PHASE II STUDY OF TOTAL THERAPY 3 WITH
ADDED BORTEZOMIB FOR MULTIPLE MYELOMA
B Barlogie, J Haessler, E Anaissie, J Shaughnessy, F van Rhee, K Hollmig,
M Pineda-Roman, A Mohiuddin, M Zangari, G Tricot and J Crowley
Myeloma Institute for Research and Therapy
University of Arkansas for Medical Sciences
Little Rock, AR
and
Cancer Research and Biostatistics, Seattle, WA

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TOTAL THERAPY 3 (TT3)
REGIMEN
OBJECTIVES
YEAR 1

0
V DTP
-
ACE
0
DTP
V-DTPACE
PBSC 1
Incorporate VELCADE (VEL) into upfront
2
THAL + DEX
therapy of myeloma to increase, in
MEL200 # 1 3
relationship to TT2, CR rate and
4
THAL + DEX
extend event-free and overall survival
5
THAL + DEX
5
MEL200 # 2 6
Shorten induction phase to 2 cycles of VDT-
7
THAL + DEX
PACE, thus facilitating completion of
8

9
V-DTPACE
intended tandem transplant
10
THAL + DEX
11
Cover drug-free phases of TT 2 by THAL +

12
V-DTPACE
months
DEX to suppress myeloma survival
signals during marrow recovery and
YEAR 2
YEARS 3 - 4
thus reduce relapse
p
rate
Monthly VDT
THAL + DEX
Perform serial MRI / PET imaging to
document level of response and
CHARACTERISTICS (303)
predict survival
Median age
59 yr
Target both myeloma PC and bone
marrow microenvironment (ME)
Albumin < 3.5 g/dL
25%
Determine whether certain VEL-
B2M > 5.5 mg/L
g
45%
induced ME gene alterations
a
are
ISS >1
54%
predictive of improved survival
Cytogenetic Abnormalities
33%

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RAPID PROGRESSION THROUGH TREATMENT
PHASES IN HIGH PROPORTIONS OF PATIENTS
Induction Cycle #2
100%
Tr
T ansplant #1
Transplant #2
Consolidation #1
80%
Consolidation #2
60%
40%
Maintenance
20%
0% 0
12
24
36
Months from Start of Induction

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CUMULATIVE PROPORTIONS OVER TIME OF
PATIENTS ACHIEVING PR, N-CR AND CR
PR
100%
PR
n-CR
80%
CCR
60%
R
40%
20%
0% 0
12
24
36
Months from Start of Induction

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SURVIVAL OUTCOMES ON TOTAL THERAPY 3
OVERALL AND EVENT-FREE SURVIVAL
RESPONSE DURATION
CR: 91% at 24mo
100%
OS
OS: 87% at 24mo
100%
P=0.003
80%
80%
EFS: 84% at 24mo
n-CR: 80% at 24mo
60%
60%
40%
40%
PR: 60% at 24mo
20%
20%
0%
0%
0
12
24
36
48
0
12
24
36
Months from Start of Protocol Therapy
Months from CR, nCR or PR
TREATMENT-RELATED MORTALITY
POST-RELAPSE SURVIVAL
100%
100%
80%
80%
60%
60%
34% at 24mo
40%
40%
5% at
a 24mo
20%
20%
20%
0%
0%
0
12
24
36
48
0
6
12
18
24
Months from Start of Protocol Therapy
Months from progression/relapse

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UNIVARIATE ANALYSIS OF BASELINE FACTORS
ASSOCIATED WITH CLINICAL OUTCOME
Overall
Event-Free
Variable (n=303)
Survival
Survival
%HR
P
HR
P
Hemoglobin <10g/dL
gg
31
2.10
0.026
2.80
<.001
Creatinine >= 2mg/dL
8
3.08
0.008
2.80
0.008
LDH >= 190U/L
27
4.12
<.001
4.31
<.001
B2M >3
>3 5
.
/L
mg
45
26
2. 1
61
0 007
.
19
1. 8
98
0 027
.
B2M >5.5 mg/L
21
3.92
<.001
3.54
<.001
ISS Stage 3
21
3.92
<.001
3.54
<.001
Cytogenetic abnormalities
33
3.51
<.001
3.02
<.001
Deletion 13 / hypodiploidy
22
2.27
0.019
2.36
0.006
GEP (91%): high-risk
15
3.79
<.001
5.29
<.001

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CLINICAL OUTCOME BY GEP-DEFINED RISK
OVERALL SURVIVAL
EVENT-FREE SURVIVAL
100%
100%
LOW RISK 90%
80%
80%
LOW RISK 91%
60%
60%
P=0.0002
P< 0.0001
HIGH RISK 70%
40%
40%
20%
20%
HIGH RISK 58%
0%
0%
0
122436
48
0
12
24
36
48
Months from start of induction
Months from start of induction
CR DURATION
100%
70 GENE MODEL
LOW RISK 94%
80%
IDENTIFIES ~15%
60%
OF PATIENTS AT
P=0.0008
40%
VERY HIGH RISK
HIGH RISK 60%
20%
0% 0
12
24
36
Months from CR

