TOTAL THERAPY FOR MULTIPLE MYELOMA
EVOLUTION FROM PALLIATION TO CURE DURING 20 YEARS
OF CLINICAL RESEARCH AT THE UNIVERSITY OF ARKANSAS
"TRANSLATED" INTO MANY LANGUAGES
Bart Barlogie, John D Shaughnessy Jr, Elias
Anaissie, Frits van Rhee and John Crowley
Myeloma Institute for Research and Therapy (MIRT)
Univer
Univ sity of Arkansas fo
f r
o Medical Sciences (UAMS)
(U
Little Rock, AR
Cancer Research and Biostatistics (CRAB)
Seattle, WA

---

TOTAL THERAPY 1
Treated: 231
100%
· PURSUIT OF DOSE
80%
Alive: 51
INTENSITY UP-FRONT TO
60%
RAISE CR RATE AND
Event-free: 24
THEREBY EXTEND
40%
SURVIVAL
20% Median follow-up: 15yr
· "TANDEM" TRANSPLANT IS
0% 0
5
10
15
20
NO MORE THAN 2 CYCLES
Years from Start of Protocol Therapy
OF MTD MEL200
100%
· LOW TRM DESPITE AGE UP
80%
TO 75YR
60%
· ADVERSE ROLE OF CA
Sustained CR:
40%
12 / 87
20%
· CURE PRINCIPLE
0% 0
5
10
15
20
ESTABLISHED
Years from Onset of Complete Response

---

TOTAL THERAPY 2
· Extended survival
v
in no
· GEP
THAL arm v TT1 by
­ Molecular subgroups
consolidation therapy
­ MGUS-like myeloma
· THAL increased CR but
­ Risk prediction
not its duration
­ 48hr post-THAL/DEX
· THAL OS benefit
pharmacogenomics
rev
e ealed
v
beyond
bey
5yr
· MRI-defined focal lesions
· THAL uniquely benefits
­ Linked to CRP
CA with low-risk GEP
­ Precede osteolysis
· CR crucial fo
f r
o high-risk
­ Poor prognosis
MM
­ Resolve slowly
· Drawn attention to MDS-
­ Sites of MM dormancy
CA
­ Cause of late relapse

---

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

---

TT2: DELAYED ONSET OF MRI-CR IN
PRESENCE OF FOCAL LESIONS (FL)
· FL-PC HAVE HIGHER DKK1 THAN RANDOM BM-ASP-PC (NOT SHOWN)
· PERSISTENCE OF FL-PC IN CCR IMPLIES NON-SECRETORY NATURE
· RECURRENCE AT ORIGINALLY INVOLVED SITES: MM STEM-CELL?
100%
MRI-CR and 0 MRI-FL
MRI-CR and MRI-FL 1-7
80%
60%
CCR
MRI-CR and MRI-FL>7
40%
Median
Events / N in Months
77 / 196
67
20%
77 / 196
107 / 185
26
260 / 457
22
60 / 76
9
0% 0
24
48
72
96
Months After Starting VAD

---

TT2: MRI-FL PRESENT IN >50% OF PATIENTS
WITHOUT OSTEOLYTIC LESIONS ON MBS
MBS-FL = 0 MBS-FL> 0 Total
MRI-FL = 0
128
32
3
20%
160
MRI-FL > 0
139 52%
312
451
Total
267
344
611
P<.0001
TT2: INFERIOR SURV
SUR IV
V AL
IV
WITH
MRI-FL BUT NOT MBS-FL (N=560)
MULTIVARIATE ANALYSIS
%
HR
P
Ab
l
norma cytogenetics
29
2 1
. 1
11
0
< 001
.
MRI > 7 FL
37
1.73 <.001
LDH > 190 U/L
27
1.56
0.006
B2M >= 5.5 mg/L
g
18
1.49
0.026
MBS > 5 FL
26
1.16 0.389

---

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%
80%
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 /
0/ 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
OVERALL SURVIVAL BY
GEP-DEFINED HIGH-RISK
IN FGFR3+ AND FGFR3- MYELOMA
100%
100%
No t(4;14)
Low-risk
70 GENE LOW-RISK
80%
80%
t(4;14)
P<.001
60%
60%
no t(4;14)
Low-risk
70 GENE HIGH -RISK
40%
40%
P<.001
Deaths / N Med Mos
t(4;14)
No t(4;14)
t(4;14)
Deaths / N
High-risk
High-risk
60 / 268
20%
77 / 305
NR
20%
20%
15 / 37
37
P < .0001
31 / 46
26
20 / 33
11 / 13
0%
0%
0
2
4
6
8
0
2
4
6
8
Years after enrollment
Years after enrollment

