Jointly sponsored by Postgraduate Institute for Medicine, the
International Myeloma Foundation, and Clinical Care Options, LLC
Multiple Myeloma:
Finding Your Way
gy Through the Treatment Maze--Selecting
the Best Treatment in the Era of Novel Agents
Friday, December 5, 2008
6:30 PM - 9:00 PM
Moscone Center
San Francisco, California
Supported by educational grants from Celgene, Genzyme Transplant, Lilly,
Millennium Pharmaceuticals, Inc., and Ortho Biotech.
Relapse /Refractory Myeloma
Salvage therapies
J. F. San Miguel
Dt
Depar
D
t
t
men
f
o Hema
H
t l
o ogy
Cancer Research Center
University Hospital Salamanca. Spain
Relapse /Refractory
//Refractory Myeloma
Salvage
g therap
thera
gpies
Novel approved
appr
drugs*
Investig
Investi ational Ag
ggents
* Thalidomide, Lenalidomide, Bortezomib
Impact of novel agents on outcome
in relapsed/refractory disease (n=387)
Ol
Overal
i
surv val from ti
time of relapse aft
fter ASCT
ASCT
1.0
Relapsed before 1998
0.8
Relapsed 19981999
Relapsed 20002001
Relapsed 20022003
Relapsed 20042005
0.6
rvivaluS 0.4
P<0.001
0.2
0.0 0
20
40
60
80
100
Time (months)
Kumar et al. Blood 2008;111:25162520
Results with Available
A
Novel Drugs in
Rl
Relapse
l
d / Rf
Ref
t
rac ory
t
P t
a i
tti
t
en s
t
Response Rate (
p( % > PR)
Single Agent
+Dexamethasone
+ Chemo
. Thalidomide
29%*
35 55%
55 76%
. Lenalidomide
25%
60%
60 - 87%
. Bortezomib
43%
?
50 88%
* ORR: 42%
Bortezomib vs Dexamethasone (APEX): (n = 669)
R(
Response(> PR): 43% (9%CR) vs 18% (2% CR)
TTP
OS
p < 0.0001
Bortezomib
0.0001
Dexamethasone
P = 0.0272
Median TTP: 6.2 vs 3.5 months
Median OS: 30 vs 24m P = 0.02
Median DOR: 11 m vs 7,6 m
1-y OS: 80% vs 67% P = 0.0002
Richardson NEJM 2005 & Blood 2007
Phase III Study of Doxorubicin + Bortezomib vs
Bortezomib In Rel/Ref MM: 646 patients
Response: (PR): 44% (27% CR+VGPR) vs 41% (19% CR+VGPR)
TTP
OS
100
PLD + Bortezomib
100
80
80
PLD + Bortezomib
9.3 mos
Bortezomib
ession-Free 60
tsAlive 60
t
Bortezomib
DOXIPLD+
L +
Bortezomib
Bortezomib
Progr 0
40
6.5 mos
Bortezomib
Patienof
Censored
91%
88%
atients 204
Statistical analysis:
20
Died
9%
12%
s:
ent
P
HR (95% CI) 1.82 (1.41-2.35)
HR (95% CI) 1.48 (0.91; 2.41)
of
p = 0.000004
Perc
p = 0.113
0
0
ercentSignificant
0
100
benefit
200
in TTP
300
and
400
PFS
500
in bortezomib/DOXIL
0
40 80 120 160 200 240arm
280 320 360 400 440 480 520
P
Days
D
No survival advantage demonstrated to date.
ays
Dox 30mg/m on day 4
Orlowski R et al. JCO 2007; 25: 3892-3901
SLIDE 7
Bortezomib-Cyclophosphamide or
Ml
Mel
e hl
ph
p a
h l
a an
l
in
i Refrac
f
tory
t
Myeloma
l
Regimen
N
> %PR
%CR + nCR
Reference
Bz-Cy-Pre1
25
88
40
Reece ASH 2006 3536)
Bz-Cy-Dex2
16
75
31
Davies Hematologica 2007
Bz-Cy-Dex3
54
82
16
Kropff BrJH 2007
Bz-Mel
35
68
15
Berenson JCO 2006
B Ml
z-Mel+Dex
53
78
34
Popat ASH 2007, abstr. 2713
Lenalidomide+Dex vs Dexamethasone (MM 009/010)
Response(
p( >PR): 60% (
)(15%CR) vs 22% (2% CR)
TTP: 11,2 vs 4,7 m
OS: 35 vs 31 m*
Time to Progression
Overall Survival
1.0
Len/Dex, median 35 months
100
0.9
MM-009 Len/Dex (11.1 m)
Placebo/Dex, median 31
MM-009 Dex alone (4.7 m)
90
months
ts08
0.8
MM 010
-
Len/D
/Dex (11
(11 3
.
