European Journal of Haematology
REVIEW ARTICLE
Emerging therapies for the treatment of relapsed or
refractory multiple myeloma
Meletios A. Dimopoulos1, Jesus F. San-Miguel2, Kenneth C. Anderson3
1Department of Clinical Therapeutics, University of Athens School of Medicine, Athens, Greece; 2University Hospital of Salamanca, Salamanca,
Spain; 3Dana-Farber Cancer Institute, Boston, MA, USA
Abstract
Encouraging progress has been made in the treatment of patients with relapsed / refractory multiple mye-
loma (MM). The rapidly evolving understanding of key pathways responsible for tumor growth and survival
has led to the development of novel agents (including immunomodulatory drugs, proteasome inhibitors,
histone deacetylase inhibitors, and other targeted agents) with the potential to provide significant improve-
ments in response and survival, and influence treatment guidelines. This review summarizes recent
advances in understanding of the biology of relapsed / refractory MM and clinical trials with novel targeted
agents that are currently under investigation for patients with this disease.
Key words multiple myeloma; immunomodulatory drug; proteasome inhibitor; Akt inhibitor; histone deacetylase inhibitor
Correspondence Meletios A. Dimopoulos, MD, Department of Clinical Therapeutics, University of Athens School of Medicine,
Alexandra Hospital, 80 Vas. Sofias, Athens 11528, Greece. Tel: +(30210) 3381541; Fax: + (30210) 3381511; e-mail: mdimop@med.uoa.gr
Accepted for publication 10 October 2010
doi:10.1111/j.1600-0609.2010.01542.x
Multiple myeloma (MM) is the second most common
There are three distinct patient populations within the
hematologic malignancy and was responsible for an
relapsed / refractory
MM
setting:
patients
who
are
estimated 21 000 deaths in the European Union in 2008
relapsed but not refractory to treatment, patients with
and more than 10 000 deaths in the United States in 2009
primary refractory disease, and patients who are relapsed
(1, 2). Newly diagnosed MM is responsive to treatment
and
refractory
(15).
Historically,
the
definition
of
with combinations of melphalan, prednisone, dexametha-
relapsed vs. refractory disease was based on sensitivity to
sone, doxorubicin, immunomodulatory drugs (IMiDs;
the vincristine, doxorubicin, and dexamethasone regimen,
such as thalidomide and lenalidomide), and proteasome
but the introduction of bortezomib, thalidomide, and
inhibitors (PIs, such as bortezomib) (3) or autologous
lenalidomide has outdated this distinction. A more
stem cell transplant following high-dose chemotherapy in
relevant definition of relapse is the presence of clinically
appropriate patients (4, 5). However, most patients even-
active disease in patients who have received one or more
tually relapse or become refractory to treatment, owing in
prior therapies. Similarly, it has been suggested that
part to the changing biology of the tumor and develop-
refractory MM be defined as either progressive disease
ment of aggressive, drug-resistant phenotypes within the
(PD) or stable disease (SD) while on prior therapy or
tumor. Although some agents used as initial therapy
PD within 3 months of the last dose of prior therapy.
(including thalidomide, lenalidomide, and bortezomib)
Patients with relapsed and refractory disease would be
have also shown activity and improved outcomes in
those who had achieved at least a minor response (MR)
patients with relapsed or refractory MM (6­11), these
before disease progression within 60 d of the last treat-
responses are often of limited duration (12­14). Thus,
ment (15).
there is an urgent unmet need to develop targeted agents
This review is focused on the current management of
that provide durable disease control and symptomatic
patients with relapsed or refractory MM who have expe-
relief in patients with MM that has relapsed or is refrac-
rienced disease progression within 60 d of the most
tory to currently approved agents.
recent treatment, although some of the studies reviewed
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Emerging therapies in multiple myeloma
Dimopoulos et al.
may have used the older definitions (15). The aims of
Similarly, the combination of lenalidomide and dexa-
this review are to discuss the biology of the advanced
methasone was not able to overcome the adverse prog-
stages of the disease, examine the current therapeutic
nostic effects of del(13) or t(4;14) in patients with
options for patients, and review clinical data on currently
relapsed / refractory MM (26).
approved and emerging treatment options for patients
The influence of cytogenetics has also been examined
who have relapsed or become refractory to treatment.
in patients with relapsed / refractory MM, with varying
results. As an example, bortezomib in combination with
doxorubicin and dexamethasone showed comparable
Biology of relapsed/refractory multiple
activity in relapsed / refractory patients with or without
myeloma
del13q
(27).
In
contrast,
relapsed / refractory
MM
Multiple myeloma is characterized by the accumulation
patients treated with lenalidomide plus dexamethasone
of clonally identical plasma cells in the bone marrow that
exhibited comparable time to progression (TTP) and
appear to develop from post-germinal center B cells (16).
overall survival (OS) regardless of del13q or t(4;14) sta-
Current criteria for the diagnosis of MM have been sum-
tus, whereas patients with del17p13 experienced worse
marized elsewhere (17).
time-to-event outcomes (28). Similarly, the presence of a
The growth, survival, adhesion, migration, and apop-
non-hyperdiploid karyotype, other poor-risk cytogenetic
totic resistance of MM cells are mediated by a large
abnormalities [i.e., presence of del13q, del17p, add1q21,
number of cytokines and adhesion molecules found in
t(4;14), or t(14;16)], and thalidomide-refractory disease
the bone marrow and tumor microenvironment (18).
were associated with reduced responses [less than a par-
Very late antigen 4 and intercellular adhesion molecule 1
tial response (PR)] to treatment with lenalidomide and
are important for the adhesion of MM cells to extracellu-
dexamethasone alone or in combination with bortezomib
lar matrix bone marrow stromal cells (BMSCs) (19, 20).
(29). These findings suggest that the presence of high-risk
Interleukin-6 (IL-6), IL-21, tumor necrosis factor-a
karyotypic abnormalities may define subsets of patients
(TNF-a), insulin-like growth factor 1, vascular endothe-
more likely to benefit from targeted therapies. Further-
lial growth factor (VEGF), and stromal cell-derived fac-
more, new agents that improve PFS or OS in high-risk
tor 1-a have been shown to mediate MM cell survival,
patients are of particular interest in the treatment of
growth, and / or resistance to apoptosis (18).
relapsed / refractory MM.
In addition to clonal expansion of myeloma cells, the
complex interplay of soluble factors in the bone marrow
microenvironment and various receptor-mediated signal-
Current treatment options for relapsed/
refractory multiple myeloma
ing pathways on BMSCs, osteoblasts / osteoclasts, and
myeloma cells [e.g., the receptor activator of nuclear fac-
Several factors should be considered in the selection of
tor-kappa B (NF-jB) / osteoprotegerin system and NF-jB
appropriate
treatment
options
for
patients
with
pathway] mediates the development of destructive bone
relapsed / refractory MM, including response to prior
disease and potentially life-threatening hypercalcemia
therapies, type of relapse (e.g., aggressive), and individ-
(21, 22). Surrogate cytokine markers of time-to-event
ual patient characteristics (e.g., comorbidities, life expec-
outcomes have been investigated in relapsed / refractory
tancy, and quality of life) (30). Currently, multiple
MM and may have prognostic potential. For example,
targeted agents, such as IMiDs and bortezomib, are
low baseline levels of VEGF were shown to be an inde-
approved for the treatment of relapsed / refractory MM.
pendent prognostic factor for reduced response and
shorter progression-free survival (PFS) in patients treated
Immunomodulatory drugs
with thalidomide (23).
Different somatic genetic abnormalities reflect the
Before the advent of immunomodulatory drugs, few
complex biology and pathogenesis of MM and have
effective treatment options were available for patients
prognostic value in patients with newly diagnosed MM.
with relapsed / refractory MM. As an example, vincristine
Chromosomal translocations such as t(4;14) and the
in combination with doxorubicin and dexamethasone
17p13 deletion (del17p13; associated with low expression
(VAD) was associated with overall response rates (ORR)
of TP53 gene) are associated with early relapse in newly
ranging
from
25%
to
61%
in
patients
with
diagnosed patients treated with high-dose therapy (24).
relapsed / refractory MM.(31­34) Although the VAD regi-
The presence of t(4;14) and deletion of chromosome 13
men was an improvement over high-dose melphalan (35,
(del13) have been associated with a significantly lower
36), the clinical benefits were limited, with response dura-
likelihood of response (defined as a >90% reduction in
tion and OS £12 months (32­34). Thus, the development
M-protein concentration) to up-front thalidomide plus
of novel targeted agents with tumor-specific mechanisms
dexamethasone in newly diagnosed MM patients (25).
of action is an important advance in the treatment of
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Dimopoulos et al.
Emerging therapies in multiple myeloma
relapsed / refractory MM, as it has led to a significant
response was 24 wk. Adverse events (AEs) were generally
improvement in 5-yr survival (increasing from approxi-
manageable (primarily grade 1­2 myelosuppression); two
mately 29% in 1990­1992 to 35% in 2002­2004,
patients developed deep vein thrombosis while receiving
P < 0.001) and 10-yr survival rates (increasing from
aspirin prophylaxis, two patients had grade 3 atrial fibril-
approximately 11­17% during the same time periods,
lation, and one patient experienced grade 3 peripheral
P < 0.001) (37).
neuropathy.
Other
recent
clinical
studies
in
patients
with
Thalidomide and lenalidomide
relapsed / refractory MM suggest that the ORR to lena-
Immunomodulatory drugs target similar pathways ­
lidomide in combination with targeted agents (e.g., bev-
including inhibition of cytokine expression (e.g., IL-6,
acizumab, dacetuzumab, and dasatinib) may vary widely
TNF-a) by BMSCs and inhibition of angiogenesis ­ that
depending on the patient population and molecular drug
contribute to decreased growth of MM cells (38). For
target involved (44­47).
example, thalidomide stimulates T lymphocytes with IL-
2 and interferon-c release and subsequent NK cell activa-
Proteasome inhibitors
tion, leading to the destruction of myeloma cells (38).