---

TT2: THAL SURVIVAL BENEFIT IN CA-TYPE
MYELOMA IN GEP-DEFINED LOW-RISK DISEASE
CA ABSENT
CS
CA PRES
CSENT
100%
Thal-/low-risk: 28 / 108
100%
80%
80%
Thal+/low-risk: 10 / 33
80%
60%
Thal+/low-risk: 33 / 116
60%
P=0.004
Thal-/high-risk: 6 / 8
Thal-/low-risk: 31 / 47
40%
40%
P=0.15
20%
Thal+/high-
hal+/high risk: 13 / 20
20%
Thal+/high-risk: 4 / 6
20%
Thal-/high-risk: 11 / 12
0%
0%
0
2
4
6
8
10
0
2
4
6
8
10
Years from start of enrollment
Years from start of enrollment

---

TOTAL THERAPY 3 (A & B)
· Introduced bortezomib upfront
· TT3 major advance v TT2
in low-risk myeloma
· Shortened induction &
­ 90% 5-yr OS and CCR
consolidation increased
treatment compliance
· Minor improvement in high-
ik
risk
l
mye oma
· Despite similar CR, longer CR
duration with TT3 v TT2+thal
· Bortezomib test-dose
implications validated in
TT3b
· Validated GEP-risk
· Identified unique benefit for
· PET-CT: FDG-avid focal
FGFR3 myeloma
lesion number linked to
FGFR3 myeloma
­ Poor prognosis
· Prognosis affected by bor
­ High-risk GEP
pharmacogenomics
­ Benefit in high-risk
myeloma with 100% FDG
­ In plasma cells and stroma
suppression pre-transplant

---

TREATMENT OUTCOMES BY GEP-DEFINED RISK
all TT3 patients
CUMULATIVE CR
CR DURATION
100%
100%
80%
Low-risk (205 / 361)
80%
Low-risk (13 / 205)
60%
60%
High-risk (40 / 77)
40%
40%
High-risk (13 / 40)
20%
P = 05
20%
P < .0001
.05
0%
0%
0
1
2
3
4
5
0
1
2
3
4
5
Years from start of treatment
Years from date of first complete response
EVENT-FREE SURVIVAL
OVERALL SURVIVAL
100%
100%
80%
80%
Low-risk (42 / 363)
Low-risk (53 / 363)
60%
60%
40%
40%
20%
P < .0001
High-risk (35 / 77)
20%
P < .0001
High-risk (30 / 77)
0%
0%
0
1
2
3
4
5
0
1
2
3
4
5
Years from start of treatment
Years from start of treatment
PROGNOSTIC POWER OF GEP-DEFINED RISK VALIDATED

---

MULTIVARIATE ANALYSIS OF FEATURES
ASSOCIATED WITH SURVIVAL
TT3A & TT3B combined
EFS
CR
GEP high-risk
LDH >= 190 U/L
Age >= 65 yr
CA
CR
GEP high-risk
LDH >= 190 U/L
CA
01
2
3
4
5
6
OS
Hazard Ratio & 95% Confidence Interval
GEP RISK DOMINATES MODEL FOR EFS AND OS

---

TREATMENT OUTCOMES BY GEP-DEFINED RISK
both TT3A & TT3B versus TT2
CUMULATIVE CR
CR DURATION
100%
100%
TT3/Low-risk (13 / 205)
80%
TT3/Low-risk (205 / 361)
()
80%
P<0.0001
TT3/High-risk (40 / 77)
TT2/Low-risk (66 / 160)
60%
60%
P=0.29
40%
TT2/Low-risk (160 / 296)
40%
TT3/High-risk (13 / 40)
20%
TT2/High-risk (22 / 46)
20%
TT2/High-
TT2/High risk (15 / 22)
0%
0%
0
2
4
6
8
0
2
4
6
8
Years from start of treatment
Years from date of first complete response
EVENT-FREE SURVIVAL
OVERALL SURVIVAL
100%
100%
TT3/Low-risk (53 / 363)
TT3/Low-risk (42 / 363)
80%
80%
P<0.0001
TT2/Low-risk (101 / 305)
60%
TT2/Low-risk (168 / 305)
60%
40%
40%
TT3/High-risk (30 / 77)
TT3/High-risk (35 / 77)
20%
P=0.02
20%
TT2/High-risk (34 / 46)
TT2/High-risk (39 / 46)
0%
0%
0
2
4
6
8
10
0
2
4
6
8
10
Years from start of treatment
Years from start of treatment
STRIKING BENEFIT OF TT3 v TT2 IN LOW-RISK MYELOMA

