Tr
T eatment
r
of Myeloma:
Cure versus Control
S. Vincent Rajkumar
Professor of Medicine, Mayo Clinic
Scottsdale,
Scottsdale Arizona
Rochester,
Rochester Minnesota
Jacksonville,
Jacksonville Florida
Mayo Clinic College of Medicine
Mayo Clinic Comprehensive Cancer Center
Disclosure information
information
Nothing to disclose
Survival in myeloma
1.0
19711976
19771982
ients 0.8
1983
1983 1988
~62% at 3 years
19891994
pat 0.6
19942000
of
20012006
on 04
0.4
0.2
Proporti
0 0
20
40
60
80
100
120
140
Time (months)
Kumar SK, et al. Blood. 2008;111:2516-20.
Tr
T eatment of myeloma cure: versus
control (1)
Control
Highly active agents
Low toxicity
Cure
Tr
T eatment of myeloma: cure versus
control (2)
Toxicity
QOL
Efficacy
Ct
Cost
QOL
Control
Cure
MP era
100
Combination chemotherapy
MP
80
(%)
iveal 60
still
42% at 3 years
40
ated
24.4
Estim
19.4
20
23.0
1.4% SD
%S 1.4
18.0
(log-rank 2p > 0.1; NS)
0
0
12
24
36
48
60
72
Time (months)
Myeloma Trialists' Collaborative Group. J Clin Oncol. 1998;16:3832-42.
Tr
T ansplant
100
75
1.00
p = 0.03 by Wilocoxon test
(%)
54
p = 0.04 by log-rank test
0.75
vival
val
42
0.50
50
sur
Survi 0.25
Intensive therapy
Standard therapy
verallO
0
O 25
Conventional dose
0
20
40
60
80
High dose
Months
Nb
Number at risk
0
Intensive therapy
201
148
79
38
8
0
15
30
45
60
Standard therapy
200
129
70 30
8
Month
Conventional dose
63 (5373) 35 (2250) 12 (140)
High dose
69 (5878) 61 (5071) 52 (3667)
Attal M. N Engl J Med 1996; 335:97.
Child J. N Engl J Med 2003; 348:1875.
VRd
Response
%
CR
26
VGPR
74
ORR 100%
PR
100
Richardson PG, et al. Blood. 2008;112:[abstract 92]
Updated data presented at ASH 2008.
Evolution trial:
trial: VCRd
VCRd
Response
%
sCR
20
CR
36
ORR 100%
VGPR
68
PR
100
Kumar S, et al. Blood. 2008;112:[abstract 93]
Updated data presented at ASH 2008.
Total therapy III
Barlogie B, Br J Haematol 2007;138:176-185.
Total therapy III
Overall and event-free survival
100
80
60
40
Events / N
24-month estimate
OS
36 / 303
86% (82.91)
20
EFS
44 / 303
84% (79.88)
0
0
12
24
36
Months from start of protocol therapy
Barlogie B, et al. Br J Haematol 2007;138:176-185.
Overall survival
100
Rd
80
75%
3-year OS rate
RD
bability
60
o
pr
40
urvivalS
20
p = 0.46 log-rank;
p = 0.01 Pepe-Fleming
0
0
6
12
18
24
30
36
Time in months
Numbers at
at risk
risk
RD
223
208
195
184
173
123
78
Rd
222
217
212
201
192
146
83
Intent to Treat One, Two, and Three-Year Survival Rates
in Recent Phase III Newly Diagnosed MM Trials
1-year
2-year
3-year
Study
Age
g
Phase
N
Regimen
g
survival
surviva
surviva
rate
l rate
l rate
Rajkumar, E1A00
Median=65
III
207
Thal Dex vs Dex
80%
72%
<70%
Rajkumar, MM003
Median=65
III
470
Thal Dex vs Dex
83%
71%
60%~
Pl
Palumbo
Md
Me i
dian=72
72
III
255
MPT vs MP
MP
87%~
83%~
60%~
Facon
Median =68
III
447
MPT vs MP vs
M100
88%
78%~
65%~
San Miguel, VISTA
Median=71
III
682
MPV vs MP
90%~
83%
72%
Attal, IFM
<65
III
200
Auto vs Chemo
88%~
80%~
65%~
Child, MRC
<65
III
401
Auto vs Chemo
87%~
75%~
70%~
Barlogie, S9321
<=70
III
516
Auto vs Chemo
84%*
78%*~
60%*~
Attal, IFM
IFM
<60
III
399
Single vs Double
399
g
90%
75%
65%
Auto
90%~
75%~
~
Barlogie, TT II
<75**
III
668
TT2 +/-Thal
92%
84%~
75%~
E4A03 Arm A
Median=65
III
223
Len + high-dose
dex
88%
78%
75%
E4A03 Arm B
Median=65
III
222
Len/Low- dose dex
96%
88%
74%
*intent to treat population; **80% age <65
Rajkumar SV. 2008.
