Ti i
m ng of Transplant in th
the
Era of
of Novel
Novel Agents
Donna Weber, MD
The University of Texas, MD Anderson Cancer Center
Houston, Texas, USA
Timing of Tr
T ansplant
r
in the
Era of Novel Agents
Survey to Invited Clinician Speakers &
Additional IMWG Clinicians
1. What is your preferred induction regimen?
a. melphalan-prednisone
b. VAD
c. thalidomide-dexamethasone
d. bortezomib-dexamethasone
e. lenalidomide- low-dose dexamethasone
f. lenalidomide-high-dose dexamethasone
g. 3 drug novel agent regimen
h. bortezomib-melphalan-prednisone
i. 4 drug nov
no el
v agent regimen
j. > 4 drug novel agent regimen
2. Should autologous transplant
tr
be used for consolidation of CR?
a. yes
b. no
Qt
Ques i
tion
What is the
advantage
g of
transplant?
Attal et al, NEJM 2003, 349: 2495
Question
Why does this
adva
adv ntage occur?
Impact of Depth of Response
Trial
Response (%) 5 Yr OS AuSct
Attal et
et al1
al
CR/VGPR (%) 38
72
(n=399)
PR (%)
43
39
Harousseau etal2 CR
32
77
(
849)
n=
VGPR
22
63
PR
37
55
Wang et al3
CR
Med. OS 9-14 yrs
(n=721)
PR
MdO
Med.
S
OS 5 9
. yrs
1NEJM 2003, 349: 2495-502
2Blood 2006 108: abst 3077
3Blood 2006 108: abst 403
Importance of Chemosensitivity
Lahuerta, J. J. et al. J Clin Oncol; 26:5775-5782 2008
Copyright © American Society of Clinical Oncology
Importance of Sustained CR
Barlogie et al, ASCO 2008, #8516
What Do We Do?
What is your goal of therapy/transplant?
n=7
100
86%
n=14
80
62%
60
50%
40
36%
28.5%
20
14%
14%
9.5%
5% 7%
0
CR CR
>nCR >nCR
>VGPR>VGPR
>PR >PR
Question
What is the impact of
novel agents?
Combination Induction Therapy for Untreated MM
Regimen
Study
(No. evaluable patients)
%CR
%VGPR %PR
%OR
Facon et al
Melphalan-Prednisone
2
5
28
35
(Lancet 2007)
Cavo et al
Vincristine-Doxorubicin-
813
39
54
(ASH 2008)
Dexamethasone
Cavo et al
Thalidomide-Dexamethasone
10
9
57
76
(ASH 2008)
Harousseau et al
21
Bortezomib-Dexamethasone
26
33
80
(ASCO 2008)
CR/nCR
Rajkumar et al
Lenalidomide -
RD
17
34
30
81
(ASH 2008)
Dexamethasone
Rd
14
26
30
70
Ri h
c
d
ar son et l
a Bi
Bortezom b
ib-Lenalidomide-
31CR
35
25
100
(IMW2009)
Dexamethasone (n=42)
9nCR
Reeder et al
Bortezomib-
64
Cyclophosphamide-
Cyclophosphamide
21
15
100
(ASCO 08;8517)
CR/nCR
Dexamethasone (n=23)
San Miguel et al
Bortezomib-Melphalan-
33
8
33
74
(NEJM 2008)
()
Prednisone
Lenalidomide-
Kumar et al
Cyclophosphamide-
238
43
83
(ASH 2008; #91)
Dexamethasone (n=53)
Combination Induction Therapy for Untreated MM
Regimen
Study
(No. evaluable patients)
%CR
%VGPR %PR
%OR
Bortezomib,
Kumar et al
Cyclophosphamide,
36
28
32
96
(IMW 2009)
Lenalidomide,
Dexamethasone (
25)
n=
Bortezomib-
Bensinger et
et al
al
Cyclophosphamide-
Cyclophosphamide
33
27
30
90
(ASH 2008;#94)
Thalidomide-
Dexamethasone (n=30)
Bortezomib-Melphalan-
Palumbo et al
Prednisone-Thalidomide
31
24
(ASH 2008;#652)
(n=193)
Question
Withd
h improved CR
d
an
VGPR in the era
er of
nov
no e
v l
e agents is
transplant
tr
still
necessary?
IFM 2005/01: Response
Post induction
-
Post AuSCT
-
CR+nCR >VGPR >PR
CR+nCR >VGPR >PR
VAD
9%
24%
71%
28%
50%
88%
Bor/Dex 22%
50%
89%
38%
66%
87%
TD
6%
62%
26%CR
BTD
31%
77%
50%CR
VBMCP/ 22%
70%
39%CR
VBAD/V
TD
12%
29%
79%
32%
58% PFS, p.04
BTD
32%
62%
94%
55%
76% 86% Vs 93%
76%
Rosinol et al. ASH 2008, abst
Harrouseau et al. ASH 2007, abst 450
Cavo et al. ASH 2008, abst updated
E4A03: OS According to Transplant at or
Treatment of Only or Beyond 4 Cycles
100
Ld
79%
ability
ASCT after 4 cycles LD or Ld
80
3-yr OS rate
b
LD
Pro
60
100
LD
40
Ld
urvival
20
lity 80
S
P=NS
l
P=NS
0
92%
0
6
12
18
24
30
36
60
Time (mo)
3-yr OS rate
Probabi
No further Tx
Tx after
after 4 cycles LD or Ld
val 40
100
Survi 20
80
Ld
P=NS
babilityo 60
0
o
60
LD
Pr
0
6
12
18
24
30
36
40
Time (mo)
20
P=NS
Survival
0 0 6 12 18 24 30 36
Time (mo)
Rajkumar SV et al. ASH 2008, abstract
What Do We Do?
