Argument in favor of Simultaneous
Therapy
Morie Gertz
Mayo Clinic
Scottsdale, Arizona
Rochester,
Rochester Minnesota
Jacksonvill
Jacksonvil e,
e Florida
Kumar, S. K. et al. Blood 2008;111:2516-2520
Copyright ©2008 American Society of Hematology. Copyright restrictions may apply.
Survival as an Endpoint is
Impractical
· If a phase 3 was designed with survival as
an endpoint with 80% likelihood of
detecting survival benefit from control 58
58
mos. to a goal of 70 months and accrual of
1 patient daily.
· Accrual target would be 675/arm
· Ff
Four years of accrual & 2 years f
o f l
ollow
up minimum
· What is a proper surrogate marker of
survival?
Q1 What are appropriate trial
endpoints?
· Multiple trials have established
established VGPR as
predictive for best outcomes measured by
survivors at
at 5, 8 & 10 years
· Bologna 96 CR/nCR independently
predicts for long OS. After 1 SCT in
in this
this
group more therapy did not impact EFS
OS.
· Validated by IFM 99 analysis by response
1. Kyle RA, et al. Cancer. 2006 May 1;106(9):1958-66. 2. Barlogie B, etal. Cancer. 2008 Jul 15;113(2):355-9. 3. Durie BG,etal. Leukemia. 2006
Sep;20(9):1467-73 4. Cavo M,. J Clin Oncol. 2007 Jun 10;25(17):2434-41
High CR rates induced by combining
novel agents & SCT in TT
Barlogie et alLeukemia 22:1650
Survival is superior on the thalidomide arm in patients
presenting with cytogenetic abnormalities
Survival is superior on the
thalidomide arm in patients
presenting with cytogenetic
abnormalities
Cumulative CR rates. The proportion of patients achieving CR was higher among
those randomized to thalidomide
Barlogie, B. et al. Blood 2008;112:3115-3121
Copyright ©2008 American Society of Hematology. Copyright restrictions may apply.
. Influence of response obtained after induction therapy on (A) event-free survival (EFS) and (B) overall survival
(OS); influence of response obtained after high-dose therapy plus autologous stem-cell transplantation on (C)
EFS and (D) OS
Lahuerta, J. J. et al. J Clin Oncol; 26:5775-5782 2008
Copyright © American Society of Clinical Oncology
Why would combinations Provide higher CR Rates?- dual apoptotic signaling
Richardson, P. Blood 2007;109:2672-2673
Copyright ©2007 American Society of Hematology. Copyright restrictions may apply.
Q2 What strategy is appropriate
· Given that
that CR/VGPR is the most
most important
important
endpoint as a surrogate of survival
· Will this endpoint best be
be achieved
achieved by
­ Sequential regimens
­ C
b
om i
binatitions f
o all avail bl
a e therapies
Impact of
of Combinations
Combinations on PFS
· VTD vs
vs TD
TD followed
followed by SCT
· VGPR 61 vs 30%
· No diff in 3C
gr3 TC
CTC toxicitity or th
therapy
cessation due to drugs
· Following SCT 1 VGPR 75 vs 53% (p<10-3)
·PFS @20mos. 93 vs 86%(p
@( =0.04
p
)
· Benefit of combination translates to higher
CR+nCR, VGPR & PFS
PFS
Cavo. Blood 158; S 158 2008
Impact of
of Combinations
Combinations-Elderly
· VMPT vs VMP
· T-50; V changed from 1,4,8,11 to
181
1,8, 52
15, 2M
22 arch
March 07
07
· CR 31 vs 16% p=.003, VGPR 55 vs 42%
02
p=.
· CR after induction, 2-year PFS was 100%
for VMPT and 79% for VMP (p=0.02).
Palumbo. Blood 112: S 652 2008
RMPT elderly relapsed
· R1
R 0m
10 gd
mg 1-
d1 21, M 1
. 8
18 mg/kg
mg/kg d1-
d1 4P
4 , P 2
mg/kg d1-4, T 50 vs 100
· T 100: PR 93 3%
.
VGPR 45%
· T 50:
PR 65% VGPR 20%
· Within multi agent studies dose intensity
may be important
· OS/PFS @ 12 mos 66 & 55%
Palumbo Blood (ASH Annual Meeting Abstracts) 2008 112: Abstract 868
Impact of Combinations-
Transplant Eligible
· TD vs VTD vs
vs VBMCP/VBAD/Vel
· Six cycles followed by HDM
CR 6
31
22%
ti l P 10 2
· CR 6
31
22% respectively P<10-
· Induction deaths 3
0
2
· Post SCT CR%
26 50
39
Mateos et al 112:S654
VRD
· V1481
V 1,4,8, 1
11
R 14
14 of
of 21
21 days 15-
15 25 mg
Dex 20 day of & after cycles 1-4 then 10
mg
· ORR 100% VGPR 74%
· No difference in
t
ou come in
ti
pa
t
en s with
ith
t(4;14) n=10
· Successful mobilization in 90%
Richardson et al Blood (ASH Annual Meeting Abstracts) 2008 112: Abstract 92
Evolution
· Phase 1 arm of
of VDCR
VDCR leading to 3 arm
arm
trial comparing with VDR & VDC
· V1481
V 1,4,8, 1D
11 ex
Dex 20
20 R1
R 51
15 4o
14 f2
of 1
21
· CTX MTD 500/M2 8-21 d cycles
· ORR 100% VGPR 68%, CR 36%
· 11 mobilized; 2 second mobilization req.
;q
· Efficacy was independent of baseline
cytogenetics or
or ISS
ISS stage
Kumar: Blood (ASH Annual Meeting Abstracts) 2008 112: Abstract 93
Conclusion
· The fastest
fastest way to
to bring
bring long term survival
to myeloma patients is to maximize CR &
VGPR of nCR rates
rates
· Combining agents both novel & traditional
therapies including high dose therapy
therapy is
clearly the best way to achieve these
endpoints.
· Presumably sequential agents may allow
ff
for emergence of drug resist t
an clones
thereby shortening OS