)
(includes 47% of patients who
80
m)
(includes 47% of patients who
80
crossed over to receive Lenalidomide)
0.7
MM-010 Dex alone (4.7 m)
70
patien0.6
60
of
)
o
50
%
0.5
(
40
0.4
Patients 30
portiono0.3
20
oPr
p < 0.001
*p=0.021
0.2
10
0.1
0
010
20
30
40
50
00
0.00 2.5 5 7.5 10 12.5 15 17.5 20 22.5
Overall survival (months)
Cut-off date: June 2005.
Weber D. & Dimopoulos M, NEJM 2007, *Updated ASH 2007, Abstr 412
* 47% Crossed over
Lenalidomide-based combinations: Pilot studies
Regimen
n > PR
CR
Abstract
Lenalid +
+doxorubicin +
31
87%
23%
Knop ASH 2007; Abst 2716
Dex
+ Peg
Peg lipos. Dox
+Vinc + Dex
62
75%
29% *
Baz et al. Ann Oncol 2006
+ Cyclo+Dex
21
65%
5%
Morgan G et al. BJH 2007
15
83%
10%
Reece D ASH
ASH 2008, 1723
*CR+nCR
ThaCyDex for re
r fractory MM
Survival at two years
y
years
100
80
Overall survival
66%
60
Event free survival
57%
Survivale
40
umulativccA
20
0
Years since the beginning of ThaCyDe
D x
0
1
2
3
García Sanz, Leukemia 2004, 18:856-63
IMID´s + Bortezomib in Refractory MM
Treatment Schedule
Patients
% > PR (CR/nCR)
Reference (ASH 2006)
Thal-Bz + Dex1
85
55 (22)
Zangari , ASH 2005
Thal-Bz +LDox2
23
56 (22)
Chanan-Khan, ASH 2006 (3539)
Thal Bz
-
+LDox + Dex
20
63 (24)
Hollming, ASH 2006 (2399)
(2399
Thal-Bz + MP3
30
67 (21)
Palumbo, (Blood 2007)
Thal-Bz + MD
60
60 (11)
Terpos, ASH 2006 (3541)
Len-Bz+ Dex4*
*41%
63
Relapse/ refractory: 67
65 (24)
(19)
Richardson , ASH 2008 (1742)
RMPT5
44
76
Palumbo, ASH 2008 (868)
1.Dox 20 mg day 1 & 15, Thal 200 mg
3.Bort 1 mg; Thal 100 mg & Dex 12 mg on days 1-4 & 17-20.
2.Escalating : at 1ª relapse : 36% CR. PFS at 1 y : 61%.
4 Bort 1mg, Len 15mg x 14d; PN grade3 only 1 pt
5 Len 10; Thal 50-100mg ( if 100mg: 93%PR)
Concl
onc us
l
i
us ons
i
on Novel
ove drugs
d
in
i
Relapse/ Refractory MM
Consolidate data based on randomized trials:
- Lenalidomide or Thalidomide plus Dex
- Bortezomib plus Dox
Promising combinations ()
(pilot studies):
- Thalidomide- Cyclo-Dex
- Lenalidomide- Doxorubicin or
or PegLD
PegLD-Dex
- Bortezomib- Cyclo or Melph Pred
The combi
d
ne use of IMIDs plus B t
or
i
ezom b
ib hl
shou d
ld be
restricted to well designed clinical trials *
* Simultaneous vs sequential
Tr
T eatment of Relapse following ASCT
Young
Y
patients
Early relapse (< 1 year post ASCT)
"Overcome drug resistance"
Combination of non cross-resistant agents
VTD-PACE or VRD +/- doxorubicin & Cyclo
----> RIC-Allo
Intermediate relapse ( 1-
1 3 years post ASCT)
ASCT)
"Prolong survival until curative treatments are developed"
Sequential novel agent combinations
- Starting ith
w
a diff
different drug to that used in maintenance.
