Myeloma and Other Plasma Cell Disorders

Question 1

where are B cells derived from?

Answer 1

derived from pluripotent haematopoietic stem cells in bone marrow

Question 2

role of B cells?

Answer 2

part of adaptive immune system
dual role
- antibody production
- acting as antigen presenting cells

Question 3

what are immunoglobulins?

Answer 3

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

Question 4

where are the antigen binding sites on antibody?

Answer 4

tip variable region of Fab portion

Question 5

structure of different types of antibody?

Answer 5

IgM = pentamer
IgA = dimer
IgG, IgD, IgE = monomer

Question 6

describe process of B cell development in bone marrow?

Answer 6

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

Question 7

describe normal B lymphocyte maturation

Answer 7

stem cells > lymphoid precursors > pro B cells > pre B cells > IgM B cells > IgG, IgE, IgA, IgM plasma cells

Question 8

function of B cells in the periphery?

Answer 8

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

Question 9

what are plasma cells?

Answer 9

type of B cell

factory cell which pumps out antibody

Question 10

what do plasma cells look like?

Answer 10

has characteristic “clock face” nucleus
open chromatin (synthesising mRNA)
plentiful blue cytoplasm laden with protein
pale perinuclear area with Golgi apparatus

Question 11

describe polyclonal increase in Ig?

Answer 11

polyclonal increase

produced by many different plasma cell clones

Question 12

immunoglobulins increase in polyclonal way in response to what?

Answer 12

infection
autoimmune
malignancy (reaction of host to the malignant clone)
liver disease

Question 13

describe monoclonal increase in Ig?

Answer 13

all derived from clonal expansion of a single B cell

all have identical antibody structure and specificity (size and charge)

Question 14

monoclonal Ig are known as what?

Answer 14

paraprotein

Question 15

monoclonal rise in Ig is a marker of what?

Answer 15

underlying clonal B cell disorder

Question 16

how are immunoglobulins detected?

Answer 16

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

Question 17

what is serum immunofixation?

Answer 17

to classify the abnormal protein band

Question 18

what is bence jones protein?

Answer 18

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

Question 19

normal amount of free light chain production per day?

Answer 19

0.5g per day

Question 20

components of free light chains (bence jones protein)?

Answer 20

kappa free light chain (monomer)

lambda = dimer)

Question 21

myeloma accounts for how many cases of paraproteinaemia?

Answer 21

18%

Question 22

what is a myeloma?

Answer 22

plasma cell malignancy

Question 23

progression from normal plasma cell to myeloma?

Answer 23

several genetic hits cause progression from normal plasma cell > MGUS clone (pre-malignant) > asymptomatic myeloma (malignant but no organ damage) > myeloma

Question 24

how can myeloma affect the body?

Answer 24

direct tumour cell effects

paraprotein mediated effects

Question 25

direct tumour cell effects?

Answer 25

bone lesions increased calcium bone pain replace normal bone marrow causing marrow failure

Question 26

paraprotein mediated effects of myeloma?

Answer 26

renal failure immune suppression hyperviscosity amyloid

Question 27

how is myeloma classified?

Answer 27

``` by type of antibody produced IgG (59%) IgA (21%) bence jones (15%) others around 1% ```

Question 28

characteristic feature of lytic bone disease on imaging?

Answer 28

punched out lytic lesions | can have wedge compression fracture in thoracic vertebra

Question 29

how does lytic bone disease occur in myeloma?

Answer 29

myeloma cells proliferate > IL-6 produced which activates osteoclasts

Question 30

features of hypercalcaemia?

Answer 30

``` stones bones abdominal groans psychiatric moans thirst dehydration renal impairment ```

Question 31

how does myeloma affect the kidney?

Answer 31

``` 30% have renal impairment at diagnosis tubular cell damage by free light chains light chain deposition sepsis hypercalcaemia and dehydration drugs (NSAIDs) hyperuricaemia amyloid ```

Question 32

how does myeloma cause kidney damage?

Answer 32

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

Question 33

management of cast nephropathy (renal damage due to myeloma)?

Answer 33

can be reversible with prompt treatment hydration stop nephrotoxic drugs switch off light chain production with steroids/chemo

Question 34

management of myeloma?

Answer 34

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

Question 35

what is autologous stem cell transplant?

Answer 35

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

Question 36

monoclonal antibody treatment for myeloma?

Answer 36

daratumumab?

Question 37

effectiveness of myeloma treatment?

Answer 37

relapse is inevitable | 5-10 year survival in young people

Question 38

symptoms control in myeloma?

Answer 38

``` 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) ```

Question 39

what is MGUS?

Answer 39

monoclonal gammopathy of undetermined significance

Question 40

features of MGUS?

Answer 40

``` 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 ```

Question 41

how is MGUS most common in?

Answer 41

increase with age of elderly

Question 42

what is AL amyloidosis?

Answer 42

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

Question 43

presenting features of AL amyloidosis?

Answer 43

``` organ damage slowly progressive multisystem disease different protein to SAA amyloidosis (chronic amyloidosis) and familial amyloidosis poor prognosis (esp if cardiac amyloid) ```

Question 44

AL amyloidosis treatment?

Answer 44

chemo | similar to myeloma to switch off light chain supply

Question 45

what organ damage can occur in AL amyloid?

Answer 45

``` kidney heart liver neuropathy (autonomic/peripheral) GI tract (malabsorption) ```

Question 46

how is amyloidosis diagnosed and staged?

Answer 46

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)

Question 47

what is SAP scan?

Answer 47

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

Question 48

how deos AL amyloid stain?

Answer 48

congo red | apple green birefringence under polarised light

Question 49

what is waldenstrom's macroglobulinaemia?

Answer 49

IgM paraprotein due to lymphoplasmacytoid neoplasm clonal disorder of cells intermediate between lymphocyte and a plasma cell has characteristic IgM paraprotein

Question 50

tumour effects of waldenstroms macroglobulinaemia?

Answer 50

lymphadenopathy splenomegaly marrow failure

Question 51

paraprotein effects of macroglobulinaemia?

Answer 51

hyperviscosity | neuropathy