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Contents lists available at ScienceDirect
Leukemia Research
journal homepage: www.elsevier.com/locate/leukres
Invited review
Combined proteasome and histone deacetylase inhibition: A promising synergy
for patients with relapsed/refractory multiple myeloma
Sundar Jagannath a,, Meletios A. Dimopoulos b, Sagar Lonial c
a St Vincent's Catholic Medical Center, 325 W. 15th Street, New York, NY 10011-8202, USA
b Department of Clinical Therapeutics, University of Athens School of Medicine, Athens, Greece
c Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA
article info
abstract
Article history:
Multiple myeloma (MM) is an incurable disease characterized by the accumulation of malignant plasma
Received 9 September 2009
cells in the bone marrow. Recently, an improved understanding of the biology of the disease has led to
Received in revised form 1 April 2010
the development of targeted agents such as the proteasome inhibitor bortezomib and the immunomod-
Accepted 4 April 2010
ulatory agents thalidomide and lenalidomide; however, MM remains incurable. The combination of
Available online xxx
bortezomib and an HDAC inhibitor synergistically induces MM cell apoptosis and may be of value in
the treatment of patients with relapsed/refractory MM. This review examines the potential of combined
Keywords:
proteasome and HDAC inhibition in the treatment of relapsed/refractory MM.
Vorinostat
© 2010 Published by Elsevier Ltd.
Multiple myeloma
Histone deacetylase inhibitor
Proteasome inhibitor
Bortezomib
Contents
1.
Introduction ............................................................................................................................... ...........
00
2.
Bortezomib and the treatment of MM ...............................................................................................................
00
3.
HDAC inhibition and DNA transcription .............................................................................................................
00
4.
Overcoming bortezomib resistance: synergistic mechanisms of combined proteasome and HDAC inhibition ...................................
00
5.
HDAC inhibition in MM ..............................................................................................................................
00
6.
Conclusions ............................................................................................................................... ...........
00
Acknowledgement ............................................................................................................................... ....
00
References ............................................................................................................................... ............
00
1. Introduction
els of circulating light chain or protein produced by plasma cells
Multiple myeloma (MM) is a malignancy of plasma cells that
can lead to significant renal dysfunction and primary amyloidosis.
accumulate in the bone marrow, where cytokines and growth fac-
As such, MM is associated with significant morbidity. At present,
tors promote plasma cell growth and resistance to therapy. MM
treatment for MM focuses on the reduction of tumor growth and
accounts for 1% of all cancers and around 10% of all hemato-
the treatment of symptoms. With an estimated overall survival rate
logic malignancies, and estimates suggest that 19,920 patients will
of 54.4% and an event-free survival of 49.3% after 5 years, MM is still
be diagnosed with MM and 10,690 MM patients will die during
considered an incurable disease [2,3].
2008 in the United States [1]. Because of the effects of malig-
Currently, there is no single standard therapy for MM and treat-
nant plasma cells on the marrow and marrow microenvironment,
ment depends on patients' age, complications, and comorbidities.
patients present with anemia, predisposition to infection, bone
Until recently, high-dose therapy and autologous peripheral blood
pain, fractures, and elevated blood calcium. In addition, high lev-
stem cell (PBSC) transplant, cytotoxic agents, and steroids have pro-
vided the mainstay of MM treatment regimens [3]. However, not
all patients are eligible for high-dose therapy and autologous PBSC
Corresponding author. Tel.: +1 212 604 6068; fax: +1 212 604 6029.
transplant. While initial therapy can be successful, the emergence
E-mail address: sjagannath@aptiumoncology.com (S. Jagannath).
of a drug-resistant clone over time results in eventual loss of con-
0145-2126/$ ­ see front matter © 2010 Published by Elsevier Ltd.
doi:10.1016/j.leukres.2010.04.001
Please cite this article in press as: Jagannath S, et al. Combined proteasome and histone deacetylase inhibition: A promising synergy for patients
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Table 1
Clinical studies examining the use of bortezomib in the treatment of MM [26]. [Reproduced from Reece et al. Treatment of relapsed and refractory myeloma. Leukemia &
Lymphoma, 2008. Reprinted with permission of the publisher, Taylor & Francis Group, http://www.informaworld.com].
