Myeloma Therapy should
should be
be Based
Based on
Risk Stratification
Angela Dispenzieri, M.D.
Mayo Clinic
Scottsdale,
Scottsdale Arizona
Rochester,
Rochester Minnesota
Jacksonville,
Jacksonville Florida
Mayo Clinic College of Medicine
Mayo Clinic Comprehensive Cancer Center
Risk Stratification
Ht
Host characteristi
tics
Th
Tumor characteristi
tics
· Age
· Burden of disease
· Performance status · Cytogenetics
· Renal function
· Proliferative indices
· Co-
Co morbidities
· GEP signatures
Risk Stratification Important
Important
· N
t
on- i
r l
a
tti
se ng
· Aware that risk factors exist and
di
order appropri t
a e t t
es s
· Apply limited information to
li
c ni l
ca practice
· Clinical trial setting
· Power studies appropriately to
answer questions p
qprospectively
Rt
Ret
t
rospec i
tive rik
isk b
d
ase
t
s d
u i
dies
1980
1990
2000
2010
Defining prognostic factors
Defining genetic
factors
Defining genetic factors
In the alkylator era
in the era of novel agents
Prospective risk based studies
IFM-99-02, 9903, 9904
E2A02
DSMM V,
NCIC t(4;14)
Outcomes with Conventional
Chemotherapy: FISH
TTP,
Ref Abn.
N
mo
P
MS, mo
P
1
17p 42
--
--
16 v 39
<0.0002
2
13
325
24 v 32 0.02 35 v 51
0.02
17p
16 v 88
0.008
3
13
89
--
--
24 v 66
0.008
1.Drach J, et al. Blood. 1998;92(3):802-809.
2. Fonseca R, et
et al
al. Cancer Res. 2002;62(3):715-20.
3. Konigsberg R, et al. J Clin Oncol. 2000;18(4):804-12; Zojer N, et al.
Blood. 2000;95(6):1925-30.
Outcomes with HSCT
Ref Abnormality
N
TTP, mo
P
MS, mo
P
1-M
Non-hyper
50
--
--
20 v NR
<.03
Hypo or 13 v
12 v 19
19 v 36 v
<.001
2-
2 M
Any CA
CA v Nl
1475
v2
v 8
28
< 001
.
51
17p
20 v 34
29 v 46
.004
3-F
t(4;14)
260
20 v 37
.003
24 v 48
<.0001
17p
91
9 v 6
16
15 v 39
01
<.01
<.
4-F
t(4;14)
168
153
8 v 18
<.01
19 v 44
<.001
13
29 v 41
<.001
68 v 83%*
.001
<.001
t(4;14)
