MIELOMA MULTIPLO
tumore delle plasmacellule
producono immunoglobuline
vivono nelle ossa
DIVISIONE UNIVERSITARIA DI EMATOLOGIA
AZIENDA OSPEDALIERA SAN GIOVANNI
TORINO, ITALY
Multiple myeloma
• uncontrolled proliferation of Ig secreting plasma cells
– most commonly IgG (57%), IgA (21%) or light chain only (18%)
• twice as common in men as women
• and in blacks as whites
• 1% of all cancers
– 2% in african americans
• incurable
• median survival 3 years
• few therapeutic advances since the introduction of melphalan
(Bergsagel, 1962)
Myeloma bone pathology
Multiple Myeloma (MM)
• B-cell neoplasia, characterized by the
expansion of plasma cells producing an
abnormal monoclonal immunoglobulin
• 21,500 new cases yearly in Europe
• Median age at diagnosis: 65 years
• incurable disease
MM – Impact for Patients
Consequences of MM include:
• Painful osteolytic bone lesions
• Bone marrow infiltration, causing
anemia, fatigue, and
immunodeficiency, with an increased
risk of serious infections
• The abnormal proteins may cause
renal dysfunction or kidney failure
Bruno B, Rotta M, and Boccadoro M,
Lancet Oncology 2004
MIELOMA MULTIPLO
CRP
IL-6
hepatocyte
OAF
IL-1
OSTEOCLAST
DIVISIONE UNIVERSITARIA DI
EMATOLOGIA
AZIENDA OSPEDALIERA S. GIOVANNI
BATTISTA
TORINO, ITALY
MIELOMA MULTIPLO
malattia dell'anziano
5/100.000/pazienti/anno
350 pazienti/anno in Piemonte
età media alla diagnosi 70 anni
DIVISIONE UNIVERSITARIA DI EMATOLOGIA
AZIENDA OSPEDALIERA SAN GIOVANNI
TORINO, ITALY
Serum protein electrophoresis (SPEP)
Elevated total protein suggests
hypergammaglobulinemia
Total protein= Albumin + Globulins
albumin 



Serum protein electrophoresis (SPEP)
Elevated total protein suggests
hypergammaglobulinemia
Total protein= Albumin + Globulins
Quantitative immunoglobulins
albumin 



measures amount of IgM, IgG and IgA
in myeloma, typically see “reciprocal
depression” of uninvolved Igs
Serum protein electrophoresis (SPEP)
Immunoeletrophoresis


albumin 




Serum protein electrophoresis (SPEP)
Immunoeletrophoresis


albumin 




Immunofixation
SP





Serum protein electrophoresis (SPEP)
IgG
57%
IgA
21%
IgD
1%
IgM or IgE
almost never
Light chain only 18%
Immunofixation
SP





Serum protein electrophoresis (SPEP)
IgG
57%
IgA
21%
IgD
1%
IgM or IgE
almost never
Light chain only 18%
M-spike stands for Monoclonal, not IgM
Immunofixation
SP





Serum protein electrophoresis (SPEP)
IgG
57%
IgA
21%
IgD
1%
IgM or IgE
almost never
Light chain only 18%
M-spike stands for Monoclonal, not IgM
IgM, IgG and IgA are all gamma-globulins
Immunofixation
SP





Serum protein electrophoresis (SPEP)
IgG
57%
IgA
21%
IgD
1%
IgM or IgE
almost never
Light chain only 18%
M-spike stands for Monoclonal, not IgM
IgM, IgG and IgA are all gamma-globulins
Light chains (Bence-Jones proteins) are not
detected in the serum, because of their low
molecular weight, they are secreted in the
urine
Immunofixation
SP





