Individualizing Tr
T eatment
r
in the Era
of Novel Agents
Agents
Progress in MM Cell
Biology
Discovery of New Drugs
Biology
yg
Prognostic factors
factors
Si
l
ngu ar Mech i
an sm f
o actition
&
Myeloma subtypes
subtypes*
Individualize & Ta
T ilor
a
Treatment
Treatment
* MM should not be considered a single entity
San Miguel et al JCO 2008
Sh
ld
ou
M
l
ye oma therapy
be based on risk stratification?
Ii
It is not the time yet
but treatment can be individualized*
. * Co-morbidities, preferences, response to prior therapy
To include patients in well designed trials (randomized)
Potential Pitfalls for Genetic Risk stratification
(I)
Some MGUS patients display cytogenetic abnormalities (similar
to MM) but apparently they don't influence outcome. Why has the
same genetic abnormality so different prognostic value in MGUS
and MM?.
In MM genetic risk factors* have shown an adverse prognostic
impact in the era of chemotherapy & ASCT........
.......But this dismal outcome may be overcome by novel agents.
* Del 17p, t(4;14) t(14;16) , Cytogenetic del 13q, hypodiploidy
cytogenetics High-risk (t(4;14), t(14;16), del 17p vs standard-risk
cytogenetics by FISH
Response: 81% vs 82% ; CR ( 35% vs 32%)
TTP
OS
100
10
1. 0
00
80
Standard risk
0.75
Standard risk
60
High risk
without
(%)
High risk
ribution
n 0.50
40
dist
event
functio
Subjects
20
0.25
Survival
Standard risk
risk (N=142):median
(N=142):median not
not reached (29 events
Standard risk (N=142): 23.1 months (34 events)
events
0
High risk (N=26): 19.8 months (7 events)
High risk (N=26): median not reached (6 events)
0.00
HR=1.297 (95% CI: 0.55, 3.06), p=0.55
HR=1.104 (95% CI: 0.444, 2.743), p=0.8311
0 2 4 6 8 10 12 14 16 18 20 22 24 26
0
4 8 12 16
20 24 28 32 36
Time (months)
Time (months)
San Miguel NEJM 2008, 359: 906-17and updated at ASH
Potential Pitfalls for Genetic Risk stratification
(II)
Currently it could be premature to mandate specific
therapies according to cytogenetic abnormalities.
It could be that the "more intensive therapies" selected
for "high risk" patients may be of even greater benefit
for "standard risk" patients.
Potential Pitfalls for Risk Stratification in Elderly
Patients "still
"
many unsolved questions"
questions (I)
Although
g novel agents
g
may overcome adverse prognosis
pg
of highr
g
isk
cytogenetics
- The number of patients analyzed is limited.
Optimal doses in novel schemes: Does dose intensity & duration
matter?
- "Lessons learned from": Len-dex; Thal Dex vs MP; VMP trials.
In elderly patients "high doses" may have a detrimental effect: early
discontinuations... ......but optimal duration of treatment has not been defined
Potential Pitfalls for Risk Stratification in Elderly
Patients "still
"
many unsolved questions"
questions (II)
Can we compare trials?
- Differences in criteria for response & PFS assessments*
- Heterogeneity
Heter
of treatment
tr
at re
r lapse (disrupt OS analysis)
How to e p
x lain
plain the diff
dif erences
f
in MPT res l
u ts?:
lts? > OS inonlly 2/
2 5
/
studies
- Insufficient number of MPT cycles?
- The use of Thal upfront & maintenance may induce resistant
relapses?
* When you look matters : the effect of assessment schedule on PFS (Panageas JNCI 2007, 99 :
428).
Tr
T eatment stratification in
in elderly patients
p
patients ?
Still many unsolved questions
may be risky
"Risk stratification"
* To stitimulate partiticipatition in clii
linical tril
ials
Paradigms around ASCT which may lead to
pitfalls in stratification
3 4
- courses of induction therapy is enough*
Mel 200 is the optimal Conditioning regimen
The high risk patients do not benefit from ASCT**
Primary refractory patients benefit more from ASCT
Patients in CR after induction (novel agents) may not benefit from
ASCT
Second ASCT should only be offered to patients < VGPR ***
*
The goal: to
to reduce
reduce tumor
tumor burden
bur
(no
(no CR/VGPR) since the
the impact of
of initial
initial therapy
therapy is
marginal
**
This may change with novel agents (TT2, TT3)
*** Concept of chemosensitivity (sensitivity to prior treatments): to stratify according to
Influence of Response to induction
with novel agents
aagents on
o
on outcome
Three trials have shown that a high initial CR/VGPR rate is
associated with prolonged PFS
- TAD vs VAD (402 patients) (Lokhorst Hematologica 2008 & ASH 2008)
- VTD vs TD (460 patients) (Cavo ASH 2008)
- BzDex vs VAD (482 patients) (Harouseau ASH 2008)
The probability
pr
of achieving CR after Trx
Trx is significantly higher
among patients achieving nCR vs PR pre Trx (52% vs 36%)
(Lahuerta JCO 2008)
Paradigms around ASCT which may lead to
pitfalls in stratification
3 4
- courses of induction therapy is enough
Mel 200 is the optimal Conditioning regimen
The high risk patients do not benefit from ASCT*
Primary refractory patients benefit more from ASCT
Patients in CR after induction (novel agents) may not benefit from
ASCT
Second ASCT should only be offered to patients < VGPR **
*
This may change
change with novel agents (TT2
(TT2, TT3)
** Concept of chemosensitivity (sensitivity to prior treatments): to stratify according to
response.
