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Vorinostat in combination with lenalidomide and dexamethasone in
JOHN THEURER
CANCERCENTER
patients with relapsed/refractory multiple myeloma: a Phase I study
AT HACKENSACK UNIVERSITY MEDICAL CENTER
D Siegel,1 DM Weber,2 CS Mitsiades,3 MA Dimopoulos,4 JL Harousseau,5 S Rizvi,6 J Howe,6 D Reiser,6 KC Anderson,3 PG Richardson3
S15
1Hackensack University Medical Center, Hackensack, NJ, USA; 2MD Anderson Cancer Center, Houston, TX, USA; 3Dana-Farber Cancer Institute, Boston, MA, USA; 4University of Athens School of
Medicine, Greece; 5Centre René Gauducheau, Saint Herblain, France; 6Merck & Co., Inc., Upper Gwynedd, PA, USA
Introduction
Pregnant or lactating females or patients with any uncontrolled intercurrent
Results
Table 3. Prior systemic anticancer therapies received by patients who had clinical benefit with vorinostat combined with lenalidomide and dexamethasone (n=13).
illness (e.g. active or systemic infection, uncontrolled hypertension, symptomatic
congestive heart failure, known HIV infection, history of Hepatitis B and/or C
Patient no.
Best response
Prior anticancer therapies

infection, plasma cell leukemia, deep vein thrombosis and/or pulmonary embolism).
1
CR
Dexamethasone, cyclophosphamide, dexamethasone, etoposide, cisplatin
Multiple myeloma (MM), the second most common hematologic malignancy,1
Efficacy
2
PR
Dexamethasone, cyclophosphamide, etoposide, cisplatin, dexamethasone
remains incurable despite recent therapeutic advances including the introduction
Patients with a history of prior malignancy excluding cervical intraepithelial

3
PR
Dexamethasone-lenalidomide, cyclophosphamide, dexamethasone, etoposide, cisplatin
Baseline patient and disease characteristics for 17 patients evaluable for
of thalidomide, bortezomib, and lenalidomide.2
neoplasia, non-melanoma skin cancer, adequately treated localized prostate
4
PR
Bortezomib, dexamethasone, cyclophosphamide, etoposide, cisplatin, dexamethasone
efficacy (as of March 27, 2009) are shown in Table 2.
5
PR
Dexamethasone, lenalidomide, cyclophosphamide, doxil, etoposide, melphalan