( if less < 55 years & suboptimal response ----> RIC-Allo? )
Late relapse( > 3 years )
Reinduction + 2nd ASCT
Treatment of relapsed/refractory Elderly
Patients
General considerations
Components of initial therapy (sequencing considerations)
Alk l
y ati
bd
ng-based
Dexamethasone-based
IMiD-based; Bortezomib-based
Efficacy of initial therapy
Degree of response
Timing of
l
re apse
Patient status and circumstances of relapse
Age, performance
performance status
status
Aggressive vs non-aggressive relapse
Bone marrow reserve
Renal function impairment
Pre-existing peripheral neuropathy
DVT
Quality of life considerations
Tr
T eatment of Elderly Patients at
RELAPSE
Fi t
rs : th
the general condition of th
the pati
tient*
t*
Cd
Can id
didate for acti
tive treat
t
men :
- 1st step.....the alternative drug to that used as
induction +/- (cyclophosphamide & steroids)
- 2nd step.....Experimental trials
No Candidate for active treatment:
- Oral Cyclophosphamide (50mg/day) + Prednisone (30 mg)
Aggressive vs non-aggressive relapse; Bone marrow reserve; Renal function impairment
Pre-existing peripheral neuropathy; DVT
Relapse /Refractory
//Refractory Myeloma
Salvage
g therap
thera
gpies
Novel approved
appr
drugs
Investig
Investi ational Ag
ggents
Novel Agents for
MM
BM stromal cell/IL6
cell/IL dependence
Increased DNA index
Ai
Aggress
A
ive growth
t
Inmortaliz
Inmortali ation
z
Malignant
th
In vitro
Non malignant acumulationTransformation Stromal independent
proliferation
Plasma cell
Normal
MGUS
MM
Cell line
leukemia
Secondary IGH Tr
T anslocations:C-
r
Primary IGH
MYC
Tr
T anslocations
r
Karyotypic inestability
11q13
Trisomies
del 13/p16
13/p1
6p21
16q23
20q11
20q1
4p16
Mt
Mu
M t t
a i
ttions of N,
N K-RAS,
RAS FGFR3
Mutaciones de p53
Adapted from Hallek, Blood 1998
Primary IgH translocations: ¿Therapeutic Targets?
Novel Agents for MM
20%
FGFR3
PD173074
CHIR258
Cyclin D3
inhibitors
D3
AB1010
Cyclin D1
15%
FGFR3
Oncogenic
q13
/
q13
receptor tyrosine
MMSE
kinase
p21
T
Cyclin D2
Nuclear SET domain
protein
p13
p16
5%
Cyclin D1
CDK
Aurora K
B-ZIP
q32
inhibitors
inhibitors
inhibitors
transcription
p
factor
CYC202
P276-00
VE-465
IgH
C-MAF
q23
PD0332991
Novel Agents for
Host-tumor interactions MM
Di
t
rec cont t
ac &
l
so ubl
ble molecules
IL-6
MM cell
IGF-1
CD138
CD44
VEGF
ICAM-2
TNF
CXCR4
1-integrins
SDF1
LFA-
VLA-4
1
ICAM-
VCAM-
ECM
1
1
(Fibronectin, laminin)