Tr
T eatment of myeloma
Melphalan and prednisone
2008:
(MP) era1
lenalidomide-based therapy2
()
py
100
100
Combination chemotherapy
MP
80
80
e(%)
aliv
95% at 3 years
(%)
60
60
stilld
42% at 3 years
years
tients
40
40
Pa
24.4 19.4
20
23.0
20
Estimate
1.4% SD 1.4
18.0
(log-rank 2p > 0.1; NS)
0
0
012 24 36 48 60 72
0
5 10 15 20 25 30 35 40 45
Time (months)
Time (months)
1. Myeloma Trialists' Collaborative Group. J Clin Oncol. 1998;16:3832-42
2. Menon SP, et al. Cancer. 2008;112:1522-80
I. Importance
Importance of CR
· Pt
Prognos itic
· Desirable
Surrogate marker
marker
10
1.0
Responders (19 patients)
Non-responders (35 patients)
alive
0.8
ts
patien
0.6
ofn
0.4
Proportio
02
0.2
0
0
510
15
20
25
Tannock I, Murphy K. J Clin Oncol 1983 Jan 1(1):66-70.
Inconsistent
Trial
Regimen
CR
Median
Comment
rate
overall
survival
(months)
IFM 99-06
MPT
13%
52
Trend to higher CR rate with Mel
Mel 100
18%
38
100, but significantly superior OS
with MPT
Bologna 96
Single ASCT
33%
65
Higher CR rate with tandem ASCT,
Tandem ASCT
47%
71
but no difference in OS
MAG trial
Early ASCT
19%
65
Higher CR rate with early ASCT, but
D l
e
d
aye ASCT
5%
64
no diff
dif erence in OS
OS
VISTA Trial:
Trial: VMP
VMP vs MP
100
t(%)n 80
eve
60
Group
N
Event
Median
ithout
40
CR
102
6
NA
w
PR
136
11
NA
20
< PR
106
28
NA
ubjects
0
S
0
2 4
6
8 10 12 14 16 18 20 22 24 26 28 30
Time (months)
Poster presented at ASH 2008: Harousseau et al.
Blood 2008;112:[abstract 2778].
San Miguel JF, ASH 2008
May increase toxicity
· OS is a
i
compos t
ite
d
en
i
po t
n
The issue of
of MGUS
MGUS
Genomic
instability
Microenvironmental
Translocation
changes in bone marrow
at 14q32
Increased
(50%)
angiogenesis
gg
Deletion of
chromosome
13 (50%)
Myeloma
Increased bone
Normal cell
resorption
If
Infectiti ?
on
Inflammation?
N-RAS, K-RAS (30%)
p16 methylation (40%)
MGUS
Secondary translocation?
Kyle RA and Rajkumar SV. Cecil Textbook of Medicine, 22nd Edition, 2004.
Kyle RA and Rajkumar SV. N Engl J Med 2004;351:1860-73.
Not a marker of cure
· At
As curren ltly d f
e ifined,
d
an measurabl
ble, CR
CR
t
represen s
profound tumor reduction, not cure
Technical
T
limitations
Complete response is critical in
patients with high-risk myeloma
Overall survival from landmark (18 months),
(), by complete
p
response:
p
TT2 with GEP 70 data
Low-risk MM (87%)
High-risk MM (13%)
100
100
80
80
(%) 60
(%)
60
60
Log-rank p = 0.01
40
Deaths/N
Median OS,
40
months
Patients
Patients
CR
18/116
NR
20
20
Deaths/N
Median OS, months
No CR
33/161
NR
CR
4/15
NR
Log-rank p = 0.18
No CR 9/13
9
0
0
0
122436
486072
012
24
36
48
Time after 18-month landmark (months)
Time after 18-month landmark (months)
GEP = gene expression profiling;
Haessler J, et al. Clin Cancer Res. 2007;13:7073-9.
