Hematology Department
Cancer Research Center
University of Salamanca
Universit
Univ
y Hospital
HDACi in Multiple Myeloma
Enrique M. Ocio
University Hospital & Cancer Research Center
University of Salamanca, Spain
HDACi in Myeloma
· Mechanism of action of HDACi
· Anti-MM activity of HDACi in monotherapy
· Combinations of HDACi in MM
1
HDACi in Myeloma
· Mechanism of action of HDACi
· Anti-MM activity of HDACi in monotherapy
· Combinations of HDACi in MM
What are Deacetylases?
DACs are enzymes that remove acetyl groups from their client proteins
and modulate their activity
Non-histone, Non-epigenetic
Histones,
Epigenetic
DAC
DAC
DAC
DAC
DAC
Proteins
modulated
by DACs
Histone
p53
-tubulin
HIF-1
HSP90
Downstream
Tumor
Loss of tumor
Microtubule
suppressor suppressor
depolymerization
VEGF
Oncoproteins
effects
gene activity
function
aggresome form.
Pro-oncogenic
Cell
Cell motility and
Cell proliferation
Invasion
and survival
activity
proliferation
Cell
Angiogenesis
proliferation
Reviewed in Ocio et al. Invest New Drugs. 2010
2
Increased DAC activity in tumor cells
There is a balance between acetyl transferase and deacetylase activity in
normal cells
HAT
DAC
TF
Ac
Ac
Ac
Ac
Ac
Deacetylation
Acetylation
Tumo
Norm r
al
Cell
Increased DAC activity in tumor cells
In tumor cells there is an increase in deacetylase activity that results in a
pro-oncogenic phenotype
HAT
Increased
Decreased
DAC
DAC Activity
HAT Activity
TF
Ac
Ac
DAC
DAC
Ac
Ac
Ac
DAC
Inhibitor
Tumor
Cell
3
HDACi in Myeloma
· Mechanism of action of HDACi
· Anti-MM activity of HDACi in monotherapy
· Combinations of HDACi in MM
Preclinical anti-MM activity of Panobinostat
Cell lines
Patients' cells
Bone Density
120
MM1S
ls 100
Untreated
100
MM1R
cel 80
Panob 10 nM
Trabecular Bone
80
U266
+
T
U266LR7
V
T
60
Panob 100 nM
Vehicle
Panobinostat
60
n
U266DOX4
%M 40
40
nnexi
20
A 20
%
0
0
0
0.1
1
10
100
[Panobinostat], nM
1
2
34
Patients
15
*
V
Survival in vivo
T
sem 10
*
±
BV/
5
sc plasmacytoma
%
ean
Disseminated MM
M
0
1.0
1.0
* p< 0.05 vs.vehicle
Panob
Vehicle
0.8
0.8
10 mg/Kg
Panob 5 mg/Kg
Vehicle
0.6
0.6
Panob 10 mg/Kg
Panob 5 mg/Kg
vival
vival
0.4
Panob 20 mg/Kg
Panob 10 mg/Kg
Sur 0.4
Vehicle
Sur
Panob 20 mg/Kg
0.2
0.2
0.0
0.0
0
20
40
60
80
0
14
28
42
56
70
Days of treatment
Days post implant
Khan SB, Br J Haem. 2004 Romidepsin
Mitsiades CS, PNAS 2004 Vorinostat
Maiso P. Cancer Res. 2006; Ocio EM, Haematologica 2010
Golay J, Leukemia 2007
Givinostat
4
Activity of HDACi in monotherapy in MM
n
ORR
Responses
Vorinostat1 (SAHA)
10
0%
1 MR, 9 SD
Panobinostat2 (LBH589)
38
3%
1PR, 1 MR, 1 SD
Givinostat3 (ITF2357)
19
0%
5 SD
Romidepsin4 (FK228)
12
0%
4 SD
1. Richardson PG, Leuk Lymphoma 2008
3. Galli M, Ann Hematol 2010
2. Wolf, ASH 2008. Abstract 2774
4. Niesvizky R, Cancer 2011
HDACi in Myeloma
· Mechanism of action of HDACi
· Anti-MM activity of HDACi in monotherapy
· Combinations of HDACi in MM
5
Rationale for combining DACi + Bortezomib
Unfolded Protein Response
Tanespymicin
HDACi
Hsp90
inhibitors
Proteasome
inhibitors
Hsp-90
Chaperone
Bortezomib
Carfilzomib
HDAC6
inhibitors
Tubacin
HDACi
Kindly provided by Dr. James Bradner and adapted
