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Transcript
Multiple Myeloma
By Dr Sameh Shamaa
Multiple Myeloma
Epidemiology:
• 1% Of all malignant diseases.
• Annual incidence: 3-4/100 000.
• Age:
- Median age: 65y.
- The diagnosis of MM in a patient < 30y
should only be made after careful evaluation of all
data.
OC precursor
OAF receptor (RANK)
OSTEOCLAST ACTIVATION
OPG/OCIF
Osteoclast
RANKL/OAF
Osteoblast/ stromal cell
/tumour cells/ myeloma
Teitelbaum Science 2000
MULTIPLE MYELOMA: Clinical Picture
MM
Monoclonal
Protein
Renal
Failure
Hyperviscosity
Marrow
Infiltration
Amyloidosis
Anaemia
Immune
Deficiency
Release of
Cytokines
Infections
LL 6
Bone
Destruction
Bone
Pains
Hypercalcaemia
Bone Marrow Failure:
*Anemia:usually normocytic normochromic :due to marrow
infiltration
and plasma volume expansion.
*Neutropenia is frequent(++ susceptibility to infection).
*Thrombocytopenia is rare.
Bone Disease:
Skeletal lytic lesions,with or without osteoperosis,wedging or
collapse of vertebral bodies or pathological fractures.
Renal Failure:
In 20-40% of cases,due to:
-BJP,and/0r hypercalcemia (in 95% of cases).
-Other causes: hyperuricemia,hypeviscosity,sepsis& nephrotoxic
drugs.
Hypercalcemia:
Secondary to osteolysis----->polyurea,and polydypsia may lead to severe
dehydration
Hyperviscosity:
usually associated with IgM M-protein----ocular,hemostatic,and
neurological disturbances.
Coagulopathy:
either:
-Hemorrhage: due to interference with action of clotting factors and
platelets.
-Thrombosis: due to acquired protein C deficiency.
Immune Paresis:
-In 70% of patients with IgG MM, 40% of IgA MM and 20% of acses with BJP MM
but cell mediated immunity is intact. So----- incresed risk of bacterial sepsis.
Amyloidosis:
In less than 5% of MM cases: more common with BJP and IgA MM-- deposition
of amyloid material--congesive heart failure, Carpal tunnel syndrome,
macroglossia, gastrointestinal disturbances and europathies., renal amyloidosis.
MULTIPLE MYELOMA
:
Lab investigation
•ESR: very high.
•Serum protein electrophoresis: M-band.
•Immunofixation or immunoelectrophoresis:
are confirmatory studies to define M-protein
heavy and light chain classes.
MULTIPLE MYELOMA
:
Lab investigation
•Serum Ca: often .
•Serum creatinine: often .
•Anaemia (not obligatory): (rouleaux formation
of RBCs).
•
In uninvolved immunoglobulins.
• +BJP in 24 hr urine collection (monoclonal
light chains).
MULTIPLE MYELOMA
BM PICTURE:
(Aspirate & Trephine Biopsy)
• >10 % myeloma cells..
• More basophilic cytoplasm.
• Increased mitotic figures or multiple nuclei.
• Coarse chromatin.
• Plasma cell nests.
MULTIPLE MYELOMA
Immunophenotyping:
• CD 38 +ve.
• CD 19, 20, 22 -ve.
• Intracytoplasmic Ig +ve.
• sIg -ve.
MULTIPLE MYELOMA
RADIODIAGNOSIS:
•Radiological survey of the entire skeleton:
is mandatory.
•MRI: is superior to CT for screening the
vertebral column for osteolytic lesions.
•Bone scan: is not indicated (cold lesions).
•REMEMBER!!
Iodine-containing contrast media may cause
acute renal failure in case of paraproteinaemia.
MM: SWOG Criteria for Diagnosis:
(At least 1 major + 1 minor or 3 minors)
Major Criteria:
(1) Plasmacytoma on tissue biopsy
(2) Marrow plasmacytosis > 30 %.
(3) Monoclonal protein:
Ig G > 3.5 g / dl.
Minor Criteria:
Ig A > 2 g / dl.
BJP > 1 g / 24 hr.
(1) Marrow plasmacytosis 10-29 %.
(2) Monoclonal protein present but
less than the above levels
(3) Lytic bone lesions
(4) Decrease in uninvolved Ig:
Ig M < 50 mg / dl.
Ig A < 100 mg / dl.
Ig G < 600 mg / dl.
MULTIPLE MYELOMA
Prognostic Factors
(1) Staging
(2) -2 microglobulin most significant)
(3) CRP (reflect IL-6 activity)
(4) PCLI
(5) Cytogenetics
(6) LDH
MM: Prognostic Factors
Risk Group
2M & CRP
Level
M.S.
(mg/l)
(mo)
Low-risk
Both
<6
54
Intermediate
2M
<6
27
High-risk
Both
>6
6
or CRP
MM: Prognostic Factors
Cytogenetics:
• Cytogenetics abnormalities occur in 80-90%
of patients.
• FISH is the best technique to discover them.
• Del 13 (partial or complete) & t involving 11q
are associated with poor prognosis in ABMT
patients only.
• Hypodiploidy is associated with drug resistance.
• Any abnormal karyotype leads to inferior
outcome with standard therapy.
MM Treatment Options
•
•
•
•
•
Chemotherapy
High dose-therapy with transplant
Radiation
Maintenance therapy (e.g. alpha interferon, prednisone)
Supportive care for
– Anaemia
– Pain
– Bone disease (Bisphosphonates)
– Hypercalcemia
– Antibiotics
– Emergency care (e.g. dialysis, plasmapheresis,
surgery)
• Management of drug-resistant or refractory disease
• New and emerging treatments
Treatment of MM
Use of Bisphosphonate in MM:
Mechanism of action:
1. Decrease IL-6 release
2. Direct effect on Myeloma (may slow tumor growth)
3. Effect of angiogenesis
Treatment of MM
Radiotherapy:
Indications:
• Big osteolytic lesions.
• Significant osteolytic lesions in
weight-bearing bone (for fear
of pathological fracture).
• Cord compression.
• Extramedullary plasmacytoma.
TREATMENT PLAN IN MM
Patients < 60 yrs of Age
3 courses of VAD
CR
PR
HLA-Typing
Another
3 courses of VAD
No HLA-Identical
Sibling
HLA-Identical
Sibling
ABMT
Mini-Transplant
CR
TREATMENT PLAN IN MM
Patients > 60 yrs
Asymptomatic
Symptomatic or PD
No treatment
MP till CR or
Max. Response
Progression < 6 months
Progression >6 months
VAD
Repeat MP
PD
PD
2nd line
VAD
Survival of Multiple Myeloma
patients
•
•
•
•
•
•
•
No treatment: 3-6 months
Conventional chemotherapy: 3 years
Chemotherapy + IFN-α: 3 years ± 6 months
Auto transplant: 5 years
25% dies within 1st year
25% survival 8 years
No cure by conventional chemotherapy