Microsoft PowerPoint - Kos_ New Response Criteria (June 29, 2007) 061307rc [Compatibility Mode]

The Importance of New and
Evolving Response Criteria
Kos, Greece
Gr
Friday, June 29th, 2007
Brian G.M. Durie, M.D.

Focus on Early Survival Prediction and
Response Assessment
Initial survival:
survival:
1 year/ 2 years/
yy
3 years
y
Primary > VGPR/ CR
Progression Free Survival

Reinventing Overall Survival Analyses
Long-term survival
Takes too long!
Is flawed because of "post-protocol" therapy
Shorter-term survival
Best early indicator "if y
yyou're not alive early,
y,
you won't be alive later"
Allows rapid assessment of:
· Early disease progression
· Serious adverse events
· Initial response

Mortality of Combination Chemotherapy vs
Melphalan/ Prednisone
Years
MP 1 yr OS = 71%
100 0
12
34
5
6+
CC 1 yr OS = 68%
90
alive 80
still 70
60
27 randomized trials
50
ercentage 40
p
30
24.4
%
19.4
20
%
1.4% SD 1.4
timated
23.0
t
Allocated cct (% ± SD)
18.0
(log-rank
Allocated cct (% ± SD)
0
(g
10
Es
2P > .1; NS)
Allocated MP (% ± SD)
0
Deaths/person-years:
CCT
642/1999 392/1456 305/1044 196/724 133/506 255/1130
MP
576/1968 407/1423 294/983 194/652 130/444 215/839
Myeloma Trialists' Collaborative Group. J Clin Oncol. 1998;16;12:3832

Non-Transplant Phase III NDMM Trials
Study
Phase
N
Regimen
CR+VG
CR +
1-yr
PR
PR
Survival
Ref
Rajkumar ECOG
JCO 2006
E1A00
III
103
Thal + HD
Dex
4%CR
73%
80%
ECOG 2007
Median Age=65
104
HD Dex
0%CR
50%
80%
Rajkumar
hl
8
MM003
III
235
Thal+HDD
44%
69%
3%
ASH 06
Median Age=65
235
HD Dex
16%
51%
78%
Facon
III
122
MP
1% CR
41%
84%
Blood 06
Median Age=70
127
HDDx2-LDD
x 10
3% CR
40%
79%
118
Mel HDD
1% CR
70%
86%
121
HDD+IFN
1% CR
42%
74%
Palumbo
III
129
MPT
28%
76%
87%~
Lancet 06
Median Age=72
126
MP
7%
48%
87%~
Facon
III
125
MPT
50%
81%
88%~
ASCO 2006
Age=65-75
196
MP
8%
40%
78%~
126
VAD+Mel
100
43%
73%
77%~

Non-Transplant Phase III NDMM Trials
1-yr
Study
Phase
N
Regimen
CR+
CR +
VGPR
PR
Survival/ Ref
Deaths
Shustik, My7
III
234
MP
48%
78%~
BJH 2007
Median age=71
232
MDex
57%
78%~
Rifkin
III
97
DV LDD
3%CR
44%
88%
Cancer 06
Mean Age=60
95
VA LDD
0% CR
41%
85%
Harousseau
III
79
Vel/Dex*
43%
82%
NA
ASH 06
Age=<65
82
VAD
26%
68%
NA
Hernandez
III
100
MP
68%
74%~
NEJM 2006
Median Age=74
100
MDex
65%
66%~
Rajkumar,
E4A03
III
223
Rev HDD
?
?
86%
ASCO 07
Median Age=65
222
Rev LDD
?
?
96.5%
5

One-year Survival rate in Phase III Newly
Diagnosed MM Trials
1-yr
Study
Age
Phase
N
Regimen
Surviva
Ref
lr
l ate
rate
Rajkumar,
E1A00
Median=65
III
103
Thal Dex vs Dex
80%
JCO 2006
Rajkumar,
Median=65
III
470
Thal Dex vs Dex
80%
ASH 06
MM003
Median=65
III
470
Thal Dex vs Dex
80%
ASH 06
Palumbo
Median=72
III
255
MPT vs MP
87%~
Lancet 06
Attal, IFM
<65
III
200
Auto vs Chemo
88%~
NEJM 1996
Child, MRC
<65
III
401
Auto vs Chemo
87%~
NEJM 2003
Barlogie, S9321
<=70
III
516
Auto vs Chemo
84%*
JCO 06
Attal, IFM
<60
III
399
Single vs Double
Auto
90%~
NEJM 2003
Auto
Barlogie, TT II
<75**
III
668
TT2 +/-Thal
92%
NEJM 2006
E4A03 Arm A
Median=65
223
223
Len + high-dose dex
87%
ASCO 2007
E4A03 Arm B
Median=65
222
222
Len + low-dose dex
96%
ASCO 2007
*intent to treat population; **80% age <65
Rajkumar, ASCO 2007