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FGFR3 (t4;14) DOES NOT AFFECT SURVIVAL
ONCE GEP RISK SCORE IS ACCOUNTED FOR
Low, t4;14
100%
Low, no t4;14
80%
P<0.0001
P<0.0001
60%
High, no t4;14
High, t4;14
40%
20%
0% 0
12
24
36
48
Months from Start of Protocol Therapy

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TT3 v TT2: SUPERIOR EVENT-FREE SURVIVAL IN
GEP-DEFINED LOW- AND HIGH-RISK CATEGORIES
100%
TT3 LOW RISK
80%
P 0
= 002
.
TT2 LOW RISK
60%
40%
TT3 HIGH RISK
P=0.05
20%
TT2 HIGH RISK
0%
0
24
48
72
96
Months from Start of Protocol Therapy

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TT3 v TT2: SUPERIOR SURVIVAL ALSO
IN FGFR3/MMSET SUBGROUP (t4;14)
100%
TT3
80%
P=0.06
60%
40%
Deaths / N @2 Yr
TT2
2 / 29
96%
23 / 44
44
77%
20%
0%
0
24
48
72
96
Months from Start of Protocol Therapy

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TT3 v TT2: SUPERIOR CR DURATION
IN GEP-DEFINED LOW-RISK CATEGORY
TT3, LOW-RISK (n=127)
100%
P=0.01
TT2, LOW-RISK (n=154)
80%
60%
TT3, HIGH-RISK
(n=20)
()
40%
TT2, HIGH-RISK
(n=21)
20%
%
0
0
2
4
6
8
Years from CR

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SUPERIOR SURVIVAL WITH SUPPRESSION OF
MICRO
MICR -ENVIRONMENT
ENVIR
-ASSOCIATED
ASSOCIA
GENE (MAG
(MA -1)
REDUCED
1.0
NO CHANGE
08
0.8
e
INCREASED
0.6
P = .0169
nAliv
tio 0.4
Deaths/N
opor 0.2
Increased
4/13
Pr
No change
3/25
Reduced
0/24
00
0.0
612
18
24
30
36
Mt
Mon h
ths From St
Start f
o Therapy

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CUMULATIVE PROPORTIONS OF PATIENTS
WITH GRADE >2 POLYNEUROPATHY AND DVT
100%
80%
60%
NEUROPATHY
40%
20%
THROMBO-EMBOLISM
0% 0
12
24
36
Months from Start of therapy

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TOTAL THERAPIES 1, 2, 3:
STEADY IMPROVEMENT IN OUTCOMES
CR
CR Duration
TT1
TT2
TT3
100%
100%
N=231
N=668
N=303
TT3
80%
P: TT2 v TT3=0.003
80%
P: TT2 v TT3=0.008
TT3
Median mos
60%
TT2
155
60
24
60%
of follow-up
TT1
TT2
40%
40%
P: TT1 v TT2=0.18
TT1
20%
20%
P: TT1 v TT2<.0001
Age >65 yr
9%
20%
28%
0%
0%
0
1
2
3
4
5
0
5
10
15
Years from Start of Induction
Years from CR (Tx1 if CR prior to Tx1)
Abnormal
32%
30%
33%
Cytogenetics
EFS
OS
P: TT2 v TT3=0.16
100%
100%
TT3
TT3
80%
80%
Completed
p
P: TT2 v TT3=0.0003
TT2
84%
85%
94%
TT2
Tx #1
P: TT1 v TT2=0.01
60%
60%
TT1
TT1
40%
40%
P: TT1 v TT2<.0001
Completed
71%
67%
83%
20%
20%
Tx #2
0%
0%
0
1
2
3
4
5
0
1
2
3
4
5
Months from Start of Protocol Therapy
Months from Start of Protocol Therapy

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CONCLUSIONS REGARDING TT3 *
· Remarkably high protocol compliance
· Low TRM of 5%
· Marked efficacy:
­ n-CR, 80%; CR: 60%
­ at 24mo: OS, 87%; EFS, 84%; continuous CR, 91%
· GEP-defined low-risk (85%) v high-risk (15%):
­ at 24mo: OS, 91% v 70%; EFS, 90% v 58%;
continuous CR, 94% v 60%
­ GEP-risk overrides prognostic implications of t(4;14)
­ Down-regulation of microenvironment gene 48h after VEL test
dose associated with superior survival ­ implications for TT4?
· TT3 superior to TT2 (attributable to bortezomib?):
­ in GEP-defined low-risk disease (EFS, CR duration)
­ in t(4;14) subgroup (OS)
* Van Rhee et al, Blood 2007, in press; Barlogie et al BJH 2007, in press

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