BMSC
1-integrins: VLA-4 (CD49d), VLA-5 (CD49e), VLA-6
(CD49f)
Cell adhesion induces a drug resistance phenotype in the Myeloma cell:
1) cell cycle arrest ( p27); 2) apoptosis inhibition ( FLIP-1 FAS inhibitor-); 3) protection from drug-induced DNA
damage
PC adhesion to Fn induces overexpresion of 53 genes ( 11 regulated by NFkB)
San Miguel, Hematol J. 2003
SIGNALING CASCADES IN MM CELLS: targets for novel therapies
IGF-
IGF 1
TNF
TNF
IL6
SDF1
SDF1
IL-21
VEGF
RAS
JAK/STAT
RAF/MEK/MAPK
PI3K/AKT
Proliferation
Prevents
apoptosis
Drugs Targeting Surface Receptors
SGN-40
HuLuc63
CD40
CS1
IMGN901
CD56
VEGFR
CNTO-328 IL-6R
IGF-1R
Mil t
a uzuma
CD74
b
EGFR Cetuximab
DR4-5
TRAIL
FGFR3
TACI
Fas
APO010
BCMA
APRIL
c-kit
Dasatinib
Imatinib
Drugs targeting surface antigens
Novel Agents for MM
Anti-IL-6 MoAb (CNTO-328)
Rossi, ASH 2008. Abstract 867
+ Bort ± Dex
Phase II
n=21 Bort naive
57% PR (14% CR, 10% VGPR, 33% PR)
Basis for
for a randomized
rrandomized trial of
of Bz
B
Bz ±CNTO-328
-
Anti-CD40 (SGN-40)
Hussein, ASH 2006. Abstract 3576
Expressed
Expr
in
i highl
hi
y
ghl prol
pr i
ol f
i er
f at
er i
at v
i e cell
cel s
l and APC
32
n=
16% SD
Anti-CD56 MoAb conjugated with DM1 (Cytotoxic Maytansinoid)
Chanan-Khan, ASH 2008. Abstract 3689
Phase I
n=18 CD56+
CD56 pts 17% MR
M
At
An
A i
Atti CS1
-
surface glycoprotein. Highly expressed in MM
Zonder, ASH 2008. Abstract 2773
Phase I
n=23 26% SD
Anti-CD74 HLA-DR associated invariant
a
chain. Highly expressed
e in MM Kaufman, ASH 2008. Abstract 3697
Phase I
n=18 17% SD
(all of them at 4 mg/Kg,
K
next cohort ongoing
ongoin )
g
Drugs targeting TK receptors
Novel Agents for MM
c-kit
· Imatinib
n=23 No responses
response
Dispenzieri, Leuk Lymphoma 2006
· Dasatinib
n=13 30% SD
Wildes, ASH 2007. Abstract 1982
Two ongoing trial
tr s
ial wi
w th Len + Dex & with Bort ±De
±D x
VEGF-R
Prince, IMMW 2007. Abstract 602
· Pazopanib
n=10 No responses
response
Raschko, ASH 2007. Abstract 1173
· Bevaci
Bevac zuma
i
b
zuma + Lenal + Dex
n=10 70% PR
IGF1-R
-
Moureau, ASH
ASH 2007. Ab t
s
t
rac 1166
· AVE-1642
AVE-164
n=14 7% MR
Lacy, ASH 2007. Abstract 1171
· CP-751,871
n=47
Single agent 7% MR
EGF-
EGF R
+ Dex 4% CR
C
%C ,
R 8%
8% PR
P
Ex
E pressed
r
in MM PC and in BMSC
Tresckow, ASH 2008. Abstract 3686
· Cetuximab + Dexamethas
Dexame
one
thas
n=13 ORR 23% (8%
(
PR, 15% MR & 23% SD)
* FGFR3 (AB1010). Single agent No responses.