Table 1 Multiple myeloma* Diagnostic criteria
1 Monoclonal plasma cells in the bone marrow 10% and/or
presence of a biopsy-proven plasmacytoma
2 Monoclonal protein present in the serum and/or urinea
3 Myeloma-related organ dysfunction (1 or more)
[C] Calcium elevation in the blood (serum calcium >10.5 mg/l or
upper limit of normal)
[R] Renal insufficiency (serum creatinine >2mg/dl)
[A] Anemia (hemoglobin o10 g/dl or 2 gonormal)
[B] Lytic bone lesions or osteoporosisc
Myeloma - clinical features
bone pain - often with loss of height
constitutional - weakness, fatigue and weight loss
anemia - responds to erythropoeitin
renal disease -renal tubular dysfunction
susceptibility to infections - neutropenia, hypogammaglobulinemia)
hypercalcemia - myeloma cells secrete osteoclast activating factors
hyperviscosity - 2 % with myeloma, 50 % with macroglobulinemia
neurologic dysfunction - spinal cord or nerve root compression
Myeloma staging
system
Median
Survival
(months)
12
2
cells x 10 /m
Stage I No anemia
No hypercalcemia
no more than one bony lesion
low M protein
>60
<0.6
Stage II
in between I and III
41
0.6-1.2
Stage III Anemia
hypercalcemia
advanced lytic bone disease
high M protein
23
>1.2
Principles of treatment
• no evidence that early treatment prolongs
survival
• wait for symptoms, or evidence of disease
progression to start treatment
• supportive measures are critically important
– drink 3l of fluids daily
– treat infections promptly
– prophylactic bisphosphonates reduce skeletal
cmplications
– anemia responds to erythropoeitin
Causes of death in multiple
myeloma
•
•
•
•
Progressive myeloma
Sepsis
Renal failure
Other (old age)
45%
25%
10%
20%
Treatment
course
Asymptomatic
MGUS
Stable MM
Years
Months
Days
Treatment
course
Asymptomatic
Symptomatic
MGUS
Stable MM
M protein
Treatments
Years
Months
Days
Treatment
course
Asymptomatic
Symptomatic
MGUS
Stable MM
Acute
Pancytopenia
Plasma cell leukemia
M protein
Treatments
Years
Months
Days
MIELOMA MULTIPLO
trattato con blande chemioterapie
parzialmente chemiosensibile
il tumore si riduce ma dopo breve
intervallo riprende a crescere
DIVISIONE UNIVERSITARIA DI EMATOLOGIA
AZIENDA OSPEDALIERA SAN GIOVANNI
TORINO, ITALY
MIELOMA MULTIPLO
chemioterapia
Melphalan e Prednisone (MP)
(Alexanian, 1969)
DIVISIONE UNIVERSITARIA DI EMATOLOGIA
AZIENDA OSPEDALIERA SAN GIOVANNI
TORINO, ITALY
MIELOMA MULTIPLO
100
sopravvivenza
50
36 mesi
DIVISIONE UNIVERSITARIA DI EMATOLOGIA
AZIENDA OSPEDALIERA SAN GIOVANNI
TORINO, ITALY
MULTIPLE MYELOMA
Melphalan dose-response curve
DOSE
DIVISIONE UNIVERSITARIA DI EMATOLOGIA
AZIENDA OSPEDALIERA SAN GIOVANNI
TORINO, ITALY
MIELOMA MULTIPLO
relazione dose-risposta
ALTA-DOSE =
+ risposte complete
+ lunga sopravvivenza
DIVISIONE UNIVERSITARIA DI EMATOLOGIA
AZIENDA OSPEDALIERA SAN GIOVANNI
TORINO, ITALY
FATTORI DI CRESCITA
CELLULE STAMINALI PERIFERICHE
RIDUZIONE DELLA TOSSICITA'
DELLE TERAPIE AD ALTE DOSI
tossicità comparabile alla terapia
convenzionale
possibilità di trattare pazienti anziani
alte percentuali di risposte complete
A PROSPECTIVE, RANDOMIZED TRIAL OF
AUTOLOGOUS BONE MARROW
TRANSPLANTATION AND CHEMOTHERAPY
IN MULTIPLE MYELOMA
Sopravvivenza a 5 anni 52% trapianto
12% convenzionale
Attal, et al., NEJM, 1996
EFS TOT
1
0,9
0,8