A review of the literature shows that treatment of
In MM, it is thought that the ubiquitin proteasome
relapsed / refractory MM with thalidomide (alone or in
system may affect tumor growth and progression via
combination with dexamethasone) is associated with
proteolysis of key proteins, including NF-jB signaling
ORR ranging from 25% to 65% (39). When combined
pathways; proapoptotic caspases; and various cytokines
with bortezomib, melphalan, and prednisone or dexa-
involved in the regulation of tumor cell growth, apopto-
methasone, thalidomide produced ORR ranging from
sis resistance, and angiogenesis (48).
55% to 67% (40­42). However, peripheral neuropathy
occurred in 6­16% of relapsed / refractory MM patients
Bortezomib
who received thalidomide alone or in combination with
The reversible PI bortezomib affects expression of a num-
high-dose chemotherapy and was the primary cause of
ber of proteins involved in cell cycle arrest and apoptosis
thalidomide dose reduction (39). Moreover, an increased
(e.g., NF-jB, caspase-9) (49). In patients with relapsed /
incidence of thromboembolic events was observed, par-
refractory MM, bortezomib alone significantly improved
ticularly when thalidomide was given in combination
TTP (6.2 vs. 3.5 month; hazard ratio, 0.55; P < 0.001)
with dexamethasone and doxorubicin (39). Consequently,
and the response rate (CR + PR, 38% vs. 18%; P <
the thalidomide analog lenalidomide was developed in an
0.001) compared with high-dose dexamethasone (50).
effort to reduce the toxicity associated with thalidomide,
Alternating combination regimens have been explored
while maintaining or improving its efficacy.
in an effort to improve the response to bortezomib-based
Studies have shown that combined treatment of
salvage
therapy.
In
a
study
in
20
patients
with
relapsed / refractory MM with lenalidomide and dexa-
relapsed / refractory MM (30% had previously received
methasone was associated with an ORR [complete
bortezomib; 5% had received previous IMiD therapy),
response (CR) / PR] of approximately 60%, significantly
28-d cycles of bortezomib (1.3 mg / m2, days 1, 4, 8, and
improved TTP, and significantly longer OS, regardless of
11) in combination with melphalan (9 mg / m2, days 1­4),
previous exposure to thalidomide (8, 9). Although low
prednisone (60 mg / m2, days 1­4), and doxorubicin (con-
rates of grade 3 peripheral neuropathy were observed
ventional, 40 mg / m2 on day 1; liposomal, 30 mg / m2 on
(<2% of patients), venous thromboembolic events were
day 1) were alternated with 28-d cycles of thalidomide
reported in approximately 10­15% of patients receiving
(200 mg daily, days 1­28) in combination with cyclo-
lenalidomide plus dexamethasone (8, 9).
phosphamide (50 mg daily, days 1­28) and dexametha-
More recently, lenalidomide has shown clinical activity
sone (40 mg daily, days 1­4). This approach resulted in
in combination with bortezomib and dexamethasone in
an ORR of 95% (immunofixation-negative CR, 42%;
patients with relapsed / refractory MM. In a phase II
near CR, 16%; PR, 47%) in nine evaluable patients,
study in 64 patients (77% had previously received thalid-
including CR in three of seven patients (42%) with high-
omide and 55% had received bortezomib therapy), the
risk cytogenetic abnormalities [e.g., t(4;14) or delRB]
combination of lenalidomide (15 mg on days 1­14), bort-
(51). The use of alternating combination therapy regi-
ezomib (1.0 mg / m2, days 1, 4, 8, and 11), and dexameth-
mens was associated with manageable toxicities, includ-
asone
(40 mg / 20 mg, cycles 1­4 / 5­8, days of / after
ing grade 3 thrombocytopenia (30%), neutropenia
bortezomib dosing) produced an objective response (21%
(30%), and infection (16%); grade 1­2 peripheral neu-
CR / near CR, 68% at least PR, 84% at least MR) in 62
ropathy occurred in three patients (15%) (51).
evaluable patients, irrespective of high-risk disease fea-
The synergistic effects of combined treatment with
tures and prior therapies (43). The median duration of
bortezomib and pegylated liposomal doxorubicin (PLD;
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Emerging therapies in multiple myeloma
Dimopoulos et al.
a novel formulation of doxorubicin with improved car-
Immunomodulatory drugs
diac safety) (52) have been evaluated in patients with
relapsed / refractory MM. In a phase III study in bortezo-
Pomalidomide
mib-naive patients (none had progressed on anthracy-
Pomalidomide, an IMiD derived from thalidomide, has
cline-based
therapy),
21-d
cycles
of
bortezomib
demonstrated greater activity in vitro (e.g., inhibition of
(1.3 mg / m2, days 1, 4, 8, and 11) in combination with
osteoclast formation, cell cycle arrest) than thalidomide
PLD (30 mg / m2 on day 4) produced a significantly
(57, 58). In a phase I / II study, pomalidomide (2­5 mg
greater quality of response [i.e., CR + very good partial
daily on days 1­21 of each 28-d cycle) demonstrated a
response (VGPR) rate] (27% vs. 19%; P = 0.0157), TTP
38% ORR and up to 46% SD when administered alone
(9.3 vs. 6.5 month; hazard ratio, 1.82; P = 0.000004),
or in combination with dexamethasone in 32 patients
duration of response (10.2 vs. 7.0 month; P = 0.0008),
with relapsed / refractory MM (59). In a phase II study in
and 15-month survival (76% vs. 65%; P = 0.03) com-
60 relapsed MM patients (62% had received prior thalid-
pared with bortezomib alone (11).
omide or lenalidomide treatment), the combination of
Several subgroup analyses have also been conducted
pomalidomide (2 mg daily during each 28-d cycle) and
in this study population to determine whether patient-
dexamethasone (40 mg daily, days 1, 8, 15, and 22)
related factors influence the response to treatment.
resulted in an ORR of 63% (5% CR, 28% VGPR, and
These analyses have shown that the significantly longer
30% PR), including confirmed responses in 74% of
TTP seen with the bortezomib-PLD regimen (relative to
patients classified as high risk (60). The primary toxicity
bortezomib alone) is consistent, even in relapsed / refrac-
was grade 3 myelosuppression; grade 3 neuropathy and
tory MM patients with prior IMiD exposure, prior stem
a thromboembolic event were each reported in a single
cell transplant, and poor prognostic factors (e.g., serum
patient. Taken together, these studies suggest that poma-
beta-2 microglobulin 5.5 mg / mL, refractory disease)
lidomide may overcome resistance to the IMiDs cur-
(53­55). Moreover, the bortezomib-PLD regimen is
rently used as initial or second-line therapy, with a lower
associated with significant improvements in TTP in both
incidence of neurotoxic and thromboembolic events.
elderly (276 vs. 205 d; hazard ratio, 1.82; P = 0.0056)
Preliminary
results
from
recent
clinical
studies
of
and younger patients (295 vs. 190 d; hazard ratio, 1.75;
pomalidomide are summarized in Table 1.
P = 0.0008)
(56).
Importantly,
combined
treatment
with bortezomib and PLD did not increase the inci-
Proteasome inhibitors
dence of grade 3 cardiac events, thromboembolic
events, or peripheral neuropathy compared with bort-
The rationale for developing new PIs is similar to the
ezomib alone (11, 54). Further investigations should
rationale for developing new IMiDs: potential improve-
establish the clinical benefits of bortezomib-based com-
ments in efficacy and / or tolerability and potentially
binations with liposomal doxorubicin in elderly and
incomplete cross-resistance within the drug class.
high-risk MM patients.
Carfilzomib
In patients who have become resistant to bortezomib,
Investigational options for relapsed/refractory
the use of a new PI with a different chemical backbone
multiple myeloma
could overcome this resistance. Carfilzomib is a second-
Although currently available agents can provide clinical
generation PI that is structurally similar to epoxomicin.
benefit in relapsed MM, not all patients will respond,
Unlike bortezomib, which has a reversible effect, carfilzo-
and even those who do respond will ultimately relapse or
mib irreversibly targets the same proteasomal subunit
become refractory to salvage therapy. Consequently, sev-
(20S chymotrypsin-like b5 subunit) and has shown activ-
eral new agents from a range of therapeutic classes are
ity (e.g., caspase activation, inhibition of proliferation)
being examined in the relapsed / refractory setting. Spe-
against bortezomib-resistant MM cell lines, as well as
cific agents in development for the treatment of bortezo-
cells from MM patients with clinical evidence of bortezo-
mib- or lenalidomide-resistant MM include new IMiDs
mib resistance (61).