cancer or other effectively treated cancer (no recurrence within 5 years).
Although people with relapsed and refractory MM constitute a specific medical
6
PR
Bortezomib, dexamethasone, melphalan, prednisone
need whose disease is especially challenging to treat, novel combinations of
Table 2. Baseline characteristics of patients evaluable for efficacy.
7
PR
Dexamethasone-doxorubicin-vincristine sulfate, interferon alfa, thalidomide, melphalan
Study design
agents have the potential to improve responses in these patients.3
8
MR
Thalidomide-dexamethasone, dexamethasone, dexamethasone-bortezomib, cyclophosphamide;
Patients were sequentially enrolled into one of five escalating doses of the
Characteristic
perifosine-bortezomib-dexamethasone
Vorinostat is an oral inhibitor of Class I and II histone deacetylase enzymes and
9
MR
Dexamethasone, dexamethasone-thalidomide, cyclophosphamide, dexamethasone, etoposide, cisplatin
combination regimen using a standard 3+3 design for
8 cycles (Table 1).
Median age, years (range)
61 (53-74)
is approved in the US for the treatment of cutaneous manifestations of T-cell
10
MR
Bortezomib, dexamethasone, lenalidomide
At the MTD, the cohort was to be expanded to 14 patients.
11
SD
Dexamethasone-lenalidomide, cyclophosphamide, dexamethasone, etoposide, cisplatin, melphalan
lymphoma in patients with progressive, persistent, or recurrent disease on or
Gender, n (%)
12
SD
Thalidomide-dexamethasonea
following two systemic therapies.4
Male
9 (53)
Table 1. Dose escalation scheme.
13
SD
Bortezomib-cyclophosphamide-thalidomide, bortezomib-dexamethasone-lenalidomide,
Female
8 (47)
cyclophosphamide-thalidomide, thalidomide, cytoxan, thalidomide, bortezomib
Vorinostat has demonstrated modest single-agent activity in patients with
Dose level
Dosing regimen
ECOG status, n (%)
a
advanced MM5 and has been shown to enhance the anti-MM activity of other
Patient also received granulocyte-colony stimulating factor for stem cell collection.
0
7 (41)
pro-apotoptic agents,6 providing potential for synergy in combination with
Vorinostat (mg qd)
Lenalidomide (mg qd)
Dexamethasone (mg qd)
1
9 (53)
lenalidomide and dexamethasone.
7 days on 7 days off
x 21 days
on Days 1, 8,
21 (6)
(Days 1-7 and Days 15-21)
(Days 1-21) in each
15, and 22 in each
Tolerability
MTD
This Phase I study aims to evaluate the safety and tolerability of vorinostat
in each 28-day cycle
28-day cycle
28-day cycle
Median number of prior systemic anticancer therapies, n (range)a
5 (2-10)
Of 21 patients assessed for safety to date, 19 patients have reported at least
The MTD has not yet been reached (Table 4):
combined with lenalidomide and dexamethasone in patients with relapsed
Previous thalidomide/lenalidomide, n (%)b
13 (76)
one AE, regardless of relationship to treatment.
or refractory MM.
1
300
10
40
- no DLTs were observed in evaluable patients sequentially accrued to dose
aPatients may have received the same anticancer agent in different lines of therapy.
2
400
10
40
b
The most common Grade 1/2 AEs were diarrhea (n=9, 43%), fatigue (n=9, 43%),
levels 1, 2, 3, and 4
Patients may have received more than one regimen containing thalidomide or lenalidomide.
anemia (n=7, 33%), and hypomagnesemia (n=7, 33%). The most common
- one patient in dose level 5 experienced a DLT of Grade 3 diarrhea
ECOG, Eastern Cooperative Oncology Group.
Objectives
3
400
15
40
Grade 3/4 AEs were diarrhea and neutropenia (both n=3, 14%).
- currently, DLT evaluation is ongoing in 1 patient enrolled in dose level 5.
4
400
20
40
A total of 8 serious AEs (SAEs) were reported in 6 patients (29%): pneumonia
Table 4. Results of dose escalation for the determination of the maximum tolerated dose.
5
400
25
40
Of these 17 patients, 13 patients had clinical benefit on treatment
(n=1, 5%) and septic shock (n=1, 5%) in the same patient; neutropenia (n=1, 5%)
Primary
(Figure 1). Prior anticancer therapies received by these 13 patients are
and sternal fracture (n=1, 5%) in the same patient; diarrhea (n=2, 10%); syncope
qd, once daily.
Dose level
No. patients evaluable for DLTs
No. treatment cycles
DLT

shown in Table 3.
(n=1, 5%), and epistaxis (n=1, 5%). Two SAEs, diarrhea and neutropenia, were
To determine the maximum tolerated dose (MTD) of vorinostat in combination
with lenalidomide and dexamethasone in patients with relapsed or refractory MM.

considered related to study treatment.
Of 21 patients currently enrolled in the study, 15 patients remain on treatment
1 (n=4)
3
12
0
Vorinostat was given orally on Days 1-7 and 15-21, lenalidomide was given
2 (n=4)
3
10
0
and 6 patients have discontinued treatment due to progressive disease.
Sixteen patients (76%) experienced a total of 33 AEs that were deemed related
3 (n=3)
3
80
Secondary and exploratory
orally on Days 1-21, and dexamethasone 40 mg was given orally on
to treatment; most of these were deemed mild or moderate in severity (Figure 2).
4 (n=3)
3
60
Days 1, 8, 15, and 22 of a 28-day cycle. Aspirin 81 mg was given daily
Figure 1. Best response to vorinostat combined with lenalidomide and dexamethasone

One patient with neutropenia was hospitalized for sepsis/pneumonia which led
5 (n=7)
6
4
Diarrhea (Grade 3)
To assess the safety and tolerability of the regimen in this patient population.
for prophylactic anticoagulation.
in patients with relapsed or refractory multiple myeloma (n=17).
to death. The death was deemed not related to vorinostat and possibly related to
DLT, dose-limiting toxicity after first cycle.
To determine the clinical activity of the combination.
lenalidomide/dexamethasone.
Assessments
6
To date, no patients have discontinued treatment due to AEs or SAEs.
Methods
Efficacy
Conclusions

Figure 2. Most common ( 10%) drug-related adverse events (AEs) (n=19).
Response to study therapy was assessed using modified European Group
for Blood and Marrow Transplantation criteria.7,8
5
Grade 1/2
Anemia
Multicenter, open-label, non-randomized, Phase I dose-escalation study of
Anorexia

Dose-limiting toxicity
These preliminary data suggest that vorinostat combined with
Grade 3/4
vorinostat administered in combination with lenalidomide and dexamethasone

