Targeting the right patients to
achieve overall survival and time to
progression benefits
Sagar Lonial, MD
Winship Cancer Institute,
Atlanta, GA, USA
Faculty disclosure information
Consultant: Millenium, Celgene, Novartis, and
BMS
Grant/Research Support: Millenium
Speakers Bureau: No
Major Stock Shareholder: No
Identifying optimal treatments for
individual patients
· Tailoring treatment to a specific
specific individual
· Requires different treatments that have been tested in
a given
g
subset
· Requires validated methods by which to separate
patients
· Requires individualized therapy that has proven
improvements in outcomes versus "standard" therapy
Major adverse prognostic factors
· Karyotypic deletion 13
13 or
or hypodiploidy
hypodiploidy
· High plasma cell labelling index
· Molecular genetics: t(4;14), t(14;16) or del(17p)
· High LDH, M, or CRP
· Increased circulating plasma cells
· Plasmablastic morphology
· Ll
Low a b
lb
i
um n
Data for most of the molecular prognostic factors
have not been validated in prospective trials with
new agents
What factors do we have data for now?
· Age
· Prior transplant
· Response to
to prior
prior therapy
· Renal function
Overview of phase III trials with novel
agents in
in relapsed/refractory
relapsed/refractory MM
MM
TTP or
Median
ORR,
CR or
VGPR,
DOR,
Regimen
Trial
PFS,
OS,
%
nCR, %
%
months months months
Len + Dex
MM-0091
009
61
24
NE
16
11
355
Len + Dex
MM-0102
60
25
NE
17
11
Bortezomib
APEX3
43
15
NE
8
6
30
Vdox
MMY-30014
44
13
27
10
9
NE
1. Weber DM, et al. N Engl J Med. 2007;357:2133-42.
2. Dimopoulos M, et al. N Engl J Med. 2007;357:2123-32.
DOR = duration of response;
3. Richardson PG, et al. Blood. 2007;110:3557-60.
NE = not evaluable;
4. Orlowski RZ, et al. J Clin Oncol. 2007;25:3892-901.
Vdox = bortezomib + pegylated liposomal doxorubicin.
5. Weber DM, et al. Blood. 2007;110:[abstract 412].
MM-009 and MM-010 pooled analysis:
response to therapy
Median duration of response to Len + Dex: 16 months
70
61%
60
PR
50
CR/nCR
(%)
40
rate
p < 0 001
.
30
24%
23%
esponse
20
R
CR 15%
R
CR
CR/nCR 24%
10
3%
CR 2%
CR/nCR 3 4%
.
0
Len + Dex
Dex
Weber D, et al. Blood. 2007;110:[abstract 412].
Updated data presented at ASH Annual Meeting, 2007.
MM-009 and MM-010 pooled analysis: time
to progression and overall survival
Survival benefit retained despite
Len + Dex
47% crossover*
100
Dex
100
75
80
Median 11.2 months
(%)
(%) 60
50
tients
atients
Pa
P 40
Mean OS,
25
months
Median 4.7 months
20 Len + Dex
> 35
p = 0.015
p < 0.001*
Dex
31
0
0
0
510
15
20
25
30 010
20
30
40
50
Overall survival (months)
Time to progression
pg
(months)
* Patients analysed at extended follow-up
remained in original groups despite crossover.
Weber D, et al. Blood. 2007;110:[abstract 412].
58% of patients on Len + Dex remain alive.
Updated data presented at ASH Annual Meeting, 2007.
Clinical benefit of Len + Dex is
independent of age
MM-009 and MM-010: subgroup analysis
100
PR
CR
p < 0.001
p < 0.001
p < 0.001
80
)
63.9
61.5
58.4
(% 60
tients 40
Pa
22.2
21.4
21.9
20
0
Len + Dex
Dex
Len + Dex
Dex
Len + Dex
Dex
Age < 65 years
Age 6575 years
Age > 75 years
Median
11.2
4.7
13.3
4.7
13.3
4.7
TTP, mos
Lonial S, et al. Haematologica. 2007;92 Suppl 2:172:[abstract PO-663];
Weber D, et al. Blood. 2007;110:[abstract 412]. Updated data presented at ASH Annual Meeting, 2007.