(e.g., pomalidomide), second-generation PIs (e.g., car-
In a phase I study, 19 patients who had relapsed fol-
filzomib, NPI-0052), the signal transduction modulator
lowing or became refractory to previous bortezomib and
perifosine, monoclonal antibody therapy (e.g., elot-
IMiD therapy received carfilzomib 15­27 mg / m2 on days
uzumab), and histone deacetylase (HDAC) inhibitors
1, 2, 8, 9, 15, and 16 of each 28-d cycle. Treatment with
(e.g.,
panobinostat,
romidepsin,
and
vorinostat).
carfilzomib resulted in an ORR of approximately 17%,
Although the goal with all of these newer agents is to
with 33% of patients achieving an MR or better. No
improve patient outcomes, the rationale for use in MM
treatment-related or newly emergent peripheral neuropa-
varies with the drug class.
thy was reported in response to carfilzomib (62). Two
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Emerging therapies in multiple myeloma
Table 1 Targeted agents in clinical investigation for the treatment of relapsed / refractory multiple myeloma
Author
Confirmed
Time-to-event
Agent
N / n
Dosing regimen
responses, %
outcome
Most common toxicities, %
Pomalidomide
Lacy (116)
28-d cycles
ORR, 26 (all PR)
NR
Grade 3­4
34
POM 2 mg daily, days 1­28
Neutropenia, 21; anemia, 12;
DEX 40 mg, days 1, 8, 15, 22
thrombocytopenia, 9;
fatigue, 9; non-infectious
pneumonitis, 3;
hyperglycemia, 3; edema, 3;
skin rash, 3; no TEEs
observed
Richardson (71)
28-d cycles
POM alone:
DOR, 11 wk
Grade 3­4
POM 2­5 mg, days 1­21
ORR MR, 38
TTP, 8.3 wk
Neutropenia,
POM 2­5 mg, days 1­21
POM + DEX:
DOR, 14.2 wk
thrombocytopenia
DEX 40 mg, weekly (after 4 cycles
ORR MR, 38
TTP, 20 wk
for lack of response or PD)
Carfilzomib
Niesvizky (117)
28-d cycles
CR / VGPR / PR, 55
NR
Grade 3­4
32 / 20
CFZ 15­27 mg / m2, days 1, 2, 8, 9,
Thrombocytopenia 15;
15, 16
anemia 15; neutropenia 8
LEN 10­27 mg, days 1­21
DEX 40 mg, days 1, 8, 15, 22
(monthly after cycle 5)
Siegel (118)
28-d cycles
CR / PR, 18
NR
Grade 3­4
35 / 33
CFZ 20 mg / m2, days 1, 2, 8, 9, 15,
Anemia, 14; neutropenia, 11;
16
peripheral neuropathy, 3
Wang (119)
28-d cycles
CR / VGPR / PR, 45
NR
Grade 3­4
57 / 51
CFZ 20 mg / m2, days 1, 2, 8, 9, 15,
Thrombocytopenia, 9;
16
fatigue, 9; neutropenia, 7;
lymphopenia, 7; anemia, 5;
pneumonia, 5;
hyperglycemia, 5
NPI-0052
Richardson (66)
28-d cycles
NR
NR
DLTs observed (grade 3
27
NPI 0.025­0.7 mg / m2, days 1, 8,
1 unconfirmed PR
fatigue, mental status
15
(71% flM-protein
change and loss of balance,
after 3 cycles)
1 patient each at highest
8SD
dose)
Perifosine
Richardson (59)
21-d cycles
ORR PR, 38
TTP, 6.4 mo
Grade 3­4
84 / 73
PER 50 mg daily
CR / PR, 20
OS, 22.5 mo
Thrombocytopenia;
BTZ 1.3 mg / m2, days 1, 4, 8, 11
neutropenia; anemia;
DEX 20 mg, day of and day after
hyponatremia; diarrhea
BTZ for PD
(5% each)
Tanespimycin
Richardson (87)
21-d cycles
ORR MR:
DOR, 12 mo
Grade 3­4
72
TSP 100­340 mg / m2, days 1, 4, 8,
BTZ-naive (n = 21),
thrombocytopenia, 25;
11
48
neutropenia, 3
BTZ 0.7­1.3 mg / m2, days 1, 4, 8,
BTZ-pretreated
11
(n = 23), 22
BTZ-refractory
(n = 23), 13
Badros (86)
21-d cycles
VGPR / PR / MR, 14
NR
Grade 3­4
22
TSP 50­340 mg / m2, days 1, 4, 8,
Thrombocytopenia, 27;
11
neutropenia, 18; peripheral
BTZ 1.3 mg / m2, days 1, 4, 8, 11
neuropathy 5
Panobinostat
Berenson (99)
28-d cycles
CR / PR, 33
NR
Grade 3­4
15 / 12
PAN 20 mg, days 1, 3, 5, 8, 10
Neutropenia;
MLP 0.05 mg / kg, days 1, 3, 5
thrombocytopenia
San Miguel (101)
21-d cycles
CR / PR, 50
NR
Grade 3­4
29 / 28
PAN 10­30 mg, 3 times weekly
Thrombocytopenia;
BTZ 1.3 mg / m2, days 1,4, 8, 11
neutropenia; anemia;
pneumonia; fatigue;
significant QTc did not occur
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Table 1 (Continued )
Author
Confirmed
Time-to-event
Agent
N / n
Dosing regimen
responses, %
outcome
Most common toxicities, %
Romidepsin
Harrison (105)
28-d cycles
CR / nCR / VGPR / PR,
NR
Dose limiting
25 / 18
RMD 8­14 mg / m2, days 1, 8, 15
67
No DLTs at MTD (romidepsin
BTZ 1.3 mg / m2, days 1,4, 8, 11
10 mg / m2); no reports of
DEX 20 mg, days 1, 2, 4, 5, 8, 11,
QTc prolongation
12
Vorinostat
Jagannath (110)
28-d cycles
PR / MR, 78
TTP, 9.8 mo
Grade 3­4:
34 / 9
VOR 200 mg BID; or 400 mg, days
Neutropenia; drug-related
1­14
toxicities included diarrhea,
BTZ 0.7 or 0.9 mg / m2, days 4, 8,
nausea, and fatigue (all
11, 15; or 0.9­1.3 mg / m2, days 1,
grades)
4, 8, 11
DEX 20 mg, days 1­4, 9­12 for PD
Siegel (112)
28-d cycles
CR / nCR / VGPR / PR,
NR
Dose limiting
28 / 25
VOR 300­400 mg, daily days 1­7,
64
Grade 3 diarrhea in 1 patient
15­21
at highest dose (VOR
LEN 10­25 mg, days 1­21
400 mg)
DEX 40 mg, days 1, 8, 15, 22
Voorhees (113)
28-d cycles
CR / VGPR / PR, 86
NR
Grade 3­4
9 / 7
VOR 200­400 mg daily, days 4­11
Sensory neuropathy;
BTZ 1.3 mg / m2, days 1,4, 8, 11
neutropenia; lymphopenia;
PLD 30 mg / m2, day 4
thrombocytopenia
BID, twice daily; BTZ, bortezomib; CFZ, carfilzomib; CR, complete response; DEX, dexamethasone; DLT, dose-limiting toxicity; DOR, duration
of response; LEN, lenalidomide; MLP, melphalan; MR, minimal response; MTD, maximum tolerated dose; nCR, near complete response; NPI,
NPI-0052; NR, not reported; ORR, overall response rate; OS, overall survival; PAN, panobinostat; PER, perifosine; PD, progressive disease; PLD,
pegylated liposomal doxorubicin; POM, pomalidomide; PR, partial response; QTc, corrected QT interval; RMD, romidepsin; SD, stable disease;
TEE, thromboembolic events; TSP, tanespimycin; TTP, time to progression; VGPR, very good partial response; VOR, vorinostat.
ongoing phase II trials are investigating the efficacy,
activate signal transduction processes controlling cell
safety, and tolerability of carfilzomib as monotherapy in
migration, growth, and survival. Signal transduction
patients with relapsed / refractory MM and prior treat-
modulators affect a variety of cellular processes, includ-
ment with bortezomib and thalidomide or lenalidomide
ing cell growth, differentiation, and death, making them
(63, 64). Preliminary data from ongoing clinical studies
rational targets for new therapies.
are summarized in Table 1.
Perifosine
NPI-0052
Perifosine is thought to target cell membranes and indi-
Like
carfilzomib,
the
non-peptide-based
inhibitor
rectly affect the phosphatidylinositol 3-kinase / Akt path-
NPI-0052 also targets all three proteasome units (i.e.,
way, which is a critical regulator of cell survival and cell
the caspase-, chymotrypsin-, and trypsin-like subunits)
growth and may underlie the pathogenesis of resistance
and irreversibly inhibits the 20S proteasome (65). In a
to conventional agents (e.g., dexamethasone, doxorubi-
phase I study, NPI-0052 (0.025­0.075 mg / m2, days 1, 8,
cin) in MM (67, 68).
and 15 of a 28-d cycle) exhibited more potent protea-
In a phase I dose-escalation study in 32 heavily pre-
some inhibitory activity than bortezomib, with no
treated patients (94% received prior dexamethasone,
reports of peripheral neuropathy or myelosuppression
83% prior thalidomide, and 47% prior bortezomib ther-
in patients (N = 27) with relapsed / refractory MM
apy), treatment with perifosine (50 or 100 mg daily dur-
(Table 1) (66).
ing a 28-d cycle) in combination with lenalidomide (15
or 25 mg, days 1­21) and dexamethasone (20 mg, days
1­4, 9­12, and 17­20 for 4 cycles; days 1­4 thereafter)
Inhibitors of signal transduction and cell adhesion
resulted in a 50% ORR (PR or better) in evaluable
Although conventional and targeted agents have dramat-
patients (n = 30) (69). Patients who achieved a PR or
ically improved response rates, MM remains incurable.
better exhibited a longer median TTP (31 vs. 23 wk in all
As noted earlier, the interactions of MM cells within the
evaluable patients). The most common grade 3­5 AEs
bone marrow microenvironment are complex and depend
were neutropenia, hypophosphatemia, thrombocytopenia,
on a number of cell­ligand and cell­cell interactions that
anemia, and fatigue (69).
6
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Dimopoulos et al.