---

TT3 / TT2: SURVIVAL IN T(4;14
(; )-TYPE
MYELOMA ACCORDING TO GEP-DEFINED RISK
TOTAL THERAPY 2
TOTAL THERAPY 3
100%
low/MS
lo
(23)
100%
low/non-MS (270)
80%
80%
low/non-MS (212)
60%
low/MS (35)
P=0.008
60%
high/MS (6)
high/non-MS (34)
40%
40%
P=0.15
20%
high/non-MS (37)
20%
NON-SIGNIFICANT
high/MS (9)
0%
0%
0
2
4
6
8
0
1
2
3
4
5
Years from start of treatment
Years from start of treatment
TRANSLOCATION (4;14) NO LONGER ADVERSE FEATURE IN TT3

---

TT3 SURVIVAL OUTCOMES ACCORDING TO
POST-BORTEZOMIB GENE ALTERATION MODEL
TRAINING SET: 142 PATIENTS (TT3A)
LOW-RISK
HIGH
TEST SET: 127 PATIENTS (TT3B)
Shaughnessy JD: #733, December 8, 6pm

---

ADVERSE IMPLICATIONS OF POST-
BORTEZOMIB HIGH-RISK SCORE
OBSERVED IN TT3A VALIDATED IN TT3B
TRAINING SET
Over
Ov all Survival
v
Event
Ev
-
ent Free Su
S r
u vi
v va
v l
a
Variable
%
HR
P
HR
P
LDH > 190U/L
26
3.60
0.004
2.83
0.004
Hb < 10g/dL
g
28
2.32
0.034
2.06
0.048
Post-BOR high-risk
18
3.17
0.006
4.40
<.001
TEST SET
Overall Survival
Event-Free Survival
Variable
%
HR
P
HR
P
Post-BOR high-risk
16
13.00
0.002
15.57
<.001
POST-BORTEZOMIB
BOR
PC-GENE ALTERA
AL
T
TERA IONS DOMINA
DOMIN TE
A
OUTCOMES
OUT
SO THAT BASELINE 70-GENE MODEL IS NO LONGER SIGNIFICANT

---

POOR TT3 OUTCOMES WHEN
MAG-1 UPREGULATED
48HR POST-BORTEZOMIB
(HR-OS=13; HR-EFS=17)
EVENT-FREE SURVIVAL
OVERALL SURVIVAL
100%
100%
80%
% Change
Change < 13
13 (4
(4 / 49)
80%
% Change < 13 (2 / 49)
80%
g(
60%
60%
%Change >= 13 (14 / 21)
40%
40%
%Change >= 13 (10 / 21)
20%
20%
P < 0.0001
P < 0.0001
0%
0%
0
1
2
3
4
5
0
1
2
3
4
5
Years After Enrollment
Years After Enrollment
POST-BORTEZOMIB GEP DATA SEEM TO OUTPERFORM BASELINE INFO
MV Analysis
GEP
%
OS
P
EFS
P
BL + PB
Group
Patients
HR
value
HR
value
2 variables
BX-PB high
30
10.80
.003
13.33
<.001
significant
PC-PB high
21
5.37
.009
3.87
.010

---

Pre-Mel Post-Mel
DOWNREGULATED
DOWNREGULA
GENES:
-IRF4
- WWOX
- IRAK2
MM-GEP
- UBE2B
- CDC20
CHANGES
- IL1RN
48HR AFTER
- PMS2
MEL 10MG/M2
- YBX1
TEST-DOSE
APPLICATION
UPREGULATED
GENES:
· PRDM10
· FAS
· BLVRA
· DDR1

