
Identify the antigen and improve the fit by somatic mutation or be deleted
May return to the marrow as plasma cell or circulate as memory cell
Describe plasma cells
Factory cells Pumps out Ab Eccentric clock face nucleus on H&E Open chromatin- synthesising mRNA Plentiful blue cytoplasm- laden with protein Pale perinuclear area- Golgi apparatus
What will polyclonal Ig’s be reactive to?
Infection
AI
Malignancy-reaction of host to malignant clone
Liver disease
What is a monoclonal Ig?
Paraprotein- marker of underlying clonal B-cell disorder
How are Ig’s detected?
Serum electrophoresis- separated serum proteins appear as distinct bands or zones
What is the most -vely charged molecule found on electrophoresis?
Albumin
What is contained in the alpha-1 band?
Alpha 1 antitrypsin
What is contained in the alpha 2 band?
Alpha 2 macroglobulin, caeruloplasmin, haptoglobin
What is contained in the beta band?
Transferrin, low density lipoprotein, C3
What is contained in the gamma band?
IgG, A, M, D, E
What is serum immunofixation used for?
To classify the abnormal protein band
What are Bence-Jones protein?
Ig light chains, detected by urine electrophoresis
What amount of free light chain is produced by normal plasma cells each day?
0.5g/day
Excess can leak into the urine as BJP
What are the causes of paraproteinaemia?
MGUS 56% Myeloma 18% Amyloidosis 10% Lymphoma 5% Asymptomatic myeloma 4% Solitary or extramedullary plasmacytoma 3% CLL 2% Waldenstroms macroglobulinaemia 2%
What are the direct tumour cell effects of clonal plasma cells in myeloma?
Bone lesions
Increased calcium
Bone pain
Replacement of normal bone marrow- leading to marrow failure
What are the paraprotein mediated effects of clonal plasma cells in myeloma?
Renal failure
Immunosuppression
Hyperviscosity
Amyloid
How is myeloma classed?
Type of Ab produced
What are the types of myeloma?
IgG 56% IgA 21% BJP myeloma- free light chain 15% Nonsecretory myeloma 3% IgD 1% Biclonal 1% IgE 0.01%
Why does myeloma cause lytic bone disease?
Increased levels of IL-6, leading to increased TGFbeta, osteoblast suppression and osteoclast activation
Leads to hypercalcaemia
What are the symptoms and signs of hypercalcaemia?
Stones Bones Abdominal groans Psychiatric moans Thirst Dehydration Renal impairment
What causes damage to the kidney in myeloma?
Tubular cell damage by light chains Light chain deposition; cast nephropathy Sepsis Hypercalcemia and dehydration Drugs; NSAIDs Amyloid Hyperuricaemia
How is cast nephropathy managed?
Damage may be reversible with prompt treatment
Switch off light chain production with steroids/chemo
What is the treatment of myeloma?
Corticosteroids; dexamethasone or prednisolone
Alkylating agents eg cyclophosphamide, melphalan
‘Novel agents’ like thalidomide, bortezomib and lenalidomide
Monoclonal antibodies against plasma cells
High dose chemo/autologous stem cell transplant in fit patients
How is myeloma response to treatment monitored?
Paraprotein level
How are myeloma symptoms controlled?
Opiate analgesia (avoid NSAIDs)
Local radiotherapy - good for pain relief or spinal cord compression
Bisphosphonates - corrects hypercalcaemia and bone pain
Vertebroplasty – inject sterile cement into fractured bone to stabilise
What is the definition of monoclonal gammopathy of uncertain significance (MGUS)?
Paraprotein <30g/l Bone marrow plasma cells <10% No evidence of myeloma end organ damage; Normal calcium Normal renal function Normal Hb No lytic lesions No increase in infections
What is the risk of progression to myeloma of MGUS?
~1%
Describe Amyloid light chain (AL) Amyloidosis
Rare
Small plasma cell clone
Mutation in light chain, leads to altered structure
Precipitates in tissues as an insoluble beta pleated sheet
Often presents late with organ damage
Accumulation in tissues causes organ damage
Slowly progressive, multisystem
Different protein to SAA amyloidosis/familial amyloidosis
Poor prognosis esp if cardiac amyloid
What organ damage can AL amyloidosis cause?
Kidney- Nephrotic syndrome Heart- Cardiomyopathy Liver- Organomegaly deranged LFT’s Neuropathy-Autonomic, Peripheral GI tract- Malabsorption
How is AL Amyloidosis diagnosed and staged?
Organ biopsy- congo red stain, rectal or fat biopsy may be done if high clinical suspicion as less invasive
Evidence of deposition in other organs- SAP scan, echo, heavy proteinuria
What is Waldenstrom’s Macroglobulinaemia(IgM paraprotein)?
Lymphoplasmacytoid neoplasm- clonal disorder of cells intermediate between a lymphocyte and plasma cell, characteristic IgM paraprotein
What are the tumour effects of Waldenstrom’s?
Lymphadenopathy
Splenomegaly
Marrow failure
What are the paraprotein effects of Waldenstrom’s?
Hyperviscosity
Neuropathy
What are the clinical features of WM?
Hyperviscosity syndrome- fatigue, visual disturbance, confusion, coma, bleeding, cardiac failure
B symptoms: night sweats, weight loss
How is WM treated?
Chemo Plasmapheresis (removes paraprotein from circulation)