Emerging therapies in multiple myeloma
In a phase II study in 64 patients with relapsed or
lidomide, and 21% received lenalidomide). Treatment
relapsed / refractory MM (95% received prior dexametha-
with elotuzumab (5­20 mg / kg weekly for the first 2 28-d
sone, 89% prior thalidomide, 73% prior bortezomib,
cycles, then every other week) combined with lenalido-
and 30% prior lenalidomide), perifosine alone (150 mg
mide (25 mg, days 1­21) produced an ORR of 82%
daily for a 21-d cycle) showed modest clinical activity,
(18% VGPR; 64% PR) in 28 evaluable patients (76).
producing best responses [according to European Blood
Interestingly, an ORR of 95% (23% VGPR; 73% PR)
and Marrow Transplant
(EBMT)
criteria]
of
MR
was seen in the 22 lenalidomide-naive patients enrolled
(n = 1) and SD (n = 22).(70) However, when adminis-
in the study. Further investigation is needed to determine
tered in combination with dexamethasone 20 mg twice
the optimal role of elotuzumab in the treatment of MM.
weekly to patients with PD, perifosine showed greater
clinical activity (38% PR + MR) in 12 of 31 evaluable
High-dose chemotherapy and targeted agents
patients; an additional 15 patients (47%) achieved SD
(70). The most common grade 3­5 AEs were nausea,
Bendamustine, a bifunctional alkylating agent that cross-
vomiting, fatigue, anemia, increased creatinine, and
links DNA and induces apoptosis and mitotic catastro-
reversible neutropenia. Peripheral neuropathy and deep
phe (77), may be another option for salvage therapy in
vein thrombosis were not reported (70).
patients with relapsed / refractory MM. This agent has
Perifosine has also been evaluated in combination with
shown some clinical activity as monotherapy (ORR, 36­
bortezomib and dexamethasone in 84 relapsed / refractory
55%) (78, 79), prompting the evaluation of combination
MM patients previously treated with bortezomib (71). As
regimens in the treatment of MM.
shown in Table 1, this regimen was associated with an
In a phase I study in 28 evaluable patients with
ORR of 38% (CR / PR, 20%) and an OS of 22.5 months
relapsed / refractory MM (14% had received prior bort-
(median not yet reached); myelosuppression, hyponatre-
ezomib and 7% received thalidomide), 28-d cycles of
mia, and diarrhea were the most common grade 3­5
bendamustine (60 mg / m2, days 1, 8, and 15) in combina-
events.
tion with prednisolone (100 mg, days 1, 8, 15, and 22)
and thalidomide (50, 100, or 200 mg, days 1­28) pro-
Elotuzumab
duced an ORR of 86% (CR + PR), including those
Further improvements in the management of relapsed
patients who had relapsed on prior conventional chemo-
and refractory MM may be achieved using monoclonal
therapy or high-dose chemotherapy and autologous stem
antibody (MAb) therapy. Elotuzumab (HuLuc63) is a
cell transplant (SCT) (80). Overall, the median duration
humanized MAb that targets CS1, a cell surface glyco-
of response was 11 months, and median OS was
protein involved in cell adhesion that is selectively
19 months; however, OS was longer in patients who had
expressed on MM cells and colocalizes with CD138 in
relapsed on prior chemotherapy (32+ vs. 16 month;
these cells (72, 73).
P = 0.03) compared with SCT (80). The most common
High rates of tumor cell lysis were observed when
grade 3 AEs were hematologic in nature, and thrombo-
CD138+ cells isolated from patients with refractory
embolic events were not observed (80).
(and newly diagnosed) MM were treated with elot-
The feasibility of adding bendamustine to bortezomib
uzumab in the presence of autologous peripheral blood
and
dexamethasone
therapy
has
been
explored
in
mononuclear cells, including natural killer cells (72).
patients with <MR to 1 cycle of bortezomib plus dexa-
Importantly, elotuzumab-induced tumor cell lysis was
methasone. In this study, a total of seven patients with
enhanced in MM cells that had been pretreated with sub-
relapsed / refractory MM who failed to respond ade-
therapeutic doses of diverse types of targeted agents (i.e.,
quately to bortezomib plus dexamethasone received 21-d
bortezomib, lenalidomide, perifosine) (72, 74).
cycles of bortezomib (1.3 mg / m2, days 1, 4, 8, and 11)
These promising preclinical findings have been vali-
combined with dexamethasone (40 mg, days 1, 4, 8, and
dated
in
early
clinical
trials
in
patients
with
11) and bendamustine (50­100 mg / m2, days 1 and 8). In
relapsed / refractory MM. In a phase I study in 28
this non-responding patient population, the combination
patients with relapsed / refractory MM (31% had received
resulted in an ORR of 86% (57% PR; 29% MR) (81).
prior bortezomib), 21-d cycles of elotuzumab (2.5­
Further clinical trials are needed to establish the role of
20 mg / kg, days 1 and 11) in combination with bortezo-
bendamustine alone and in combination with other tar-
mib (1.3 mg / m2, days 1, 4, 8, and 11) produced a best
geted agents in the treatment of relapsed / refractory MM.
response (MR) of 60% (40% PR) in 20 evaluable
patients who had completed at least 2 treatment cycles
Targeted inhibition of heat shock protein
(75). Elotuzumab has also been evaluated in combination
with lenalidomide in a phase I / II study in 29 patients
Novel treatment approaches targeting diverse pathways
(69% had received prior bortezomib, 59% received tha-
complementary to those targeted by conventional and
ª 2010 John Wiley & Sons A/S
7

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Emerging therapies in multiple myeloma
Dimopoulos et al.
newer approved agents show promise for inducing
tanespimycin (50, 175, or 340 mg / m2, days 1, 4, 8, and
myeloma cell cytotoxicity and downregulating signaling
11 of each 21-d cycle) with bortezomib (1.3 mg / m2, days
pathways that induce myeloma growth, survival, and
1, 4, 8, and 11) demonstrated clinical activity, with 14%
therapeutic resistance. Heat shock proteins (e.g., HSP27,
of patients achieving MR or better. The most common
HSP90) are potential therapeutic targets because expres-
grade 3­5 AEs were hematologic in nature, and one
sion of these Bcl-2-like proteins interferes with the mito-
patient experienced grade 3 peripheral neuropathy (86).
chondrial stress response and activation of proapoptotic
signaling (e.g., activation of Bax, caspase-3) that can
Histone deacetylase inhibitors
result in the development of drug resistance (82, 83). For
example, overexpression of HSP27 correlated with resis-
Histone deacetylase inhibitors are another new class of
tance to dexamethasone in myeloma cells, whereas block-
molecules that show promise as a complementary
ade of HSP27 restored sensitivity to bortezomib (84, 85).
approach for the treatment of relapsed / refractory MM,
and a number of phase I and II studies have recently
Tanespimycin
been conducted with these agents. HDAC inhibition pro-
Tanespimycin, an inhibitor of HSP90, has shown activity
motes acetylation of histone and non-histone proteins
in
combination
with
bortezomib
in
MM
patients
(Fig. 1).
Histone
acetylation
affects
higher-order
(Table 1) (86, 87). In a phase I / II study in 72 pretreated
DNA / chromatin structure, and HDAC inhibition leads
MM patients (74% had received prior bortezomib ther-
to increased transcription of genes that have been down-
apy and 69% had received prior lenalidomide), tanespi-
regulated by histone acetylation (88). Therefore, inhibi-
mycin [340 mg / m2 intravenously (IV), days 1, 4, 8, and
tion of HDAC affects epigenetic mechanisms that help
11 of each 21-d cycle] in combination with bortezomib
restore or increase expression of genes that may play a
(0.7­1.3 mg / m2 IV, days 1, 4, 8, and 11) inhibited
critical role in the control of tumor growth and survival.
HSP90 and proteasome activity and showed antitumor
As is the case with PIs, HDAC inhibitors may help
activity based on modified EBMT criteria. The ORR
restore or increase the expression of proapoptotic pro-
(defined as MR or better) was 48% in bortezomib-naive
teins in tumors.
patients, 22% in bortezomib-pretreated patients, and
Non-histone proteins are also regulated by acetylation,
13% in bortezomib-refractory patients, with a median
with evidence for non-histone-mediated effects on tumor
response duration of 12 months. There were no reports
cell growth. Transcription factor acetylation disrupts
of grade 3­5 peripheral neuropathy (87). In another
control of cell cycle transit and apoptosis in cancer.
study in 22 heavily pretreated MM patients (96% had
Direct acetylation of p53 affects its growth-regulatory
received prior thalidomide therapy), the combination of
and proapoptotic functions. Treatment of a variety of
Condensed chromatin
Decondensed chromatin
Gene transcription
HAT
activation/repression
Ac
Ac
Ac
Ac
HDAC
HDACi
Ac
Transcription factors
Ac
E2F
HDAC
Apoptosis
p53
NF-B
Cell cycle arrest
STAT-1
HAT
Ac
Immune modulation
Ac
Non-histone proteins
Deacetylated
Acetylated
VEGF
Angiogenesis inhibition
protein
protein
hsp90
hif1
-Tubulin
Figure 1 Effects of histone deacetylase (HDAC) inhibitors on histone protein acetylation and chromatin structure, acetylation of transcription fac-
tors resulting in changes in gene expression, and acetylation of other non-histone proteins leading to diverse biologic effects underlying the patho-
genesis and treatment of multiple myeloma. Reprinted with permission. Paik PK, Krug LM. HDAC inhibitors in malignant pleural mesothelioma:
preclinical rationale and clinical trials. J Thorac Oncol 2010; 5: 275­279.
8
ª 2010 John Wiley & Sons A/S

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Dimopoulos et al.
Emerging therapies in multiple myeloma
tumor cells with HDAC inhibitors resulted in hyperacet-
relapsed or refractory cutaneous T-cell lymphoma who
ylation of p53 and induction of p21 / Waf / Cip1­mediated
have received at least 1 prior systemic therapy (102). In
cell cycle arrest, increased expression of proapoptotic
patients with relapsed or refractory MM, romidepsin is
proteins (e.g., cytochrome c, BAX, Bid, activated cas-
currently being evaluated in combination with bortezo-
pase), and downregulated expression of antiapoptotic
mib (103, 104) or with bortezomib and dexamethasone
proteins (e.g., Bcl-2) (89­91).
(105).
In addition, increased acetylation of HSP90 can dis-
In a phase I study in relapsed or refractory MM
rupt its chaperone function, resulting in decreased intra-
patients (N = 25; 37% had received prior vincristine,
cellular levels of progrowth and antiapoptotic proteins
50% received prior thalidomide, and 25% received prior
(e.g., Akt), possibly through enhanced proteasomal deg-
bortezomib therapy), treatment with romidepsin at the
radation of proteins (92, 93). HDAC6 links acetylation
maximum tolerated dose (MTD) of 10 mg / m2 in combi-
of HSP90 with aggresome formation and the accumula-
nation with bortezomib resulted in an ORR of 71%
tion of ubiquinated proteins (94, 95).