21 v 37
<.001
50 v 74%*
<.001
5-F
17p
1000
15 v 35
<.001
42 v 75%*
<.001
* % alive at
at 41
41 months
months
1. Smadja NV, et al. Blood 2001; 98:2229-2238.
2. Fassas AB, Br J Haematol 2002; 118:1041-1047.
4. Gertz, M. A. et al. Blood 2005;106:2837-2840
3. Gutierrez NC, et al. Leukemia 2007; 21:143-150.
5. Avet-Loiseau H,. Blood 2007; 109:3489-95.
Post HSCT Outcomes, Labeling
Index
N
PCLI 3 17
PFS
PCLI < 3 262
OS
1
1
23.7 vs 7.2 mo p<0.001
60.1 vs 12.6 p<0.001
.8
.8
tion
ival
.6
.6
Surv
propor
.4
.4
PFS,
Overall
.2
.2
0
0
0
20
40
60
80
100
120
1400
20
40
60
80
100
120
Time, months
Time, Months
Gertz, unpublished data
mSMART : Classification of
of Active
Active MM
MM
High-
High Risk
-
(25%)
Standard-
Standard Risk
-
(75%)
FISH
Del 17p
All others
others including:
including:
t(4;14)*
t(14;16)
Hyperdiploid
Cytogenetic Deletion
Deletion 13
13
t(11;14)
Cytogenetic
t(6;14)
hypodiploidy
PCLI >3%
*P ti
a
t
en s i
w th
ith t(4 14)
;
, b2M<4 mg/l/l and Hb
Hb 10g/dl may have int
di
erme
t
a e ri k
s di
disease
Dispenzieri et al. Mayo Clin Proc 2007;82:323-341; v5 Revised and updated: Feb 2009
Redefining Risk in the Modern
Modern Era
· CCT vs HSCT
· Single HSCT vs Tandem HSCT
· Thalidomide
· Bortezomib
· Lenalidomide
Redefining Risk in the Modern
Modern Era
· CCT vs Single HSCT
HSCT
· No prospective data, but cross
t i
r l
a comparison, MS 9 vs 26
26 mos
Smadja et al Blood. 2001;98:2229-2238)
· Single HSCT
HSCT s
v Tandem HSCT
HSCT
· No prospective data, but cross
trial comparison
comparison, MS
MS 25
25 vs
vs 36
36 mos
mos
Facon (2001)Blood 97(6): 1566-71
Garban (2006) Blood 107(9):3474-80
Moreau (2006) Blood 107(1):397-403
IFM Tandem
Tandem Transplant
Transplant 1000 Pts
B2M
FISH
LT4
Nml
LT4
13
GT4
Nml
GT4
13
LT4
4;14;
;; 17p
GT4
4;14, 17p
Avet-Loiseau, H. et al. Blood 2007;109:3489-3495
Copyright ©2007 American Society of Hematology. Copyright restrictions may apply.
Redefining Risk in the Modern
Modern Era
· CCT vs HSCT
· Single HSCT vs Tandem HSCT
· Thalidomide
· Bortezomib
· Lenalidomide
IFM 99
99 02
-
Thalidomide Maintenance
Maintenance
after ASCT
Patients ineligible
g
if both 2m > 3 & del 13 present
p
Month 3
Randomized
if no prog
Obs
Median f/u
n=197
36 months
VAD
Mel,
Mel,
VAD
Pamidronate,
x 3-4
140
200
ASCT
ASCT
n=195
No benefit in EFS
Pamidronate,
Thalidomide,
· if del 13, or
100 mg/day
n=201
· if b2M 2.5 mg/ml
Thalidomide as
as Induction
Induction and Maintenance
Maintenance
Abrogates Risk in Patients with Abnormal
Cytogenetics
OS by Thal and Cytogenetics OS by Thal and Cytogenetics
In GEP-defined low risk pts
CA + Thal
CA + Thal
CA No thal
CA No thal
Barlogie, B. et al. Blood 2008;112:3115-3121
The median follow-up is 72 months
Copyright ©2008 American Society of Hematology. Copyright restrictions may apply.
MRC IX:
IX: Thal Maintenance
Maintenance & del
del 17p
CTD v CVAD
MP v aCTD
HSCT
Thal v no Thal
Thal v no Thal
· Thalidomide maintenance in 17p- group (n=30)
· PFS: inferior with thal maintenance
· OS: inferior with thal (HR = 4.55, p=.02)
· Tenative Conclusion: thalidomide given
given at
induction and again in maintenance, may be
particularly detrimental in 17p- patients.
Morgan, G. J., et al. (2008). Blood (ASH Annual Meeting Abstracts) 112(11): 656-.
Thalidomide in
in High
High Risk
Risk
Patients
· Barlogie, B et al. Blood 2008;112:3115-
PRO
3121
· Attal et
et al.
al. Blood 2006;108:3289-3294
CON
· Morgan, G. J., et al. Blood 2008; 112(11): CON
(Abstr) 656-.
Redefining Risk in the Modern
Modern Era
· CCT vs HSCT
· Tandem HSCT vs Single HSCT
· Thalidomide
· Bortezomib
· Lenalidomide
Outcomes In Rel/Ref MM: Based on Presence or
Absence of Del 13 by Metaphase Cytogenetics
·WITH BOR, NO
NO DIFFER
DIFFERENCE IN
IN OUTCOME
OUTCOME REGARDLESS
REGARDLESS OF 13.
·WITH DEX, WORSE OS WITH 13.
TTP,
Treatment
Abn.
N
mo
P
MS, mo
P
Bortez-SUMMIT
26
2.6
NS
10
NS
Bortez -SUMMIT
No
26
3.3
NR
Bortez -APEX
64
2.6
0.06
12.5
0.8
Bortez -APEX
No
64
7.7
NR
Dex -APEX
61
2.8
0.2
3.3
0.002
Dex -APEX
No
61
56
5.6
NR
Jagannath S, et al. Leukemia 2007; 21:151-157.