Preclinical activity of HDACi + Bort + Dex in MM
Activity in vitro
Changes in GEP
120
1.0
l)
Apoptosis 15-25%
0.8
tro 100
n
0.6
co
80
fect
2000
s
Ef 0.4
(%
ne
60
0.2
1500
1206
ge
takep
0
ted 1000
u
40
0
1
2
3
4
TT
Dose
466
M
20
500
Panob+Bort
Bort + Dex
regula
156
219
De
0
Panob + Dex
Panob + Bort + Dex
0
-
Panob
Bort
Dex
PBD
+ - +
- +
- +
Panob
CI in the highly synergistic range (0.1-0.2)
Bort
Dex
Bort+Dex
895 genes exclusive of PBD
Activity in vivo
) 3600
3
1.0
3000
C
(mm
B
P
PB*
0.8
2400
D
BD
PBD **
al
PB*
lume 1800
iv 0.6
o
rv
v 1200
Su 0.4
mor
PD*
u
600
*
0.2
BD
PD
PBD **
T
CP
BD
0
0.0
0
1020
30
40
5060
70
80
0
20
40
60
80
100
120
Days of treatment
Days of treatment
* p<0.05 related to singles
** p<0.05 related to doubles
Ocio EM, Haematologica 2010
6
Efficacy of HDACi + Bortezomib +/- Dex
Vorinostat1
Vorinostat2
Panobinostat3
Romidepsin4
Vor 400 mg po 4-11
Vor 400 mg po 1-14
Pan 20 mg po L,X,V x 2w/3w
Rom 10 mg/m2 iv 1, 8, 15
Dose
Bort 1.3 mg/m2 1,4,8,11
Bort 0.7-1.3 mg/m2 1,4,8,11
Bort 1.3 mg/m2 1,4,8,11
Bort 1.3 mg/m2 1,4,8,11
Dex* 20 mg po 4-8
Dex* 20 mg po 1-4, 9-12
Dex* 20 mg 1-2, 4-5, 8-9, 11-12
Dex 20 mg 1-2, 4-5, 8-9, 11-12
n
23
34
62
25
PR
43%
47%
55%
60%
MR
NR
NR
65%
72%
% prior Btz
83%
38%
63%
24%
% Btz Refr.
39%
NR
31%
NR
* Dex added in cycle 2 if suboptimal response
** 100% prior Thal & 74% prior Len
Bortezomib (APEX)5 PR 43%
Bortezomib + Dex6,7 PR 51%*-59%
1. Badros A. Clin Cancer Res 2009
3. San Miguel JF, IMW 2011 Abs P-238
5. Richardson PG, NEJM 2005 & Blood 2007
2. Weber, IMW 2009 Abs 246, 248
4. Harrison S, IMW 2011. Abs P-233
6. Mikhael JR, Br J Haematol 2009
7. Corso A, Eur J Haematol 2009
Efficacy of HDACi + Bortezomib +/- Dex
in Bortezomib-refractory pts
· Vorinostat1,2
· n=8 37% PR, 50% SD
· n=7 29% PR, 29% MR
M
· Panobinostat3
· n=19 37% PR, 26% MR
M
· 14 patients previously progressing under Btz 57% MR

1. Badros A. Clin Cancer Res 2009
2. Weber D, ASH 2008 Abs 3711
3. San Miguel JF, IMW 2011 Abs P-238
7
Efficacy of HDACi + Bortezomib +/- Dex
Two ongoing randomized trials will answer this question
A Phase 3, International, Multicenter,
Global randomized Phase III trial
Randomized, Double-Blind Study of the
evaluating oral Panobinostat in
HDAC Inhibitor Vorinostat or Placebo in
combination with Bortezomib and
Combination With Bortezomib in Patients
Dexamethasone in relapsed or relapsed
With MM
& refractory MM
Safety of HDACi + Bortezomib +/- Dex
Vorinostat1
Panobinostat2
Romidepsin3
All (%)
G3/4 (%)
All (%)
G3/4 (%)
All (%)
G3/4 (%)
Haematological
Thrombocytopenia
74
57
87
79
-
64
Neutropenia
30
13
71
55
-36
Anemia
70
22
52
18
-
36
Non Haematological
Diarrhea
48
9
73
14
-
4
Nausea
52
0
61
3-
-
Fatigue
48
22
52
10
-
20
Pyrexia
17
0
47
6
-
-
Asthenia
--
44
26
--
Anorexia
--
42
2
-
-
P. Neuropathy
61
4
37
3
-
8
1. Badros A. Clin Cancer Res 2009
2. San Miguel JF, IMW 2011 Abs P-238
3. Harrison S, IMW 2011. Abs P-233
8
Preclinical activity of HDACi + Len + Dex in MM
Activity in vitro
Changes in GEP
120
1.0
l)
Apoptosis 15-25%
0.8
tro 100
n
0.6
2008
co
80
fect
2000
s
(%
Ef 0.4
ne
60
0.2
1500
ge
takep
0
ted
u
40
0
200
400
600
800
1.000
1000
695
TT
Dose
466
M
20
500
Panob + Lenal
regula
219