---

ADVANCING OUTCOMES WITH TOTAL THERAPY
Overall Survival
Event-free Survival
100%
100%
80%
TT3 (58/303)
80%
TT3 (77/303)
00
p=0. 9
09
p=0.01
60%
60%
TT2+Thal (123/323)
p=0.04
TT2+Thal (173/323)
40%
40%
TT2-Thal (164/345)
p=0.0007
p=0.05
TT2-Thal (229/345)
20%
20%
TT1 (178/231)
TT1 (205/231)
p=0.0002
0%
0%
0
5
10
15
20
0
5
10
15
20
Years from start of treatment
Years from start of treatment
Updated
10 01 08
Cumulative Incidence of CR
Duration of CR from Onset
100%
100%
TT3 (22/190)
80%
80%
TT3
p=0.001
TT2+Thal
60%
60%
TT2+Thal (86/200)
TT2-Thal
p=0.25
40%
40%
TT2-Thal (72/147)
TT1
p=
p 0.003
0.003
20%
20%
TT1 (78/94)
0%
0%
0
5
10
15
0
5
10
15
20
Years from Start of Induction
Years from date of first complete response

---

MRI & FDG-PET IN MM
Sagittal STIR MRI
Sagittal FDG PET
Ant MIP FDG PET

---

PET-CT SCANNING IN MULTIPLE MYELOMA
GEP proliferation index >= 10
GEP proliferation subgroup
GEP low bone subgroup
GEP high-risk
FDG-FL > 3
MRI-FL > 7
CRP >= 8mg/L
MBS-FL > 2
FL-SUV
SU
> 3.9
LDH >= 190U/L
DI-SUV < 2
CT-FL > 50
B2M > 5.5mg/L
B2M >= 3.5mg/L
-4
-3
-2
-1
0
1
2
3
LOG ODDS RATIO

---

LOGISTIC REGRESSION ANALYSIS
OF VARIABLES LINKED TO FDG FL
-
> 3
Multivariate Analysis
N = 215
FDG-FL > 3
FDG ­ FL =< 3
OR
P
CRP >= 8 mg/L
48%
27%
1.98
0.045
GEP: LOW BONE
DISEASE
7%
38%
0.14
0.012
DISEASE
7%
38%
0.14
MRI-FL > 7
64%
23%
4.09
<.001
MBS-FL > 2
53%
26%
2.32
0.018

---

TT3 SURVIVAL BY GEP RISK & FDG-FL AT BASELINE
OV
O ERALL
V
SURV
SUR IV
V AL
IV
EVENT-FREE SURV
SUR IV
V AL
IV
100%
Low-risk/FL<3 (14/129)
100%
Low-risk/FL< 3 (19/129)
p=0.003
p=0.003
80%
Low-risk/FL>3 (15/55)
80%
Low-risk/FL> 3 (20/55)
%
60
%
60
High-risk/FL< 3 (5/13)
High-risk/FL< 3 (5/13)
p=0.22
40%
p=0.43
40%
High-risk/FL> 3 (13/19)
High-risk/FL> 3 (10/19)
20%
20%
0%
0%
0
12
24
36
48
60
0
12
24
36
48
60
Months from enrollment
Months from enrollment
TT3 SURV
SUR IV
V AL
IV
BY GEP & 100% FDG SUPPRESSION PRE-Tx
OVERALL SURVIVAL
EVENT-FREE SURVIVAL
100%
100%/low-risk (10/112)
100%
100%/low-risk (17/112)
p=0.04
p0.04
p=01
0. 1
< 100%/low-risk (8/36)
11
80%
80%
< 100%/low-risk (10/36)
100%/high-risk (4/15)
100%/high-risk (4/15)
60%
60%
p=0.11
p=0.009
40%
40%
< 100%/high-
100%/high risk (8/13)
20%
20%
< 100%/high-risk (10/13)
0%
0%
0
12
24
36
48
60
0
12
24
36
48
60
Months from first transplant
Months from first transplant