(based on EBMT criteria), including one CR, three PR,
and one MR among seven evaluable patients (103). No
Panobinostat
grade 3 or 4 non-hematologic AEs or dose-limiting toxic-
Panobinostat (LBH589) is an oral HDAC inhibitor (96)
ities were reported (103).
that is currently being investigated alone (97) and in
In a phase I / II study, romidepsin was shown to have
combination with lenalidomide and dexamethasone (98),
clinical activity in combination with bortezomib and
melphalan (99), or bortezomib for the treatment of
dexamethasone in patients with relapsed or refractory
patients with relapsed or relapsed / refractory MM (100,
MM (Table 1) (105). No dose-limiting toxicities were
101).
reported among seven evaluable patients who completed
In a phase II study, single-agent panobinostat showed
at least two cycles (range, 1­8) of treatment with romi-
clinical activity with a durable VGPR and MR (based on
depsin 8 or 10 mg / m2 once weekly; however, grade 3
EBMT criteria) in 2 of 38 patients with heavily pretreat-
fatigue (n = 2), peripheral neuropathy (n = 1), neutro-
ed (including bortezomib, lenalidomide, and thalidomide)
penia (n = 1), and sepsis (n = 2) were reported in this
refractory MM, and there were no reports of significant
small cohort of patients (105). Importantly, 12 of 18
thromboembolic events (97).
evaluable patients (67%) experienced at least a PR (four
Panobinostat is also being investigated as a component
CR / near CR, four VGPR, four PR); five additional
of combination regimens for the treatment of relapsed or
patients (28%) achieved an MR (105). Of the seven
refractory MM (summarized in Table 1). In a phase I
patients receiving long-term maintenance therapy with
study, panobinostat in combination with melphalan
romidepsin (10 mg / m2 on days 1 and 8 of every 28-d
demonstrated clinical activity with an ORR of 33% (one
cycle), four experienced disease progression, including
immunofixation-positive CR, three PR) in 12 patients
three who had progressed on a previous bortezomib
with relapsed or refractory MM previously treated with
maintenance regimen.
melphalan (99). The most common grade 3­5 AEs were
reversible neutropenia (n = 6) and thrombocytopenia
Vorinostat
(n = 6) (99).
Vorinostat is an oral HDAC inhibitor that was approved
Combination therapy with panobinostat and bortezo-
in the United States in 2006 for the treatment of patients
mib is also being investigated in patients with advanced
with cutaneous T-cell lymphoma who have progressive,
MM. In a phase IB study in 29 heavily pretreated
persistent, or recurrent disease on or following 2 systemic
patients (55% had received prior bortezomib therapy),
therapies (106­108).
treatment with panobinostat combined with bortezomib
In patients with relapsed / refractory MM, vorinostat is
resulted in at least a PR in 14 of 28 evaluable patients
currently being investigated in combination with bortezo-
(50%), including four patients with immunofixation-
mib (109­111), in combination with lenalidomide and
negative CR (101). Importantly, an objective response
dexamethasone (112), or in combination with PLD and
(PR + MR) was observed in 6 of 10 (60%) evaluable
bortezomib (113). In a phase I study in 23 heavily pre-
patients who were refractory to previous bortezomib
treated patients (100% had received prior thalidomide;
therapy (101). The most common grade 3­5 AEs were
83% had received prior bortezomib), vorinostat demon-
thrombocytopenia (n = 25), neutropenia (n = 18), and
strated clinical activity at the MTD of 400 mg daily on
anemia (n = 6) (101).
days 4­11 in combination with bortezomib 1.3 mg / m2 on
days 1, 4, 8, and 11 of each 21-d cycle, with 55% of
Romidepsin
patients achieving PR or better (109). The most frequent
Romidepsin, an HDAC inhibitor administered as a 4-h
grade 3 AEs were reversible myelosuppression and fati-
infusion, is approved for the treatment of patients with
gue; 1 patient had grade 3 peripheral neuropathy.
ª 2010 John Wiley & Sons A/S
9

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Emerging therapies in multiple myeloma
Dimopoulos et al.
In another phase I study, the addition of vorinostat
Disclosures
200­400 mg daily on days 4 to 11 to PLD 30 mg / m2 on
Dr. Dimopoulos has received honoraria from Merck,
day 4 and bortezomib 1.3 mg / m2 on days 1, 4, 8, and 11
Sharp, and Dohme, a subsidiary of Merck & Co., Inc.,
in 21-d cycles showed clinical activity in six of seven
Celgene Corporation, and Centocor Ortho Biotech.
evaluable patients (1 CR, 1 VGPR, and 4 PR) based on
Dr. Anderson has served as an advisor for Celgene
International Myeloma Working Group criteria (114)
Corporation, Novartis Oncology, Millenium Pharma-
and was generally well tolerated. No dose-limiting toxici-
ceuticals, Inc., Onyx Pharmaceuticals, and Nereus Phar-
ties, serious AEs, or deaths were reported, although some
maceuticals. Dr. San-Miguel has served as an advisor for
neurologic (grade 3 sensory neuropathy in two of nine
Celgene Corporation, Novartis Oncology, Millenium
patients) and hematologic toxicities (grade 3 neutrope-
Pharmaceuticals, Inc., and Janssen-Cilag.
nia, lymphopenia, and thrombocytopenia in 2, 3, and
two patients, respectively) were identified in this small
cohort of patients (113). Another study (summarized in
Acknowledgements
Table 1) showed that extended treatment (12 cycles)
The authors wish to thank Craig Albright, PhD, for
with vorinostat 200 mg twice daily or 400 mg once daily
writing and editorial assistance during the development
in combination with bortezomib was well tolerated (one
of this manuscript. Dr. Albright is employed by Com-
patient had grade 4 neutropenia, and five patients had
plete Healthcare Communications, Inc., a medical com-
grade 3 treatment-related AEs). Long-term clinical activ-
munications company under contract with Merck, Sharp,
ity was observed, with five PR, two MR, and two SD
and Dohme, a subsidiary of Merck & Co., Inc.
among nine evaluable patients. The duration of PR ran-
ged from 147 to 609 d (110).
The safety and tolerability of vorinostat has been well
References
documented in patients with hematologic malignancies
1. Ferlay J, Parkin DM, Steliarova-Foucher E. Estimates of
and those with solid tumors. In an analysis of 341
cancer incidence and mortality in Europe in 2008. Eur J
patients who had received vorinostat as monotherapy,
Cancer 2010;46:765­81.
the most common grade 3­4 drug-related adverse events
2. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ.
were fatigue (12% of patients) and thrombocytopenia
Cancer statistics, 2009. CA Cancer J Clin 2009;59:
(11%). In an analysis of 157 patients who had received
225­49.
vorinostat in combination, the most common grade 3­4
3. NCCN. Clinical Practice Guidelines in Oncology: Multiple
drug-related adverse event was fatigue (13% of patients).
Myeloma v.2.2010. Fort Washington, PA: National Com-
Furthermore, an analysis in more than 1845 vorinostat-
prehensive Cancer Network, 2009.
treated patients revealed that the rate of thromboembolic
4. Child JA, Morgan GJ, Davies FE, Owen RG, Bell SE,
events related to treatment was <2.6% (115).
Hawkins K, Brown J, Drayson MT, Selby PJ. High-
Ongoing clinical studies include a pivotal phase IIB
dose chemotherapy with hematopoietic stem-cell
rescue for multiple myeloma. N Engl J Med 2003;348:
study and a randomized, blinded, phase III study to
1875­83.
determine the ORR, TTP, PFS, OS, and tolerability of
5. Fermand JP, Katsahian S, Divine M, et al. High-dose
vorinostat in combination with IV bortezomib.
therapy and autologous blood stem-cell transplantation
compared with conventional treatment in myeloma
Conclusions
patients aged 55 to 65 years: long-term results of a ran-
domized control trial from the Group Myelome-Auto-
The development and application of targeted therapies,
greffe. J Clin Oncol 2005;23:9227­33.
such as bortezomib and lenalidomide, have improved
6. Singhal S, Mehta J, Desikan R, et al. Antitumor activity
treatment outcomes in patients with relapsed / refractory
of thalidomide in refractory multiple myeloma. N Engl J
MM. Emerging studies suggest that new combination
Med 1999;341:1565­71.
therapies targeting complementary signaling pathways
7. Kumar S, Gertz MA, Dispenzieri A, et al. Response rate,
may further improve prognosis in treating this advanced
durability of response, and survival after thalidomide
form of MM. Completion of the numerous ongoing clini-
therapy for relapsed multiple myeloma. Mayo Clin Proc
cal investigations should determine which if any of these
2003;78:34­9.
newly emerging therapies are viable treatment options
8. Dimopoulos M, Spencer A, Attal M, et al. Lenalidomide
for patients with relapsed / refractory MM. Regardless of
plus dexamethasone for relapsed or refractory multiple
outcome, the clinical study results will further improve
myeloma. N Engl J Med 2007;357:2123­32.
our understanding of the biology of MM and the role
9. Weber DM, Chen C, Niesvizky R, et al. Lenalidomide
for targeted therapies in providing durable disease con-
plus dexamethasone for relapsed multiple myeloma in
trol and symptomatic relief in MM patients.
North America. N Engl J Med 2007;357:2133­42.
10
ª 2010 John Wiley & Sons A/S

---

Dimopoulos et al.
Emerging therapies in multiple myeloma
10. Richardson PG, Barlogie B, Berenson J, et al. A phase 2
23. Mileshkin L, Honemann D, Gambell P, et al. Patients
study of bortezomib in relapsed, refractory myeloma. N
with multiple myeloma treated with thalidomide:
Engl J Med 2003;348:2609­17.
evaluation of clinical parameters, cytokines,angiogenic
11. Orlowski RZ, Nagler A, Sonneveld P, et al. Randomized
markers, mast cells and marrow CD57+ cytotoxic
phase III study of pegylated liposomal doxorubicin plus
T cells as predictors of outcome. Haematologica
bortezomib compared with bortezomib alone in relapsed
2007;92:1075­82.
or refractory multiple myeloma: combination therapy
24. Avet-Loiseau H, Attal M, Moreau P, et al. Genetic
improves time to progression. J Clin Oncol 2007;25:3892­
abnormalities and survival in multiple myeloma: the
901.
experience of the Intergroupe Francophone du Myelome.
