Case Report
Vorinostat Plus Bortezomib for the Treatment of
Relapsed/Refractory Multiple Myeloma: A Case
Series Illustrating Utility in Clinical Practice
Amitabha Mazumder,1 David H. Vesole,2 Sundar Jagannath1
Abstract
Introduction: Increasing numbers of patients are presenting with relapsed/refractory multiple myeloma (MM) follow-
ing treatment with bortezomib. Therefore, there is a need for effective and well-tolerated treatment strategies after
failure of bortezomib-based regimens. Vorinostat, a histone deacetylase inhibitor, has demonstrated antiproliferative
and proapoptotic activity alone and in combination with bortezomib in preclinical models of MM. Preliminary results
from ongoing phase I trials have demonstrated the clinical activity of vorinostat in combination with bortezomib in
patients with MM. This case series reports our experience of combined vorinostat and bortezomib in 6 patients with
relapsed/refractory MM after previous bortezomib. Materials and Methods: Patients received oral vorinostat 300 mg
or 400 mg once daily (days 1-14) and bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11 in a 21-day cycle. Results: All pa-
tients derived clinical benefit from combined vorinostat and bortezomib, with objective response observed in 5 of the
6 patients ( minimal response), including 1 very good partial response; stable disease was observed in the remaining
patient. Patients remained on therapy until disease progression. Combined vorinostat and bortezomib therapy was
well tolerated: grade 2 nausea and diarrhea were the only adverse events reported. No patients discontinued therapy
because of toxicity, and no dose adjustments were required for either agent. Conclusion: These results suggest that
combined vorinostat and bortezomib therapy is effective in patients with relapsed/refractory MM after failure of previ-
ous bortezomib-based regimens and support further evaluation of this combination in randomized trials.
Clinical Lymphoma, Myeloma & Leukemia, Vol. 10, No. 2, 149-151, 2010; DOI: 10.3816/CLML.2010.n.022
Keywords: HDAC, Histone deacetylase inhibitor, Proapoptotic, Proteasome inhibitor, Synergistic, Vorinostat
Introduction
MM is still considered incurable.2 Therefore, there remains a need
Multiple myeloma (MM) is an incurable hematologic malig-
for alternative treatment strategies that are active against the disease
nancy. Common clinical features of MM include hypercalcemia,
or can enhance the efficacy of existing treatments for heavily pre-
anemia, renal insufficiency, impaired immunity, and lytic bone
treated patients with relapsed or refractory MM.
disease. It is estimated that in the United States in 2008 there were
Vorinostat (suberoylanilide hydroxamic acid) is a histone deacet-
19,920 new MM cases and 10,690 deaths.1
ylase (HDAC) inhibitor approved by the United States Food and
In recent years, the spectrum of treatments available for patients
Drug Administration in October 2006 for the treatment of cuta-
with MM has expanded significantly with the use of bortezo-
neous manifestations in patients with cutaneous T-cell lymphoma
mib, thalidomide, and lenalidomide providing significant survival
who have progressive, persistent, or recurrent disease on or follow-
advantages.2 However, despite improved survival in recent years,
ing 2 systemic therapies.4,5 In preclinical models of MM, vorino-
with a median survival of 44.8 months for patients diagnosed dur-
stat has demonstrated antiproliferative and proapoptotic activity
ing the decade 1996-2006 compared with 29.9 months for patients
as monotherapy6,7 and synergistically enhanced cell sensitivity to
diagnosed between 1971 and 1996,3 responses are transient and
bortezomib and thalidomide analogues.7-10 Vorinostat has also
demonstrated modest single-agent activity in patients with MM11
1St Vincent's Comprehensive Cancer Center, New York, NY
and preliminary results from 2 phase I clinical studies indicate that
2Division of Hematology/Oncology, Loyola University, Chicago, IL
vorinostat in combination with bortezomib is general y wel tolerated
Submitted: Jul 26, 2009; Revised: Aug 27, 2009; Accepted: Oct 14, 2009
and effective in patients with relapsed/refractory MM. Herein, we
Address for correspondence: Amitabha Mazumder, MD, St. Vincent's Comprehensive
report single-institution results of a retrospective case history review of
Cancer Center, 325 West 15th Street, New York, NY 10011
heavily pretreated patients with relapsed/refractory MM who received
Fax: 1-212-604-6029; e-mail: amazumder@aptiumoncology.com
open-label treatment with bortezomib and vorinostat.