Outcome according to the Conditioning regimen
BU-
BU MEL vs
vs MEL200
MEL200 (PETHEMA/ GEM
GEM 2000 trial)
PFS
1,0
BUMEL, n 152. median 46.4 m
0,9
MEL200, n 423, median 33,4 m
0,8
LogRank 0.002
0,7
0,6
PFS
05
0,5
0,4
0,3
0,2
0,1
0,0
0
10
20
30
40
50
60
70
80
90
100
Months
Lahuerta et al ( umpublished data))
Outcome according to the Conditioning regimen
BU-MEL vs MEL200 (PETHEMA/ GEM 2000 trial)
OS:
OS: all patients
Only patients who had access
All patients,
p, except tandem transplantation
Treatment for first relapse/progression: only patients treated with TAL or VEL on monotherapy or
& received
received novel drugs at relapse
1,0
combinations based on TAL and/or VEL
1,0
0,9
BUMEL n=156, median 72 m
BUMEL, n=41. Median 54.6
MEL200, n=445, median 69,8 m
MEL200, n=135. Median 34.7
0,9
0,8
LogRank 0 5
LogR
Log a
R nk
n 0.01
01
ing
LogRank 0.5
0,8
g
0,7
rviv
ivin
u
rv 0,7
S
u
0,6
S
tion
n 0,6
io
or 05
rt
0,5
o
rop
0,5
rop
0,4
P
tiveP
ive 0,4
lau
at
0,3
ul
um
m 0,3
C
u
C
C
0,2
0,2
0,1
0,1
0,0
0,0
0
10
2030405060
70
80
90
100
0
10
203040506070
8090
100
110
Time
m
Lahuerta et al ( umpublished data))
Paradigms around ASCT which may lead to
pitfalls in stratification
3 4
- courses of induction therapy is enough.
Mel 200 is the optimal Conditioning regimen
The high risk patients do not benefit from ASCT*
Primary refractory patients benefit more from ASCT
Patients in CR after induction (novel agents) may not benefit from
ASCT
Second ASCT should only be offered to patients < VGPR **
*
This may change with novel agents (TT2, TT3)
** Concept of chemosensitivity (sensitivity to prior treatments): to stratify according to
response.
Paradigms around ASCT which may lead to
pitfalls in stratification
3 4
- courses of induction therapy is enough.
Mel 200 is the optimal Conditioning regimen
The high risk patients do not benefit from ASCT*
Primary refractory patients benefit from ASCT
Patients in CR after induction (novel agents) may not benefit from
ASCT
Second ASCT should only be offered to patients < VGPR **
*
This may change
change with novel agents (TT2
(TT2, TT3)
** Concept of chemosensitivity (sensitivity to prior treatments): to stratify according to
response.
The Primary Refractory patient
Myeloablative regimens supported by ASCT appeared to be useful in patients
with primary resistant disease ( Alexanian 1994, Vesole 1996, Rajkumar 1996, 2004)
Diagnosis
Non-responding (81)
VBCMP/VBAD
No Ch
Change
Ch
(50)
(50)
(x4)
Progressive disease
1,0
(31)
0,9
0,8
Double SCT
Surviving
0,7
No Change (50)
val portion 06
0,6
ePro
Chemosensitive (900)
0,5
Survi 0,4
Cumulativ
0,3
0,2
Progressive disease (31)
0,1
p<0,000
0,0
02
4
6
8
10
12
14
Years
Years
Rosinol et
al
Paradigms around ASCT which may lead to
pitfalls in stratification
3 4
- courses of induction therapy is enough.
Mel 200 is the optimal Conditioning regimen
The high risk patients do not benefit from ASCT*
Primary refractory patients benefit more from ASCT
Patients in CR after induction (novel agents) may not benefit from
ASCT
Second ASCT should only be offered to patients < VGPR **
*
This may change
change with novel agents (TT2
(TT2, TT3)
** Concept of chemosensitivity (sensitivity to prior treatments): to stratify according to
response.
