SHOULD AUTOTRANSPLANTS BE PART OF
THE PRIMARY TREATMENT OF MYELOMA
PRO: BART BARLOGIE
THE BIPARTISAN APPROACH TO MYELOMA THERAPY
- THE BEST OF BOTH -
MYELOMA INSTITUTE FOR
RESEARCH AND THERAPY
UNIVERSITY OF ARKANSAS
FOR MEDICAL SCIENCES
2628 CHILDREN WITH
NEWLY DIAGNOSED ALL
Event-free Survival (Panel A)
()
A SUCCESS STORY
PAR EXCELLENCE
Overall Survival (Panel B)
Pui C-H and Evans E:
Treatment of acute ly
Pui,
mphoblastic
C.-H. et al.
leukemia.
N Engl J Med 2006;354:166-178
N Engl J Med 2006;354;166-178
TOTAL THERAPY 1: LONG-TERM OUTCOMES
OS AND EFS
CR DURATION
Events / N @10yr
@10y
Events / N @10yr
@10y
100%
176 / 231
33%
100%
79 / 94
18%
201 / 231
15%
80%
80%
OS
40% CR, MEDIAN TIME TO CR: 18MO
60%
60%
40%
40%
20%
EFS
20%
0%
0%
0
5
10
15
20
0
5
10
15
Years after enrollment
Years after CR
BJH 2007
TOTAL THERAPY 1 & 2
INDUCTION
TRANSPLANT
CONSOLIDATION
MAINTENANCE
VAD X 3
MEL 200
TT 1
HD CTX
None
Interferon
X 2
EDAP
231 patients accrued
VAD
DCEP
TT 2
MEL 200
Interferon
DPA
DP C
A E
C
Randomize
X 2
+ DEX yr 1
CAD
+/- THAL
668 patients accrued
DCEP
TOTAL THERAPY 2: HIGHER CR RATE
AND LONGER EVENT-FREE SURVIVAL
ONSET OF CR
EVENT-FREE SURVIVAL
Events / N
@4-Year
Events / N
Med Mos
196 / 314
61%
153 / 323
71
100%
145 / 337
42%
100%
203 / 345
51
80%
80%
Thalidomide Arm
Thalidomide Arm
60%
60%
P < .0001
P = .002
40%
40%
Control Arm
Control Arm
20%
20%
0%
0%
0
2
4
6
8
10
0
2
4
6
8
Years after enrollment
Years after enrollment
OVERALL SURVIVAL
POST-RELAPSE SURVIVAL
Deaths / N
Med Mos
100%
100%
Deaths / N
Med Mos
110 / 323
NR
68 / 142
32
129 / 345
85
55 / 98
17
80%
80%
Thalidomide Arm
Control Arm
60%
60%
Control Arm
P = .39
40%
40%
P = .02
20%
20%
Thalidomide Arm
0%
0%
0
2
4
6
8
10
0
2
4
6
8
Years after enrollment
Years after relapse/progression
NEJM 2006
TT2-THAL v TT1: SUPERIOR CR DURATION,
EFS AND OS DESPITE SIMILAR CR RATE:
ROLE OF POST TRANSPLANT
-
CONSOLIDATION
ONSET OF CR
CR DURATION
Events / N @4-Yr
100%
100%
Events / N
@4-Yr
145 / 337
42%
63 / 145 50%
94 / 230
41%
79 / 94
31%
80%
80%
60%
60%
TT2 no THAL
TT2 no THAL
40%
40%
TT 1
P = .70
P = .0001
TT 1
20%
20%
0%
0%
0
2
4
6
8
0
2
4
6
8
10
Years after enrollment
Years after CR
EVENT-FREE SURVIVAL
OVERALL SURVIVAL
100%
100%
Events / N @5-Yr
Deaths / N @5-Yr
203 / 345
44%
129 / 345
65%
80%
192 / 231
28%
80%
149 / 231
57%
60%
60%
TT2 no THAL
TT 1
TT2 no THAL
TT 1
40%
40%
P = .04
P = .0007
20%
20%
0%
0%
0
2
4
6
8
10
0
2
4
6
8
10
Years after enrollment
Years after enrollment
BLOOD 2006
MRI FOCAL LESIONS SECRET TO MM
BIOLOGY: STEM CELL CHARACTERISTICS
Diffuse
Iso-intense
Decrease
