Introduction
Immunoglobulin genetics and the relationship of gene segments to the antibody protein. The top portion of the figure is a schematic of the organization of the immunoglobulin genes, ? on chromosome 22, ? on chromosome 2, and the heavy chain locus on chromosome 14. The heavy chain locus is >2 megabases, and some of the D region gene segments are only a few bases long, so the figure depicts the schematic relationship among the segments, not their actual size. The bottom portion of the figure outlines the steps in going from the noncontiguous germline gene segments to an intact antibody molecule. Two recombination events juxtapose the V-D-J (or V-J for light chains) segments. The rearranged gene is transcribed, and RNA splicing cuts out intervening sequences to produce an mRNA, which is then translated into an antibody light or heavy chain. The sites on the antibody that bind to antigen (the so-called CDR3 regions) are encoded by D and J segments for heavy chains and the J segments for light chains.
Monoclonal gammopathy(MGUS, pre-malig.) ? MM / Waldenström
? ? heavy chain disease, cryoglobulinemia, amyloidosis ?
Multiple myeloma, MM
Definition
Most common primary malignancy of bone.
High serum IL-6 is sometimes present; stimulates plasma cell growth and immunoglobulin production
IgG(55%) > A(25%) > D > E, light chain
Etiology
Myeloma cells stimulate osteoclast maturation by producing RANKL and by destroying OPG
Inhibit osteoblast activity by secreting cytokines that block osteoblast function (e.g., IL-3, IL-7, Wnt pathway inhibitors)
Incidence and prevalence
Global considerations
Pathogenesis and clinical manifestations
- Bone pain with hypercalcemia
- Neoplastic plasma cells activate the RANK receptor on osteoclasts, leading to bone destruction.
- [A] Lytic, ‘punched-out’ skeletal lesions are seen on x-ray, especially in the vertebrae and skull; increased risk for fracture
- Elevated serum protein
- Neoplastic plasma cells produce immunoglobulin
- M spike is present on serum protein electrophoresis (SPEP), most commonly due to monoclonal IgG or IgA.
- ?Gamma gap; total protein and albumin difference
- Increased risk of infection
- Monoclonal antibody lacks antigenic diversity
- Infection is the most common cause of death in multiple myeloma.
- Pneumonia – S.pneumonia is the m/c.
- LIght cain
- Circulate in serum and deposit in tissues ? Primary AL amyloidosis
- Excreted in the urine as Bence Jones protein ? deposition in kidney tubules leads to risk for renal failure (myeloma kidney).
- Blood smear
- [B] Rouleaux formation of RBCs; increased serum protein decreases charge between RBCs
- [C] Numerous plasma cells with “clock-face” chromatin and intracytoplasmic inclusions containing immunoglobulin.
- Basophilic cytoplasm, well-developed Golgi apparatus (perinuclear paleness)
Diagnosis and staging
Serum/urine M(monoclonal) protein>3g/dL
BM plasmacytosis >10%
Related organ/tissue impairment (ROTI-CRAB)
Ca? / Renal failure / Anemia / Bone lesion
?; Bone scan, ALP – ????? ???
IVP? renal failure? ????? ??!
Monoclonal gammopathy of undetermined significance (MGUS)
lncreased serum protein with M spike on SPEP; other features of multiple myeloma are absent (e.g., no lytic bone lesions, hypercalcemia, AL amyloid, or Bence Jones proteinuria).
Common in elderly (seen in 5% of 70-year-old individuals)
1% of patients with MGUS develop multiple myeloma each year.
Acute complications are treated with plasmapheresis, which removes lgM from the serum.
- Increased serum protein with M spike (comprised of lgM)
Prognosis
?2 microglobulin : single most powerful predictor of survival
???? (ISS)
I — ?2 microglobulin <3.5 & Albumin >3.5
III — ?2 microglobulin >5.5 & Albumin any
?? ??? ????. ?? ??? II? ??.
Treatment
- ???: ???? ??
- ?????? O (65? ?? & good fxal status)
- Induction CTx
- Velcade
- Thalidomide
- Dexamethasone
- ??? autologous BMT
- Induction CTx
- ???? ?? X (65~75?)
- Bortezomib + thalidomide + prednisone
- Salvage Tx: ??? ?? ??? ??? ??. Bortezomib or lenalidomide
- ??? ??
- Hypercalcemia: ????, bisphosphonate
- ??? ??: ?? ?? ??, UTI ?? ??
- Hyperviscosity: plasmapheresis
Waldenström macroglobulinemia
B-cell lymphoma with monoclonal IgM production
Clinical features
- Generalized lymphadenopathy; lytic bone lesions are absent.
- Hyperviscosity syndrome
- Visual and neurologic deficits (e.g., retinal hemorrhage or stroke)
- Diplopia, tinnitus, headache, dilated/segmented funduscopic findings
- Bleeding: viscous serum results in defective platelet aggregation.
- Peripheral neuropathy
- Infiltrative disease
- Hypatosplenomegaly
- Anemia, thrombocytopenia
- Cryoglobulinemia
- Renal insufficiency
Physical exam
“Sausage-link” (dilated, segmented tortuous) retinal veins
Diagnosis
- SPEP
- If positive, BM biopsy
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