Lenal + Dex
De
0
Panob + Dex
Panob + Len + Dex
0
- +
-
Panob Lenal
Dex
PLD
+
- +
- +
Panob
CI in the highly synergistic range (<0.1)
Len
Dex
Len+Dex
1323 genes exclusive of PLD
Activity in vivo
3600
)3
1.0
3000
C
PL*
(mm
P
2400
0.8
L
D
PLD **
al
lume 1800
LD
0.6
PL
iv
*
ov
rv
LD
1200
*
PD
Su 0.4
moru 600
T
L
0.2
0
CP
D
*
PD
PLD**
010
20
30
40
50
60
70
80
0.0 0
20
40
60
80
100
Days of treatment
Days of treatment
* p<0.05 related to singles
** p<0.05 related to doubles
Ocio EM, Haematologica 2010
Efficacy of HDACi + Lenalidomide + Dex
Vorinostat1
Panobinostat2
Vorinostat3
Vor 400 mg po 1-7, 15-21
Panob 20 mg L, X, V
Vor 300-400 mg po 1-7, 15-21
Dose
Lenalidomide 25 mg po 1-21
Lenalidomide 25 mg po 1-21
Lenalidomide 10-25 mg po 1-21
Dex 40 mg po 1, 8, 15, 22
Dex 40 mg po 1-4, 9-12, 17-20*
Dex 20-40 mg po 1, 8, 15, 22
n
31
46
25
PR
53%
59%
28%
MR
70%
65%
48%
Thal
68%
63%
-
% Prior
Len
45%
17%
100%**
Bort
68%
61%
-
* 1-4 after cycle 5
** all of them previously refractory to Len-Dex
Lenalidomide + Dex4 PR: 60% (15% CR)
1. Richardson PG, ASH 2010 Abstr 1951
3. Bilotti E, IMW 2011. Abs P-215
2. Mateos MV, ASCO 2010. Abs 8030
4. Dimopoulos M, Leukemia 2009
9
Safety of HDACi + Lenalidomide + Dex
Vorinostat1
Panobinostat2*
All
G 3/4
All
G 3/4
Haematological
Thrombocytopenia
48
16
54
50
Neutropenia
39
26
50
48
Anemia
32
10
46
26
Non Haematological
Diarrhea
48
13
48
6
Nausea
26
3
48
2
Fatigue
52
10
37
13
Pyrexia
--
43
4
Asthenia
13
0
37
9
Anorexia
23028
9
*In the Panobinostat study a high incidence of DLTs and SAEs were observed (mostly infectious),
probably related to the high doses of Dexamethasone and the continuous treatment with Panobinostat.
1. Richardson PG, ASH 2010 Abs 1951
2. Mateos MV, ASCO 2010. Abs 8030
Other combinations with DACi in MM
Panobinostat + Melphalan1
PR 16%
64% previous Melph. Haem toxicity
Panobinostat + MPT2
PR 50%
Haem tox (70% neutropenia G ¾)
Vorinostat + PLD + Bort3
PR 72%
In Bz refr PR 44%. General & GI AEs
Vor + Len + Bort + Dex
Refr. to RVD4
PR 44%
General & Haem tox (89% Thromb G3/4)
Newly diagnosed5 41% nCR/CR, 24% VGPR, 29% PR
47% PN (6% G3)
1. Berenson J, IMW 2011 Abstr P-206
5. Kaufmann J, IMW 2011 Abstr P-235
3. Voorhes. ASH 2010 Abstr 1955
2. Offidani. IMW 2011 Abstr P-191
4. Siegel D, IMW 2011 Abstr P-216
10
HDACi IN RR MM
Summary
· There is a clear preclin
pr
ical
eclin
rational
ra
e
tional for the use
us of
o HDACi in MM base
bas d
e on
epigenetic and non-epigenetic mechanisms
· The clinical
clini
activ
ac
i
tiv t
i y of HDACi in monotherapy
m
in MM has
ha been
b
quite
qui
modest,
m
neve
nev rtheless,...
· , ... several
sev
combinations such as those with Bortezomib or Lenalidomide and
Dex have
hav demonstrated activity
activ
eve
v n in
i prev
p
i
rev ously
i
refractory patients.
p
· The most si
s gnific
i
a
gnific nt AEs associat
associa ed
t
with
i
thes
the e drugs
d
ar
a e
r Haemat
aema ological
ol
side effects, constitutional sym
y ptoms
m
and GI symptoms
sy
Hematology Department
Cancer Research Center
University of Salamanca
Universit
Univ
y Hospital
HDACi in Multiple Myeloma
Enrique M. Ocio
University Hospital & Cancer Research Center
University of Salamanca, Spain
11