Study design
Regimen (dose)
N
ORR (%)
CR (%)
Median survival (months)
PFS (%)
OS (%)
Single-agent trials
1
Phase III (APEX)
Bortezomib (1.3 mg/m2)
333
43*
9*
6.2* (TTP)
29.8*
Dexamethasone
336
18
1
3.5 (TTP)
23.7
2
Randomized Phase II (CREST)
Bortezomib (1.3 mg/m2)
26
38
4
13.7 (TTP)
NR
Bortezomib (1.0 mg/m2)
27
30
4
9.5 (TTP)
26.7
3
Phase II (SUMMIT)
Bortezomib (1.3 mg/m2)
193
28
4
7 (TTP)
17
Combination trials
1
PHASE III (MMY-3001)
Bortezomib/PLD
324
52*
4
9.3* (TTP)
82*,
Bortezomib (1.3 mg/m2)
322
44
2
6.5 (TTP)
75
2
Phase II
VDC
54
76
15
12 (EFS)
22
3
Phase I/II
BM (po)
35
47
6
8
NR
4
Phase I/II
VMPT
30
67
17
61
84
5
Phase II
Weekly VMp
29
62
3
6.6
20.2
6
Phase I/II
ATO/B/AA
22
9
0
5
74
Single agent trials: Study 1 [17,18], Study 2 [14], and Study 3 [15,16].
Combination trials: Study 1 [22,24], Study 2 [23], Study 3 [20], Study 4 [25], Study 5 [27], and Study 6 [21]. N, number; ORR, overall response rate; CR, complete response; PFS,
progression-free survival; OS, overall survival; TTP, time to progression; PLD, pegylated liposomal doxorubicin; VDC, bortezomib, dexamethasone, cyclophosphamide; EFS,
event-free survival; BM, bortezomib and melphalan; po, oral delivery; VMPT, bortezomib, melphalan, prednisone, thalidomide; VMp, bortezomib and methylprednisone;
ATO/B/AA, arsenic trioxide, bortezomib, ascorbic acid.
* p < 0.05.
At 14 months.
At 1 year.
trol of the disease [3]. Over recent years, a better understanding
rently, in the United States bortezomib is approved for first-line
of the biology of the disease has led to the development of tar-
treatment of MM [12]. In Europe, it is approved for use in combina-
geted agents such as the proteasome inhibitor bortezomib and the
tion with melphalan and prednisone for the treatment of patients
immunomodulatory agents thalidomide and lenalidomide. While
with previously untreated MM who are not eligible for high-dose
these agents have prolonged the overall survival of MM patients,
chemotherapy with peripheral blood stem cell (PBSC) transplant,
it is still generally accepted that almost all patients with MM will
or as monotherapy for the treatment of progressive MM in patients
eventually develop resistance to these treatments [3]. Patients who
who have received at least one prior therapy and who have already
relapse and are non-responsive to second-line treatment, or who
undergone or are unsuitable for PBSC transplantation [13].
exhibit disease progression within 60 days of therapy (refractory
The efficacy of bortezomib monotherapy in patients with
disease), have a particularly poor prognosis.
relapsed/refractory MM was reported in several trials including
Given the eventual development of refractory disease for nearly
the SUMMIT (Study of Uncontrolled MM managed with protea-
all patients, there is a need to develop specific new approaches
some Inhibition Therapy), CREST (Clinical Response and Efficacy
that are active against the disease or agents that will enhance
Study of bortezomib in the Treatment of relapsing MM), and APEX
the efficacy of existing treatments. One promising approach is
(Assessment of Proteasome inhibition for Extending Remissions)
the inhibition of the enzyme histone deacetylase (HDAC) which
trials (Table 1 [14­18]). Among patients with first relapse, the over-
has shown anti-myeloma activity in preclinical and clinical stud-
all response rate (ORR) for single agent bortezomib was 50%, and
ies. This review examines the potential role of HDAC inhibitors
based on the results of these studies, bortezomib was approved for
when used in combination with bortezomib, in MM patients with
the treatment of patients with relapsed and refractory MM.
relapsed or refractory disease following treatment with bortezomib
Although the use of bortezomib has resulted in high ORR, CR, and
monotherapy.
improvements in survival, many patients have either short dura-
tion or no response to bortezomib-based salvage therapy [19].In
order to overcome primary or acquired drug resistance, bortezomib
2. Bortezomib and the treatment of MM
has been combined with many other anti-MM agents leading to
improved responses (Table 1 [14­18,20­28]).