+ Dex (n=11) 1 nCR, 1 PR,
2mR
Drugs Targeting Signaling pathways in MM PC
TNF
TNF
IL6 IGF-1
FT inhibition
STAT3 inhibition
SDF1
SDF1
(Tipifarnib)
(Atiprimod)
IL-
IL 21
VEGF
RAF inhibition
RAS
JAK/STAT
PI3K inhibition
(BEZ235)
(RAF265)
RAF/MEK/MAPK PI3K/AKT
AKT
MEK
inhibition
inhibition
(P
( erifos
eosine)
(AZD6244
(
)
Proliferation
Prevents
mTOR
apoptosis
inhibition
P38/MAPK
(RAD001)
inhibition (SCIOS-
(Rapamycin)
469)
(CCI-779)
Signaling pathways in MM PC Novel Agents for
MM
Farnesyl-transferase inhibitor (Tipifarnib)
Lonial, ASH 2008. Abstract
3706
· + Bort
n=16 (12 previous Bort) 12% MR + 31% SD
mTOR inhibitor (Temsiro
(Temsir limus - CCI-779)
Ghobrial, ASH 2008. Abstract 3696
· + Bort
n=20 (all previous Bort)
p) ORR 33%:
33% 7% nCR, 27% MR
M
p38/MAPK inhibitor (SCIO-469)
SCIO-469
Siegel DS, ASH 2006. Abstract 3580
· + Bort (n=34) ORR
O
32% (26%
(
PR, 6% MR
M , 9% SD)
AKT inhibitor (Perifosine)
Perifosine
Richardson, ASH 2007. Abstract 1164
· +/- Dex
D
n=48 ORR 38% (13% PR, 25% MR
M ,
R 47% SD)
· + Bort ± Dex*
n=76. In 35 Bort refrac. ORR 37% (3% CR, 11% PR)
· + Len + Dex**
n=30 ORR 70% (7%
(
nCR, 43% PR)
*Richardson, ASH 2008. Abstract 870**Jakubowiak, ASH 2008. Abstract 3691
Ig production and DNA regulation in MM PC
Agents
acting on
epigenetics
Inhibitors of
the unfolded
protein
Ac
Ac
response
Ac
Ac
Unfolded Protein Response
Tanespimycin
Alvespimycin
Ub
Hsp90
inhibitors
Novel
proteasome
inhibitors
Hsp-90
NPI-0052
C fil
ib
Chaperone
Carfilzom
AB1010
HDAC6
inhibitors
Tubacin
Kindly provided by Dr. James Bradner and adapted
Heat Shock Protein 90 Inhibitors in MM
Novel Agents for MM
Tanespimycin (KOS-953 / 17-AAG)
· Single agent
Richardson, ASH 2005. Abstract 361
Phase I trial n=22
ORR 15% (10% PR, 5% MR
M ,
R 30% SD)
· +B
+ o
+B rt
r ezomib
Bortezomib Richardson, ASH 2006. Abstract 406
Phase II trial n=63
ORR 35% (5% CR, 9% nCR, 22% PR)*
(16% in Bz refr)
KW-2478
Cavenagh, ASH 2008. Abstract 2777
Phase I trial
trial
n=15 relapsed/refractory
relapsed/refractory patients
patients
No responses yet.
Median of three 14 days-cycles. 1 patient 19 cycles.
Novel Agents for
Novel Proteasome Inhibitors MM
Richardson, ASH 2008. Abstract 2770
NPI-0052
· Inhibits the three catalytic activities of the proteasome (Trypsin-, Chymotrypsin and
Caspase-like)
· Phase I n=10 2 pts SD for 6 & 12 months
Carfilzomib (PR-171)
PR-171
· 2 Phase I MR
M 38% - 51%
Orlowsky, ASH 2007. Abstract 409
Alsina, ASH 2007. Abstract 411
· 2 Phase II
PX
P -
X 171-003*
n=46
refract. Brtz & IMID
IM
ORR 26% (13% PR, 13% MR)
PX-
PX 172-
172 004**
004
n=31
Brtz treated (16) ORR 25% (19% PR,
PR 6% MR)
Brtz naive (13) ORR 54% (8% CR, 46% PR)
No exacerbation of neuropathy. Creatinine increase
*Jagannath, ASH 2008. Abstract 864**Vij, ASH 2008. Abstract 865
Nuevas dianas
Histone Deacetylase Inhibitors terapéuticas
Balanced HAT and HDAC Activity Results in Regulated
yg
Gene
Expression
Histone deacetylation prevents
Histone acetylation allows
i
gene expression
gene express on
HAT
HDAC
TF
Ac
Ac
Ac
Ac
Ac
Deacetylation
Acetylation
Normal
Cell
· DNA is packaged by wrapping around histone
octamers
Nuevas dianas
Histone Deacetylase Inhibitors terapéuticas
In tumor cells unbalance: deacetilation and inhibition of
transcription
Increased
Decreased
HAT
Increased
Decreased
HDAC Activity
HAT