Hypo-intense
Early Relapse w/
Hyper-intense
Unmasking
in # / Size
No FL
Reappearing
No FL
FL
of FL
`MRI-CR'
FL
April 99
June 00
Sept 00
June 01
Dec 02
FOCAL LESIONS AND RANDOM BONE MARROW
SAMPLES HAVE DIFFERENT GEP IN PC AND ME
PLASMA CELLS
BONE MARROW MICRO-ENVIRONMENT (ME)
FOCAL
RANDOM
RANDOM
FOCAL
DKK1
CYR61
TT2: MRI-DEFINED FOCAL LESIONS PERSIST
IN CLINICAL CR AND RESOLVE SLOWLY
MRI-CR LAGS BEHIND
CLINICAL CR
SURVIVAL BY MRI-CR
100%
100%
MRI-CR
MRI-CR and 0 MRI-FL
80%
MRI-CR / 0<MRI-FL<=7
80%
60%
CCR
60%
no MRI-CR
40%
40%
Events / N Med/Mos
Deaths / N
@ 3-yr
77 / 196
67
21 / 146
79%
20%
MRI-CR and MRI-FL>7
107 / 185
26
20%
31 / 134
69%
260 / 457
22
P = .05
60 / 76
76
9
0%
0%
0
24
48
72
96
0
1
2
3
4
5
Months After Starting VAD
Years from 36 months after Enrollment
JCO 2007
TT2: CYTOGENETIC ABNORMALITIES (CA)
AND MRI BOTH AFFECT OVERALL SURVIVAL
Deaths / N
@ 5yr
62 / 286
75%
44 / 141
63%
43 / 117
57%
41 / 61
61
33%
100%
80%
MRI-FL <= 7 and no CA
60%
MRI-
MRI FL <= 7a
7 nd
and CA
CA
P=
P 0.001
0.001
40%
P<0.001
MRI-FL > 7 and no CA
MRI-FL > 7 and CA
CA
20%
0% 0
2
4
6
8
Years from TT2 Enrollment
GEP IN TT2: 3 MODELS WITH CLINICAL IMPACT
OVERALL SURVIVAL BY SUBGROUPS
OVERALL SURVIVAL BY MGUS-Like GEP
100%
100%
MGUS-Like GEP
80%
80%
60%
Deaths / N Med Mos
60%
Non-MGUS-Like GEP
CD1
5 / 22
NR
CD2
9 / 43
NR
40%
HY
19 / 66
NR
40%
Deaths / N Med Mos
MF
7 / 21
NR
MY
20 / 95
95
NR
18 / 101
NR
20%
LB
7 / 31
72
20%
90 / 250
NR
MS
23 / 44
54
P = .002
PR
18 / 29
39
0%
0%
0
2
4
6
8
0
2
4
6
8
Years after enrollment
Years after enrollment
OVERALL SURVIVAL BY
GEP-70 MODEL DISTINGUISHES RISK
GEP-DEFINED HIGH-RISK
IN FGFR3+ AND FGFR3- MYELOMA
100%
100%
No t(4;14)
70 GENE LOW-RISK
Low-risk
80%
80%
t(4;14)
P<.001
60%
60%
no t(4;14)
70 GENE HIGH -RISK
Low-risk
40%
40%
P<.001
Deaths / N Med Mos
t(4;14)
No t(4;14)
t(4;
(;14)
Deaths / N
)
77 / 305
NR
20%
60 / 268
High-risk
High-risk
P < .0001
31 / 46
26
20%
15 / 37
20 / 33
0%
11 / 13
0
2
4
6
8
Years after enrollment
0% 0
2
4
6
8
Years from Enrollment
BLOOD 2007
TT2: COMPLETE RESPONSE IN CONTEXT
OF STANDARD AND GEP DEFINED
-
RISK
SPF + CR + 2nd transplant
SPF + CR + 2nd transplant + GEP
(N=326)
(N=326)
n (%)
HR (95% CI)
p
n (%)
HR (95%CI)
p
Creatinine > 2.0
36/326
1.89
mg/dL
0.016
(11%)
(1.13,3.16)
LDH >= 190 U/L
113/326
1.91
113/326
1.71
0.011
0.002
(35%)
(1.26,2.88)
(35%)
(1.13,2.59)
Cytogenetic
106/326
2.44
106/326
1.86
0.004
abnormalities
<.001
(33%)
()
(1.64,
(,3.64)
(33%)
()
(1.22,
(,2.85)
CR
0.58
0.67
0.128
0.021
(0.37,0.92)
(0.39,1.12)
Second
0.68
0.58
0.021
Tr
T ansplant
0.107
ant
(0 43
.