Bortezomib potently and selectively inhibits the function of the
Currently, there is a need for novel treatment strategies that
proteasome, a key regulator of intracellular protein degradation [4].
can improve the response to bortezomib in early relapse or among
Proteasome inhibition results in the accumulation of mis-folded
patients with bortezomib-resistant disease. Preclinical data have
and damaged proteins, which, in turn, triggers a heat-shock pro-
demonstrated robust in vitro responses for the combination of an
tein response leading to apoptosis [5]. Malignant plasma cells, as a
HDAC inhibitor with bortezomib [29,30]. With ongoing preclinical
result of increased immunoglobulin production, are more depen-
and clinical experience, combined proteasome and HDAC inhibition
dent upon protein regulation for homeostasis than other normal
has shown some promise in the treatment of relapsed/refractory
cells, rendering them more sensitive to the effects of proteaso-
MM.
mal inhibition. Proteasome inhibition therefore appears to have a
greater effect on MM cells compared with normal cells [6].
In patients with newly-diagnosed MM, including those with
3. HDAC inhibition and DNA transcription
poor prognostic factors (advanced-stage disease, high tumor bur-
den, renal impairment, and high-risk cytogenetics), bortezomib has
The transcription of DNA is, in part, regulated by the action of
consistently shown rapid and durable therapeutic benefit, with
histone acetyltransferases (HAT) and HDAC enzymes, which act in
high rates of complete response (CR) both as monotherapy and
conjunction to regulate the acetylation of histones. HAT enzymes
when used in combination with other anti-MM agents [7­11]. Cur-
work by transferring an acetyl group from acetyl CoA to a lysine
Please cite this article in press as: Jagannath S, et al. Combined proteasome and histone deacetylase inhibition: A promising synergy for patients
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Table 2
Classes of HDAC inhibitors.
Classes of HDAC inhibitors
Agent
HDAC targets
Hydroxamic acids
Vorinostat
Pan-HDAC inhibitor
Panobinostat
Pan-HDAC inhibitor
Benzamides
Belinostat
Pan-HDAC inhibitor
Entinostat
Specific Class I inhibitor
Mocetinonostat
Specific Class I inhibitor
Cyclic tetrapeptides
Romidepsin
Specific Class I inhibitor
Pan-HDAC inhibitor: inhibitor of Class I and II HDACs; specific Class I inhibitor: inhibitor of primarily class I HDACs.
amino acid on the histone molecule to form
-N-acetyl lysine.
shown to alter gene expression [32,33]. For instance, acetylation
This acetylation has the effect of neutralizing the overall positive
of p53 opens the DNA binding domain of p53 and prevents associ-
charge of the histone molecule, reducing its affinity for binding
ation with MDM2 and ubiquitination and subsequent destruction
to negatively charged DNA. By this process, HATs confer an open
[34]. As a result of these transcriptional and non-transcriptional
chromatin structure which renders DNA more accessible to tran-
events, HDAC inhibitors cause tumor cell differentiation, cell-cycle
scription factors. In contrast, HDAC enzymes remove acetyl groups
arrest and apoptosis [31,33].
from -N-acetyl lysine, increase the positive charge on the histone,
Four classes of HDAC enzymes have been indentified. Classes I,
and promote binding to DNA. This causes a condensing of the DNA,
II, and IV are Zn2+-dependent enzymes whereas Class III are Zn2+-
preventing gene transcription. By inhibiting HDAC enzyme activity,
independent, NAD+-dependent enzymes [35]. The Class I HDACS
HDAC inhibitors modulate the expression of both pro- and non-
(HDAC1, HDAC2, HDAC3, and HDAC8) are primarily nuclear, ubiq-
apoptotic factors. In cancer cells where the balance favors cellular
uitously expressed, and have histone protein substrates [35]. Class
proliferation, HDAC inhibitors may alter the gene expression favor-
II enzymes (IIa; HDAC4, HDAC5, HDAC7, and HDAC9 and IIb; HDAC6
ing growth arrest, differentiation or apoptosis. The transcription
and HDAC10) are primarily localized in the cytoplasm, shuttle in
of pro-apoptotic genes subsequently leads to the suppression of
and out of the nucleus, are expressed in a tissue specific man-
anti-apoptotic proteins [31]. In addition, HDAC-inhibitor-mediated
ner, and have both histone and non-histone protein substrates
acetylation of transcription factors and other proteins has been
[35,36]. Class III HDACs (SIRT 1­7) are sirutins, which are subcellu-
Please cite this article in press as: Jagannath S, et al. Combined proteasome and histone deacetylase inhibition: A promising synergy for patients
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Fig. 1. Potential mechanism of combined proteasome and HDAC inhibition in myeloma cells [30,43]. Proteasome inhibition results in the accumulation of large quantities
of ubiquitin-conjugated proteins; MM cells organize these proteins into perinuclear aggresomes. The formation of perinuclear aggresomes requires HDAC 6 activity. It is
thought that the disruption of bortezomib-induced aggresome formation and sensitisation of aggresome-positive cells to apoptosis by HDAC inhibition may mediate the
synergistic effect of combined proteasome and HDAC inhibition.