This summary may include the discussion of investigational and/or unlabeled uses of drugs and/or devices that may not be approved by the FDA.
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149
Vorinostat Plus Bortezomib in Multiple Myeloma
Table 1 Patient Demographics and Key Clinical Characteristics
Patient
Age,
ECOG
Relapsed or
Best Response
Duration of Previous
Number Years
Sex
Stage/Ig
Previous Treatments
PS
Refractory
to Previous
Bortezomib Response
Bortezomib
1
53
Male
1
III/IgA
Refractorya
Auto/allo PBSCT, DCEP/bortezomib
MR
< 6 Months
2
56
Male
0
III/IgA
Refractorya
Bortezomib/LD, auto PBSCT
SD
1 Year
3
62
Female
1
II/IgG°
Refractorya
Bortezomib/lenalidomide, bortezomib/LD
MR
< 1 Year
4
60
Female
1
II/IgG
Refractorya
IMiD/bortezomib, auto PBSCT
PR
< 6 Months
5
54
Male
0
II/IgG°
Refractorya
IMiD/bortezomib, auto PBSCT
MR
< 3 Months
6
45
Female
1
III/IgG
Refractorya
IMiD/bortezomib, auto PBSCT
SD
< 6 Months
aWithin 60 days of treatment.
Abbreviations: DCEP = dexamethasone, cyclophosphamide, etoposide, and cisplatin; ECOG = Eastern Cooperative Oncology Group; Ig = immunoglobulin; IMiDTM = immunomodulatory drug;
LD = liposomal doxorubicin; MR = minimal response; PBSCT = peripheral blood stem cel transplantation; PR = partial response; PS = performance status; SD = stable disease
old man with Durie-Salmon stage III/IgA disease that had
Table 2 Duration of Response
relapsed following previous therapy with bortezomib/liposomal
Patient
Best
Time to
Duration of
doxorubicin, and autologous peripheral blood stem cell transplan-
Number Response Response, Months Response, Months
tation (PBSCT). The most durable response (minimal response
[MR] for 12 months) was observed in patient 1, a 53-year-old man
1
MR
2
12
with Durie-Salmon stage III/IgA disease refractory to previous
2
VGPR
2
8
autologous/allogeneic PBSCT, and dexamethasone, cyclophospha-
3
MR
1
3
mide, etoposide, and cisplatin (DCEP)/bortezomib.
4
SD
1
3
The combination of vorinostat and bortezomib was generally well
5
MR
1
2
tolerated in these patients and none of the patients required dose
6
MR
2
4
adjustments or discontinued treatment because of adverse events
(AEs). The only grade 2 toxicities reported were gastrointestinal
Abbreviations: MR = minimal response; SD = stable disease; VGPR = very good partial response
(nausea and diarrhea) and were experienced by 3 of the 6 patients
during their treatment. There were no grade 3 toxicities.
Retrospective Chart Review
The charts of 6 heavily pretreated patients with relapsed/refrac-
Discussion
tory MM who had received bortezomib treatment (within 6 months)
These observations indicate that the combination of bortezo-
before initiation of combined vorinostat and bortezomib therapy were
mib and vorinostat afforded clinical benefit to all patients with
reviewed. The patients represent al those treated by our group with a
relapsed/refractory MM who had failed previous bortezomib-based
commercial drug during the period and not eligible for ongoing clini-
therapies, with 5 of the 6 patients achieving at least an MR and 1
cal trials. Patients received open-label treatment with oral vorinostat
patient a VGPR. These observations add to the growing body of
300 mg once daily on days 1-14 (except for 1 patient who started
evidence that supports the combination of vorinostat and bortezo-
at 400 mg once daily on a clinical trial) combined with bortezomib
mib as an effective treatment strategy for patients with relapsed/
1.3 mg/m2 on days 1, 4, 8, and 11 between 2006 and 2008. Al
refractory MM.