0,7
0,6
0,5
MEL100
0,4
0,3
0,2
p<0.001
0,1
MP
0
0
10
20
30
Months
40
50
60
DIVISIONE UNIVERSITARIA DI EMATOLOGIA
AZIENDA OSPEDALIERA SAN GIOVANNI
TORINO, ITALY
OS TOT
1
,9
,8
MEL100
,7
,6
,5
,4
MP
,3
,2
p<0.005
,1
0
0
10
20
30
40
Months
50
60
70
DIVISIONE UNIVERSITARIA DI EMATOLOGIA
AZIENDA OSPEDALIERA SAN GIOVANNI
TORINO, ITALY
MULTIPLE MYELOMA
AGE AT DIAGNOSIS
55
60
65
70
AGE
DIVISIONE UNIVERSITARIA DI EMATOLOGIA
AZIENDA OSPEDALIERA SAN GIOVANNI
TORINO, ITALY
MULTIPLE MYELOMA
AGE AT DIAGNOSIS
HIGH-DOSE
55
CONVENTIONAL
60
65
70
AGE
DIVISIONE UNIVERSITARIA DI EMATOLOGIA
AZIENDA OSPEDALIERA SAN GIOVANNI
TORINO, ITALY
MALATTIA INCURABILE
100
survival
%
years
DIVISIONE UNIVERSITARIA DI EMATOLOGIA
AZIENDA OSPEDALIERA SAN GIOVANNI
TORINO, ITALY
Multiple myeloma
Relapsed
Disease
Diagnosis
• Survival 3-5 yrs
• Transient
Response
to Therapy
• Survival 13 years
Relapsed and
Refractory
• Resistant to all therapy
• Universally fatal
• Survival 6-9 months
Unmet
Medical Need
DIVISIONE UNIVERSITARIA DI EMATOLOGIA
AZIENDA OSPEDALIERA SAN GIOVANNI
TORINO, ITALY
Bruno B, Rotta M, and Boccadoro M,
Lancet Oncology 2004
DIVISIONE UNIVERSITARIA DI EMATOLOGIA
AZIENDA OSPEDALIERA SAN GIOVANNI
TORINO, ITALY
Advancing Treatment Options in
MM
1962
Prednisone +
melphalan
Melphalan
1999
First report
thalidomide
From 1990s
Myeloablation +
ASCT
Thalidomide
Pharmion licence
Aus/NZ 2003
VELCADE® US licence 2003
VELCADE® EU positive
opinion 2004
DIVISIONE UNIVERSITARIA DI EMATOLOGIA
AZIENDA OSPEDALIERA SAN GIOVANNI
TORINO, ITALY
MULTIPLE MYELOMA
scenario
+
DIVISIONE UNIVERSITARIA DI EMATOLOGIA
AZIENDA OSPEDALIERA SAN GIOVANNI
TORINO, ITALY
Thalidomide
Originally developed in 1950s as a
treatment for insomnia and morning
sickness in pregnancy
Thalidomide is an immunomodulatory
agent
– Precise mechanism of action not yet understood
– Multiple actions, including anti-angiogenic effects
• Anti-angiogenic effects of thalidomide provide
the rationale for its use in MM
• Angiogenesis in bone marrow supports growth
and development of MM cells
DIVISIONE UNIVERSITARIA DI EMATOLOGIA
AZIENDA OSPEDALIERA SAN GIOVANNI
TORINO, ITALY
Antitumor activity of thalidomide
in refractory multiple myeloma.
Singhal S, Mehta J, Desikan R, Ayers D, Roberson P, Eddlemon P,
Munshi N, Anaissie E, Wilson C, Dhodapkar M, Zeddis J, Barlogie B.
N Engl J Med 1999 Nov 18;341(21):1565-71
Myeloma and Lymphoma Program, South Carolina Cancer Center, University of South Carolina, Columbia,
USA.
BACKGROUND: Patients with myeloma who relapse after high-dose chemotherapy have few therapeutic options. Since increased bone marrow
vascularity imparts a poor prognosis in myeloma, we evaluated the efficacy of thalidomide, which has antiangiogenic properties, in patients with
refractory disease. METHODS: Eighty-four previously treated patients with refractory myeloma (76 with a relapse after high-dose chemotherapy)
received oral thalidomide as a single agent for a median of 80 days (range, 2 to 465). The starting dose was 200 mg daily, and the dose was increased by
200 mg every two weeks until it reached 800 mg per day. Response was assessed on the basis of a reduction of the myeloma protein in serum or Bence