Reproduced with kind permission [30,43], ©American Society of Hematology and ©National Academy of Sciences, respectively.
larly located and have non-histone protein substrates [37]. Class IV
systemic therapies [38]. Since 2006, vorinostat has shown promis-
comprises of HDAC 11 of which little is known [35].
ing activity in the treatment of other hematologic malignancies as
The current HDAC inhibitors in the clinic comprise of two
well as solid tumors.
classes; non-specific pan-HDAC inhibitors and Class I HDAC
inhibitors (Table 2). Vorinostat (suberoylanilide hydroxamic acid;
4. Overcoming bortezomib resistance: synergistic
Zolinza®) is a nanomolar inhibitor of Class I and II HDAC enzymes,
mechanisms of combined proteasome and HDAC inhibition
and was approved by the US Food and Drug Administration in Octo-
ber 2006 for the treatment of cutaneous manifestations of T-cell
Resistance to bortezomib monotherapy presents a challenge
lymphoma, a type of non-Hodgkin's lymphoma, in patients with
to the successful treatment of relapsed/refractory MM. Although
progressive, persistent or recurrent disease on or following two
the exact mechanism underlying bortezomib resistance remains
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Table 3
Clinical studies examining the use of HDAC inhibitors in combination with bortezomib in the treatment of MM: preliminary results.
Study design
Treatment
N
Preliminary results
[54,55]
Phase I ­ `3+3' dose
Vorinostat:
Overall: 33 evaluable patients
12 (36.4%) PR
escalation
200 mg bid or 400 mg qd for 14
6 (18.2%) MR
Relapsed/refractory
days
13 (39.4%) SD
MM
Bortezomib:
0.7 or 0.9 mg/m2
on Days 4, 8, 11, and 15
OR
0.9, 1.1, or 1.3 mg/m2
on Days 1, 4, 8, and 11
Prior bortezomib: 17 evaluable
6 (35.3%) PR
patients
4 (23.5%) MR
7 (41.2%) SD
[49]
Phase I ­ dose
Vorinostat:
Overall: 21 evaluable patients
2 (9.5%) VGPR
escalation
100­400 on Days 4­11
7 (33.3%) PR
Relapsed/refractory
Bortezomib:
10 (47.6%) SD
MM
1­1.3 mg/m2
2 (9.5%) PD
on Days 1, 4, 8, and 11
Prior bortezomib: 17 evaluable
1 (5.9%) VGPR
patients
5 (29.4%) PR
9 (52.9%) SD
2(11.8%) PD
[52]
Phase I/II study
Romidepsin:
Overall: 18 evaluable patients
Overall response
Relapsed/refractory
8­14 mg/m2 on Days 1, 8, and 15
rate: 67%
MM
Bortezomib:
(12 patients) 4
1.3 mg/m2 on Days 1, 4, 8, and 11
(22%) CR/near CR
Dexamethasone:
4 (22%) VGPR
20 mg/m2 on Days 1, 2, 4, 5, 8, 9,
4 (22%) 4 PR
11, and 12
5 (28%) MR
unknown, a number of pathways have been shown to promote
have demonstrated that vorinostat in combination has resulted
myeloma cell survival; these include (i) the interaction between
in synergistic apoptotic effects with associated increases in ROS
MM cells and host bone marrow microenvironment; (ii) upregu-
and mitochondrial injury, caspase and poly (ADP-ribose) poly-
lated expression of growth factor receptors and related signaling
merase activation [29,45]. Similar results have been seen in
pathways; (iii) over-expression of anti-apoptotic proteins, such as
MM cell lines, not only with vorinostat [40,42] but also with
Bcl-2; (iv) defects in drug-induced apoptotic signaling pathways,
panobinostat, a hydroxamic acid pan-HDAC inhibitor [30] and
including those that occur at the level of mitochondria or endo-
the more specific HDAC-6 inhibitor tubacin [43]. In MM cells,
plasmic reticulum; and (v) over-expression of P-glycoprotein [39].
