Combined vorinostat,
lenalidomide, and dexamethasone
therapy in patients with relapsed
or refractory multiple myeloma:
A Phase I Study
David S. Siegel
Hackensack University Medical Center,
Hackensack, New Jersey
Supported by research funding from
Merck Research Laboratories
Multiple myeloma
MM is a malignancy characterized by the accumulation of
clonal plasma cells and is the second most common
hematologic malignancy1
In the US in 2008, there were an estimated 19,920 new cases
and 10,690 deaths due to MM1
The overall 5-year survival rate is 37.1%2
Despite recent therapeutic advances (including the
introduction of thalidomide, bortezomib, and lenalidomide3),
MM remains largely incurable
Novel treatment combinations may improve response in
patients with relapsed / refractory MM
1. Jemal A et al. CA Cancer J Clin. 2008;58:7196
2. Horner MJ et al. SEER Cancer Statistics Review. www.seer.gov Accessed October 22, 2009
MM, multiple myeloma
3. Reece DE et al. Leuk Lymphoma. 2008;49:14701485
Proposed mechanism of action of
HDAC inhibitors
Ac
Ac
Ac Ac
Ac
AcAc
Ac
Ac
HAT
Ac
Histone
Histone
X
Ac
Ac
Ac
Ac
Ac Ac
Ac Ac
Ac
Ac
Ac
Ac
HDAC
Deacetylated histones
Hyperacetylated histones
B
L
Positively charged Lys
O
Positive charge neutralized
residues bind tightly to
C
resulting in an open
phosphate DNA backbone
K
chromatin structure
Transcriptional repression
HDAC
Transcriptional activation
inhibitors
Cell growth
Cell growth arrest, differentiation,
and / or apoptosis
Tumor growth
Tumor growth
HAT, histone acetyl transferase;
HDAC, histone deacetylase
Marks et al. J Natl Cancer Inst. 2000;92:12101216
Preclinical rationale for combining vorinostat
and immunomodulatory drugs (IMiDs®) in MM
Survival
120
(% of control) 100
80
60
40
20
0
Control
IMiD®-1
Vorinostat
IMiD®-1 +
Vorinostat
· Pre-treatment with vorinostat enhances sensitivity of human MM
cells to apoptosis by IMiD®-1
IMiD®-1, immunomodulatory thalidomide derivative 1
Mitsiades CS et al. Proc Natl Acad Sci USA. 2004;101:540545
Study objectives
Dose-escalation Phase I study
to evaluate the safety and tolerability of vorinostat
combined with lenalidomide and dexamethasone in
patients with relapsed or refractory MM
Primary objective
MTD for the combination regimen of vorinostat,
lenalidomide, and dexamethasone
Secondary objectives
safety and tolerability of the combination regimen
clinical activity of the combination regimen
MTD, maximum tolerated dose
Study design
Multicenter, open-label, non-randomized, Phase I, dose-escalation study
in patients with relapsed / refractory MM
Dose level
Dosing regimen
Vorinostat (mg qd)
Lenalidomide (mg qd)
Dexamethasone (mg qd)
7 days on, 7 days off
x 21 days
(Days 1-7 and Days 15-21)
(Days 1-21)
(Days 1, 8, 15, and 22)
in each 28-day cycle
in each 28-day cycle
in each 28-day cycle
1
300
10
40
2
400
10
40
3
400
15
40
4
400
20
40
5
400
25
40
qd, once daily
Demographics
Demographics
Overall
Lenalidomide
N=31
refractory* n=6
Median age, years (range)
63 (52-79)
64 (61-74)
Gender, n (%)
Male
18 (58)
3 (50)
Female
13 (42)
3 (50)
ECOG performance status, n (%)
0
10 (32)
2 (33)
1
17 (55)
3 (50)
2
4 (13)
1 (17)
IgA / IgG / Kappa / Lambda / Oligo-secretory
10/16/1/3/2
2/3/0/1/0
Number of prior systemic anticancer regimens,
2 (1-12)
3 (2-4)
median (range)a
Previous therapy, n (%)
thalidomide
15 (48)
1 (17)
lenalidomideb
12 (39)
6 (100)
bortezomib
18 (58)
6 (100)
Prior autologous PBSCT, n (%)
25 (81)
4 (67)
Preliminary unaudited data; data cut-off as of September 14, 2009
*Lenalidomide refractory; no response to prior lenalidomide-containing regimens or progression on or 60 days of
receiving lenalidomide-containing regimen, or relapsed, refractory, intolerant, and / or ineligible for other therapies,
including bortezomib; aPatients may have received the same anticancer agent in different lines of therapy; bPatients may
have received more than one regimen containing thalidomide or lenalidomide; ECOG, Eastern Cooperative Oncology
Group; PBSCT, peripheral blood stem cell transplant
Dose-finding results
Maximum number
Dose
Patients evaluable
of treatment
DLT
