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Profili Assistenziali del Mieloma
Multiplo Tiziano Barbui Ematologia, Ospedali
Riuniti, Bergamo Pescara, 30 giugno 2004
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Multistep molecular pathogenesis of MM
Primary Ig translocations cyclin D1 or D3 FGFR3
MMSET c-maf others
Karyotypic instability 13q deletion
Somatic mutations N-ras, K-ras, FGFR3
Secondary Ig translocations c-mic others
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Multistep progression of MM
Feature Stroma-dependence Drug
resistance Cytogenetics FISH Metaphase Pote
ntial for long-term disease control
MGUS/ Smouldering MM Micro- environment
Abnormal Normal N/A
Intra-Medullary MM Micro- environment Epige
netic Abnormal Normal Good
Extra-Medullary MM Genetic
Micro- environment Epigenetic Abnormal Abnormal
Poor
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Clinical Profiles Definitions for Treatment
Feature Serum MC g/dl Marrow PC BJ
proteinuria Immuneparesis Lytic
lesions ROTI Symptoms Treatment
MGUS lt 3.0 lt10 Rare Rare No No No No
Solitary Plasma- cytoma in 50
lt5 Maybe Rare Solitary No Local RTx
Asymptomatic MM gt 3 g/dl gt10 Maybe Maybe No No
No No
MM variable gt10 in 50 Yes Yes Yes Often Yes
PCL variable 40-95 75-90 Yes Yes Yes Often Ye
s
ROTI myeloma-Related Organ/Tissue Impairment
(hypercalcemia, renal impairment, anemia, lytic
bone lesions, symptomatic hyperviscosity,
amyloidosis, recurrent bacterial infections)
International Myeloma Working Group, BJH
2003121749
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Clinical Profiles Definition of Response
Feature Serum MC Urine MC BM PC Size/No.
of bone lesions Disappearance of soft tissue
plasmacytoma Hypercalcemia
CR IF- IF- lt5 No Yes No
VGPR IF IF lt5 No Yes No
PR gt50 gt90 gt50 No gt50 No
Relapse from CR IF IF gt5 Yes Yes Yes
Progression from PR gt25 gt25 gt25 Yes Yes
Yes
Blade J et al, BJH 19981021115
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New Diagnosis of Multiple Myeloma Bergamo,
January 1997 - May 2004
Number Sex, M / F Age, year median (range) Type
(n 331) IgG / A / D Light chain Non-secretory
Plasma cell leukemia Plasmacytoma Clinical
stage (n 310) I A / B II A / B III A / B
352 185 / 167 64 (28-94) 183 / 58 /
3 47 9 5 26 44 / 1 37 / 4 185 / 42
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MM Patients Overall Survival
41 at 5 yrs
Bergamo, 1997-2004
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Bergamo, 1997-2004
9
Bergamo, 1997-2004
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Patients with Multiple Myeloma Characteristics
according to treatment
Sex, M / F Age, years median
(range) Comorbidity, n () Heart Liver Lung Va
scular GI tract CNS Diabetes Hypertension
Transplant, n 182 100 / 82 59 (28-71) 12
(7) 10 (6) 14 (8) 17 (9) 11 (6) 2 (1) 13 (7) 39
(22)
Others, n 132 69 / 69 73 (32-92) 36 (27) 12
(9) 29 (22) 12 (9) 16 (12) 4 (3) 11 (8) 41 (31)
Bergamo, 1997-2004
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MM Patients Overall Survival Intention-to-treat
analysis
AutoTx
Others
years
AutoTx, n 182 48 at 5 yrs Others, n 132 24 at
5 yrs
Bergamo, 1997-2004
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MM Patients Overall Survival by Autotransplant
Procedures
AutoTx yes
AutoTx no
0
2
4
6
8
AutoTx yes, n 141 (77) 54 at 5 yrs AutoTx no,
n 41 (23) 21 at 5 yrs
Bergamo, 1997-2004
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TTI Treatment of 120 MM Patients
VAD x 3, n 120
EDX G-CSF, n 120
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gt 6x10 CD34/kg in all cases purged n 40
Mel-200, n 120
hepatitis HBsAg, n 10 polineuropathy, n
1 cardiomyiopathy, n 1 progression death, n
3 alloTx, n 3 bad PS after 1autoTx, n 1
n 19 (16)
Mel-200 (n 87), or Mel-140 TBI (n 14), Total n
101 (84)
NO TRM
Bergamo, 1997-2004
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Outcome of 120 MM Patients Treated with TTI
Overall OS EFS
Median OS 82 months, 43 at 118 months Median
EFS 42 months, 21 at 118 months
Bergamo, 1997-2004
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TT-I Response Rate ()

Bergamo, 1997-2004
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Outcome of 120 MM Patients Treated with TTI OS
by pre-AutoTx state
100
CR/VGPR
75
50
Probability,
PR/NR
25
p0.015
0
0
84
24
48
60
120
months
At risk Event m. CR/VGPR 32
6 77 102 PR/NR 89 40 34 118
Bergamo, 1997-2004
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Bergamo, 1997-2004
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Novel Therapies for treatment of MM
Drug Velcade Thalidomide Revlimid Arsenic
trioxide 2ME2 SAHA NVP-LAQ824 PTK787 17-AAG
Mechanism Proteasome inhibitor Immunomodulatory,
antiangiogenic Immunomodulatory ROS induction,
GSH inhibitor ROS induction, microtubule
inhibition Histone deacetylase inhibitor Histone
deacetylase inhibitor VEGFR inhibitor Hsp90
inhibitor
RR 35/50 32/70 70/NA 21/42 NA NA NA NA NA
Clinical phase III III II II II I I I I
single agent / combination therapy
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Supportive Care of MM
Anemia rHuEPO / Blood transfusions Bone disease
and pain Morphine / other pain
killers Bisphosphonates Vertebroplasty /
Kyphoplasty Radiotherapy Hypercalcemia Hydratio
n Bisphosphonates Infection Antibiotics /
Antivirals General nursing Home / Hospital /
Hospice