vorinostat has also been shown to suppress the stimulation of
More recently, heat shock protein 27 and aggresome formation
interleukin-6 (IL-6) secretion triggered by MM cell adhesion to
have been cited as potential mediators of bortezomib resistance
bone marrow stromal cells, downregulate IL-6 and insulin-like
[39,40].
growth factor receptor signaling cascades, reduce the expression
The mechanism by which synergistic activity of HDAC inhi-
of anti-apoptotic members of the proto-oncogene Bcl-2 fam-
bition and bortezomib in MM cells acts is also unknown, but
ily, and downregulate the expression and activity of oncogenic
HDAC inhibitors exhibit a plethora of molecular mechanisms that
kinases, DNA synthesis/repair enzymes and transcription factors
may enhance the activity of bortezomib [29,41]. These mech-
[41,46].
anisms work on similar pathways implicated in bortezomib
Vorinostat has also been shown to enhance the anti-myeloma
resistance. Initial studies in MM cell lines suggested that vorino-
effect of other anti-cancer agents. In human MM cell lines, vorinos-
stat suppressed the expression of proteasome subunits and several
tat enhanced the cytotoxic and apoptotic effects of tumor necrosis
ubiquitin conjugating enzymes [29]. Further to this, the disruption
factor-related apoptosis-inducing ligand [47], and reduced the
of bortezomib-induced aggresome formation and sensitisation of
viability of tumor cells isolated from patients with MM when com-
aggresome-positive cells to apoptosis by vorinostat was reported
bined with interferon
2b [48]. Furthermore, sequential exposure
in pancreatic cancer cells, suggesting a potential mechanism by
of human MM cell lines and primary patient-derived MM cells to
which vorinostat could augment the activity of bortezomib [40,42].
bortezomib and vorinostat resulted in a marked increase in mito-
Proteasome inhibition results in the accumulation of large quan-
chondrial injury, caspase activation, and the synergistic induction
tities of ubiquitin-conjugated proteins. MM cells are thought to
of apoptosis [45]. Additionally, a subset analysis from a Phase I clini-
organize these proteins into perinuclear structures called aggre-
cal trial showed reductions in nuclear factor-kappaB (NF- B), Bcl-2,
somes, which are cytoprotective [40]. The formation of aggresomes
Bcl-xl, cyclin-dependent kinase inhibitor 1A (p21) and X-linked
requires HDAC-6 activity so the addition of an HDAC inhibitor
inhibitor of apoptosis protein in patients with a treatment response
could provide a synergistic approach to treatment (Fig. 1 [30,43]).
to vorinostat in combination with bortezomib, as compared with
The inhibition of bortezomib-induced aggresome formation results
those patients with PD or SD [49]. In addition to HDAC inhibition
in the dispersal of toxic microaggregates which in turn induce
(Class I, excluding HDAC 8 and Class IIa excluding HDAC 9), valproic
endoplasmic reticulum (ER) stress that may contribute to reac-
acid (VPA), a carboxylic acid HDAC inhibitor, has also been shown
tive oxygen species (ROS) generation [44]. This ROS generation,
to decrease vascular endothelial growth factor secretion and inhibit
coupled with that simultaneously induced by the HDAC inhibitor,
angiogenesis (a mechanism essential for tumor growth), increase
leads to overwhelming oxidative stress that has been associ-
p21 accumulation, reduce cyclin D1, and induce G0/G1 cell-cycle
ated with enhanced apoptosis [45]. Various preclinical models
arrest [50].
Please cite this article in press as: Jagannath S, et al. Combined proteasome and histone deacetylase inhibition: A promising synergy for patients
with relapsed/refractory multiple myeloma. Leuk Res (2010), doi:10.1016/j.leukres.2010.04.001
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5. HDAC inhibition in MM
were considered refractory were evaluable for efficacy; the best
responses observed in these patients were a PR in 3 patients, SD in
HDAC inhibitors have demonstrated preclinical and clinical
4 patients, and PD in 1 patient [49]. The majority of AEs were hema-
activity in a number of malignancies [31] and, in combination with
tologic and 2 patients experienced DLTs (Grade 3 fatigue and Grade
bortezomib, have shown potential in the treatment of MM (Table 3)
3 prolonged QTc interval). The MTD was established as vorinostat
[29,30,45,49,51­55].