level
for DLTs
cycles
1 (n=4)
3
18
0
2 (n=4)
3
15
0
3 (n=3)
3
11
0
4 (n=3)
3
11
0
5 (n=7)
6
11
Diarrhea (Grade 3)
Expansion (n=10)a
96
0b
Preliminary unaudited data; data cut-off as of September 14, 2009
aPatients in expansion cohort received same dose as the patients in dose level 5
bDLTs not formally assessed
DLT, dose-limiting toxicity after first cycle
Response in evaluable
population (n=28)
Patients 50
(%)
40
n=11
30
n=6
20
n=5
n=4
10
n=2
0
CR
PR
MR
SD
PD
Best overall single response rate (CR+PR): 46% (13/28)
Preliminary unaudited data; data cut-off as of September 14, 2009
European Group for Blood and Marrow Transplantation Criteria
CR, complete response; PR, partial response; MR, minimal response; SD, stable disease; PD, progressive disease
Response in evaluable patients previously
treated with lenalidomide (n=12)
Non-refractory patients (n=6)
Refractory* patients (n=6)
Patients 60
(%)
(n=3)
50
(n=3)
40
(n=2)
30
20
(n=1)
(n=1)
(n=1)
(n=1)
10
0
0
0
CR
PR
MR
SD
PD
Best overall single response rate (non-refractory) (CR+PR): 50% (3/6)
Best overall single response rate (refractory) (CR+PR): 17% (1/6)
Best overall single response rate (refractory) (CR+PR+MR+SD): 50% (3/6)
Preliminary unaudited data; data cut-off as of September 14, 2009
European Group for Blood and Marrow Transplantation Criteria
*Lenalidomide refractory; no response to prior lenalidomide-containing regimens or progression on or 60 days of
receiving lenalidomide-containing regimen, or relapsed, refractory, intolerant, and / or ineligible for other therapies,
including bortezomib
11
Tolerability
AEs were reported by 30 of the 31 patients (97%) assessed for
safety
Majority were mild / moderate in severity
the most common AEs were diarrhea (48%), fatigue (48%),
thrombocytopenia (42%), neutropenia (39%), and anemia (35%)
Serious AEs considered to be related to study regimen occurred
in 6 patients (19%)
neutropenia (Grade 4 and 2, n=2), diarrhea (Grade 3, n=2),
increased QTc (Grade 2, n=1), extrasystole (Grade 2, n=1),
dehydration (Grade 2, n=1), increased troponin (Grade 2, n=1),
and fever (Grade 2, n=2)
No treatment related deaths
Preliminary unaudited data; data cut-off as of September 14, 2009
AEs, adverse events ; QTc, QT interval corrected for heart rate
Most common adverse
events by grade
Total, n (%)
AE
Grade 1
Grade 2
Grade 3
Grade 4
Anemia
3 (9.7)
5 (16.1)
3 (9.7)
0
Diarrhea
6 (19.4)
6 (19.4)
3 (9.7)
0
Fatigue
10 (32.3)
4 (12.9)
1 (3.2)
0
Neutropenia
2 (6.5)
2 (6.5)
4 (12.9)
4 (12.9)
Thrombocytopenia
5 (16.1)
3 (9.7)
3 (9.7)
2 (6.5)
Grade 3 deep vein thrombosis was observed in two patients
Preliminary unaudited data; data cut-off as of September 14, 2009
AE, adverse event
Conclusions
Preliminary data suggest that vorinostat combined with
lenalidomide and dexamethasone may represent a
convenient oral combination therapy that is
active and generally well tolerated in
patients with relapsed / refractory MM
may also exhibit activity in patients who
have received prior lenalidomide
The maximum tolerated dose of this combination regimen
was not achieved as dose escalation continued to the
maximum administered dose defined in the protocol
The study continues to further characterize the tolerability
profile and efficacy of this combination
Acknowledgments
The study investigators would like to thank the patients for
participating in this trial as well as the nurses and clinical
research associates who contributed to the implementation
of these studies
Study investigators & clinical research teams, fellows, RNs:
DS Siegel; Hackensack University Medical Center, Hackensack, NJ, USA
DM Weber; MD Anderson Cancer Center, Houston, TX, USA
CS Mitsiades, KC Anderson, PG Richardson; Dana-Farber Cancer Institute, Boston, MA, USA
MA Dimopoulos; University of Athens School of Medicine, Greece
JL Harousseau; Centre René Gauducheau, Saint Herblain, France
S Rizvi, J Howe, D Reiser; Merck & Co., Inc., Upper Gwynedd, PA, USA
C Byrne; Celgene Corporation, Summit, NJ, USA
Medical writing assistance from Complete Medical Communications was funded by Merck & Co., Inc.