2. Multiple myeloma (MM)
It is a plasma cell malignancy in which monoclonal
plasma cells proliferate in bone marrow, resulting in
an overabundance of monoclonal paraprotein (M
protein)
There is destruction of bone, and displacement of
other hematopoietic cell lines.
3.
4.
5. Etiology
The precise etiology of MM has not yet been
established.
Genetic causes
Environmental or occupational causes
MGUS
Radiation
Chronic inflammation
Infection-Human herpesvirus 8 (HH8) infection of
bone marrow dendritic cells
6. Genetic defects - MM
About 50% are hyperdiploid, with extra copies of the
odd-numbered chromosomes.
A primary translocation involving the Ig heavy-chain
gene at 14q32.
Gysregulation of the cyclin D/retinoblastoma (cyclin
D/RB) pathway.
This genetic heterogeneity contributes to the rapid
emergence of drug resistance in MM.
7. Pre MM conditions
MM is commonly preceded by monoclonal gammopathy of
undetermined significance (MGUS), a premalignant
condition
In MGUS, these clonal plasma cells take up less than 10% of
bone marrow.
The serum protein value is less than 3 g/dL and myeloma-
related end-organ damage is absent.
An intermediate disease stage between MGUS and MM,
termed smoldering MM, is characterized by an M protein
level of 3 g/dL or more and over 10% clonal plasma cells in
bone marrow
But no symptoms of myeloma-related end-organ damage.
9. MM and cytokines
Interleukin (IL)-6 is also an important factor
promoting the in vitro growth of myeloma
cells.
Other cytokines are tumor necrosis factor
and IL-1b.
MM involves the skeletal, hematologic,
renal, and nervous systems
10. Skeletal manifestations
Plasma-cell proliferation causes extensive skeletal
destruction with osteolytic lesions, anemia,
and hypercalcemia through production of the
osteoclast-activating factor.
Destruction of bone and its replacement by tumor may
lead to pain, spinal cord compression, and pathologic
fracture.
Compression fracture of a vertebral body destroyed by
multiple myeloma
Bony involvement is typically lytic in nature.
11. Hematologic processes
Bone marrow infiltration by plasma
cells results in neutropenia, anemia,
and thrombocytopenia.
M components may interact with
clotting factors, leading to defective
aggregation.
12. Renal processes
Direct tubular injury, amyloidosis, or
involvement by plasmacytoma.
Hypercalcemic nephropathy, hyperurcemia
Due to renal infiltration of plasma cells
resulting in myeloma, light-chain
nephropathy
Amyloidosis
Glomerulosclerosis.
13. Hyperviscosity syndrome.
Due to overproduction of IgG1, IgG3, or
IgA. Sludging in the capillaries
It results in purpura, retinal hemorrhage,
papilledema, coronary ischemia, or central
nervous system (CNS) symptoms (eg,
confusion, vertigo, seizure).
Cryoglobulinemia causes Raynaud
phenomenon, thrombosis, and gangrene in
the extremities.
14. Complications
Renal failure
Nephrocalcinosis due to hypercalcemia
Anemia, neutropenia, or thrombocytopenia
is due to bone marrow infiltration of plasma
cells.
Thrombosis and Raynaud phenomenon due
to cryoglobulinemia may be present.
15. Clinical features
Severe bone pain, pathologic fracture due to
lytic lesions
Increased bone resorption leading to
hypercalcemia
Spinal cord compression: Symptoms
typically include back pain, weakness or
paralysis in the legs, numbness, or
dysesthesias in the lower extremities.
16. Clinical features
Radiculopathy and/or cord compression may occur
because of skeletal destruction and nerve
compression.
Bacterial infection may develop
Purpura, retinal hemorrhage, papilledema,
coronary ischemia, seizures, and confusion may
occur as a result of hyperviscosity syndrome.
Hypercalcemia may cause polyuria and polydipsia,
muscle cramps, constipation
A change in the patient’s mental status.
21. Exudative macular detachment, retinal
hemorrhage, or cotton-wool spots
Dermatologic evaluation
Pallor from anemia
Ecchymoses or purpura from thrombocytopenia
Extramedullary plasmacytomas
Bony tenderness or pain without tenderness
Sensory level change, neuropathy, myopathy,
positive Tinel sign, or positive Phalen sign
Abdominal examination: Hepatosplenomegaly
Cardiovascular evaluation: Cardiomegaly
22.
23. Myeloma-defining events
Serum calcium level >0.25 mmol/L (>1 mg/dL) higher than
the upper limit of normal or >2.75 mmol/L (>11 mg/dL)
Renal insufficiency (creatinine >2 mg/dL [>177 μmol/L] or
creatinine clearance < 40 mL/min)
Anemia (hemoglobin < 10 g/dL or hemoglobin >2 g/dL
below the lower limit of normal)
One or more osteolytic bone lesions on skeletal
radiography, CT, or PET-CT
Clonal bone marrow plasma cells ≥60%
Abnormal serum free light chain (FLC) ratio ≥100 (involved
kappa) or < 0.01 (involved lambda)
One or more focal >5 mm lesions on MRI scans
24. Differential Diagnoses
Primary (Malignant) Lymphoma of
Bone
Metastatic Bone Disease
Monoclonal Gammopathies of
Undetermine Significance (MGUS)
Waldenstrom Macroglobulinemia
25.
26. Lab tests
Serum and urine assessment for monoclonal
protein (densitometer tracing and
nephelometric quantitation;
immunofixation for confirmation)
Serum-free light chain assay
Bone marrow aspiration and/or biopsy
Serum beta-2 microglobulin
Albumin,
LDH
28. Lab tests
Total protein, albumin, and globulin
Blood urea nitrogen (BUN) and creatinine
Uric acid
Quantitative Immunoglobulin Levels (IgG, IgA, IgM)
C-reactive protein (CRP) is a surrogate marker of
interleukin (IL)-6 activity.
IL-6 is often referred to as the plasma cell growth
factor.
beta-2 microglobulin is useful for prognostic marker
29. Urine Collection
24-hour urine for quantification of the
Bence Jones protein (ie, lambda light
chains), protein, and creatinine clearance.
> 1 g of protein in 24 h is a major criterion
for MM
For monitoring the response to therapy
Creatinine clearance - renal impairment.
30. Serum Viscosity
Check the serum viscosity in patients
with central nervous system (CNS)
symptoms, nosebleeds, or very high M
protein levels.
These findings may
indicate hyperviscosity syndrome.
37. Prognosis
C-reactive protein (CRP) and beta-2
microglobulin:
If levels of both proteins are less than 6
mg/L, the median survival is 54 months.
If the level of only one component is less
than 6 mg/L, the median survival is 27
months.
If levels of both protein values are greater
than 6 mg/L, the median survival is 6
months.