Jones protein in urine that lasted for at least six weeks. RESULTS: The serum or urine levels of paraprotein were reduced by at least 90 percent in eight
patients (two had a complete remission), at least 75 percent in six patients, at least 50 percent in seven patients, and at least 25 percent in six patients, for
a total rate of response of 32 percent. Reductions in the paraprotein levels were apparent within two months in 78 percent of the patients with a response
and were associated with decreased numbers of plasma cells in bone marrow and increased hemoglobin levels. The microvascular density of bone
marrow did not change significantly in patients with a response. At least one third of the patients had mild or moderate constipation, weakness or fatigue,
or somnolence. More severe adverse effects were infrequent (occurring in less than 10 percent of patients), and hematologic effects were rare. As of the
most recent follow-up, 36 patients had died (30 with no response and 6 with a response). After 12 months of follow-up, Kaplan-Meier estimates of the
mean (+/-SE) rates of event-free survival and overall survival for all patients were 22+/-5 percent and 58+/-5 percent, respectively.
CONCLUSIONS: Thalidomide is active against advanced
myeloma. It can induce marked and durable responses in
some patients with multiple myeloma, including those who
relapse after high-dose chemotherapy
Bruno B, Rotta M, and Boccadoro M,
Lancet Oncology 2004, in Press
DIVISIONE UNIVERSITARIA DI EMATOLOGIA
AZIENDA OSPEDALIERA SAN GIOVANNI
TORINO, ITALY
Thalidomide: mechanism of action ??
“Thal metabolism required for its anti-myeloma efficacy”
Human
myeloma
Human
liver
Thal
Human
myeloma
reduced
Thal
~
unchanged
Yaccoby et Al, Blood, 2002
DIVISIONE UNIVERSITARIA DI EMATOLOGIA
AZIENDA OSPEDALIERA SAN GIOVANNI
TORINO, ITALY
GRUPPO ITALIANO PER LO STUDIO DEL MIELOMA
MULTIPLO
INTERIM ANALYSIS
PROSPECTIVE RANDOMIZED TRIAL
NEWLY DIAGNOSED PATIENTS, AGE > 65 YEARS
MELPHALAN, PREDNISONE + THALIDOMIDE (MPT)
versus
MELPHALAN PREDNISONE (MP)
DIVISIONE UNIVERSITARIA DI EMATOLOGIA
AZIENDA OSPEDALIERA SAN GIOVANNI
TORINO, ITALY
ADVERSE EVENTS
MP
MPT
WHO (grade)
Hematologic (%)
Constipation (%)
Neurologic (%)
Cardiac (%)
Cutaneous (%)
Infection (%)
Thromboemb.(%)
Early death (%)
1-2
3-4
1-2
3-4
29
28
32
17
15
14
18
7
9
3
2
10
35
11
3
3
12
25
4
1
19
5
4
5
DIVISIONE UNIVERSITARIA DI EMATOLOGIA
AZIENDA OSPEDALIERA SAN GIOVANNI
TORINO, ITALY
RESPONSE TO THERAPY
100
80
77.1%
15.6%
60
40
20
33.8%
46.7%
28%
27.7%
PR (50-74)
PR (75-99)
CR + nCR
13.3%
5.4%
0
MPT
MP
Dept. Hematology, University of Torino
EVENT-FREE SURVIVAL
(median follow up 13.6 months)
1
0,8
0,6
MPT
0,4
p<0.001
0,2
MP
0
0
5
10
15
20
Months
25
30
35
DIVISIONE UNIVERSITARIA DI EMATOLOGIA
AZIENDA OSPEDALIERA SAN GIOVANNI
TORINO, ITALY
RESPONSE TO THERAPY
% CR
27.7%
30
20
10
5%
3-5%
MP
Thal
MP +
Thal
DIVISIONE UNIVERSITARIA DI EMATOLOGIA
AZIENDA OSPEDALIERA SAN GIOVANNI
TORINO, ITALY
O O
H
N
O
N
O
N
O
NH2
Thalomid®
(thalidomide)
O O
N
O
H
N
O
O
Actimid™ (CC-4047)
H
N
O
NH2
Revlimid ™ (lenalidomide)
(CC-5013)
The Proteasome: A Target for Novel Therapies
Bruno B, Rotta M, and Boccadoro M,
Lancet Oncology 2004, in Press
DIVISIONE UNIVERSITARIA DI EMATOLOGIA
AZIENDA OSPEDALIERA SAN GIOVANNI
TORINO, ITALY
TNF
p65
p65
P
IkB
P
P
IkB
P
P
P