APEX: impact of age on bortezomib
treatment in relapsed/refractory setting
Bortezomib
Dexamethasone
100
12
) 80
10
% 80
(%
8
p < 0.0001
rate 60
se
onths)
p < 0.0001
p = 0.002
n
p = 0 0004
.
m
6
(
40
TTP
4
Respo
20
2
0
0
(n = 199)
() (n = 197)
() (n = 116)
() (n = 115)
()
(n = 208)
() (n = 216)
() (n = 125)
() (n = 120)
()
< 65 years
65 years
< 65 years
65 years
Richardson PG et al, 2007. Br. J. Hematol. 137:429-35.
MMY-3001 trial: subanalysis by age
Younger patients
Elderly patients
(< 65 years)
( 65 years)
V
Vdox
V
Vdox
n* (n evaluable)
193 (183)
203 (191)
129 (127)
121 (112)
Median TTP, months (days)
6.2 (190)
9.7 (295)
6.7 (205)
9.1 (276)
p value for TTP comparison
0.0008
0.0056
CR + nCR, %
11
17
10
9
ORR, %
46
47
39
49
Median duration of response,
p
6 7 (204)
10 2 (310)
7 5 (227)
10 2 (311)
months (days)
6.7 (204)
10.2 (310)
7.5 (227)
10.2 (311)
* Intent-to-treat population.
San Miguel JF, et al. Haematologica. 2007;92 Suppl 2:[abstract PO-620].
MM-009 and MM-010 pooled analysis: impact
of prior autologous
autologous stem cell transplant
transplant
80
No prior ASCT
ASCT
Prior ASCT
ASCT
70
63%
(%)
60
55%
PR
ate
CR/nCR
a
50
r
40
30
sponse
24%
s
20%
Re
20
39%
43%
10
8%
13%
0
LD
Len + Dex
Dex
LD
Len + Dex
Dex
(n = 147)
(n = 148)
(n = 206)
(n = 203)
Median TTP, mo
13.2
4.7
10.9
4.7
p = 0.44
Ni
Neutropenia, %
28.6
2.0
40.3
4.4
Thrombocytopenia, %
18.4
8.8
14.6
7.4
Weber D, et al. Blood. 2007;110:[abstract 412]. Updated data presented at ASH Annual Meeting, 2007.
MMY-3001 trial: impact of prior autologous
stem cell transplant
transplant
No prior SCT
Prior SCT
V
Vdox
V
Vdox
n* (n evaluable)
()
149 (146)
()
138 (130)
()
173 (164)
()
186 (173)
()
Median TTP, mo (days)
6.5 (197)
10.9 (331)
6.5 (197)
9.1 (276)
p value for TTP comparison
0.0009
0.0011
CR + C
n R
CR, %
10
14%
11%
11
14%
ORR, %
39
45%
46%
50%
Median duration of response, mo (days)
6.7 (204)
13.0 (394)
7.5 (227)
10.2 (309)
* Intent-to-treat population.
Nagler A, et al. Haematologica. 2007;92 Suppl 2:[abstract PO-625].
MM-009 and MM-010 pooled analysis:
impact of prior therapies
therapies
MM-009 and MM-010: prospective subgroup analysis
in relapsed/refractory MM
MM
Response rate
TTP
(CR + nCR + PR)
100
20
p < 0.05
Len + Dex
NS
Dex
80
15
(%)
60
ths)
60
tsn
on
e
10
m
ti
40
64
57
(
16.5
Pa
TTP
5
20
10.2
27
21
4.7
4.7
0
0
1> 1
1> 1
Prior lines of therapy
Prior lines of therapy
Stadtmauer E, et al. Presented at ASH Annual Meeting, 2006 [abstract 3552].