---

MV ANALYSIS OF BASELINE VARIABLES &
100% FDG SUPPRESSION ON TT3 SURVIVAL
Overall Survival
Event-free Survival
Multivariate Analysis
from 1st transplant
from 1st transplant
without gene array data
(n = 196)
%
HR
P
R²
HR
P
R²
100% FDG-FL
reduction
71
0.33
0.001
37%
0.47
0.013
48%
FDG-FL > 3
35
NS
NS
NS
2.01
0.028
37%
LDH >= 190 U/L
23
2.27
0.024
43%
2.61
0.002
25%
B2M > 5.5 mg/L
19
2.45
0.015
49%
2.00
0.033
43%
with gene array data
%
HR
P
R²
HR
P
R²
(n = 175)
100% FDG-FL
72
041
0 017
37%
051
0 038
56%
reduction
72
0.41
0.017
37%
0.51
0.038
GEP high-risk
16
2.64
0.015
52%
2.12
0.032
48%
Cytogenetic
35
2.59
0.018
58%
NS
NS
NS
abnormalities
CRP >= 8 mg/L
33
2.43
0.018
57%
NS
NS
NS
Clinical CR did not enter the model!

---

TOWARD TOTAL THERAPIES 4 AND 5:
LOW-RISK MYELOMA:
DIFFICULT TO IMPROVE UPON TT3 RESULTS
HIGH-RISK MYELOMA:
HIGH RATE BUT SHORT DURATION OF CR
OVERALL SURVIVAL
NEW PROTOCOLS:
100%
NEW PROT
80%
P< .0001
LOW RISK
Low risk: TT4 (reduce toxicities)
60%
HIGH RISK
Randomize TT3 v TT3-lite
30 / 235
40%
18 / 40
High risk: TT5 (sustain CR)
20%
MEL80-VTD- PACE
R-VD / M-VD maintenance
0% 0
1
2
3
4
Years from Start of Protocol Therapy
EVENT-FREE SURVIVAL
CR DURATION
100%
100%
80%
80%
LOW RISK
S
P< .0001
P< .0001
LOW RISK
60%
60%
18 / 189
38 / 235
HIGH RISK
40%
HIGH RISK
40%
22 / 40
20%
15 / 32
Bodes we
w ll
e fo
f r
o cure!!!
20%
0% 0
1
2
3
4
Years from Start of Protocol Therapy
0% 0
1
2
3
4
Years from Date of First CR or near-CR

---

TOTAL THERAPIES ­ WHAT WE HAVE LEARNED
· Steady progress by
· Provided rationale for GEP
introducing new treatment
risk-driven treatment
principles and novel agents
assignment in TT4 and TT5
up-front
­ first real step toward
personalized medicine
· Introduced and validated
metaphase karyotyping and
· Clarified biological and
gene expression profiling
prognostic implications of
as powerful prognostic
X-ray, MRI & PET-CT
variables
· Provided basis for targeting
· 90% sustained CR at 5 yr in
focal lesions (anti-DKK1) as
low-risk MM with TT3 bodes
their persistence (dormant
well for high cure rate of >
myeloma stem cells?) may
65% at 10yr
be source of relapse

---

REASONS FOR RETAINING TANDEM HIGH-DOSE
MELPHALAN TRANSPLANTS FOR CURE OF MM
· O l
n y
d
mo lit
a y hi
w
h
c , t
t
oge h
ther
· Cave:
with novel agents, has
­ Reliance on secretory products
generated cure platform, now
· Non-secretory relapse
projected at ~65% at 10yr, in
increasingly more common
the context of data going out
­ MM stem cells:
to 20
20yr
· Lik l
e y
t
non-secre ory
· "hiding" in focal lesions
persisting long after s-CR onset
· Difficulty of projecting >10-yr
­ Are all CR's equal?
clinical outcomes from early
· Issue of unmaintained remission
surrogates currently being
after
tested:
­ Novel agents
­ Novel/cytotoxic combinations
­ Novel agents + mel transplants
­ Flow cytometry-defined CR
­ GEP of bone marrow biopsy to
· Focus on high-risk disease:
define cure signature in
comparison to normal donors
­ Likely a source of treatment
failure also in low-risk MM
­ MRI/PET-defined CR
· Transformation
· Expansion of subclone

---

BART'
BART S RECIPE
· Eb
Embrace th
the b t
es
!
now
­ Tandem transplants safe in outpatient setting
­ Focus on approaches of maintaining CR's beyond 5yr
· Ud
Unpreced t
en d
e opport i
un t
ity for
h
researc i t
n o
­ Methods of defining minimal residual disease
­ Re-program the MM-usurped micro-environment
­ Test vaccine strategies
­ Heal bones
· Why take chances when superior outcomes have been
attained in >80% of myeloma cases?
­ Target high-risk myeloma upfront
­ Fully define mechanisms of early / late recurrences
· Just imagine how much more could be learned and
how many more patients cured!!!