400 mg once daily on Days 4­11 plus bortezomib 1.3 mg/m2 on
As a single agent, vorinostat demonstrated the ability to induce
Days 1, 4, 8, and 11 of a 21-day cycle [49].
early growth arrest and subsequent apoptosis in human MM cell
These preliminary data from two Phase I studies suggest that
lines and primary MM cells isolated from MM patients [56]. A Phase
the combination of vorinostat with bortezomib shows activity in
I study of oral vorinostat enrolled 13 heavily pretreated myeloma
patients with relapsed/refractory MM who had previously received
patients. All patients had previously received either dexametha-
or were naļve to treatment with bortezomib. The final results of
sone or prednisone and the median number of prior systemic
these studies are eagerly awaited.
anti-cancer therapies received was 3, with a range of 1­10. Six
Other HDAC inhibitors have shown activity in the treatment of
patients had relapsed disease with the remaining 7 patients hav-
MM. The anti-neoplastic activity of VPA was first reported in 1997
ing relapsed and refractory disease. The results showed modest
and was thought to be mediated through HDAC inhibition [58,59].
single-agent activity: of the 10 evaluable patients, 1 had a mini-
Although a relatively weak HDAC inhibitor [60], VPA has shown
mal response (MR) and 9 had SD, including 5 patients who were
in vitro activity against various myeloma cell lines and primary
progression-free at 3 months, and 1 patient who was progression-
MM cells [50,61,62]. The anti-myeloma effects of VPA are time-
free at 6 months. Only small changes in the Eastern Cooperative
and dose-dependent and characterized by an accumulation of p21,
Oncology Group (ECOG) performance status throughout the study
reduced levels of cyclin D1 and G0/G1 cell-cycle arrest [50,61,62].
were seen in the 9 patients with SD [57]. Vorinostat was generally
Interestingly, VPA has also been reported to reduce myeloma cell
well tolerated with the most common drug-related adverse events
vascular endothelial growth factor secretion and inhibit angiogen-
(AEs) reported being fatigue, anorexia, dehydration, diarrhea, and
esis, which is thought to be essential for tumor growth [50,61].
nausea; only 1 patient experienced a dose-limiting toxicity (DLT)
Moreover, the anti-angiogenic effects of VPA were potentiated in
(Grade 3 fatigue) [57]. Although there were no safety concerns, the
the presence of thalidomide [61]. VPA has also been shown to
study was terminated early due to a sponsor decision.
potentiate dexamethasone-mediated apoptosis in myeloma cells
In a Phase I combination study by Weber et al [55], patients
[61,63] and the effects of proteasome inhibition in leukemia cells
with active relapsed or refractory MM were randomized in a con-
[61,63].
ventional `3 + 3' dose-escalation scheme to receive oral vorinostat
In preclinical studies, romidepsin, a cyclic peptide HDAC
(200 mg twice daily or 400 mg once daily for 14 days) in combi-
inhibitor that preferentially inhibits Class I HDACs, induced apopto-
nation with bortezomib (0.7 or 0.9 mg/m2 on Days 4, 8, 11, and
sis in MM cell lines, an effect that was potentiated by the addition
15 or 0.9, 1.1, or 1.3 mg/m2 on Days 1, 4, 8, and 11) [55]. The best
of melphalan [64]. Other studies have shown that romidepsin in
responses observed in the 33 evaluable patients were as follows;
combination with bortezomib has potential for the treatment of
12 (36.4%) patients had an partial response (PR), 6 (18.2%) patients
leukemia [65]. Romidepsin has shown promise in the treatment
exhibited a MR, and 13 (39.4%) patients had SD. Of 34 patients
of patients with relapsed/refractory MM when used in combina-
enrolled, a total of 29 (85.3%) patients discontinued treatment;
tion with bortezomib and dexamethasone [52]. Of 18 evaluable
17 (50.0%) due to PD, 11 (32.4%) due to AEs, and 1 (2.9%) patient
patients in a Phase I/II study, the combination of romidepsin, borte-
withdrew consent [55]. Within the treatment cohort, 17 patients
zomib, and dexamethasone was associated with an ORR of 67% (12
had received prior treatment with bortezomib; the best responses
patients), with a CR or near CR, a VGPR, or a PR (in 22% [4 patients]
observed in these patients were a PR in 6 patients, an MR in 4
each). An additional 28% (5 patients) experienced an MR [52]. The
patients, and SD in 7 patients [54]. Of these, 7 were considered
most common drug-related toxicities included fatigue (Grade 3,
refractory to bortezomib and the best responses observed were a PR
n = 2), neutropenia (Grade 3, n = 1), sepsis (Grade 3, n = 2), periph-
in 2 patients, an MR in 2 patients, and SD in 3 patients [54]. In total,
eral neuropathy (Grade 3, n = 1; Grade 2, n = 6), and nausea (Grade
14 patients previously treated with bortezomib discontinued treat-
2, n =1) [52].