1
, 09)
.
(0 36
.
0
, 92)
.
GEP-defined
44/326
5.74
<.001
high-risk
-
--
(13%)
(3.23,10.21)
Interaction
0.35
0.040
between
betw
CR and
--
-
(0
(0.1309
13,0. 6)
96)
GEP high-risk
CLIN CA RES 2007
TT2: THE IMPORTANCE OF CR REVISITED
OS: LOW-RISK
OS: HIGH-RISK
100%
100%
CR
CR
80%
80%
60%
no CR
60%
no CR
40%
40%
20%
16 / 98
NR
20%
4 / 15
NR
P = 0.25
39 / 183 NR
P = 0.01
9 / 13
9
0%
0%
0
24
48
72
0
12
24
36
48
Months after 12 month Landmark
Months after 18 month Landmark
CLIN CA RES 2007
TT2: 2nd TRANSPLANT ESPECIALLY BENEFICIAL
IN CASE CR ATTAINED AFTER 1st TRANSPLANT
(9-MO LANDMARK ANALYSIS)
OS BY Tx2: CR POST Tx1
OS BY Tx2: NO CR POST Tx1
100%
Tx 2
100%
Tx 2
80%
80%
P = .01
P = .08
60%
60%
no Tx 2
Dt
Dea h
ths / N Md
Me /M
d/Mos
Dt
Dea h
ths / N Md
Me /M
d/Mos
No Tx 2
40%
12 / 79
NR
40%
51 / 183
76
27 / 80
NR
103 / 274
81
20%
20%
0%
0%
0
24
48
72
96
0
24
48
72
96
Months after 9 month Landmark
Months after 9 month Landmark
CLIN CA RES 2007
TOTAL THERAPY 3 (TT3) FOR PATIENTS WITH
NEWLY DIAGNOSED MULTIPLE MYELOMA
REGIMEN
OBJECTIVES
YEAR 1
0
V-DTPACE
V-DTPACE
PBSC 1
Incorporate VELCADE (
p(VEL) into upfront
1
p
2
THAL + DEX
therapy of myeloma to increase, in
MEL200 # 1 3
relationship to TT2, CR rate and
4
extend event-free and overall survival
5
THAL + DEX
MEL200 # 2 6
Shorten induction phase to 2 cycles of VDT-
7
THAL + DEX
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 rate
Monthly VDT
THAL + DEX
Perform serial MRI / PET imaging to
document level of response and
CHARACTERISTICS
CHARA
(303)
pr di
e ct sur i
v
l
va
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
45%
induced ME gene alterations are
ISS >1
54%
predictive of improved survival
Cytogenetic Abnormalities
33%
RAPID PROGRESSION OF PATIENTS
THROUGH TREATMENT STEPS
Induction Cycle #2
100%
Transplant #1
Tr
T ansplant #2
Consolidat
Consolida ion
t
#1
80%
Consolidation #2
60%
40%
Maintenance
20%
0% 0
12
24
36
Months from Start of Induction
HIGHER CUMULATIVE RESPONSE RATES
WITH TT3 THAN WITH TT2
TT2 v. TT3: PR p<.0001, n-CR p<.0001, CR p<.0001
100%
TT3: PR
80%
TT3:
TT3: PR
n-CR
60%
TT3: CR
24-Month
Events / N
Estimate
40%
a TT3, PR
272 / 303
92%
b TT2, PR
538 / 668
80%
c TT3, nC
232 / 303
84%
20%
d TT2, nC
467 / 668
68%