Outcomes In
In Rel/Ref
Rel/Ref MM: Presence or
Absence of Deletion 13 by FISH
·WITH BOR, NO DIFFERENCE IN OUTCOME REGARDLESS OF 13.
·WITH DEX, WORSE OS IF 13.
Treatment
Abnormality
N
TTP, mo
P
MS, mo
P
Bortez -APEX 1
18
6.2
0.2
NR
-
Bortez -APEX 1
No
18
4.6
NR
Dex -APEX 1
20
3.5
0.6
NR
-
Dex -APEX 1
APEX
No
20
28
2.8
NR
Bortez 2
33
4.6*
.95
9.9
0.06
Bortez 2
No
29
6.7*
NR
1. Jagannath S, et al. Leukemia 2007; 21:151-157. 2. Sagaster V, et al. Leukemia 2007; 21:164-168.
VMP: Consistent efficacy in Patients with
High Risk FISH (t(4;14), t(14;16), del 17p)
TTP
OS
100
100
80
)
80
)
(%
ithout
60
60
w
(%
40
urvival
40
Standard risk
jects
event
Standard risk
S
Sub
20
20
High risk
High risk
0
0
0
4
8
12 1620
24
283236
0
2
4
6
8 10 12 14 1618 20 222426
Time (months)
Time (months)
Standard risk (N=142): 23.1 mo. (34 events)
Standard risk (N=142): median NR (29 events)
High risk (N=26): 19.8 mo. (7 events)
High risk (N=26): median NR (6 events)
HR=1.297 (95% CI: 0.55, 3.06), p=0.55
HR=1.104 (95% CI: 0.444, 2.743), p=0.83
San Miguel et al IMW, 2009 and ASH 2008.
Percent of
of Patients
Patients with
with VGPR to Therapy
Before ASCT in Phase III Studies
Regimen
VD v VAD*
VTD v TD
VTD v TD PAD v VAD
(Pts)
223 219
226 234
56 63
150 150
Del 13
13
47 15
73 25
64 48
t(4;14)
40 17
81 25
36 18
52 29
Del 17p
73
6
Limited to no data on PFS and OS
*With
*W
2 year median follow up
-
t(4;14) has no impact on PFS in VD pts
Del 17p has no impact on PFS in VD pts
Harousseau, et al ASH 2008; IMWG Meeting, Washington D.C. 2009
Rosinol et al ASH 2008 (abs 654)
Cavo et al ASH 2008 (abs. 158)
Sonneveld P et al ASH 2008 (abs653)
Effect of Risk and Novel
Novel Agents
on Outcomes: Total Therapy
BORTEZOMIB APPEARS TO DOUBLE EFS AND OS IN
"GEP HIGH RISK" WHEREAS THAL HAS NO EFFECT
Low Risk
High Risk
Risk
High
EFS
OS
Barlogie et al Leukemia 2008; 22, 16331636
Bortezomib in High Risk Patients
· Jagannath S, et al. Leukemia 2007; 21:151-157
· Sagaster V, et al. Leukemia 2007; 21:164-168
· Mateos MV, et al. Haematologica 2008; 93:560-565.