APEX: impact of prior therapies
APEX: subgroup analysis
Response rate (CR + PR)
TTP
100
20
80
NS
15
s)
(%)
60
h
NS
ts
ont
n
10
e
m
ti
40
(
Pa
TPT 5
20
45
34
26
7.0
5.6
4.9
13
2.9
0
0
1> 1
1> 1
Prior lines of therapy
Prior lines of therapy
Richardson PG, et al. Br J Haematol. 2007;135:429-35.
MM-009 and MM-010 pooled analysis: efficacy
of Len + Dex after
after prior
prior Thal
Thalidomide naive vs thalidomide exposed
Median time from diagnosis: 2.8 yrs vs 4.0 yrs (p < 0.05)
Median lines of prior therapy: 2 vs 3 (p < 0.05)
Overall
Median TTP,
n
response rate, %
months
Thalidomide naive
226
65
13.9
Prior thalidomide
127
54
8.4
Thalidomide sensitive (CR/PR)
54
65
9.3
SD (relapsed)
31
42
78
7.8
Refractory
20
50
7.2
Wang, M. et al. Blood 2008;112:4445-51.
Longer TTP with Len + Dex than with Dex
alone regardless of prior Thal
Len + Dex no prior Thal; Median TTP 13.9 months
Len + Dex prior Thal; Median TTP 8.4 months
100
Dex no prior Thal; Median TTP 4.7 months
Dex prior Thal; Median TTP 4.6 months
80
(%) 60
nts
40
Patie
20
0
010
20
30
Time
Time to progression (months)
Wang, M. et al. Blood 2008;112:4445-4451.
Impact of prior Thal on time to progression
and overall response
response*
Thal naive
Thal exposed
Vdox1
Len + Dex2
Vdox1
Len + Dex2
()
(n = 194)
()
(n = 226)
()
(n = 130)
()
(n = 127)
Median TTP, days
295
431
270
252
Duration of OR, days
310
486
319
402
OR, %
47
65
48
54
VGPR, %
14
39
13
21
* Not a head-to-head trial comparison.
1. Sonneveld P, et al. J Clin Oncol. 2007;24 18 Suppl:[abstract 8023].
2. Wang M, et al. Blood 2008;112:4445-51.
MMY-3001 trial: subanalysis by
risk category
High 2-M
Low 2-M
V
Vdox
Vdox
n* (n evaluable)
99 (95)
98 (95)
226 (208)
Median TTP, mo (days)
5.9 (178)
9.1 (276)
9.3 (282)
p value
0.0007
CR + nCR, %
13
15
13
ORR, %
33
49
47
Median DOR, mo (days)
6.9 (211)
(211)
10.2 (310)
(310)
10.3 (312)
*Intent-to-treat population.
DOR = duration of response;
Spencer A, et al. Haematologica. 2007; 92 Suppl 2:[abstract PO-629].
NR = not reached.
Updated data presented at IMW Annual meeting, 2007.
ORR and TTP are comparable in low- and
high-
high risk patients treated
treated with Len + Dex
Dex
Risk group
N
ORR, %
p value
Median TTP,
p value
months
ECOG 0
152
59
0.52
10.2
0.30
ECOG 1
192
62
13.1
Durie-Salmon I or II
123
61
0.89
13.6
0.21
Durie-Salmon III
229
60
10.6
2-microglobulin 2.5 mg/L
103
73
0.002
15.2
0.004
2-microglobulin > 2.5 mg/L
250
56
9.5
ORR and TTP were better in patients with 2-microglobulin 2.5 mg/L than in patients with
2-microglobulin > 2.5 mg/L.
ECOG = Eastern Cooperative Oncology Group.
Chanan-Khan A, et al. Blood. 2008;112:[abstract 3701].
Bortezomib vs high-dose dexamethasone:
response rates and renal function
APEX: prospective subgroup analysis of MM patients
with renal insufficiency
insufficiency
70
PR
CR or nCR
60
50
47
50
40
(%)
37
40
36
30
tients
25
47
Pa
28
32
20
17
31
10
25
11
10
15
10
9
8
10
8
2
4
0
1
Bor
Dex
Bor Dex
Bor Dex
Bor
Dex
ClCr, mL/min
< 30
3049
5079
80
Median TTP,
4.2
2.1
5.6
2.9
6.2
4.9
6.3
2.8
months
San Miguel JF, et al. Leukemia. 2008;22:842-9.