e TT3, CR
159 / 303
59%
f TT2, CR
342 / 668
44%
0%
0
12
24
36
Months from Start of Induction
SURVIVAL OUTCOMES WITH TOTAL THERAPY 3
OVERALL AND EVENT-FREE SURVIVAL
RESPONSE DURATION
100%
OS
OS: 87% at 24mo
CR: 91% at 24mo
100%
P=0.003
80%
80%
EFS: 84% at 24mo
n-CR: 80% at 24mo
60%
60%
40%
40%
PR: 60% t
a 24mo
20%
20%
0%
0%
0
12
24
36
48
Months
Month from Start of
of Protocol
Protoco Therapy
0
12
24
36
Therapy
Month
ths from CR, CR
n
or PR
TREATMENT-RELATED MORTALITY
POST-RELAPSE SURVIVAL
100%
100%
80%
80%
80%
60%
60%
34% at 24mo
40%
40%
5% at 24mo
20%
20%
0%
0%
0
12
24
36
48
0
6
12
18
24
Months from Start of Protocol Therapy
Months from progression/relapse
BJH 2007
TT3: CLINICAL OUTCOME BY GEP-DEFINED RISK
OVERALL SURVIVAL
EVENT-FREE SURVIVAL
100%
100%
80%
80%
LOW RISK 91%
LOW RISK 90%
60%
60%
P=0.0002
P< 0.0001
HIGH RISK 70%
40%
40%
20%
20%
HIGH RISK 58%
0%
0%
0
12
24
36
48
Months from start of induction
0
12
24
36
48
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%
VERY HIGH RISK
20%
0% 0
12
24
36
Months from CR
TT3: FGFR3 STATUS DOES NOT AFFECT SURVIVAL
ONCE GEP RISK SCORE IS ACCOUNTED FOR
LOW FGFR3+
100%
LOW FGFR3-
80%
P<0.0001
P<0.0001
60%
HIGH FGFR3-
60%
HIGH FGFR3+
40%
20%
0% 0
12
24
36
48
Months from Start of Protocol Therapy
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
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-
HIGH RISK
(n=21)
20%
0% 0
2
4
6
8
Years from CR
TT3 v TT2: SUPERIOR SURVIVAL
IN FGFR3/MMSET SUBGROUP
100%
TT3
80%
P=0.06
60%
40%
Deaths / N @2 Yr
TT2
2 / 29
96%
23 / 44
77%
20%
0%
0
24
48
72
96
Months from Start of Protocol Therapy
SUPERIOR SURVIVAL WITH SUPPRESSION OF
MICRO
MICR -
O ENVIRONMENT
ENVIR
-
ONMENT ASSOCIATED
ASSOCIA
GENE (MAG
(MA -
G 1)
REDUCED
10
1.0
NO CHANGE
0.8
INCREASED
e
0.6
Aliv
P = .0169
ortion
04
p
0.4
p
Pro
Deaths/N
0.2
Increased
4/13
No change
3/25
Reduced
0/24
0.0
612
18
24
30
36
Months From Start of Therapy
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%
Age >65 yr
9%
20%
28%
P: TT1 v TT2<.0001
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%
P: TT2 v TT3=0.0003
TT2
Completed
TT2
Tx #1
84%
85%
94%
P: TT1 v TT2=0.01
60%
60%
TT1
TT1
40%
40%
P: TT1 v TT2<.0001
Completed
20%
20%
Tx #2
71%
67%
83%