TT2 = total therapy 2.
Importance of CR
· If cure is th
the
l
goa , then CR is a necessary fifi t
rs t
s ep
· If control is the goal, CR as currently defined has
some disadvantages.
Alternatives
· CR l
p us VGPR
VGPR
t
ra e is a b tt
e er more
reproducible metric of depth of
response
· "Stringent CR" may be more useful
and needs validation
II. Combination versus sequential
(phase III MPT trials)
TTP
Study
Regimen
N
Overall
PFS/EFS
Survival
Palumbo
MPT
129
22
45 vs 48
(Blood 2008)
MP
126
15
P = 0.79
Facon
MPT
125
28
52 vs 33
(Lancet 2007)
MP
196
18
P = 0.0006
Hulin
MPT
113
24
45 vs 28
(ASH 2007)
MP
116
19
P = 0.03
Wijermans
MPT
165
13
37 vs 30
(ASH 2008)
MP
168
10
P = 0.16
Gulbrandsen
MPT
363
20
29 vs 33
(EHA 2007)
MP
18
P = 0.46
ECOG: VRd versus Vd
E1A05: Phase III Novel non-transplant consolidation
R
A
VRd
C
t
on i
tinue th
therapy till
N
CR/PR/
till
D
Stable
progression or
O
toxicity
M
I
Z
A
Progression
anytime
Off prescription
T
prescription
I
Vd
O
N
CTEP and CIRB approved
Combination versus sequential
· If cure is th
the
l
goa , then
l
ear y i
ti
ncorpora on f
o ALL
ALL
active agents is a necessary first step
· If control is
is the
the goal, then a sequential
sequential approach
reserving in order to minimize early toxicity, provide
early QOL benefits, and reserving some agents for
relapse is
is preferred
preferred
III. Role of auto-transplant
100
75
1.00
p = 0.03 by Wilocoxon test
(%)
54
p = 0.04 by log-rank test
0.75
vival
val
42
0.50
50
sur
Survi 0.25
Intensive therapy
Standard therapy
verallO
0
O 25
Conventional dose
0
20
40
60
80
High dose
Months
Nb
Number at risk
0
Intensive therapy
201
148
79
38
8
0
15
30
45
60
Standard therapy
200
129
70 30
8
Month
Conventional dose
63 (5373) 35 (2250) 12 (140)
High dose
69 (5878) 61 (5071) 52 (3667)
Attal M. N Engl J Med 1996; 335:97.
Child J. N Engl J Med 2003; 348:1875
Tandem
T
transplantation
100
75
IFM 94 trial
(%)
vival
50
sur
verallO
25
Single-transplant group
Double-transplant group
0
0
24
48
72
96
Months
Probability of
of overall
overall survival
survival (95% CI)
CI)
Single-transplant group
50 (4357) 31 (2438) 20 (1329)
Double-transplant group
57 (4964) 42 (3550) 42 (3449)
Attal M, et al. N Engl J Med 2003; 349:2495
PETHEMA trial
ASCT versus conventional dose chemotherapy in responders to
induction therapy
216 patients; 164 responders randomized
Auto (median: 33 months
Auto (median: 33 months
Chemo (median: 42 months)
Chemo (median: 42 months)
1.0
1.0
0.8
0.8
lity
ility
l
b
0.6
0.6
0.4
Proba 0.4
Probabi
02
0.2
02
0.2
p = NS
p = NS
0
0
0 10 20 304050 6070 8090100 110
0 10 20 304050 6070 8090100 110
Mt
Mon h
ths
Mt
Mon h
ths
Blade, J. et al. Blood 2005;106:3755-59.