---

2628 CHILDREN WITH
Event-free Survival
NEWLY DIAGNOSED ALL
CURE PLATEAU
APPARENT
AT 5-6 YEARS
IN HIGHLY
PROLIFERATIVE
Overall Survival
DISEASE
IN MM LATER!!!
5-6 yr
y
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

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THANK YOU!
· PATIENTS
· REFERRING MD'S
· MIRT STAFF
·NCI AND S
CSTAFF
· PRIVATE DONORS

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UPDATE ON IFM / S9321 / TT TRIALS
as of December 1, 2008
OVERALL SURVIVAL
EVENT-FREE SURVIVAL
Overall Survival by Trial: UARK Total Therapy (TT) 1, TT2 and TT3,
Event-Free Survival by Trial: TT1, TT2, TT3,
SWOG 9321 and IFM 90, IFM 94 and IFM 99
SWOG 9321, IFM 90, IFM 94 and IFM 99
100%
5-Year
100%
5-Year
Deaths / N Estimate
Deaths / N Estimate
a) TT3
61 / 303
78%
a) TT3
80 / 303
71%
TT3
80%
b) TT2
287 / 668
66%
80%
b) TT2
405 / 668
50%
TT3
c) IFM 99
340 / 889
66%
c) IFM 99
659 / 889
29%
d) TT1
180 / 231
57%
d) TT1
207 / 231
27%
TT2
e) IFM 94
303 / 402
44%
e) IFM 94
367 / 402
21%
60%
f) IFM 90
160 / 194
43%
60%
f) IFM 90
177 / 194
24%
g) SWOG 9321 602 / 821
43%
g) SWOG 9321 565 / 821
26%
Logrank P-value < .0001
TT2
Logrank P-value < .0001
40%
40%
IFM99
IFM94
TT1
IFM90
IMF99
S9321
20%
20%
TT1
S9321
IFM94
S9321
IFM90
0%
0%
0
5
10
15
20
0
5
10
15
20
Years from Registration
Years from Registration

---

1
EX
n
GEP BM ASPIRATES
1
e
/D
2
ps
Completed
t1
tio
n
nt
a
la
ance
2
3
4
e
ther
HAL
la
la
lid
Procured
p
o
en
nce
nce
nce
,R
,O
e
s
tT
s
s
n
s
n
n
int
na
na
na
Not Obtained
li
o
a
te
t
te
te
te
tudy
tudy
hr
e
tra
transp
e
C
M
r
8
-
-
-
-M
S
S
rs
S
s
e
e
e
e
in
in
in
f
f
h
4
1
E
1
e
Not Due
Ba
48hr
Pr
Pr
Pr
Pr
Ma
Ma
Ma
Of
Of
48
C
ion
ps
A
t1
t2
la
n
n
ance
2
3
e
ther
TP
la
la
lidat
lcade
O
D
e
p
p
ten
nce
nce
,R
,
e
V
s
s
so
V
n
n
in
na
na
in
1
on
a
e1
e
ra
ra
te
te
tudy
tudy
sel
cl
cl
-t
-t
-C
-M
in
in
S
a
y
y
e
e
e
e
y
a
a
ffS
ff
s
1
ff
e
B
C
C
Pr
Pr
Pr
Pr
M
M
O
O
s
hr
n
1
s
hr
t1
t2
tio
ce
p
8
48
n
n
a
lae
ther
4
E
la
la
an
C
O
p
p
lid
,
s
s
o
en
,R
e
n
n
s
y
n
int
d
in
lcade
TPA
o
a
e
tra
tra
tu
tudy
V
-
-
-C
-M
asel
1
VD1
re
re
re
re
ffS
ffS
B
C
C
P
P
P
P
O
O
TT2
TT3
TT3B