Does autologous transplant have a role in
the era of novel agents?
100%
n=7
100
n=14
80
60
40
20
0%
0
Yes
No
What Do We Do?
hf
What is your preferred
d
in uction regimen?
n=7
100
86%
n=14
80
67%
60
57%
50%
40
38%
20
14%
14%
14%
7%
4.8%
4.8%
4.8%
0
TD
BD
Rd
3-drug
VBCMP
> 4
VTD or
/VBAD
drug
VRD or
CyBorD or
any B
What Do We Do?
What is your preferred induction regimen
for pts >65 yrs?
n=7
100
n=14
80
60
57%
50%
43%
43%
40
29%
33%
21%
20
21%
14%
9.5%
4.8%
7%
0
RMP
VMP
Rd
3-drug
4 drug
MPT
Question
If CR is achieved
achiev
with
induction therapy is
transplant necessary?
Is Complete Response Necessary?
Copyright © American Society of Clinical Oncology
Dingli, D. et al. J Clin Oncol; 25:4933-4937 2007
Importance of Chemosensitivity
Lahuerta, J. J. et al. J Clin Oncol; 26:5775-5782 2008
Copyright © American Society of Clinical Oncology
What Do We Do?
Should transplant be used for consolidation
of CR?
n=7
100%
100
n=14
80
76%
60
57%
60
43%
40
24%
20
0
Yes
No
Question
Does transplant
tr
need
to be done in first
remission?
What Do We Do?
Should AutoSCT be used for consolidation
of ....
n=7
100%
100
n=14
86%
79%
80
60
40
29% 29% 29%
20
0
yes
yes
First Remission?
Second Remission?
Question
Do we need to do
tandem transplants in
thf
he era of nov l
e
agents?
Impact of Depth of Response
Trial
AuSCT x 1
AuSCT x 2
7y
7 rO
yr
S
OS
7y
7 rO
yr
S
OS
Attal et al1
CR/VGPR
NS
NS
(n=399)
< VGPR
11%
43%
Cavo et al2
CR/nCr (after 1)
NS
NS
(n=849)
<CR/nCR
47%
p=NS
60%
1NEJM 2003, 349: 2495-502
2J Clin Oncol 2007, 25: 2434-41
Autologous SCT (1 Vs 2)
Trial
2A
2 uSCT
AuSCT (%)
(%) 1A
1 uSCT
AuSCT (%)
(%)
Attal et al1
CR/VGPR (%)
50
42
(n=399)
7yr OS(%)
(n=399)
7 yr OS (%)
42
20
Fermand et al2
CR
39
37
(n=193)
OS
NS
NS
(n=193)
OS
NS
Cavo et al3
CR/nCR
33
47
(n=220)
OS
65
71
Sonneveld et al4
CR
32
13
(n=441)
6y
6 r
yr OS
OS
36
39
Abdelkefi et al5
CR
50
66
(n=xx)
3y
3 r
yr OS
OS
65
85 + thal
thal
1NEJM 2003, 349: 2495-502 3
2
JCO 2007 25: 2434-41 X IMW 2005
4Haematologica 2007 92: 928-35 5Blood 2008 111: 1805-1810
Total Therapy (TT) Trials: Treatment Schema
Phase
TT1
TT2
TT3
Randomization
±Thal (400 mg/d)
di
Induction
VAD
VAD 3
DCEP
VDT-DPACE
HDCTX
CAD
VDT-DPACE
EDAP
DCEP
Transplant
MEL-200 × 2
MEL-200 × 2
MEL-200 × 2
Consolidation
None
D-PACE × 4
VDT-PACE × 2
Maintenance
IFN indefinitely
IFN + Dex
VRD 3 yr
indefinitely
Median f/u
14 yr
6 yr
3 yr
Barlogie B et al. Blood. 1999;93:55; Shaughnessy J Jr et al. Br J Haematol. 2003;120:44;
Barlogie B et al. Br J Haematol. 2007;138:176
Barlogie B et al. ASCO 2008, abst:8516
PADMEL-100LPL
PBSC Mobilization
MEL-100
PAD
LP
L
(Cyclophosphamide + G-CSF)
ASCT
4 cycles
2 cycles
2 cycles
4 cycles
100
100
100
100
90
90
90
90
95%
80
80
80
80
73
89%
70
70
70
70
60%
59
87%
60
60
60
60
73%
atients
47
50
50
43
44
50
50
Pf 40
36
40
40
40
o
30
30
%
30
30
30
22
20
13
20
12
20
20
9
10
3
10
10
10
5
3
1
1
2
0
0
00
0
0
0
0
CR VGPR PR
SD
PD
CR VGPR PR
SD
PD
CR VGPR PR
SD
PD
CR VGPR PR
SD
PD
PAD 4 Cycles
PADMEL-100
PADMEL-100LP
PADMEL-100LPL
(n=102)
()
(n=77)
()
(n=56)
()
(n=40)
*Per protocol
Palumbo A et al. Blood. 2008;112:65 [abstract 159]; updated results presented at:
50th ASH Annual Meeting; December 69, 2008; San Francisco, CA
PADMEL-100LPL
VADMEL-200*
n=40
n=124
95%
100
100
90
90
80
73
80
70
70
60
60
50
50
37%
44
fPatients 40
fPatients 40
o
o
30
22
30
22
%
%
18
20
20
15
10
5
10
00
1
0
0
CR VGPR PR
SD
PD
CR VGPR PR
SD
PD
VADMEL-200*
PADMEL-100
P
2-yr EFS,
63
83
.01
%
2 yr
-
OS, %
85
92
46
.