Upfront versus delayed transplantation
SWOG study
MAG study
1.0
0.8
HDCTX + PBSC before
bability
chemotherapy
o
100
o
HDCTX + PBSC b f
e ore aut l
o ogous
pr 0.6
80
BMT
0.4
60
rvivalu
rcentage 40
S 0.2
Early HDT
Pe
Late HDT
20
0
0 10 20 30 40 50 60 70 80 90 100
0
3
6
9
12
Months
Years from random assignment
Deaths
Number
7-year
estimate
HDCTX + PBSC before
149
255
39% (32, 46)
ht
chemo h
therapy
HDCTX + PBSC before
151
261
38% (31, 45)
autologous BMT
Fermand J, et al. Blood. 1998;92:3131-36.; Barlogie B, et al. JCO 2006;24:929-36
Overall survival with tandem or single
g
transplant for myeloma
Tandem
Single
transplant
transplant
Hazard ratio
Hazard ratio
transplant
Study
(overall survival)
Events
Events
IV, random
IV, random, 95% CI
(total)
(total)
(95% CI)
Abdelkefi, 20081*
34 (97)
15 (98)
2.17 (1.044.56)
Attal, 20032
2003
11
113 (200)
143 (199)
07
0. 2
72 (05
(0. 7
57 0
.93)
Cavo, 20073*
83 (158)
82 (163)
0.98 (0.721.33)
Fermand, 20054*
77 (114)
76 (113)
0.75 (0.541.05)
Goldschmidt, 20075*
90 (180)
()
89 (178)
()
1.02 (0.7613.7)
Sonneveld, 20076
108 (155)
105 (148)
1.03 (0.811.31)
Total
505 (904)
510 (899)
0.94 (0.771.14)
* Estimated numbers of events.
Heterogeneity: tau2 = 0.03; chi2 = 11.66; df = 5 (p = 0.04); I2 = 57%.
0.5
0.7
1.0
1.5 2.0
Test for overall effect: z = 0.62 (p = 0.53).
Tandem transplant
Single transplant
1. Abdelkefi A, et al. Blood. 2008;111:1805-10.
better
better
2. Attal M, et al. N Engl J Med. 2003;349:2495-502.
3. Cavo M, et al. J Clin Oncol. 2007;25:2434-41.
4. F
d
erman J, t
e l
a . P
t
resen d
e
t
a Xth I t
n ernatiti
l
ona M l
ye oma F
d
oun ti
a on W k
or h
s op, 2005.
5. Goldschmidt H. Presented at XIth International Myeloma Workshop, 2007.
6. Sonneveld P, et al. Haematologica. 2007;92:928-35.
Kumar A, et al. J Natl Cancer Inst. 2009;101:100-6
Role of transplant
· If cure is th
the
l
goa , then early i
ti
ncorpora on f
o t d
an em
transplantation following induction is the preferred
approach
· If control is the goal, then a patient selected approach
of early vs delayed transplant, and considering
tandem only in
in selected
selected but not all patients is
is
preferred.
IV.
IV Role
Role of
of Allo-
Allo SCT
100
100
p = 0.03
p = 0.07
(%)
(%)
rvival 50
rvival
50
50
u
su
s
Overall
0
Overall
0
12
024 36 48 60 72 84 96
12
024 36 48 60 72 84 96
Months
Months
Autograft-allograft
-
group
Autograft-allograft
-
group
Double autologous-transplant group
Double autologous-transplant group
Number at risk
Number at risk
Autograft-allograft group
58 58 48 37 22 9 4 1 0
Autograft-allograft group
58 58 41 23 15 8 3 1 0
Dbl
tl
46 43 32 16 7 5 2 1 0
Double-autologous-
46 45 40 29 19 14 8 4 0
Double-autologous-
transplant group
transplant group
Bruno B et al. N Engl J Med 2007;356:1110-1120
Role of Allo-
Allo SCT
1.0
09
0.9
0.8
0.7
surviving
0.6
0.5
roportion
0.4
p
0.3
0.2
mulativeu 0.1
C
0
0
10
20
30
40
50
60
70
80
90
100
Mt
Mon h
ths
Rosinol, L. et al. Blood 2008;112:3591-3593.
Cure or Control?
· In trials: Explore both approaches
· Off-study: Control, for now....until more active agents
available
· This means:
· Goal of therapy: VGPR or better in std-risk
and CR in high-risk
· Favor sequential approaches
· Auto-transplant- timing takes into account
patient preference
· Tandem transplant- only in selected
patients
· Ai
Avo di
iding l
all t
o-
l
ransp
t
an s
t
ou side li
c i
n
l
ca
trial settings
Qt
Ques i
ti
?
ons