---

SURVIVAL IN CONTEXT OF GEP RISK AND CA
TO
T T
O A
T L
A THERAPY 2
100%
CA CONFERS
80%
low-risk/CA-: 61/224
SHORTER
60%
P=0.0004
0.0004
SURVIVAL
low-risk/CA+: 41/80
40%
IN LOW RISK
high-risk/CA-: 10/14
MYELOMA
20%
high-risk /CA+: 24/32
0% 0
2
4
6
8
10
Years from start of enrollment
TOTAL THERAPY 3A
TOTAL THERAPY 3B
low-risk/CA-: 19/169
low-risk/CA-: 4/88
100%
P=0.004
100%
P=0.04
low-risk/CA+: 6/37
80%
low-risk/CA+: 17/66
80%
high-risk/CA-: 2/8
high-risk/CA-: 5/11
60%
60%
high-risk /CA+: 8/27
40%
40%
high-risk /CA+: 18/29
20%
20%
0%
0%
0
1
2
3
4
5
0
1
2
3
Years from start of enrollment
Years from start of enrollment

---

TT3A: IMAGING IN MYELOMA
X- RAY
MRI
PET-CT
Baseline
+168 days

---

TT3A: PET-CT IMAGING AND PROGNOSIS
EMD CONFERS SHORT SURVIVAL
FDG-AVID FOCAL LESIONS AND SURVIVAL
100%
No EMD: 43 / 225
100%
FL <= 3: 22 / 157
80%
80%
60%
60%
FL > 3: 28 / 82
40%
EMD: 7 / 14
40%
20%
P = 0.002
20%
P = 0.0002
0%
0%
0
12
24
36
48
60
0
12
24
36
48
60
Months from start of treatment
Months from start of treatment
CUMULATIVE INCIDENCE OF CR
SURVIVAL BY PRE-Tx FDG SUPPRESSION
PET-CR: 128 / 137
100%
Clinical n-CR: 123 / 137
100%
100%: 16 / 141
80%
MRI-CR (FL=0): 10 / 12 80%
Clinical CR: 88 / 137
60%
60%
< 100%: 19 / 56
40%
40%
MRI
MRI--CR
CR (FL >0): 65 / 125
20%
20%
P = 0.0002
0%
0%
0
12
24
36
48
60
0
12
24
36
48
60
Months from start of treatment
Months from first transplant

---

MULTIVARIATE ANALYSIS OF BASELINE
VARIABLES ASSOCIATED WITH TT3 SURVIVAL
MULTIVARIATE ANALYSIS
WITHOUT GEP DATA
N= 215
HR
P-value
Cumulative
HR
P-value
Cumulative
WITHOUT GEP DATA
N 215
HR
P value
R2
HR
P value
R2
Cytogenetic abnormalities
34%
2.88
<.001
20%
1.85
0.022
11%
FDG-FL > 3
34%
2.43
0.002
33%
2.28
0.002
29%
LDH >= 190 U/L
24%
2.04
0.017
42%
2.00
0.012
36%
B2M > 5.5 mg/L
22%
NS
NS
NS
1.83
0.033
42%
EMD
6%
3.13
0.008
44%
2.29
0.038
46%
MULTIVARIATE ANALYSIS
WITH GEP DATA
N= 215
HR
P-value
Cumulative
R2
HR
P-value
Cumulative
R2
Cytogenetic abnormalities
36%
2.62
0.004
20%
1.83
0.036
52%
FDG-FL > 3
34%
2.45
0.006
33%
2.63
<.001
33%
LDH >= 190 U/L
23%
2.28
0.010
37%
2.38
0.002
21%
Albumin < 3.5 g/dL
27%
2.11
0.023
38%
2.20
0.006
51%
GEP high-risk
15%
1.76
0.104
44%
1.86
0.048
47%

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TT3 OUTCOME PROJECTIONS IN CONTEXT
OF 4-YR & MATURE DATA WITH TT1 AND TT2:
LET'S QUIT SAYING: "MYELOMA IS INCURABLE"
>50% 10-yr EFS w/ TT3
>60% 10-yr CCR w/ TT3
100%
100%
100%
80%
80%
TT3
TT3
P=0.18
60%
60%
TT2
P=0.004
TT2
TT2
4yr
4yr
P=0.0006
40%
40%
TT2
TT1
P<0.0001
TT1
4yr
20%
4yr
20%
TT1
TT1
0%
0%
0
5
10
15
20
0
5
10
15
20
Years from date of start of treatment
Years from date of first CR
Initial 4-yr and current outcomes in
TT1 and TT2 are super-imposable;
PLATEAU = CURE
hence, TT3 projections are realistic

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