12. Gerecke C, Knop S, Topp MS, Liebisch P, Vollmuth C,
Blood 2007;109:3489­95.
Platzbecker U, Ma¨der U, Einsele H, Bargou RC. Lena-
25. Cavo M, Testoni N, Terragna C, et al. Up-front
lidomide, Adriamycin and dexamethasone (RAD) in
thalidomide-dexamethasone (THAL) and double autolo-
relapsed and refractory multiple myeloma: final results
gous transplant (Double TX) for multiple myeloma:
from a phase I / II trial of ``Deutsche Studiengruppe Mul-
comparison with double TX without added thalidomide
tiples Myelom'' [ASH abstract]. Blood 2008;112:2782.
and prognostic implications of chromosome 13 deletion
13. Knop S, Gerecke C, Liebisch P, Topp MS, Hess G,
and translocation t(4;14) [abstract]. Blood 2006;108:
Platzbecker U, Frohnert S, Einsele H, Bargou R. The
3081.
efficacy and toxicity of the RAD regimen (RevlimidÒ,
26. Avet Loiseau H, Soulier J, Fermand J-P, et al. Impact of
AdriamycinÒ, dexamethasone) in relapsed and refractory
chromosomal abnormalities del(13), t(4;14), and del(17p)
multiple myeloma-a phase I / II trial of ``Deutsche Studi-
and prior treatment on outcomes in patients with
engruppe Mutiples Myelom'' [ASH abstract]. Blood
relapsed or refractory multiple myeloma treated with
2007;110:2716.
lenalidomide [ASH annual meeting abstract]. Blood
14. Reece DE, Masih-Khan E, Khan A, Dean S, Anglin P,
2008;112:3685.
Chen C, Kukreti V, Mikhael JR, Trudel S. Phase I-II
27. Palumbo A, Gay F, Bringhen S, et al. Bortezomib,
trial of oral cyclophosphamide, prednisone and lenalido-
doxorubicin and dexamethasone in advanced multiple
mide (RevlimidÒ) (CPR) for the treatment of patients
myeloma. Ann Oncol 2008;19:1160­5.
with relapsed and refractory multiple myeloma [ASH
28. Reece D, Song KW, Fu T, et al. Influence of cytogenet-
abstract]. Blood 2009;114:1874.
ics in patients with relapsed or refractory multiple mye-
15. Anderson KC, Kyle RA, Rajkumar SV, Stewart AK,
loma treated with lenalidomide plus dexamethasone:
Weber D, Richardson P. Clinically relevant end points
adverse effect of deletion 17p13. Blood 2009;114:522­5.
and new drug approvals for myeloma. Leukemia
29. Dimopoulos M, Kastritis E, Christoulas D, Migkuo M,
2008;22:231­9.
Gavriatopoulou M, Iakovaki M, Roussou M, Efstathiou
16. Vescio RA, Cao J, Hong CH, Lee JC, Wu CH, Der Dani-
E, Terpos E. Treatment of patients with relapsed / refrac-
elian M, Wu V, Newman R, Lichtenstein AK, Berenson
tory multiple myeloma (MM) with lenalidomide and
JR. Myeloma Ig heavy chain V region sequences reveal
dexamethasone with or without bortezomib: prospective
prior antigenic selection and marked somatic mutation but
evaluation of the impact of cytogenetic abnormalities
no intraclonal diversity. J Immunol 1995;155:2487­97.
[ASH abstract]. Blood 2009;114:958.
17. Kyle RA, Rajkumar SV. Criteria for diagnosis, staging,
30. San Miguel JF. Relapse / refractory myeloma patient:
risk stratification and response assessment of multiple
potential treatment guidelines. J Clin Oncol 2009;27:
myeloma. Leukemia 2009;23:3­9.
5676­7.
18. Hideshima T, Anderson KC. Molecular mechanisms of
31. Anderson H, Scarffe JH, Ranson M, Young R, Wieringa
novel therapeutic approaches for multiple myeloma. Nat
GS, Morgenstern GR, Fitzsimmons L, Ryder D. VAD
Rev Cancer 2002;2:927­37.
chemotherapy as remission induction for multiple mye-
19. Uchiyama H, Barut BA, Chauhan D, Cannistra SA,
loma. Br J Cancer 1995;71:326­30.
Anderson KC. Characterization of adhesion molecules
32. Browman GP, Belch A, Skillings J, Wilson K, Bergsagel
on human myeloma cell lines. Blood 1992;80:2306­14.
D, Johnston D, Pater JL. Modified adriamycin-vincris-
20. Hideshima T, Chauhan D, Schlossman R, Richardson P,
tine-dexamethasone (m-VAD) in primary refractory and
Anderson KC. The role of tumor necrosis factor alpha in
relapsed plasma cell myeloma: an NCI (Canada) pilot
the pathophysiology of human multiple myeloma: thera-
study. The National Cancer Institute of Canada Clinical
peutic applications. Oncogene 2001;20:4519­27.
Trials Group. Br J Haematol 1992;82:555­9.
21. Edwards CM, Zhuang J, Mundy GR. The pathogenesis
33. Gertz MA, Kalish LA, Kyle RA, Hahn RG, Tormey
of the bone disease of multiple myeloma. Bone 2008;42:
DC, Oken MM. Phase III study comparing vincristine,
1007­13.
doxorubicin (Adriamycin), and dexamethasone (VAD)
22. Oyajobi BO. Multiple myeloma / hypercalcemia. Arthritis
chemotherapy with VAD plus recombinant interferon
Res Ther 2007;9:S4.
alfa-2 in refractory or relapsed multiple myeloma. An
ª 2010 John Wiley & Sons A/S
11

---

Emerging therapies in multiple myeloma
Dimopoulos et al.
Eastern Cooperative Oncology Group study. Am J Clin
and efficacy in treatment of relapsed / refractory multiple
Oncol 1995;18:475­80.
myeloma patients with or without history of peripheral
34. Lokhorst HM, Meuwissen OJ, Bast EJ, Dekker AW.
neuropathy [ASH abstract]. Blood 2009;114:3873.
VAD chemotherapy for refractory multiple myeloma. Br
46. Facon T, Leleu X, Stewart AK, et al. Dasatinib in com-
J Haematol 1989;71:25­30.
bination with lenalidomide and dexamethasone in
35. Barlogie B, Hall R, Zander A, Dicke K, Alexanian R.
patients with relapsed or refractory multiple myeloma:
High-dose melphalan with autologous bone marrow
preliminary results of a phase I study [ASH abstract].
transplantation for multiple myeloma. Blood
Blood 2009;114:1876.
1986;67:1298­301.
47. Raje N, Richardson P, Hari PN, et al. An open-label
36. Barlogie B, Alexanian R, Smallwood L, Cheson B,
phase I study of the safety and efficacy of RAD001 in
Dixon D, Dicke K, Cabanillas F. Prognostic factors with
combination with lenalidomide in the treatment of
high-dose melphalan for refractory multiple myeloma.
patients with relapsed and relapsed / refractory multiple
Blood 1988;72:2015­9.
myeloma [ASH abstract]. Blood 2009;114:3856.
37. Brenner H, Gondos A, Pulte D. Ongoing improvement
48. Chauhan D, Bianchi G, Anderson KC. Targeting the
in long-term survival of patients with Hodgkin disease at
UPS as therapy in multiple myeloma. BMC Biochem
all ages and recent catch-up of older patients. Blood
2008;9:S1.
2008;111:2977­83.
49. Strauss SJ, Higginbottom K, Juliger S, Maharaj L,
38. Teo SK. Properties of thalidomide and its analogues:
Allen P, Schenkein D, Lister TA, Joel SP. The protea-
implications for anticancer therapy. AAPS J 2005;7:E14­
some inhibitor bortezomib acts independently of p53
9.
and induces cell death via apoptosis and mitotic catas-
39. Palumbo A, Facon T, Sonneveld P, et al. Thalidomide
trophe in B-cell lymphoma cell lines. Cancer Res
for treatment of multiple myeloma: 10 years later. Blood
2007;67:2783­90.
2008;111:3968­77.
50. Richardson PG, Sonneveld P, Schuster MW, et al. Bort-
40. Terpos E, Kastritis E, Roussou M, Heath D, Christoulas
ezomib or high-dose dexamethasone for relapsed multiple
D, Anagnostopoulos N, Eleftherakis-Papaiakovou E,
myeloma. N Engl J Med 2005;352:2487­98.
Tsionos K, Croucher P, Dimopoulos MA. The combina-
51. Colado E, Mateos MV, Moreno MJ, et al. VAMP / Tha-
tion of bortezomib, melphalan, dexamethasone and inter-
CyDex: VelcadeÒ (bortezomib), adriamycin, melphalan,
mittent thalidomide is an effective regimen for
and prednisone alternating with thalidomide, cyclophos-
relapsed / refractory myeloma and is associated with
phamide and dexamethasone as a salvage regiment in
improvement of abnormal bone metabolism and angio-
relapsed multiple myeloma patients [ASH abstract].
genesis. Leukemia 2008;22:2247­56.
Blood 2008;112:3694.
41. Palumbo A, Ambrosini MT, Benevolo G, et al. Bortezo-
52. Safra T. Cardiac safety of liposomal anthracyclines.
mib, melphalan, prednisone, and thalidomide for relapsed
Oncologist 2003;8(Suppl. 2):17­24.
multiple myeloma. Blood 2007;109:2767­72.