HA Activity
HDAC
TF
Ac
Ac
HDAC
HDAC
Ac
Ac
Ac
Uncontrolled Cell
Growth and Survival
Tumor
Cell
Decreased Tumor
Suppressor Gene
Activity (p21, p27)
Nuevas dianas
Histone
Pan-
Deacetylase Inhibitors terapéuticas
DAC
Inhibitor
DAC
DAC
DAC
DAC
DAC
Proteins
modulated
by DACs
Histon
p53
-tubulin HIF-1
HSP90
e
Tumor
Loss of
Microtubule
Downstream
suppressor
tumor
depolymerization/
VEGF
Oncoproteins
effects
gene activity suppressor
aggresome
function
formation
Cell motility
Cell
Cell-cycle
and
proliferation
Tumor
arrest
effects
Ii
Invasion
di
and survival
Angiogenesi
Apoptosis
s
DAC depicts individual deacetylases, e.g. HDAC1, HDAC4, HDAC6
Novel Agents for
Deacetylase inhibitors in MM
MM
Vo
V rinostat (SAHA)
SAHA
Richardson, ASH 2007. Abstract 1179
· Single agent. n=10 10% MR
Weber, ASH 2008. Abstract 871 & 3711
· +B
+ o
+B r
o t
Bort
2 trials
ttrials (n=57)
((n=57)
ORR 43% & 47%Weber, ASH 2008. Abstract 871 &
47%
n=13 prev Bort
ORR 46% (38% PR, 8% MR, 54% SD)
Siegel, ASH 2008. Abstract 3705
· + Len + Dex
n=7
ORR 28% (14% PR, 14% MR)
Panobinostat (LBH589)
LBH589
Wolf, ASH 2008. Abstract 2774
Siegel, ASH 2008. Abstract 2781
· Novel oral Pan-Dac inhibitor
· Single agent
Phase II
n=38 pts refrac. to Bort & IMIDs ORR 6%
· Bort ± Dex
D
Phase Ib
n=14 ORR 35% (7% CR, 7% VGPR, 21%
PR)
Romidepsin (Depsipeptide)
Depsipeptide
Harrison, ASH 2008. Abstract 3698
· +B
+ o
+B r
o t+D
Bort + e
t+D x
Dex (+ Rom as
as maint.
maint )
n=25 ORR 67% (22% CR,
CR 22% VGPR,
VGPR 22%
PR)
ITF-2357 n=15 7% Galli,
PR
ASH 2007. Abstract 1175
Novel Agents for
Other novel compounds MM
Pomalidomide (CC-4047)
Lacy, ASH 2008. Abstract 866
·
New immunomodulatory agent
·
Orally bioavailable
bioavailable
·
Phase II
·
n=37 pts (62% previous IMID therapy)
·
62% PR (24% VGPR, 38% PR) + 16% SD
Among 13 Len refractory patients 4 (29%) responders
Aplidin
Mateos, ASH 2008. Abstract 3700
·
Phase II n=52
Monotherapy n=45 ORR 15% (4% PR, 11% MR, 40% SD)
+ Dex
n=15 ORR 22% (11% PR, 11% MR,
,, 50% SD)
GRN163L
·
Direct inhibitor of telomerase
Chanan-Khan, ASH 2008. Abstract 3688
·
Phase I
n=12 No responses yet
Conclusions
Novel Agents for
MM
·
Ai
A w d
ide array of novel
d
compoun s
·
Targeted therapies
gp
have little efficacy as single
yg agents
g
·
Combination therapies should be based on "in vitro" and animal
std
tu i
dies
·
Tr
T eatment with experimental agents
agents should
should be
be reserved for patients
patients
refractory to IMIDs & proteasome inhibitors. Combination trials
should be carefully designed ( either randomized or selected
refractory populations).
·
Attractive drugs
g for combinations: Hsp90 inhibitors, HDAC
inhibitors, pAKT inhibitors, novel proteasome inhibitors, novel
IMID´s, Aplidin
Myeloma Patients
HsP inh.AKTi
AKT nh.
i
HDAC inh
inh. Aplidine.
Lenalidomide
Bortezomib
Th lid
a
id
om e
id
Melphalan Corticosteroids
Jointly sponsored by Postgraduate Institute for Medicine, the
International Myeloma Foundation, and Clinical Care Options, LLC
Multiple Myeloma:
Finding Your Way
gy Through the Treatment Maze--Selecting
the Best Treatment in the Era of Novel Agents
Friday, December 5, 2008
6:30 PM - 9:00 PM
Moscone Center
San Francisco, California
Supported by educational grants from Celgene, Genzyme Transplant, Lilly,
Millennium Pharmaceuticals, Inc., and Ortho Biotech.