ment due to PD (9) and AEs (5). Two patients experienced a DLT;
Belinostat is a low-molecular-weight hydroxamic acid HDAC
Grade 3 transient aspartate aminotransferase elevation in 1 patient
(Class I/II) inhibitor with potent anti-proliferative and HDAC
receiving vorinostat 400 mg once daily and bortezomib 0.9 mg/m2
inhibitory activity. In preclinical studies, the combination of belino-
and Grade 4 thrombocytopenia in 1 patient receiving vorinostat
stat and bortezomib has resulted in selective synergistic anti-tumor
400 mg once daily and bortezomib 1.3 mg/m2 [55]. The maximum
activity and inhibition of osteoclast activity [51]. Increased oxida-
tolerated dose (MTD) was not reached (non-occurrence of 2 DLTs
tive stress, caspase activation and induction of apoptosis mediated
in 6 patients at any dose level); consequently, the highest dose level
the synergistic effects of exposure to this treatment regimen [51].
(vorinostat 400 mg once daily plus bortezomib 1.3 mg/m2 on Days
While results of a Phase I study in patients with advanced hema-
1, 4, 8, and 11) was considered the maximum administered dose
tologic cancers indicated that single-agent belinostat may have
and is being investigated in an additional 10 patients who have
activity in the treatment of MM [66], a Phase II study examining the
been enrolled in the expansion cohort [55].
efficacy and safety of belinostat in combination with bortezomib
The study by Badros et al. [49] has also shown promising
was recently terminated due to the development of DLTs [67]. The
responses to combined vorinostat and bortezomib treatment in
future of belinostat in the treatment of MM remains unknown.
patients with relapsed and refractory MM. Of the 21 patients evalu-
Finally, in vitro, panobinostat, a potent pan-HDAC inhibitor,
able for efficacy, the best response to vorinostat plus bortezomib
induces both caspase-dependent and caspase-independent apop-
was a very good partial response (VGPR) in 2 (9.5%) patients, a PR
tosis and potentiates the effects of dexamethasone, melphalan,
in 7 (33.3%) patients, SD in 10 (47.6%) patients, and PD in 2 (9.5%)
and bortezomib in drug-resistant MM cell lines and primary cells
patients [49]. Of 19 patients who had received prior bortezomib
isolated from both treatment-naļve and treatment-refractory MM
therapy, 17 were evaluable for efficacy. Of these, 1 (5.9%) patient
patients [53]. Panobinostat has also shown the ability to overcome
achieved a best response of a VGPR, 5 (29.4%) patients had a PR, 9
bortezomib resistance by inhibiting the formation of aggresomes
(52.9%) patients had SD, and 2 (11.8%) patients had PD [49]. Eight
[30]. A Phase II/III study of panobinostat in relapsed/refractory MM
of the 9 patients who had received prior bortezomib therapy and
has recently been terminated by the sponsor [68,69]. A Phase I
Please cite this article in press as: Jagannath S, et al. Combined proteasome and histone deacetylase inhibition: A promising synergy for patients
with relapsed/refractory multiple myeloma. Leuk Res (2010), doi:10.1016/j.leukres.2010.04.001
G Model
LR-3859;
No. of Pages 8
ARTICLE IN PRESS
S. Jagannath et al. / Leukemia Research xxx (2010) xxx­xxx
7
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underway in patients with relapsed and refractory MM [70].
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patients will ultimately relapse and others are refractory to these
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innovative agents. Therefore, there is a need for novel medications
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or new treatment combinations that can improve the treatment of
phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med
2003;348(26):2609­17.
MM.
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While the characterization of HDAC inhibitors in MM is still
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