Myeloma Flashcards
Which immune system are the B-cells a part of?
What are their roles?
- part of the adaptive immune system
2. Roles: Ab prodn/ Antigen presenting cells
What are immunoglobulins?
- Abs made by B-cells and plasma cells
Where do B-cells develop?
in the Bone marrow
How is the Ig variable element genrated from?
- from the V-D-J region recombination found at Ag binding site
- early in development
What do the naive B cells do in the periphery?
- travel to the FOLLICLE germinal centre of the lymph node
- identify the Ag and improve the fit by somatic mutation or be deleted.
- may return to marrow as a plasma cell or as a memory B-cell
What does a b-cell appear on histology?
- clock-face nucleus
- open chromatin (synthesizes mRNA)
- -plentiful BLUE cytoplasm (laden with protein)
- –pale perinuclear area (gogli apparatus)
What is polyclonal incr. in immunoglobulins?
Why may it occur?
- produced by MANY diff. plasma cell CLONES
- reactive to INFECTION/ AUTOIMMUNE/ MALIGNANCY/ LIVER DISEASE
What is monoclonal rise in immunoglobulins?
- Ig all derived from clonal expansion of a SINGLE B-cell —-IDENTICAL Ab specificity and structure
monoclonal Ig= paraprotein
What may monoclonal rise in Ig indicate?
marker of UNERLYING clonal B-cell disorder.
How are Ig detected?
- by serum electrophoresis
- —serate serum proteins appear as dstinct bands
- –proteins move at differing rates determined by their SIZE and CHARGE
Where willl albumin be seen on electrophoresis?
- given it’s the MOST NEGATIVELY charged molecule
- —it will be seen close to ANODE
Why is there a rise in the amount of free light chains in the plasma and in the urine?
- when Ig is produced in the plasma cells, MORE LIGHT chains are made than heavy chains
- –the free light chains are secreted into the plasma along with intact Ig
IN what conditions may free light chains INCREASE in the plasma?
- polyclonal INCREASE (d.t INFECTION)
- MONOCLONAL incr. in plasma cells (d.t multiple myeloma)
both of which will result in INCR. of free light chains in the plasma
Name causes of paraproteinaemia.
- Myeloma
- MGUS (56%)
- Amyloidosis (10%)
- Lymphoma
- aymptomatic myeloma
- solitary/ extramedullary plasmocytoma
- Chronic lymphocytic leukaemia
- Waldenstrom Macroglobulinaemia
What is Bence Jones protein?
- immunoglobulin light chains
- detected by urine electrophoresis
How does myeloma develop?
normal plasma cells hit with genetic mutations> MGUS clone (benign) > few more genetic hits> ASYMPTOMATIC MYELOMA (MALIGNANT but no organ damage)
> more hits= MYELOMA
How does myeloma affect the body?
- clonal PLASMA cells
How does myeloma bring about organ damage?
- Direct tumor cell effects
2. Paraprotein mediated effects
What are exs. of DIRECT tumor cell defect?
- bone lesions
- incr. CALCIUM
- bone pain
- replaced normal bone marrow–> MARROW failure
What are some paraprotein mediated efx?
- renal failure
- immune supression
- hyperviscocity
- amyloid
What kind of bony lesions are seen with multiple myeloma?
lesions arise from medullary cavity> erosion of cancellous bone> cortical bone destruction»FRACTURES (usually in vertebral column and femur) – compression fractures
- punched out defects
- diffuse SKELETAL demineralization (rise in Ca)
How can myeloma be classified?
- by the type of Ab produced (seen in serum/ urine)
- –60% produce IgG
- Bence Jones myeloma (15%)
- —some don’t produce monoclonal proteins at all (Non-secretory myeloma)
Why do myelomas cause lytic bone disease?
- flourish of myeloma cells> RISE in IL-6> further rise in IL-6 and TGF-beta
- the rise in these chemokines> OSTEOCLAST ACTIVATION (and suppression of osteoblasts)
—-BONE RESORPTION! in bone matrix
–RISE in Ca2+
What is the risk of hypercalcemia?
- renal stones
- bone pain (spinal cord impingement is possible on vertebral #)
- abdominal groans
- neuro: confusion and lethargy
- thirst and dehydration
- renal impairment
How common is renal impairment in myeloma pt?
30% present with renal impairment at dx
Why are light-chains pathological in the kidney with myeloma?