Increased ALT
lenalidomide and dexamethasone may represent an effective
Dose-limiting toxicity (DLT) was assessed during the first treatment cycle.
in patients with relapsed or refractory MM.
Increased AST
Toxicity was graded according to the National Cancer Institute Common
4
oral combination therapy that is active and well tolerated in the
Diarrhea
Terminology Criteria for Adverse Events version 3.0.
DVT
treatment of relapsed or refractory MM.
Inclusion criteria
Dysgeusia

If a patient experienced a DLT or an adverse event (AE) related to vorinostat
Dyspepsia
Dose escalation continues for determination of the MTD.
Eligible patients were aged
18 years with an established diagnosis of MM with
patients
3
a maximum of up to two dose reductions were allowed.
Fatigue
relapsed or refractory measurable disease after at least one prior anti-myeloma
of
Hyperglycemia
therapy, Eastern Cooperative Oncology Group performance status
2, and
A DLT was defined as any AE leading to a dose modification or occurrence
No.
Hypocalcemia
References
adequate hematologic, hepatic, and renal function.
of one or more of the following events during the first cycle of therapy:
Hypomagnesemia
2
Hypophosphatemia
Patients must not have received chemotherapy, radiation therapy, major surgery or
- Grade 4 neutropenia, Grade 4 thrombocytopenia or any Grade 5
Insomnia
1. Jemal A et al. CA Cancer J Clin 2008; 58: 71-96.
Muscle spasm
other investigational anticancer therapy for at least 3 weeks prior to study entry.
hematologic toxicity
2. Reece DE et al. Leuk Lymphoma 2008; 49: 1470-1485.
Nausea
3. Richardson P et al. Hematology Am Soc Hematol Educ Program 2007; 2007: 317-323.

1
Neutropenia
All patients must have followed the mandatory pregnancy testing guidelines and
- Grade 3, 4 or 5 non-hematologic DLT except Grade 3 nausea, vomiting,
4. Mann BS et al. Oncologist 2007; 12: 1247-1252.
Rash
5. Richardson P et al. Leuk Lymphoma 2008; 49: 502-507.
acceptable birth control methods required for lenalidomide administration.
diarrhea, and dehydration due to inadequate compliance with supportive
Thrombocytopenia
6. Mitsiades CS et al. Proc Natl Acad Sci U S A 2004; 101: 540-545.
care, Grade 3 acidosis or alkalosis, isolated Grade 3 elevation of liver
Thrombophlebitis superficial
7. Bladé J et al. Br J Haematol 1998; 102: 1115-1123.
Exclusion criteria
function tests and elevation of amylase without clinical symptoms,
Vomiting
8. Attal M et al. N Engl J Med 2003; 349: 2495-2502.
0
CR
PR
MR
SD
PD

Grade 3 hypocalcemia, hypokalemia, hypomagnesemia, hyponatremia or
This study was supported by funding from Merck Research Laboratories. David Siegel has no relevant conflicts of interest to
Allogenic bone marrow transplant prior to the study or within 4 weeks of initiation
01
2
3
4
5
6
7
8
9
10
hypophosphatemia, hypercholesterolemia, and hypertriglyceridemia.
disclose. Donna Weber is an occasional speaker for and has received honoraria from Celgene and Millennium and was an unpaid
No. of patients (n=19)
of vorinostat therapy, previous treatment with a histone deacetylase inhibitor,
participant at a recent Merck advisory board. Paul Richardson is on the advisory board and Speaker's Bureau of Celgene.
CR, complete response; PR, partial response; MR, minimal response;
Constantine Mitsiades has received consultant honoraria from Merck, Millennium, Pharmion, and Novartis. Ken Anderson
ALT, alanine aminotransferase; AST, aspartate aminotransferase; DVT, deep vein thrombosis.
use of lenalidomide within 3 months before the first dose, and antibiotic,
The MTD was the highest dose level in which no more than one patient out
SD, stable disease; PD, progressive disease.
has received consultant honoraria and research funding from Celgene, Novartis, and Millennium. Syed Rizvi, Jason Howe,
Patients may appear in more than one AE category and may have had more than one occurrence
of a specific AE. Only the highest grade of a given AE was counted per patient.
and David Reiser are employees of Merck Research Laboratories. The authors would like to thank Belinda Burton from
antiviral or antifungal therapy within 2 weeks prior to the start of the study.
of six patients experienced a DLT during the first cycle of treatment.
Complete Medical Communications, who provided medical writing assistance funded by Merck & Co., Inc.
Poster presented at the American Society of Clinical Oncology, Orlando, FL, USA, May 29-June 2, 2009.

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