53. Nagler A, Hajek R, Sonneveld P, Spencer A, Blade J,
42. Zangari M, Barlogie B, Burns M, Bolejack V, Hollmig
Robak T, Mundle S, Zhuang S, harousseau J, Orlowski
K, van Rhee F, Pineda-Roman M, Elice F, Tricot G.
R. Doxil + velcade in previously treated myeloma
Velcade (V)-thalidomide(T)-dexamethasone (D) for
w / prior SCT. Haematologica 2007;92:161.
advanced and refractory multiple myeloma (MM): long-
54. Sonneveld P, Hajek R, Nagler A, Spencer A, Blade J,
term follow-up of phase I-II trial UARK 2001-37: supe-
Robak T, Zhuang SH, Harousseau JL, Orlowski RZ.
rior outcome in patients with normal cytogenetics and no
Combined pegylated liposomal doxorubicin and
prior T [ASH annual meeting abstract]. Blood
bortezomib is highly effective in patients with recurrent
2005;106:2552.
or refractory multiple myeloma who received prior
43. Anderson KC, Jagannath S, Jakubowiak A, Lonial S,
thalidomide / lenalidomide therapy. Cancer 2008;112:
Raje N, Alsina M, Ghobrial I, Knight R, Esseltine D,
1529­37.
Richardson P. Lenalidomide, bortezomib, and dexameth-
55. Spencer A, Hajek R, Nagler A, Sonneveld P, Blade J,
asone in relapsed / refractory multiple myeloma (MM):
Robak T, Mundle S, Zhuang S, Harousseau J, Orlowski
encouraging outcomes and tolerability in a phase II
R. Doxil + velcade in previously treated high risk mye-
study [ASCO abstract]. J Clin Oncol 2009;27:8536.
loma. Haematologica 2007;92:162.
44. Agura E, Niesvizky R, Matous J, Munshi N, Hussein M,
56. San Miguel J, Hajek R, Nagler A, et al. Doxil + velcade
Parameswaran RV, Tarantolo S, Whiting NC, Drachman
in previously treated 65y myeloma pts. Haematologica
JG, Zonder JA. Dacetuzumab (SGN-40), lenalidomide,
2007;92:159.
and weekly dexamethasone in relapsed or refractory mul-
57. Anderson G, Gries M, Kurihara N, et al. Thalidomide
tiple myeloma: multiple responses observed in a phase Ib
derivative CC-4047 inhibits osteoclast formation by
study [ASH abstract]. Blood 2009;114:2870.
down-regulation of PU.1. Blood 2006;107:3098­105.
45. Delforge M, Facon T, Bravo M-L, Dimopoulos M. Le-
58. Verhelle D, Corral LG, Wong K, et al. Lenalidomide
nalidomide plus dexamethasone has similar tolerability
and CC-4047 inhibit the proliferation of malignant B
12
ª 2010 John Wiley & Sons A/S

---

Dimopoulos et al.
Emerging therapies in multiple myeloma
cells while expanding normal CD34+ progenitor cells.
combination with dexamethasone (dex) for patients with
Cancer Res 2007;67:746­55.
relapsed or relapsed / refractory multiple myeloma: prom-
59. Richardson P, Siegel D, Baz R, et al. A phase 1 / 2 multi-
ising activity as combination therapy with manageable
center, randomized, open label escalation study to deter-
toxicity [ASH abstract]. Blood 2007;110:1164.
mine the maximum tolerated dose, safety, and efficacy of
71. Richardson P, Wolf JL, Jakubowiak A, et al. Perifosine
pomalidomide alone or in combination with low-dose
in combination with bortezomib and dexamethasone
dexamethasone in patients with relapsed and refractory
extends progression-free survival and overall survival in
multiple myeloma who have received prior treatment that
relapsed / refractory multiple myeloma patients previously
includes lenalidomide and bortezomib [ASH abstract].
treated with bortezomib: updated phase I / II trial results
Blood 2009;114:301.
[ASH abstract]. Blood 2009;114:1869.
60. Lacy MQ, Hayman SR, Gertz MA, et al. Pomalidomide
72. Tai YT, Dillon M, Song W, et al. Anti-CS1 humanized
(CC4047) plus low-dose dexamethasone as therapy for
monoclonal antibody HuLuc63 inhibits myeloma cell
relapsed multiple myeloma. J Clin Oncol 2009;27:5008­
adhesion and induces antibody-dependent cellular
14.
cytotoxicity in the bone marrow milieu. Blood 2008;112:
61. Kuhn DJ, Chen Q, Voorhees PM, et al. Potent activity
1329­37.
of carfilzomib, a novel, irreversible inhibitor of the
73. Hsi ED, Steinle R, Balasa B, et al. CS1, a potential new
ubiquitin-proteasome pathway, against preclinical models
therapeutic antibody target for the treatment of multiple
of multiple myeloma. Blood 2007;110:3281­90.
myeloma. Clin Cancer Res 2008;14:2775­84.
62. Badros AZ, Vij R, Martin T, Zonder JA, Woo T,
74. van Rhee F, Szmania SM, Dillon M, et al. Combinato-
Wang Z, Lee S, Wong A, Niesvizky R. Phase I study
rial efficacy of anti-CS1 monoclonal antibody elot-
of carfilzomib in patients (pts) with relapsed and
uzumab (HuLuc63) and bortezomib against multiple
refractory multiple myeloma (MM) and varying degrees
myeloma. Mol Cancer Ther 2009;8:2616­24.
of renal insufficiency [ASH abstract]. Blood
75. Jakubowiak A, Benson DM Jr, Bensinger W, et al. Elot-
2009;114:3877.
uzumab in combination with bortezomib in patients with
63. Phase 2 study of carfilzomib in relapsed and refractory
relapsed / refractory multiple myeloma: a phase I study.
multiple myeloma (NCT00511238). Available at: http://
J Clin Oncol 2010;28:8003.
clinicaltrials.gov/ct2/show/NCT00511238. Accessed
76. Lonial S, Vij R, Harousseau J, T F, Moreau P, Leleu X,
March 10, 2010.
Westland C, Singhal A, Jagannath S, Multiple Myeloma
64. Phase 2 study of carfilzomib in relapsed multiple mye-
Research Consortium. Elotuzumab in combination with
loma (NCT00530816). Available at: http://clinicaltrials.
lenalidomide and low-dose dexamethasone in relapsed or
gov/ct2/show/NCT00530816. Accessed March 10, 2010.
refractory multiple myeloma: a phase I / II study. J Clin
65. Williamson MJ, Blank JL, Bruzzese FJ, et al. Compari-
Oncol 2010;28:8020.
son of biochemical and biological effects of ML858 (sali-
77. Leoni LM, Bailey B, Reifert J, Bendall HH, Zeller RW,
nosporamide A) and bortezomib. Mol Cancer Ther
Corbeil J, Elliott G, Niemeyer CC. Bendamustine (Tre-
2006;5:3052­61.
anda) displays a distinct pattern of cytotoxicity and
66. Richardson P, Hofmeister C, Jakubowiak A, et al. Phase
unique mechanistic features compared with other alkylat-
1 clinical trial of the novel structure proteasome inhibitor
ing agents. Clin Cancer Res 2008;14:309­17.
NPI-0052 in patients with relapsed and relapsed / refrac-
78. Michael M, Bruns I, Bolke E, Zohren F, Czibere A, Sa-
tory multiple myeloma (MM) [ASH abstract]. Blood
faian NN, Neumann F, Haas R, Kobbe G, Fenk R. Ben-
2009;114:431.
damustine in patients with relapsed or refractory
67. Hideshima T, Catley L, Yasui H, et al. Perifosine, an
multiple myeloma. Eur J Med Res 2010;15:13­9.
oral bioactive novel alkylphospholipid, inhibits Akt and
79. Knop S, Straka C, Haen M, Schwedes R, Hebart H, Ein-
induces in vitro and in vivo cytotoxicity in human multi-
sele H. The efficacy and toxicity of bendamustine in
ple myeloma cells. Blood 2006;107:4053­62.
recurrent multiple myeloma after high-dose chemother-
68. Mitsiades CS, Mitsiades N, Poulaki V, et al. Activation
apy. Haematologica 2005;90:1287­8.
of NF-kappaB and upregulation of intracellular anti-
80. Ponisch W, Rozanski M, Goldschmidt H, et al. Com-
apoptotic proteins via the IGF-1 / Akt signaling in human
bined bendamustine, prednisolone and thalidomide for
multiple myeloma cells: therapeutic implications. Onco-
refractory or relapsed multiple myeloma after autologous
gene 2002;21:5673­83.
stem-cell transplantation or conventional chemotherapy:
69. Jakubowiak A, Richardson P, Zimmerman TM, et al.
results of a Phase I clinical trial. Br J Haematol
Phase I results of perifosine (KRX-0401) in combination
2008;143:191­200.
with lenalidomide and dexamethasone in patients with
81. Fenk R, Michael M, Zohren F, Graef T, Czibere A,
relapse or refractory multiple myeloma (mm) [ASH
Bruns I, Neumann F, Fenk B, Haas R, Kobbe G. Esca-
abstract]. Blood 2008;112:3691.
lation therapy with bortezomib, dexamethasone and ben-
70. Richardson P, Lonial S, Jakubowiak A, et al. Multi-cen-
damustine for patients with relapsed or refractory
ter phase II study of perifosine (KRX-0401) alone and in
multiple myeloma. Leuk Lymphoma 2007;48:2345­51.
ª 2010 John Wiley & Sons A/S
13

---

Emerging therapies in multiple myeloma
Dimopoulos et al.
