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Multiple Myeloma
www.MansFans.com
Epidemiology 1% Of all malignant diseases. Annual incidence: 3-4/100 000. In the US 16,000 people are diagnosed and more than 11,000 die with MM each year
Age: - Median age: 65y. - The diagnosis of MM in a patient < 30y should only be made after careful evaluation of all data.
www.MansFans.com
Epidemiology •
•
•
Incurable in almost all patients Median survival from diagnosis is 4-5 years More frequent in men than women
www.MansFans.com
Multiple Myeloma • Malignancy of plasma cells •Plasma cells >10% of bone marrow Hallmarks • Presence of monoclonal protein • Anemia • Renal failure • Bone destruction (lytic bone lesions) • Hypercalcemia • Increased risk of infection
www.MansFans.com
Multiple Myeloma Clinical Picture Paraprotein
TRIAD
Osteolytic Bone Lesions
++ Myeloma cells in BM
MULTIPLE MYELOMA: Clinical Picture MM M o n o c lo n a l P r o te in Renal F a ilu r e
H y p e r v is c o s ity
M a rro w In filtr a tio n A m y lo id o s is
A n a e m ia
Im m u n e D e fic ie n c y
R e le a s e o f C y to k in e s
In fe c tio n s
LL 6
Bone D e s tr u c tio n Bone P a in s
H y p e r c a lc a e m ia
Symptoms Bone pain Tumor release of IL-6 (osteoclast activating factor), causing lytic bone lesions
Infection due to low Antibody production
Renal failure Commonly due to hypercalcemia, Bence Jones protein tubular damage, recurrent pyelonephritis
www.MansFans.com
Symptoms Normocytic normochromic anemia Weakness and fatigue Confusion Headache and retinopathy due to blood hyperviscosity
www.MansFans.com
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).
www.MansFans.com
Multiple Myeloma BM PICTURE: (Aspirate & Trephine Biopsy) • >10 % myeloma cells..
• More basophilic cytoplasm. • Increased mitotic figures or multiple nuclei. • Coarse chromatin. • Plasma cell nests.
www.MansFans.com
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.
Lateral skull x-ray with typical findings of MM
Typical lesion in a tibia
Multiple Myeloma 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. Ig A > 2 g / dl. BJP > 1 g / 24 hr.
Multiple Myeloma Criteria for Diagnosis: Minor Criteria: (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.
www.MansFans.com
Multiple Myeloma Prognostic Factors (1) Staging (2) β-2 microglobulin (3) CRP (4) Cytogenetics (5) LDH
www.MansFans.com
Treatment of MM
Criteria of Response:
CR:
•No M-band in serum or urine on electrophoresis. •BJP < 200 mg/24 hrs •Plasma cells in BM < 5%
N.B. Immunofixation in serum and urine may still be positive.
VG PR:
•Decrease of M-band or light chains > 90 %. •Plasma cells in BM < 10%
Treatment of MM
Criteria of Response: PR: Decrease of M-band or light chains in urine > 50 %.
Minimal Response (MR): Decrease of M-band or light chains in urine > 25 %.
No Change (NC): No change in any parameter.
Treatment of MM
Criteria of Response: Progressive Disease(PD):
• Increase in M-band or light chains in urine > 25 %. • Development of new osteolytic lesions. • Newly developed hypercalcaemia.
Primary Resistance: Response rate < 25 % after at least 4 full-dose treatment cycles.
Multiple Myeloma Main Causes of Death: • Uncontrolled infections • Renal failure • Bleeding • Secondary leukaemia
35% 20% 20% 5%
T R E A T M E N T P L A N IN M M P a tie n ts > 6 0 y r s A s y m p to m a tic
S y m p to m a tic o r P D
N o tre a tm e n t
M P till C R o r M ax. R esponse
P r o g r e s s io n < 6 m o n th s
P r o g r e s s io n > 6 m o n th s
VAD
R epeat M P
PD
PD
2 n d lin e
VAD
T R E A T M E N T P L A N IN M M P a tie n ts < 6 0 y r s o f A g e 3 c o u rs e s o f V A D
C R
PR
H L A -T y p in g
A n o th e r 3 c o u rs e s o f V A D
N o H L A - Id e n t ic a l S ib lin g
H L A - Id e n t ic a l S ib lin g
AB M T
M in i-T r a n s p la n t
C R
TREATM ENT PLAN IN M M P a tie n ts w ith M in im a l R e s p o n s e
> 6 0 yrs
< 6 0 y rs
VAD
S e c o n d L in e
Chemotherapy of MM First line: MP
•Melphalan 8 mg/m2 P.O. day 1-4
(0.25mg\Kg\day X 4 days) •Prednisone 60 mg/m2 P.O. day 1-4 Repeat every 4 weeks VAD •VCR 0.4 mg C.I. day 1-4 •Adriamycin 9 mg/ m2 C.I. day 1-4
•Dexamethasone 40 mg P.O. day 1-4 & 9-12 (& day 17-20 in cycle 1 only)
Repeat every 3 weeks
Chemotherapy of MM Second line: High dose dexamethasone: 40 mg I.V. day 1-4, 9-12,19-21. DCEP •Dexamethasone 40 mg I.V. day 1-4 •Cyclophosphamide 300 mg/ m2 C.I. day 1-4 •Etoposide 30 mg/ m2 C.I. day 1-4 •Platinol 15 mg/ m2 C.I. day 1-4 CEP to be mixed together in 1L normal saline. Not compatible with Mg or Kcl
Treatment of MM
Radiotherapy: Indications: • Big osteolytic lesions. • Significant osteolytic lesions in weight-bearing bone (for fear of pathological fracture). • Cord compression. • Extramedullary plasmacytoma.