patients were progressing on their last therapy and had had bortezomib
The safety and efficacy of vorinostat in combination with bort-
discontinued in the past with minimal response. Treatment cycles were
ezomib is currently under investigation in 2 ongoing phase I clinical
repeated every 21 days and patients remained on therapy until disease
trials and preliminary results from these studies have recently been
progression or unacceptable toxicity. Response to treatment was mea-
reported.12 In the first study, patients with active relapsed or refrac-
sured according to International Myeloma Working Group criteria and
tory MM received oral vorinostat (200 mg twice daily or 400 mg
adverse events were graded according to the National Cancer Institute
once daily for 14 days) and bortezomib (0.7 or 0.9 mg/m2 on days
Common Terminology Criteria for Adverse Events version 3.0.
4, 8, 11, and 15 or 0.9, 1.1, or 1.3 mg/m2 on days 1, 4, 8, and
11).12 Of 33 evaluable patients, 12 (36.4%) had a partial response
Results
(PR), 6 (18.2%) had an MR and 13 (39.4%) had stable disease
Six patients with relapsed/refractory MM were included in this
(SD). Of the 17 patients who had received previous bortezomib,
retrospective case review; baseline patient and clinical characteristics
6 (35%) patients had a PR, 4 (24%) had an MR, and 7 (41%)
are shown in Table 1. All 6 patients derived clinical benefit from
had SD. Of the 7 patients who were deemed refractory to previous
combined vorinostat and bortezomib treatment (Table 2).
bortezomib, 2 (29%) had a PR, 2 (29%) an MR, and 3 (43%) had
The best response to therapy, a very good partial response
SD.13 Overal , treatment was wel tolerated. Two patients experi-
(VGPR; duration, 8 months), was observed in patient 2, a 56-year-
enced dose-limiting toxicities (DLTs; grade 3 transient aspartate
150 | Clinical Lymphoma, Myeloma & Leukemia April 2010
Amitabha Mazumder et al
aminotransferase elevation and grade 4 thrombocytopenia).12 The
Acknowledgments
maximum tolerated dose (MTD) was not reached; consequently,
The authors would like to thank Dr. Steven G. Burke from
the highest dose level (vorinostat 400 mg once daily plus bortezo-
Complete Medical Communications who provided medical writing
mib 1.3 mg/m2 on days 1, 4, 8, and 11) was considered the maxi-
support funded by Merck & Co., Inc.
mum administered dose and is being investigated in an additional
10 patients enrol ed in the expansion cohort.12
Disclosures
In the second study, 21 of the 23 patients enrol ed to receive
Amitabha Mazumder has served as a member of a speaker's bureau,
vorinostat (100 or 200 mg twice daily, or 400 or 500 mg once
research/advisory panel, and received research funding from Mil ennium
daily on days 4-11) and bortezomib (1 or 1.3 mg/m2 on days 1,
Pharmaceuticals, Inc. David H. Vesole has served as a member of a
4, 8, and 11) were evaluable for efficacy, and 2 patients (9.5%)
speaker's bureau for Mil ennium Pharmaceuticals, Inc., and has stock or
had a VGPR, 7 (33.3%) had a PR, and 10 (47.6%) had SD.12 Of
equity ownership in Merck & Co., Inc. Sundar Jagannath has served as
the 17 evaluable patients who had received previous bortezomib,
a consultant or been on an advisory/research panel for and has received
1 patient (5.9%) achieved a VGPR, 5 (29.4%) had a PR, and 9
research funding from Mil ennium Pharmaceuticals, Inc.
(52.9%) had SD.12 In addition, of 8 evaluable patients deemed
refractory to bortezomib, 3 (38%) achieved a PR, and 4 (50%)
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