· San Miguel JF et al. NEJM 2008,359:906-917
· Harousseau IMW meeting 2009
· Barlogie B, et al. Leukemia 2008; 22, 16331636
Redefining Risk in the Modern
Modern Era
· CCT vs HSCT
· Tandem HSCT vs Single HSCT
· Thalidomide
· Bortezomib
· Lenalidomide
L
lid
ena
omide Overcomes Poor P
i
rognos s
Conferred by Del 13q & t(4;14), but not Del
17p in Relapsed/Refractory Myeloma
Var
Va ia
i b
a l
b e
l
PFS
OS
HR, 95% CI
P value
HR, 95% CI
P value
t(4;14)
0.92 (0.292.13)
0.92
1.26 (0.463.42)
0.64
Del 13
0.90 (0.441.83)
0.78
0.56 (0.251.29)
0.18
Del 17p
6.26 (2.4815.77)
<0.05
3.83 (1.3410.9)
0.01
MM 016 Trial
Bahlis, N. J. et al. ASH Meeting, Nov 2007 (Abstract)
Up-front Lenalidomide-Dex: PFS &
OS by Risk-Stratification
1
1
Sd
Standard
Risk
.8
ree
P < 0.001
.8
-Fn
g
.6
.6
High Risk
.4
Standard Risk
rogressio
Survivin .4
r
n
PN
P= S
P
NS
.2
.2
Fractio
ractionF
High Risk
F 0
0
0
10
20
30
40
50
0
10 20 30 40 50 60
Time (months)
Time (months)
Median estimated follow-up of the entire cohort was 36 months
Kapoor et al ASH 2008
Mounting Evidence
Evidence For Risk
Based Therapy with Novel Agents
· Thalidomide -- unclear
· Barlogie, B et al. Blood 2008;112:3115-3121
PRO
· Attal et
et al
al. Blood
Blood 2006;108:3289-3294
CON
· Morgan, G. J., et al. Blood 2008; 112(11): (Abstr) 656-.
·
CON
Bortezomib abrogates risk
· Jagannath S, et
et al
al. Leukemia 2007; 21:151-157
PRO
· Sagaster V, et al. Leukemia 2007; 21:164-168
· Mateos MV, et al. Haematologica 2008; 93:560-565.
· San Miguel JF et al. NEJM 2008,359:906-917
g,
· Harousseau IMW meeting 2009
· Barlogie B, et al. Leukemia 2008; 22, 16331636
· Lenalidomide -- unclear
· Bahlis, N. J. et al. ASH 2007 (Abstract)
PRO
· Kapoor, et al. ASH 2008 (Abstract)
CON
mSMART Off-Study
Transplant Ineligible
High Risk
Standard Risk*
MP + Bortezomib**
MP + Thalidomide** or Rd
Observation
Ob
i
servat on
*Bortezomib containing regimens preferred in
renal failure or if rapid response needed
Continuing Rd is an option for patients
responding well to induction with low toxicities;
** In patients in whom administration of
Dex is usually discontinued after first year
thalidomide or bortezomib is of concern,
consider MP or Rd
Dispenzieri et al. Mayo Clin Proc 2007;82:323-341; v5 Revised and updated: Feb 2009
mSMART Off-Study
Transplant Eligible
High
g Risk
Standard Risk
4-6 cycles of bortezomib
4 cycles of Rd*
containing regimen (CBD, VRd, VTD etc)
Collect Stem Cells**
Collect Stem Cells
If not in CR, consider autologous stem
Autologous stem cell
OR
Continue
cell transplant (ASCT)
transplant (ASCT)
Rd
All pati
ti
t
en s receive Rd
Rd
If not in CR/VGPR after
til
If not in CR/VGPR
until
progression
1st ASCT, consider
consolidation (eg.,
second ASCT or IMiD)
* Bortezomib containing regimens preferred in
renal failure
failure or if rapid response
response needed
needed
Continuing Rd is an option for patients
(**If age >65 or > 4 cycles of Rd
responding well to induction with low toxicities;
Consider G-CSF plus cytoxan or plerixafor )
Dex is usually discontinued after first year
Dispenzieri et al. Mayo Clin Proc 2007;82:323-341; v5 Revised and updated: Feb 2009
Myeloma Therapy should be
be
Based on Risk Stratification
· If we know that certain treatments
work poorly in certain populations,
why use them?
· If we know
t
cer i
a n
t
pa i
tients have an
excellent prognosis, why subject
them to high risk treatments?
Acknowledgements
Rochester
Vince Rajkumar, MD
Francis Buadi, MD
Arizona
David Dingli, MD, PhD
Leif Bergsagel, MD
Mi
Morie Gertz, MD
MD
Rf
Rafael Fonseca, MD
MD
Phil Greipp, MD
Joseph Mikhael
Suzanne Hayman, MD
Craig Reeder, MD
Shaji Kumar,
j, MD
Keith Stewart
Stewart, MD
Robert Kyle, MD
Martha Lacy, MD
Nelson Leung, MD
John Lust, MD
MD
Jacksonville
Greg Nowakowski, MD
Vivek Roy, MD
Steve Russell, MD, PhD
Tom Witzig, MD
S Zeldenrust, MD, PhD