Patients in CR IFx(-) after induction: Do they benefit from
ASCT?
Influence of ASCT in re
r ducing
e
MRD (n=44)
PFS
OS
1,0
1,0
0,8
0,8
66%
Median not
reached
0,6
58%
0,6
Median not
58%
reached
0,4
0,4
Median:
97 months
22%
02
0,2
02
Median:
0,2
36 months
0,0 p= 0.04
0,0 NS (p= 0.2)
0,00
20,00
40,00
60,00
80,00
100,00
0,00
20,00
40,00
60,00
80,00
100,00
5y
5y
Months
Months
MRD negative (n=25)
MRD positive (n=19)
Paiva et al; Blood. 2008 Jul 31 [Epub] (data not repo
Caveats around Maintenance stratification
following ASCT
4/6 studies have shown benefit in TTP & OS for Thal
maintenance1......but....
- IFM99...............only in standard risk patients ( in 13q... No benefit ).
-Arkansas(TT2)..........survival
advantage
for
patients
with
abnormal
cytogenetics.
cytogenetics
-MMRC...........More resistant relapses after Thal and worse survival for
del 17p.
Have we abandoned IFN too early?
-Ludwig(n=1615)&MyelomaTrialìst`group(n:1543)3
benefit in PFS (4-8 months) and OS (7-4 months)
- Bjorkstrand (EBMT,
(EBMT n=
n 900) 4:
900)
78 vs 47 month OS
1 Attal (Blood
(Blood 2006) Spencer (A
(ASH
SH 2006), Offidani (A
(ASH
SH 2006), Barlogie (NEJM
(NEJM 2006
OS
, Blood 2008) Aldelkef (Blood 2007)
Morgan ASH 2008 (Abstract 656)
2.
Acta Oncol 2000, 39:815, 3. Br J.H 2001, 113:1020, 4. BMT 2001, 27:511
*
Is
Foseca ( Lenalidomide
Cancer Res 2002,
the
62:715).
ideal
Patients
maintenance
with 13q del who recei agent?
ved IFN: worse survival
Should we stratify Relapse treatment
di
accor ng
di
to ris
i k factors
f
?
At relapse the most important prognostic features are:
- Prior treatments : response and duration (PFS)*
- Toxicity
Area for investigation:
- Differences in genetic lesions at diagnosis and at relapse......
....do new abnormalities influence response and outcome?.
* Particularly important in patients relapsing after several lines of treatment
Proposals for Myeloma Tr
T eatment
r
(2009-
) To search for "cure" in patients <65 years
To search for "disease control" in patients 65-80
years
To search for "quality of life" in patients >80 years
Balance
-
between
between increase
incr
in efficacy vs
vs toxicity
toxicity
-Balance between degree of benefit and cost
-T
- o
To adapt treatment
tr
to
to co-
co morbidities
-
-To stimulate participation in clinical trials
Proposals for Myeloma Tr
T eatment
r
(2009- )
Comprehensive biological characterisation of all patients
patients
included in clinical trials.
To improne assessment of treatment efficacy (response)
- At BM level: Immunophenotypic & molecular remision.
- Ot
Outsid
ide BM
BM: Imaging techniques
Why is Myeloma differently evaluated from other diseases? : "The poor
brother"
Proposals for Myeloma Tr
T eatment
r
(2009- )
Under a common diagnosis of MM very different subgroups are
hidden*
- Rapid responders but early relapsing
- Non responding non progressive
- Refractory patients (to
(
Corticosteroids, Alkylating,
yg, IMID's, Proteasome
Inhib)
- Indolent course ("MGUS profile")
Investigation of "tailor-adapted" treatment strategies in these
subgroups
To pay more attention to the response with each line of treatment
To search for "sensitive" and "resistant" therapeutic approaches
("chemoresistance").........but..........in well characterized patients
ht
cohorts
. no different from other LPD.
Impact of Chemosensitivity on Outcome
Analysis of survival of patients in nCR after ASCT by comparing patients who
were already in nCR
CR b f
e ore ASCT
d
an did
t
no improve with
ith M l
e 200
l200 vs those
h
w o
improved from PR to nCR with the ASCT
An apparent uniform response may translate into different outcome
Persistent nCR after HDT/SCT, n= 42
nCR only after HDT/SCT, n= 82
EFS
OS
1,0
1,0
0,9
0,9
0,8
0,8
g 07
07
0,7
0,7
0,6
0,6
Survivin
p= 0.04
p= 0.001
Surviving
0,5
Free
0,5
vent 0,4
portion 0,4
nE
ePro
0,3
0,3
Proportio 0,2
0,2
Cumulativ
ative 0,1
0,1
Cumul 0,0
0,0
0
12
24
36
486072
84
96
012
24
36
48
60
72
84
96
months from diagnostic
months from diagnostic