PBL 5 – Back pain from minor fall
Rick Allen
Multiple Myeloma
Definition
A malignant proliferation of plasma cells derived from a single clone,
with multifocal involvement of the skeleton.
Aetiology
The cause is unknown, however evidence exists relating to chromosomal
alterations;
-13q14/17p13 deletions.
-11q abnormalities
-t(11;14)(q13;q32) – cyclin D1 (cell cycle regulatory genes) and
t(4;14)(p16;q32) – heavy chain gene (with a tyrosine kinase receptor –
control cell proliferation)
-mys, ras, p53 and Rb-1 mutations.
Control blood cell development
Pathophysiology
A monoclonal Ig Id’d in the blood is called an M (myeloma) component.
If complete, are restricted to the plasma and extracellular fluid; kept out of
urine (assuming no glomerular damage).
Neoplastic plasma cells often produce excess heavy or light chains,
as well as complete Ig’s. Tend to stick to only one. Light chains are small
enough to fit through the glomerular apparatus and be excreted in urine
(Bence-Jones Proteins). These can be measured in blood and urine. IgG – 55%,
IgA – 25%
Attach to bone marrow stromal cells via adhesion molecules and ECM which
trigger the tumours growth (via IL-6, IGF -1 insulin like growth factor, , drug
resistance and migration/survival.
G genes of myeloma cells show somatic hypermutation, meaning that
the cell is a differentiated plasma (B) cell
PBL 5 – Back pain from minor fall
Rick Allen
Proliferation and survival due to adhesion to bone stromal cells as well
as cytokines – IL-6 (produced by tumour cells and stromal cells)
Bone destruction – tumour cytokines cause the upregulation of RANKL
expression of marrow stromal cells/osteoblasts  activating osteoclasts via
(RANK). Other cytokines inhibit osteoblast activity  hypercalcaemia and
pathologic fractures, generalized osteoporosis.
Malignant plasma cells stimulate osteoclasts to erode bone. (Osteoclast
Activating Factors, inc. IL-1/6) OPG, which blocks this interaction, is inhibited.
Bring on bisphosphonates!
Epidemiology
-1,115 Australians are diagnosed every year
-Risk increases with age - 80%>60 y.o., uncommon in <40 y.o.
-Men>women
Blacks 2x> whites
Cause of 15% of cancer deaths???
4 x more likely to get if you have a family member with it.
1% of all cancers, 10% haematological cancers
Clinical Features
Are due to: 1.plasma cell growth in tissue (bones)
2.Production of excessive Ig’s with abnormal
physiochemical properties
3.Normal humoral immunity suppression
 pathologic fractures and chronic pain.
 hypercalcaemia  neurologic symptoms (confusion,
weakness, lethargy, constipation, polyuria) and renal dysfunction
Bone resorption
Bone pain, usually precipitated by movement.
PBL 5 – Back pain from minor fall
Rick Allen
↓ normal Ig’s produced  recurrent bacterial infection. Cell immunity not
affected. Breakdown of Ig (spec. IgG) dependant on concentration of Ig,
therefore increases with increased numbers.
IgA  hyperviscosity of blood  headache, retinopathy, fatigue, visual
disturbance.
Renal failure: multifactorial causes, however the greatest cause is the Bence
Jones proteinuria as the light chains are toxic to renal tubal epithelial cells
(metabolised). Can also see pyelonephritis, metastatic calcification, protein
casts in distal convoluted and collecting ducts  atrophy of tube cells and
presence of giant cells. Light chains can also cause amyloidosis which
exacerbates renal dysfunction and get into other tissues (tongue, heart,
peripheral nerves, kidneys).
Marrow involvement  normocytic, normochromic anaemia, leukopenia and
thrombocytopenia. Pancytopenia
Morphology
Destructive plasma cell tumours in the axial skeleton. Vertebral column,
ribs, skull, pelvis, femur, clavicle, scapula.
Begins in the medullary cavity  erodes cancellous (trabecular, spongy) bone
destroys cortical bone
Lesions appear as punched-out defects 1-4cm diameter. Soft, gelatinous red
tumour masses
Away from tumour masses, increased marrow plasma cellularity (10-90%
abnormal plasma cells). Can infiltrate the interstitium and other organs.
Cells appear with potentially multiple nuclei, prominent nucleoli, cytoplasmic
droplets (Ig), perinuclear clearing (golgi apparatus)
High level of M protein/Igs causes rouleaux formation (may give ↑ MCV)
Dx.
99% of pts - ↑ levels of Igs in the blood and/or light chains in the urine (24hr
specimen).
Radiographic and lab findings. Strongly suspected with distinct radiograph
images, but require bone marrow examination to confirm.
PBL 5 – Back pain from minor fall
Rick Allen
Protein electrophoresis to determine Ig/chains.
DDx.
Some leukaemia’s can also produce M components (CLL), as well as
lymphomas.
Tx./Mx.
Cytotoxic agents induce remission in 50-70% of pts. Sensitive to proteasome
inhibitors (cell organelle degrades unwanted/misfolded proteins)  misfolded
proteins encourage apoptosis. Also seem to retard bone resorption with
effects on stromal cells.
Thalidomide (combination chemo)  alters interactions b/n myeloma cells and
bone marrow stromal cells. Also inhibit angiogenesis
Bisphosphonates  inhibit bone resorption therefore reduce pathologic
fractures and hypercalcaemia.
Bone marrow transplant prolongs life but is not curative. No known cure.
Radiotherapy for bone pain.
Basically systemic treatment + symptomatic treatment
Px.
Generally poor: median survival is 4-6 years. Multiple bony lesions  if
untreated rarely survive past 6-12 months.
Death usually a result of Renal failure or infection
Plasmacytoma – myeloma that is isolated to a local area. “Solitary myeloma”.
Found in osseous areas similar to multiple myeloma and are likely to spread
(can take 10-20 years). Can be located in lungs, oronasopharynx, nasal sinus
(these can be cured by resection)
Monoclonal Gammopathy of Uncertain Significance – Contains the same
genetic abnormalities as found in multiple myeloma. MGUS is the most
common form of plasma cell dyscrasia (bad blood mix), US – occurs in 3% > 50
y.o. and 5% > 70 y.o.
PBL 5 – Back pain from minor fall
Rick Allen
Pts are asymptomatic with elevated M protein levels (<3 gm/dL). 1% of pts
with MGUS will progress to MM. Progression is unpredictable.
References
Robbins and Cotran, pp 609-611
Harrisons, pp 701-706
Underwood, pp 667-669
Leukaemia association of Australia
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