Len + Dex is effective
regardless of renal insufficiency
MM-009 and MM-010: prospective subgroup analysis
of MM patients with renal insufficiency
insufficiency
CR
PR
70
64
64
62
VGPR
ORR
60
50
50
40
s(%)
33
31
30
27
22
26
Patient
21
20
17 14
13
12
12
10
6
0
None
Mild
Moderate
Severe
Renal impairment
Weber D, et al. J Clin Oncol. 2008;26 [abstract 8542].
Impact of renal insufficiency on time to
progression and overall survival*
None
Mild
Moderate
Severe
(ClCr > 80 mL/min)
(50 ClCr 80
(30 ClCr < 50
(ClCr < 30 mL/min)
mL/min)
mL/min)
Len +
Bort2
Len +
Bort2
Len +
Bort2
Len +
Bort2
Dex1
Dex
Dex1
Dex
Dex1
Dex
Dex1
Dex
Patients, n
158
118
125
137
42
43
16
15
TTP
11.3
6.3
12.1
6.2
11.4
5.6
7.9
4.2
median,
months
OS
NR
NR
34.7
30.0
30.4
22.8
18.6
22.0
median,
months
*Not a head-to-head trial comparison.
1. Weber D, et al. J Clin Oncol. 2008;26: [abstract 8542].
2. San Miguel JF, et al. Haematologica. 2007;92 Suppl 2:214 [abstract PO-114].
Can novel treatment regimens overcome
poor prognosis associated with
cytogenetic abnormalities?
Whole population
del(13)
t(4;14)
del(17p)
Trial
(regimen)
n
ORR,
TTP,
n
ORR,
TTP,
n
ORR,
TTP,
n
ORR,
TTP,
%
mo
%
mo
%
mo
%
mo
APEX (Bort)1
333
38
6.0
11
20
2.6*
Richardson
65
100
786
10
100
(RVD)2
Avet-Loiseau
207
59
9.6
41
43*
5.0*
14
39*
5.5*
(Len + Dex)3
MM-
MM 016
130
83
71
7.1
54
76*
59
5.9
28
79
80
8.0
12
58*
22
2.2*
(Len + Dex)4
Dimopolous
48
52
33
33
17*
(Len + Dex
± Bort)5
Bort)
Data for most of the molecular prognostic factors
Knop (RAD)6
69
73
10.4
15
67
NS
4
50
NS
5
20*
4.6*
Cavo (VTD)7
199
61
71*
79*
have not been validated in prospective trials for
Knop (VCD)8
100
79
34
74
8
100
14
57
any of the novel agents
* Significant difference vs no
any
cytogenetic
of the
abnormalities;
novel
indicates VGPR. NS = no significant difference.
1. Jagannath S, et al. Leukemia. 2007;21:151-7. 2. Richardson PG, et al. Blood. 2008;112:[abstract 92]. Updated data presented at ASH 2008.
3. Avet-Loiseau H, et al. Blood 2008;112:[abstract 3685]. Updated data presented at ASH 2008. 4. Bahlis NJ, et al. Blood. 2008;112:[abstract 1731].
Updated data presented at ASH 2008. 5. Dimopoulos MA, et al. Blood. 2008;112:[abstract 1726]. 6. Knop S, et al. Blood. [Epub ahead of print 2009 Jan 30].
7. Cavo M, et al. Blood 2008;112:[abs 1662]. 8. Knop S, et al. Blood 2008;112:[abstract 2776].
Conclusions
· Many clinical adverse prognostic factors
factors can be
be
overcome by the use of new agents
· Identifying
yg which patients
p
will benefit optimall
p
y from a
given agent or combination of agents can be gleaned
from retrospective analysis of large randomized trials
· Prospective testing of certain clinical or lab subsets of
patients are needed to optimally suggest which
treatments are best suited for these subsets