82. Havasi A, Li Z, Wang Z, Martin JL, Botla V, Ruchalski
perspectives for cancer therapy. Cancer Lett
K, Schwartz JH, Borkan SC. Hsp27 inhibits Bax activa-
2009;280:201­10.
tion and apoptosis via a phosphatidylinositol 3-kinase-
96. Khan N, Jeffers M, Kumar S, et al. Determination of
dependent mechanism. J Biol Chem 2008;283:12305­13.
the class and isoform selectivity of small-molecule histone
83. Ciocca DR, Calderwood SK. Heat shock proteins in can-
deacetylase inhibitors. Biochem J 2008;409:581­9.
cer: diagnostic, prognostic, predictive, and treatment
97. Wolf JL, Siegel D, Matous J, et al. A phase II study of
implications. Cell Stress Chaperones 2005;10:86­103.
oral panobinostat (LBH589) in adult patients with
84. Chauhan D, Li G, Hideshima T, et al. Hsp27 inhibits
advanced refractory multiple myeloma [ASH abstract].
release of mitochondrial protein Smac in multiple mye-
Blood 2008;112:2774.
loma cells and confers dexamethasone resistance. Blood
98. Spencer A, Taylor KM, Lonial S, Mateos MV, Jalalud-
2003;102:3379­86.
din M, RHazell K, Bourquelot PM, San Miguel JF. Pan-
85. Chauhan D, Li G, Shringarpure R, Podar K, Ohtake Y,
obinostat plus lenalidomide and dexamethasone phase I
Hideshima T, Anderson KC. Blockade of Hsp27 over-
trial in multiple myeloma (MM) [ASCO abstract]. J Clin
comes bortezomib / proteasome inhibitor PS-341 resis-
Oncol 2009;27:8542.
tance in lymphoma cells. Cancer Res 2003;63:6174­7.
99. Berenson JR, Yellin O, Boccia RV, Nassir Y, Rothstein
86. Badros AZ, Richardson PG, Albitar M, Jagannath S,
S, Swift R. A phase I study of oral melphalan combined
Tarantolo S, Wolf JL, Messina M, Berman D, Anderson
with LBH589 for patients with relapsed or refractory
KC. Tanespimycin + bortezomib in relapsed / refractory
multiple myeloma (MM) [ASH abstract]. Blood
myeloma patients: results from the Time-2 study [ASH
2009;114:1855.
abstract]. Blood 2009;114:1871.
100. Siegel D, Sezer O, San Miguel J, Mateos MV, Prosser I,
87. Richardson P, Chanan-Khan AA, Lonial S, Krishnan
Cavo M, Jalaluddin M, Hazell K, Bourquelot PM,
AY, Carroll MP, Albitar M, Kopit J, Berman D, Ander-
Anderson KC. A phase IB, multicenter, open-label, dose-
son KC. Tanespimycin + bortezomib demonstrates
escalation study of oral panobinostat (LBH589) and I.V.
safety, activity, and effective target inhibition in
bortezomib in patients with relapsed multiple myeloma
relapsed / refractory myeloma patients: updated results of
[ASH abstract]. Blood 2008;112:2781.
a phase 1 / 2 study [ASH abstract]. Blood 2009;114:2890.
101. San Miguel J, Sezer O, Siegel D, et al. A phase IB,
88. Kim TY, Bang YJ, Robertson KD. Histone deacetylase
multi-center, open-label dose-escalation study of oral
inhibitors for cancer therapy. Epigenetics 2006;1:14­23.
panobinostat (LBH589) and I.V. bortezomib in patients
89. Ruefli AA, Ausserlechner MJ, Bernhard D, Sutton VR,
with relapsed multiple myeloma [ASH abstract]. Blood
Tainton KM, Kofler R, Smyth MJ, Johnstone RW. The
2009;114:3852.
histone deacetylase inhibitor and chemotherapeutic agent
102. ISTODAXÒ (romidepsin). Full Prescribing Infor-
suberoylanilide hydroxamic acid (SAHA) induces a cell-
mation. Cambridge, MA: Gloucester Pharmaceuticals,
death pathway characterized by cleavage of Bid and pro-
Inc, 2009.
duction of reactive oxygen species. Proc Natl Acad Sci
103. Prince M, Quach H, Neeson P, et al. Safety and efficacy
USA 2001;98:10833­8.
of the combination of bortezomib with the deacetylase
90. Condorelli F, Gnemmi I, Vallario A, Genazzani AA,
inhibitor romidepsin in patients with relapsed or refrac-
Canonico PL. Inhibitors of histone deacetylase (HDAC)
tory multiple myeloma: preliminary results of a phase I
restore the p53 pathway in neuroblastoma cells. Br J
trial [ASH abstract]. Blood 2007;110:1167.
Pharmacol 2008;153:657­8.
104. Berenson JR, Yellin O, Mapes R, Eades B, Abaya CD,
91. Peart MJ, Tainton KM, Ruefli AA, Dear AE, Sedelies
Strayer A, Nix D, Swift RA. A phase II study of a
KA, O'Reilly LA, Waterhouse NJ, Trapani JA, John-
1-hour infusion of romidepsin combined with bortezomib
stone RW. Novel mechanisms of apoptosis induced by
for multiple myeloma (MM) patients with relapsed or
histone deacetylase inhibitors. Cancer Res 2003;63:4460­
refractory disease [ASCO abstract]. J Clin Oncol
71.
2009;27:e19508.
92. Bali P, Pranpat M, Bradner J, et al. Inhibition of histone
105. Harrison SJ, Quach H, Yuen K, et al. High response
deacetylase 6 acetylates and disrupts the chaperone func-
rates with the combination of bortezomib, dexametha-
tion of heat shock protein 90: a novel basis for antileuke-
sone and the pan-histone deacetylase inhibitor romidep-
mia activity of histone deacetylase inhibitors. J Biol
sin in patients with relapsed or refractory multiple
Chem 2005;280:26729­34.
myeloma in a phase I / II clinical trial [ASH abstract].
93. Lane AA, Chabner BA. Histone deacetylase inhibitors in
Blood 2008;112:3698.
cancer therapy. J Clin Oncol 2009;27:5459­68.
106. Mann BS, Johnson JR, Cohen MH, Justice R, Pazdur
94. Boyault C, Zhang Y, Fritah S, et al. HDAC6 controls
R. FDA approval summary: vorinostat for treatment of
major cell response pathways to cytotoxic accumulation
advanced primary cutaneous T-cell lymphoma. Oncolo-
of protein aggregates. Genes Dev 2007;21:2172­81.
gist 2007;12:1247­52.
95. Richon VM, Garcia-Vargas J, Hardwick JS. Develop-
107. Duvic M, Talpur R, Ni X, et al. Phase 2 trial of oral
ment of vorinostat: current applications and future
vorinostat (suberoylanilide hydroxamic acid, SAHA) for
14
ª 2010 John Wiley & Sons A/S

---

Dimopoulos et al.
Emerging therapies in multiple myeloma
refractory cutaneous T-cell lymphoma (CTCL). Blood
114. Durie BG, Harousseau JL, Miguel JS, et al. International
2007;109:31­9.
uniform response criteria for multiple myeloma. Leuke-
108. Olsen EA, Kim YH, Kuzel TM, et al. Phase IIb multi-
mia 2006;20:1467­73.
center trial of vorinostat in patients with persistent,
115. Siegel D, Munster PN, Rubin EH, et al. The combined
progressive, or treatment refractory cutaneous T-cell lym-
safety and tolerability profile of vorinostat-based therapy
phoma. J Clin Oncol 2007;25:3109­15.
for solid or hematologic malignancies [ASH abstract].
109. Badros A, Burger AM, Philip S, et al. Phase I study of
Blood 2009;114:1710.
vorinostat in combination with bortezomib for relapsed
116. Lacy MQ, Gertz MA, Hayman SR, et al. Pomalido-
and refractory multiple myeloma. Clin Cancer Res
mide (CC4047) plus low dose dexamethasone (Pom / -
2009;15:5250­7.
dex) is active and well tolerated in lenalidomide
110. Jagannath S, Weber D, Sobecks R, Schiller GJ, Lupinac-
refractory multiple myeloma (MM) [ASH abstract].
ci L, Allen J, Rizvi S. The combination of vorinostat and
Blood 2009;114:429.
bortezomib provides long-term responses in patients with
117. Niesvizky R, Wang L, Orlowski RZ, Bensinger W, Alsi-
relapsed or refractory multiple myeloma [ASH abstract].
na M, Gabrail N, Gutirrez A, Kunkel L, Kauffman M,
Blood 2009;114:3886.
(MMRC) TMMRC. Phase 1b multicenter dose escala-
111. Siegel D, Jagannath S, Lonial S, Dimopoulos MA, Graef
tion study of carfilzomib plus lenalidomide and low dose
T, Pietrangelo D, Lupinacci L, Reiser D, Rizvi S, Ander-
dexamethasone (CRd) in relapsed and refractory multiple
son KC. Update on the phase IIb, open-label study of
myeloma (MM) [ASH abstract]. Blood 2009;114:304.
vorinostat in combination with bortezomib in patients
118. Siegel D, Wang L, Orlowski RZ, et al. PX-171-004, an
with relapsed and refractory multiple myeloma [ASH
ongoing open-label, phase II study of single-agent
abstract]. Blood 2009;114:3890.
carfilzomib (CFZ) in patients with relapsed or refractory
112. Siegel D, Weber DM, Mitsiades C, et al. Combined vori-
myeloma (MM): updated results from the bortezomib-
nostat, lenalidomide and dexamethasone therapy in
treated cohort [ASH abstract]. Blood 2009;114:303.
patients with relapsed or refractory multiple myeloma: a
119. Wang L, Siegel D, Kaufman JL, et al. Updated results
phase I study [ASH abstract]. Blood 2009;114:305.
of bortezomib-naive patients in PX-171-004, an ongoing
113. Voorhees PM, Gasparetto C, Richards KL, et al. Vori-
open-label, phase II study of single-agent carfilzomib
nostat in combination with pegylated liposomal doxoru-
(CFZ) in patients with relapsed or refractory myeloma
bicin and bortezomib for patients with
(MM) [ASH abstract]. Blood 2009;114:302.
relapsed / refractory multiple myeloma: results of a phase
I study [ASH abstract]. Blood 2009;114:306.
ª 2010 John Wiley & Sons A/S
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