www.MansFans.com
Epidemiology 1% Of all malignant diseases. Annual incidence: 3-4/100 000. In the US 16,000 people are diagnosed and more than 11,000 die with MM each year
Age: - Median age: 65y. - The diagnosis of MM in a patient < 30y should only be made after careful evaluation of all data.
www.MansFans.com
Epidemiology •
•
•
Incurable in almost all patients Median survival from diagnosis is 4-5 years More frequent in men than women
www.MansFans.com
Multiple Myeloma • Malignancy of plasma cells •Plasma cells >10% of bone marrow Hallmarks • Presence of monoclonal protein • Anemia • Renal failure • Bone destruction (lytic bone lesions) • Hypercalcemia • Increased risk of infection
www.MansFans.com
Multiple Myeloma Clinical Picture Paraprotein
TRIAD
Osteolytic Bone Lesions
++ Myeloma cells in BM
MULTIPLE MYELOMA: Clinical Picture MM M o n o c lo n a l P r o te in Renal F a ilu r e
H y p e r v is c o s ity
M a rro w In filtr a tio n A m y lo id o s is
A n a e m ia
Im m u n e D e fic ie n c y
R e le a s e o f C y to k in e s
In fe c tio n s
LL 6
Bone D e s tr u c tio n Bone P a in s
H y p e r c a lc a e m ia
Symptoms Bone pain Tumor release of IL-6 (osteoclast activating factor), causing lytic bone lesions
Infection due to low Antibody production
Renal failure Commonly due to hypercalcemia, Bence Jones protein tubular damage, recurrent pyelonephritis
www.MansFans.com
Symptoms Normocytic normochromic anemia Weakness and fatigue Confusion Headache and retinopathy due to blood hyperviscosity
www.MansFans.com
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).
www.MansFans.com
Multiple Myeloma BM PICTURE: (Aspirate & Trephine Biopsy) • >10 % myeloma cells..
• More basophilic cytoplasm. • Increased mitotic figures or multiple nuclei. • Coarse chromatin. • Plasma cell nests.
www.MansFans.com
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.
Lateral skull x-ray with typical findings of MM
Typical lesion in a tibia
Multiple Myeloma 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. Ig A > 2 g / dl. BJP > 1 g / 24 hr.
Multiple Myeloma Criteria for Diagnosis: Minor Criteria: (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.
www.MansFans.com
Multiple Myeloma Prognostic Factors (1) Staging (2) β-2 microglobulin (3) CRP (4) Cytogenetics (5) LDH
www.MansFans.com
Treatment of MM
Criteria of Response:
CR:
•No M-band in serum or urine on electrophoresis. •BJP < 200 mg/24 hrs •Plasma cells in BM < 5%
N.B. Immunofixation in serum and urine may still be positive.
VG PR:
•Decrease of M-band or light chains > 90 %. •Plasma cells in BM < 10%
Treatment of MM
Criteria of Response: PR: Decrease of M-band or light chains in urine > 50 %.
Minimal Response (MR): Decrease of M-band or light chains in urine > 25 %.
No Change (NC): No change in any parameter.
Treatment of MM
Criteria of Response: Progressive Disease(PD):
• Increase in M-band or light chains in urine > 25 %. • Development of new osteolytic lesions. • Newly developed hypercalcaemia.
Primary Resistance: Response rate < 25 % after at least 4 full-dose treatment cycles.
Multiple Myeloma Main Causes of Death: • Uncontrolled infections • Renal failure • Bleeding • Secondary leukaemia
35% 20% 20% 5%
T R E A T M E N T P L A N IN M M P a tie n ts > 6 0 y r s A s y m p to m a tic
S y m p to m a tic o r P D
N o tre a tm e n t
M P till C R o r M ax. R esponse
P r o g r e s s io n < 6 m o n th s
P r o g r e s s io n > 6 m o n th s
VAD
R epeat M P
PD
PD
2 n d lin e
VAD
T R E A T M E N T P L A N IN M M P a tie n ts < 6 0 y r s o f A g e 3 c o u rs e s o f V A D
C R
PR
H L A -T y p in g
A n o th e r 3 c o u rs e s o f V A D
N o H L A - Id e n t ic a l S ib lin g
H L A - Id e n t ic a l S ib lin g
AB M T
M in i-T r a n s p la n t
C R
TREATM ENT PLAN IN M M P a tie n ts w ith M in im a l R e s p o n s e
> 6 0 yrs
< 6 0 y rs
VAD
S e c o n d L in e
Chemotherapy of MM First line: MP
•Melphalan 8 mg/m2 P.O. day 1-4
(0.25mg\Kg\day X 4 days) •Prednisone 60 mg/m2 P.O. day 1-4 Repeat every 4 weeks VAD •VCR 0.4 mg C.I. day 1-4 •Adriamycin 9 mg/ m2 C.I. day 1-4
•Dexamethasone 40 mg P.O. day 1-4 & 9-12 (& day 17-20 in cycle 1 only)
Repeat every 3 weeks
Chemotherapy of MM Second line: High dose dexamethasone: 40 mg I.V. day 1-4, 9-12,19-21. DCEP •Dexamethasone 40 mg I.V. day 1-4 •Cyclophosphamide 300 mg/ m2 C.I. day 1-4 •Etoposide 30 mg/ m2 C.I. day 1-4 •Platinol 15 mg/ m2 C.I. day 1-4 CEP to be mixed together in 1L normal saline. Not compatible with Mg or Kcl
Treatment of MM
Radiotherapy: Indications: • Big osteolytic lesions. • Significant osteolytic lesions in weight-bearing bone (for fear of pathological fracture). • Cord compression. • Extramedullary plasmacytoma.
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