Myeloma and Other Plasma Cell Disorders Flashcards
where are B cells derived from?
derived from pluripotent haematopoietic stem cells in bone marrow
role of B cells?
part of adaptive immune system
dual role
- antibody production
- acting as antigen presenting cells
what are immunoglobulins?
antibodies produced by B cells and by plasma cells
proteins made of 2 heavy chains (long) and 2 light chains (short)
each antibody recognizes a specific antigen
where are the antigen binding sites on antibody?
tip variable region of Fab portion
structure of different types of antibody?
IgM = pentamer
IgA = dimer
IgG, IgD, IgE = monomer
describe process of B cell development in bone marrow?
under control/influence of microenvironment
variable region of Ig generated from V-D-J region recombination early in development
self reactive cells are removed
immature B cells with Ig on their surface exit bone marrow ready to meet their target
describe normal B lymphocyte maturation
stem cells > lymphoid precursors > pro B cells > pre B cells > IgM B cells > IgG, IgE, IgA, IgM plasma cells
function of B cells in the periphery?
travel to the follicle germinal centre of the lymph node
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 B cell
what are plasma cells?
type of B cell
factory cell which pumps out antibody
what do plasma cells look like?
has characteristic “clock face” nucleus
open chromatin (synthesising mRNA)
plentiful blue cytoplasm laden with protein
pale perinuclear area with Golgi apparatus
describe polyclonal increase in Ig?
polyclonal increase
produced by many different plasma cell clones
immunoglobulins increase in polyclonal way in response to what?
infection
autoimmune
malignancy (reaction of host to the malignant clone)
liver disease
describe monoclonal increase in Ig?
all derived from clonal expansion of a single B cell
all have identical antibody structure and specificity (size and charge)
monoclonal Ig are known as what?
paraprotein
monoclonal rise in Ig is a marker of what?
underlying clonal B cell disorder
how are immunoglobulins detected?
serum electrophoresis
- the separated serum proteins appear as distinct bands or zones (proteins move at different rates depending on their size and charge)
can detect abnormal protein bands
what is serum immunofixation?
to classify the abnormal protein band
what is bence jones protein?
excess free Ig light chains detected in urine electrophoresis
some excess always produced but more excess can indicate polyclonal increase in number of plasma cells due to infection or monoclonal increase such as multiple myeloma
normal amount of free light chain production per day?
0.5g per day
components of free light chains (bence jones protein)?
kappa free light chain (monomer)
lambda = dimer)
myeloma accounts for how many cases of paraproteinaemia?
18%
what is a myeloma?
plasma cell malignancy
progression from normal plasma cell to myeloma?
several genetic hits cause progression from normal plasma cell > MGUS clone (pre-malignant) > asymptomatic myeloma (malignant but no organ damage) > myeloma
how can myeloma affect the body?
direct tumour cell effects
paraprotein mediated effects
direct tumour cell effects?
bone lesions
increased calcium
bone pain
replace normal bone marrow causing marrow failure
paraprotein mediated effects of myeloma?
renal failure
immune suppression
hyperviscosity
amyloid
how is myeloma classified?
by type of antibody produced IgG (59%) IgA (21%) bence jones (15%) others around 1%
characteristic feature of lytic bone disease on imaging?
punched out lytic lesions
can have wedge compression fracture in thoracic vertebra
how does lytic bone disease occur in myeloma?
myeloma cells proliferate > IL-6 produced which activates osteoclasts
features of hypercalcaemia?
stones bones abdominal groans psychiatric moans thirst dehydration renal impairment
how does myeloma affect the kidney?
30% have renal impairment at diagnosis tubular cell damage by free light chains light chain deposition sepsis hypercalcaemia and dehydration drugs (NSAIDs) hyperuricaemia amyloid
how does myeloma cause kidney damage?
free light chains are small enough to filter through glomerular pores
kidneys function to prevent loss of small proteins like light chains so proximal tubules reabsorb these
proximal tubules can be overwhelmed or damaged then light chains pass into loops of henle producing tamm Horsfall protein which can combine with light chains to form insoluble casts which block the nephron
management of cast nephropathy (renal damage due to myeloma)?
can be reversible with prompt treatment
hydration
stop nephrotoxic drugs
switch off light chain production with steroids/chemo
management of myeloma?
combination chemo = mainstay
combination with
- corticosteroids
- alkylating agents (cyclophosphamide, melphalan)
- novel agents (thalidomide, bortezomib)
- can do high dose chemo/autologous stem cell transplant in fit patients
what is autologous stem cell transplant?
way of delivering very high dose chemo relatively safely
give drugs to release blood stem cells from marrow > collect stem cells > freeze stem cells until needed > give chemo to remove immune system > return thawed stem cells > give supportive treatment for 4 weeks
monoclonal antibody treatment for myeloma?
daratumumab?
effectiveness of myeloma treatment?
relapse is inevitable
5-10 year survival in young people
symptoms control in myeloma?
opiate analgesia (avoid NSAIDs) local radiotherapy (pain relief or spinal cord compression) bisphosphonates (hypercalcaemia and bone pain) vertebroplasty (inject sterile cement into fractured bone to stabilise)
what is MGUS?
monoclonal gammopathy of undetermined significance
features of 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
how is MGUS most common in?
increase with age of elderly
what is AL amyloidosis?
rare disorder
small plasma cells clone
due to mutation in the light chain > altered structure
results in precipitation of light chain in the tissues as an insoluble beta pleated sheet
often presents late with organ damage
presenting features of AL amyloidosis?
organ damage slowly progressive multisystem disease different protein to SAA amyloidosis (chronic amyloidosis) and familial amyloidosis poor prognosis (esp if cardiac amyloid)
AL amyloidosis treatment?
chemo
similar to myeloma to switch off light chain supply
what organ damage can occur in AL amyloid?
kidney heart liver neuropathy (autonomic/peripheral) GI tract (malabsorption)
how is amyloidosis diagnosed and staged?
organ biopsy confirming AL amyloid deposition
- congo red stain
- (rectal/fat biopsy if high clinical suspicion)
evidence of deposition in other organs (SAP scan, ECHO, nephrotic range proteinuria)
what is SAP scan?
indium labelled serum amyloid scintography used to monitor disease burden and response
localises rapidly and specifically to amyloid deposits in proportion to quantity of amyloid present
how deos AL amyloid stain?
congo red
apple green birefringence under polarised light
what is waldenstrom’s macroglobulinaemia?
IgM paraprotein due to lymphoplasmacytoid neoplasm
clonal disorder of cells intermediate between lymphocyte and a plasma cell
has characteristic IgM paraprotein
tumour effects of waldenstroms macroglobulinaemia?
lymphadenopathy
splenomegaly
marrow failure
paraprotein effects of macroglobulinaemia?
hyperviscosity
neuropathy