Protein
kinases
p50
p50
p65
IkB
P
p65
IkB
P
p50
P
Degradation of IkB
by 26S proteasome
TNFR
p50
NFkB-IkB
complex
TNF
p65
p65
P
IkB
P
P
IkB
P
P
P
Protein
kinases
p50
p50
p65
IkB
P
p65
P
IkB
Degradation of IkB
by 26S proteasome
TNFR
p50
NFkB-IkB
complex
P
p50
NFkB binding site
NFkB
Nuclear
translocation
PS 341
p65
p50
Increase in
Cytokine
production
NFkB
Induced
protein
s
Block of
programmed
cell death
Increase in
adhesion
molecules
TNF
p65
p65
P
IkB
P
P
IkB
P
P
P
Protein
kinases
p50
p50
p65
IkB
P
p65
P
IkB
Degradation of IkB
by 26S proteasome
TNFR
p50
NFkB-IkB
complex
P
p50
NFkB binding site
NFkB
Nuclear
translocation
PS 341
p65
p50
Increase in
Cytokine
production
NFkB
Induced
protein
s
Block of
programmed
cell death
Increase in
adhesion
molecules
TNF
p65
p65
P
IkB
P
P
IkB
P
P
P
Protein
kinases
p50
p50
p65
IkB
Degradation of IkB
by 26S proteasome
P
P
p65
P
P
IkB
p65
P
P
IkB
p65
p50P IkB
p50P
p50
NFkB
NFkB binding site
Nuclear
translocation
NFkB-IkB
complex
P
PS 341
Increase in
Cytokine
production
NFkB
Induced
protein
s
TNFR
p50
Block of
programmed
cell death
Increase in
adhesion
molecules
TNF
p65
p65
P
IkB
P
P
IkB
P
P
P
Protein
kinases
p50
p50
p65
IkB
Degradation of IkB
by 26S proteasome
P
P
p65
P
P
IkB
p65
P
P
IkB
p65
p50P IkB
p50P
p50
NFkB
Nuclear
translocation
NFkB-IkB
complex
P
PS 341
Increase in
Cytokine
production
NFkB
Induced
protein
s
TNFR
p50
Block of
programmed
cell death
Increase in
adhesion
molecules
TNF
p65
p65
P
IkB
P
P
IkB
P
P
P
Protein
kinases
p50
p50
p65
IkB
Degradation of IkB
by 26S proteasome
P
P
p65
P
P
IkB
p65
P
P
IkB
p65
p50P IkB
p50P
p50
NFkB
Nuclear
translocation
NFkB-IkB
complex
P
PS 341
Increase in
Cytokine
production
NFkB
Induced
protein
s
TNFR
p50
Antimyeloma
effectBlock of
programmed
cell death
Increase in
adhesion
molecules
SUMMIT (025):
A Phase II Study of VELCADE™ (bortezomib) for
Injection in Patients With Relapsed and
Refractory Multiple Myeloma
Paul G. Richardson,1 Bart Barlogie,2 James Berenson,3 Seema Singhal,4 Ann Traynor,4 Sundar
Jagannath,5 David Irwin,6 Vincent Rajkumar,7 Gordan Srkalovic,8 Melissa Alsina,9 Raymond Alexanian,10
David Siegel,11 Robert Orlowski,12 David Kuter,13 Steven Limentani,14 Dixie Esseltine,15 Gretchen
Richards,15 Michael Kauffman,15 Julian Adams,15 David P. Schenkein,15 and Kenneth C. Anderson1
1Dana-Farber Cancer Institute, 2University of Arkansas, 3Cedars-Sinai Medical Center, 4Northwestern University Medical
Center, 5St Vincent’s Comprehensive Cancer Center, 6Alta Bates Cancer Center, 7Mayo Clinic, 8Cleveland Clinic Foundation,
9H. Lee Moffitt Cancer Center, 10M.D. Anderson Cancer Center, 11Carol G. Simon Cancer Center, 12University of North
Carolina at Chapel Hill, 3Massachusetts General Hospital, 14Charlotte Medical Clinic, 15Millennium Pharmaceuticals, Inc
SUMMIT – Prior Therapy
99.5%
100%
90%
92%
83%
Median number of lines of
prior therapy = 6 (range
2-15)
81%
80%
70%
64%
60%
50%
40%
30%
92% of patients received
at least 3 of the drug
therapies listed here
(excluding stem cell
transplant)
20%
10%
0%
t
s
nts m ide
ds
i
e
li ne sp lan
o
g
r
c
o
A
e
y
id
St
rac ll Tran
ting
ha l
h
t
a
T
l
An
Ce
Aky
m
e
St
91% of patients were
refractory to the last prior
therapy
SUMMIT – Response Rates with
VELCADE® Alone
24%
25%
35%
20%