E4A03 Overall Survival at 1 year
Revlodex
RD

E4A03 Overall Survival (months):
Age<65
Revlodex
RD
12

E4A03 Overall Survival (months):
Age 65

Revlodex
RD
12

PFS and OS of MPR vs MPT
MPR: median follow
follow--up
up 21.8 months (17.8
(17.8--28.8)
28.8) [N=53]
MPT:
MPT median follow
follow--up
up 17.6 months (0.23
(0.23--44.3)
44.3) [N=129]*
PFS
OS
*Historical control Palumbo
Palumbo et al, Lancet 2006

PFS according to prognostic factors
Deletion (13) [N=42] t(4;14) [N=14]

R-MP: EFS according to response
VGPR vs PR+MR
[N=53]
p=0.034

Rationale
MP
RD
MPT
MPV
n=126
n=34
n=129
n=64
CR
2.4%
6%
15.5%
32%
PR
47.6%
91%
76%
89%
EFS
27% @ 24
59% @ 24
54% @ 24
83% @ 16
months
months
months
months
OS
64% @ 36
36
90% @ 24
24
80% @ 36
36
90% @ 16
months
months
months
months
Palumbo et al, Lancet 2006; 367:825
Rajkumar et al, Blood 2005; 106: 4050
Mateos et al, Blood 2006;108:2165

Fine-tuning Response Assessment
Facilitating response
response documentation
documentation
Expanding "Best Response"
Ed
End it
points
VGPR
CR
sCR
sC
Add FREELITE

International Uniform Response Criteria in
Myeloma1
Stringent CR:
Normal free light chain ratio
Absence of clonal PC in BM by IHC or IF
Complete response (CR)
Serum and urine IFE negative
BM bx 5% PC
Disappearance
Disappear
of soft tissue
tissue plasmacytoma
plasmacytoma
Normalization of FLC ratio in pts not measurable using
above 2 methods
VGPR
IF
iti
positive b t
u SPEP
SPEP
t
nega itive
or
90% in serum M-protein, and urine M-protein < 100 mg/24 h
Partial response (PR)
in serum M-protein by
py 50% and
in urine M-protein by 90% or to < 200 mg/24 h and
in plasmacytoma size by 50% (if present)
Non-secretory MM: 50% in BM PC
50% id
in iff
difference b t
e ween i
l
nvo
d
ve
d
an uni
l
nvo
d
ve
[sFLC]
Stable disease: not meeting criteria for CR, sCR, PR or PD
1Durie et al. Leukemia. 2006; Jul 20 epub.

Overall Survival From Six-Month and One-Year
Landmarks By Resp
yponse and Progression
Median
Median
Dh
Deaths / N iM
in Months
Dh
Deaths / N iM
in M
h
ont s
Complete Remission388 / 424 34 (30,38)
Complete Remission467 / 508 35 (32,39)
Stable Disease
618 / 658 34 (31,37)
Partial Remission
201 / 214 34 (29,40)
Partial Remission
195 / 209 32 (28,36)
Stable Disease
269 / 291 30 (26,34)
Progression
82 / 85
10 (4,19)
Progression
202 / 218 15 (12,19)
100%
P < .0001
100%
P < .0001
80%
80%
60%
60%
Six-Month Landmark
One-Year Landmark
40%
40%
20%
20%
0%
0%
0
5
10
15
20
0
5
10
15
20
Years From Six-Month Landmark
Years One Year From Landmark

Prognostic versus Predictive Factors
Prognostic Marker
Predictive Marker
Main Effect
Interaction
Effect does not vary
Effect differs by
with treatment
treatment
Cannot be used for
Can be used for
targeted therapy
targeted therapy
May be used for risk-
stratified treatment
Only makes sense in the context of
treatment (s)
Predictive Marker needed for targeted
treatment strategies

Consensus Goals for Trials* 2007
Overall Survival
@1y
@ 1 ear
year > 90%
@ 4 years > 50%
Progression Free Survival
@1y
@ 1 ear
year > 80%
@ 2 years > 50%
Response
CR/CR
s
> 20%
> VGPR
> 40%
> PR
> 90%
Follow-up
> 3 years
Statistics
Exp/ Control Hazard Ratio > 0.75

Thalidomide/ Dexamethasone Frontline

Bortezomib Frontline

Lenalidomide/ Dexamethasone Frontline
Longer-term follow-up
VGPR/ CR
Ongoing
67%
Lenalidomide/ Dex
Single autotransp
gplant
58%
Rajkumar, et al. ASH 2006

MEL200 Diagnosis (age 59),Tal + MEL200
Diagnosis (age 57-59), VMPT Relapse (age 67)
70
60
MEL200
50
40
MEL200-
Tmaintenance
30
TD-MEL200
20
VMPT
10
0
VGPR
Macro et al. Blood 2006; 2006;108:21; Attal et al. Blood 2006;108:3289; Palumbo et al Blood 2006;108:407

VAD, Vel-Dex, Tal-Dex
Diagnosis (
g(age 56-57), VMPT Relapse (
p(age 67)
60
50
40
VAD
30
Vel-Dex
Tal-Dex
20
VMPT
10
0
VGPR
Macro et al. Blood 2006; 2006;108:21; Harousseau et al. Blood 2006;108:23; Palumbo et al Blood 2006;108:407