Microsoft PowerPoint - Barlogie - Ninety Percent Sustained Complete Response (CR) bolder 113008.bb..VEGAS [Compatibility Mode]

90% CR SUSTAINED 4 YEARS
AFTER ONSET OF CR
IN GENE ARRAY-DEFINED LOW-RISK MYELOMA
TREATED WITH TOTAL THERAPY 3:
BASIS FOR RISK-ADAPTED TT4 AND TT5
Bart Barlogie, Elias Anaissie, John D Shaughnessy Jr,
Frits van Rhee, Mauricio Pineda-Roman, Jeff Haessler,
Kl
Klaus Hollllmig, Yazan Al
Alsayed, S
h
ara W h
a
d
ee , M i
on ca
Grazziutti, Elias Kiwan and John Crowley
M l
ye oma I t
ns it
tit t
u e for Resear h
c
d
an Therapy (MIRT)
(MIR
University of Arkansas for Medical Sciences
Little Rock, AR
C(
Cancer Research and Biostatistics C
(C
)
RAB
Seattle, WA

TOTAL THERAPY 3 (TT3)
(TT3A = 303; TT3B = 177; total = 480)
· INDUCTION
VTD-PACE x 2 CYCLES (PBSC, >20x106/KG)
· TRANSPLANT
MELPHALAN 200MG/M2 x 2 CYCLES
· CONSOLIDATION
VTD-PACE x 2 CYCLES
· MAINTENANCE
TT3A: VTD x 1YR, TD x 2YR
TT3B: VRD FOR 3 YR

TOTAL THERAPY 3: OBJECTIVES
· TT3A
· TT3B
Determine whether up-front
Validate the strong
incorporation of bortezomib
prognostic implications of
plus reducing induction
post-bortezomib myeloma
prior to and consolidation
gene alterations observed
cylces after transplant from
in TT3A
4 to 2 can improve efficacy
and safety vis-à-vis TT2
Determine whether
superiority of TT3A over
Validate 70-gene risk model
TT2 for t(4;14)-type
developed in TT2
myeloma can be validated
Det
e er
e mine
m
whether post-
Det
e er
e mine
m
whether 3 years
bortezomib test-dose gene
of maintenance with VRD is
array data can improve
superior and less toxic than
prognostic implications
1 year of VTD plus 2 years
over baseline data
of Thal-DEX in TT3A

PATIENT CHARACTERISTICS (n=480)
PARAMETER
P
TT3A
TT3B
P-
n=303
n=177
value
Age > 65yr
28%
26%
NS
Male gender
64%
61%
NS
ISS I
46%
30%
<0.001
B2M >= 3.5mg/dL
g
45%
57%
0.01
Albumin < 3.5g/dL
25%
44%
<0.001
CRP > 8mg/dL
33%
42%
0.07
Creatinine > 2mg/dL
8%
6%
NS
LDH >= 190U/L
27%
24%
NS
Cytogenetic abnormalities
33%
42%
0.05
(CA)
GEP high-risk (70 gene model)
15%
22%
0.04
GEP FGFR3/MMSET
12%
13%
NS
GEP MAF/MAF-B
8%
5%
NS
GEP PROLIFERATION
10%
16%
0.06
DENOTES GREATER FRACTION WITH HIGH RISK FEATURES

TREATMENT OUTCOMES IN TT3 PROTOCOLS
TT3B versus TT3A
CUMULATIVE CR
CR DURATION
100%
100%
80%
TT3A (190 / 302)
80%
TT3B (4 / 77)
TT3A (22 / 190)
60%
60%
TT3B (77 / 175)
40%
40%
20%
20%
P = .06
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%
TT3A (77 / 303)
TT3A (60 / 303)
80%
80%
TT3B (19 / 177)
60%
TT3B (19 / 177)
60%
40%
40%
20%
20%
0%
0%
0
1
2
3
4
5
0
1
2
3
4
5
Years from start of treatment
Years from start of treatment
SIMILAR OUTCOMES WITH 2 TRIALS

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
012
3
45
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

GEP-DEFINED RISK-DIRECTED
THERAPIES
THERAPIES TT4 AND TT5
TT5
A FIRST IN MYELOMA!
· TT4 FOR LOW-RISK MM
· TT5 FOR HIGH-RISK MM
PHASE III: reduce toxicity
PHASE II: avoid host
while sustaining efficacy
exhaustion
TT3 STANDARD versus
DOSE-DENSE BUT LESS
TT3 LIGHT
DOSE-INTENSE
· M-VTD-PACE
· M-VTD-PACE
induction x 1
induction x 1
· MEL50x4 + VTD
· MEL80-
MEL80 VRD-
VRD PACE
tandem transplants
tandem transplants
· M-VTD-PACE
· MEL20-VTD-PACE X 2
consolidation x 1
peri-transplant
· VRD maintenance
· R-VD alternating ith
w
Post-BOR/MEL GEP of
M-VD maintenance
both PC and marrow
Post-BOR/MEL GEP of
biopsies
both PC and marrow
· Drug action & prognosis
biopsies
· Drug action & prognosis

HIGH COMPLIANCE WITH BOR AND MEL
PHARMACOGENOMIC STUDIES IN TT4
PHASE OF STUDY
STUD
GEP/
Total
BA
B SELINE
A
20/20
48HR POST-BOR
19/20
48HR POST-MEL
19/20
PRE-Tx-1
10/13
PRE-Tx-2
0/0

CONCLUSIONS
· OBSERVATIONS IN TT3A - TT2 COMPARISON
VALIDATED IN EXTENSION TRIAL TT3B
Discriminatory power of 70-gene baseline risk
model
Adverse implications of translocation (4;14) in
TT2 overcome in TT3 with added bortezomib
Superiority of TT3 over TT2 especially in low-
risk myeloma
Post-bortezomib 80-gene model developed in
TT3A validated in TT3B
Issue of VRD x 3yr in TT3B v VTD x 1yr and TD
x 2yr in TT3A
it
awa s longer f l
o lllow-up
· JUSTIFICATION FOR GEP-BASED RISK
ASSIGNMENT IN TT4 AND TT5 THERAPIES