- ligh chain deposition in the DISTAL convoluted tubules and collecting ducts==> CAST nephropathy
- tubular cell damage (necrosis or atrophy) d.t toxic effect of Bence Jones proteins (light chains)
What are other causes renal problems in myeloma?
- sepsis (bacterial pyelonephritis)
- metastatic calcification of the kidneys (d.t hypercalcemia and bone resorption)
- use of NSAIDS
- hyperuricemia
- amyloidosis —involving glomeruli and vessel walls
How to casts form in the nephrons?
- light chains usually meant to be reabsorbed at the PCT
- when PCT is overwhelmed or damaged; light chains make it to the thick ascending limb where Tamm-Horsfall protein is formed
-this protein combined with free light chains==> insoluble CASTS; which BLOCK the nephron
Name the most common ft of multiple myeloma
- renal failure
- cast nephropathy is greatest cause
How to manage cast nephropathy>
- reversible with prompt rx
- HYDRATION; stop nephrotoxic drugs
- steroids and chemo will SWTICH OFF light chain production
What is involved with the rx of myeloma?
- corticosteroids (DEXAMEHTASONE or PREDNISOLONE)
- alkylating agents (cyclophosphamide/ melphalan)
- novel agents (thalidomide/ lenalidomibe/ bortezomib)
- —–in FIT pts: high dose CHEMO and stem cell transplant
How to monitor response of myeloma to rx?
monitor PARAPROTEIN levels
Name novel agents for rx of myeloma.
thalidomide/ lenalidomibe/ bortezomib)
What could be done to deliver very HIGH dose chemo, relatively safe?
AHSCT
(autologous haematopoietic stem cell transplant)
—-deliver v.HIGH dose chemo, safely
—–collect and freeze pts blood stem cells (after inducing stem cell release from the bone marrow) PRIOR to chem
- give chemo
- return blood cells by infusion to vein
What is the survival rate for younger pts?
5-10 YEARS
- relapse is inevitable
How to control symtpoms?
- opiate analgesia (AVOID NSAIDS)
- loacl radiotherapy (pain relief/ spinal cord compression)
- biphosphonates (corrects hypercalcemia and BONE pain)
- Vertebroplasty- inject sterile cement into FRACTURED bone
What is MGUS?
- monoclonal gammopathy of undetermined significance
`
—-paraprotein <3g/dL
—–bone marrow plasma cells <10%
—–no evidence of myeloma and organ damage!
MGUS is commonly seen in whom>
- 5% (greatest %) in their 8th decade
What occurs in AL amyloidosis?
- small plasma cell clone
- –mutation in the LIGHT chain > altered structure
- —precipitates in tissues as an insoluble beta pleated sheet
What is the pathophysiology of AL amyloidosis?
- accumulation (of beta-pleated sheets) in tissues> organ damage
- slowly progressive
- multisystem disease
- —-POOR prog. if cardiomyopathy
Rx of AL amyloidosis?
- same as MYELOMA
- chemo to switch of light chain prodn
What kind of organ damage occurs with AL amyloid?
- nephrotic syndrome
- cardiomyopathy
- organomegaly (LFTS messed up)
- autonomic and peripheral neuropathy
- malabsorption
How to dx AL amyloidosis?
- organ biopsy CONFIRM deposition of AL amyloid —-CONGO RED STAIN
- -rectal and fat biopsy done; if HIGH clinical suspicion
What evidence sought for AL amyloid deposition in other orgasn?
- SAP scan
- echocardiogram (cardiac MRI)
- nephrotic range proteinuria
What is used in SAP scan for AL amyloid?
- I-123 labelled serum amyloid P used to monitor disease burden and response
- —SAP localises rapidly and specifically to amyloid deposits —in proportion to the quantity of amyloid present
What is Waldenstrom’s Macroglobulinaemia?
IgM paraprotein
- neoplasm of the lymphoplasmacytoid
- —tumor effects
- -paraprotein effects
What are tumor effects?
- splenomegaly
- marrow failure
- lymphadenopathy
What are protein effects?
- hyperviscocity
- neuropathy
How does hyperviscosity syndrome present as?
- fatigue
- bleeding
- visual disturbance
- confusion
- coma
B sx: wgt loss/ night sweats
Who is at risk of lymphoplasmacytoid?
those in 60s-70s
What is the rx of Waldenstroms?
chemo plasmapheresis (removes paraprotein from circulation)
How does plasmapheresis help?
removes pt plasma rich in IgM paraprotein —–replace with donor plasma