35% response rate
18%
10% CR (IF+ and IF-)
15%
28% CR+PR
10%
59% of patients SD
or better
7%
6%
5%
0%
4%
Mean duration of
response 12 months
CR IF-
CR IF+
-
PR
MR
SD
+
Prior treatment had no significant effect on response rate
DIVISIONE UNIVERSITARIA DI EMATOLOGIA
AZIENDA OSPEDALIERA SAN GIOVANNI
TORINO, ITALY
Treatment plan – APEX
Randomization
Dexamethasone
Bortezomib
8 cycles
Induction
1.3 mg/m2 IV push
Days 1, 4, 8, 11 Q3W cycle
3 cycles
40 mg po
Days 1–4, 9–12, 17–20 Q5W cycle
Maintenance
1.3 mg/m2 IV push
Days 1, 8, 15, 22 Q5W cycle
273 treatment days
4 cycles
5 cycles
40 mg po
Days 1–4 Q4W cycle
280 treatment days
Richardson et al. NEJM 2005
APEX: Time to Progression (n=669)
78% improvement in median TTP with bortezomib
Median TTP: Bortezomib 6.2 months vs dexamethasone 3.5 months
Richardson et al. NEJM 2005
APEX: Response rates (CR, PR)
100
Median time to response (TTR)
– 43 days in both arms
Duration of response
– Bortezomib 8.0 months
– Dexamethasone 5.6 months
– Median follow-up ~8.3 months
90
Response (%)
80
70
P<.0001
60
50
40
30
38%
25% PR
20
10
0
7% nCR
6% CR
18%
<1% nCR
16% PR
<1% CR
Bortezomib Dexamethasone
Richardson et al. NEJM 2005
APEX: 1-year survival (n=669)
80%
66%
41% decreased risk of death with bortezomib
Richardson et al. NEJM 2005
APEX: Overall survival (n=669)
Median duration of follow-up 8.3 months
Richardson et al. NEJM 2005
Conclusion
Phase III APEX:
Bortezomib demonstrated superior efficacy to highdose dexamethasone in relapsed MM
– Significant TTP benefit (P<.0001)
– Response rate advantage (P<.0001)
– Superior 1-year survival (P=.0005, HR=.53)
– Superior overall survival (P=.0013, HR=.57)
Richardson et al. NEJM 2005
Most common adverse events from
Phase I, SUMMIT, CREST and APEX trials
Toxicities were predictable and manageable
Phase I1
(%)
SUMMIT2
(%)
CREST3
(%)
Thrombocytopenia
74
40
30
35
Fatigue
59
41
70
42
Nausea
52
55
54
57
Diarrhea
37
44
44
57
Constipation
30
16
37
42
Vomiting
30
27
NR
35
Peripheral neuropathy
19
31
41
36
Adverse event
APEX4
(%)
NR = not recorded
1Orlowski et al. J Clin Oncol 2002;20:4420; 2Richardson et al. N Engl J Med 2003;348:2609;
3Jagannath et al. Br J Hematol 2004;127:165; 4Richardson et al. ASH 2004 (abstract 336.5)
Combinations therapies
in Multiple Myeloma
M-COMPONENT
Bortezomib + Thalidomide
+/- cytotoxic drugs
induction
relapse
High dose
remission
Multiple Myeloma Studies in Development:
Front Line
Study
PI
Location
Phase II VELCADE + high-dose
dexamthasone 1st line, pre-transplant
Harousseau
CHU de
Nantes
Phase II VELCADE alone in 1st line tx
Richardson
Dana Farber
Phase II VELCADE + Total Therapy III in high
risk myeloma 1st line
Barlogie
U. Arkansas
Phase I/II VELCADE + DT-PACE, 1st line
Badros
U. Maryland
Dispenzieri
ECOG/CTEP
Orlowski
CALGB
Jagannath
Salick Group
Phase II VELCADE in high risk myeloma, 1st
line
Phase II VELCADE + Doxil
Phase II VELCADE monotx
Dex after 2 cycles for less than optimal
response
MULTIPLE MYELOMA
Proteasome
inhibitors
Thalidomide
Mini allo
AUTOLOGOUS FIRST STEP
DIVISIONE UNIVERSITARIA DI EMATOLOGIA
AZIENDA OSPEDALIERA SAN GIOVANNI
TORINO, ITALY
MULTIPLE MYELOMA
Chemo
Thalidomide
Proteasome
inhibitors
Lanilomide
DIVISIONE UNIVERSITARIA DI EMATOLOGIA
AZIENDA OSPEDALIERA SAN GIOVANNI
TORINO, ITALY