*Historical control (Palumbo A et al. Blood. 2007;223a:108 [abstract 727] )
Palumbo A et al. Blood. 2008;112:65 [abstract 159]; updated results presented at:
50th ASH Annual Meeting; December 69, 2008; San Francisco, CA
What do we do?
Wh t
a pts should
ld receive t
d
an em
transplants?
n=7
100
86%
n=14
80
71%
64%
60
40
24%
29%
24%
20
14%
5%
7%
0
All pts
Pts with <VGPR
No pts
What do we do?
Wh t
a pts should
ld receive
i
ma t
n enance after
AuSCT?
n=7
100
n=14
80
60
57%
57%
48%
43%
43%
40
36%
20
16%
14%
7%
0
All pts
Pts until VGPR
High risk
Question
How should we treat pts
with high risk
//
cytogenetics/FISH/GEP?
Novel Agents: del 13q, 17p13 and
t(4;14) by FISH
FISH (MM 016)
-
(
1
n= 59)
159)
Bortezomib
PFS (med. mos.)*
OS (med. mos)*
Del 13 q
+ 5.9 (n=10)
- 9.9 (n=13)
+ 11.3 (n=13) - 21.3 (n=26)
t(4;14)
+ 10.5 (n=4)
-6.8 (n=18)
()
+ 15.1 (n=6)
()
- 12.3 (n=34)
()
CKS1B
+ 5.9 (n=8)
- 6.8 (n=13)
+ 11.3 (n=11) - 12.9 (n=25)
*N
* No Si
Si
i
gn fi
ifi
t
can P
l
va ues
t
no d
e
Chang t
e
l
a , L
k
eu Res 31
31 779
:
-82, 2007
Lenalidomide
n
PFS (HR, 95% CI)
OS (HR, 95% CI)
Del 13 q
57
0.9
p.78
0.56
p.18
t(4;14)
21
0.92
p.92
1.26
p.64
Del17p13
11
6.26
p.00
3.83
p.01
Bahlis, Blood, 2007;110 (abst 3597)
What Do We Do?
Should AutoSCT be used for patients with
high-risk cytogenetics/FISH?
n=7
100
95% 86%
n=14
79%
80
60
40
21%
20
14%
0
yes
yes
Second Remission?
Lenalidomide
No
BM-CTN Trial
Consolidation
Maintenance
Register
MEL
VRD x 4
Lenalidomide
and
Maintenance
200mg/m2
Randomize
MEL
Lenalidomide
200mg/m2
Maintenance
IFM 2009-
2009 DFCI Tr
T ial
r
Lenalidomide x
PBSCT
VRD x 2
1 yr
Register
and
VRD x 3
Randomize
Lenalidomide x
VRD x 5
1y
1 r
yr
Summary
·Aut ll
ologous transplant
l
current y
warrented for MM Arguably early
·Novel Agents for high-risk
cytogenetics/FISH/GEP
·Some form of maintenance/consolidation
seems warranted
Qt
Ques i
tions
·Adva
Adv ntage
a
to multiple agents upfront or
should some be reserved for relapse?
Questions
·Does data from CCT translate to novel
agents?
·Best induction? Duration?
·Aim of therapy: cure, sustained CR,
molecular CR, sCR, CR, VGPR, QOL?
·Ta
T ndem
a
transplant
tr
Vs or plus
maintenance/consolidation? Endpoint?
·Is Transplant warranted for > 65 yrs?
MDs
Research nurses, PAs
S Giralt, R Orlowski R Alexanian,
M Gavino, Christine O Sam
,muel,
J Shah, S Thomas, M Wang,
Emily Cao, A Nguyen, T Richards
Q Yi, M Qazilbash,
Data Coordinators
S
i
pec l
a Th k
an s To All The
Kim Rankin, Kay Delasalle
Patients and Their Families
Clinic Nurses
For Participating
pg in our
S. Polk
Polk-Davis, J Song
Trials