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
TT3 v TT2: OS FROM 2-YR LANDMARK FOR
THOSE ENTERING MAINTENANCE IN 2YR
THE IMPORTANCE OF BORTEZOMIB
OVERALL SURVIVAL
EVENT-FREE SURVIVAL
TT3
100%
100%
TT3
P=0.12
80%
80%
P=0.004
60%
TT2
60%
TT2
TT2
40%
40%
20%
Deaths / N
20%
Events / N
1 / 119
3 / 118
29 / 167
26 / 60
0%
0%
0
24
48
72
96
0
24
48
72
96
Months from 2 years from enrollment
Months from 2 years from enrollment
HAZARD RATE (OVERALL SURVIVAL) OVER TIME
GEP-BASED RISK CATEGORIES
High Risk
TT2
Low Risk
012
34
5
Year
Y
s from start of treatm
ea
ent
High Risk
TT3
Low Risk
0
123
4
5
HAZARD RATE (CR DURATION) OVER TIME
GEP-BASED RISK CATEGORIES
High Risk
TT2
Low Risk
01
2
3
4
TT3
Low Risk
High Risk
01
23
4
CURING MULTIPLE MYELOMA REQUIRES:
· UNDERSTANDING OF TUMOR BIOLOGY:
1012 TUMOR CELLS PRESENT AT DIAGNOSIS
109 TUMOR CELLS AT TIME OF CLINICAL CR
<106
<10 TUMOR CELLS TO ASSURE DURABILITY OF CR
· CR RATES >50% REQUIRED FOR SOME PATIENTS TO
ACHIEVE SUCH PROFOUND TUMOR CYTOREDUCTION
· INTENT AND STRATEGY
COMBINATION THERAPY
OBSERVATION OF PRINCIPLES ESTABLISHED IN
CURATIVE PURSUIT OF OTHER MALIGNANCIES:
· INDUCTION, CONSOLIDATION, MAINTENANCE
MINIMIZE SECONDARY RESISTANCE
TARGET TUMOR STEM CELLS AS SOURCE OF
RECURRENCE
INCREASING THE CURABILITY OF MYELOMA
THROUGH AUTOTRANSPLANT-SUPPORTED
PRIMARY THERAPY WITH MEL ET AL
· PROGRESSIVE OUTCOME
· MEL' ROLE IN STANDARD
IMPROVEMENT WITH TT
TRIALS (FACON)
THAL & POST-Tx
· MEL IMPROVES OUTCOMES
CONSOLIDATION IN TT2 v
OF NEW AGENT COMBOS
TT1
(V-MPT, PALUMBO) VIA
HIGHER COMPLIANCE
TARGETING MM STEM-
WITH INTENDED
THERAPIES & ROLE OF
CELL CAUSING RELAPSE?
BORTEZOMIB IN TT3 v TT2
· AUTO-
AUTO Tx CRITICAL TO
· CR MORE DURABLE IN TT3
SAFE EXPLORATION OF
THAN N-CR/PR AND THAN
MEL DOSE-RESPONSE IN
WITH TT2/TT1
NEW AGENT SYNERGISM &
PRESERVING NORMAL
· PROGRESS WITH TT3 IN
85% OF GEP LOW-RISK
STEM CELL FUNCTION
AND IN FGFR3 HIGH-RISK
THUS FACILITATING
GROUPS
RELAPSE MANAGEMENT
THANKS TO
· Past and present
· Basic research staff
clinical faculty
· Nursing staff
· PO1 grant from NCI
· Research nurses
· Data managers
· Lebow fund for the
Cure
· Referring physicians
· Patients and their
· Lambert laboratory
families for their
trust
· Grand foundation