Embed Size (px)
Citation preview
Blood Reviews 24 Suppl. 1 (2010) S13–S19
Contents lists available at ScienceDirect
Blood Reviews
journal homepage: www.elsevier .com/locate /b l re
REVIEW
Lenalidomide mode of action: linking bench and clinical findings
Faith Daviesa, *, Rachid Bazb
a The Institute of Cancer Research and Royal Marsden Hospital, United Kingdomb Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, United States
a r t i c l e i n f o
Keywords:
Multiple myeloma
Immunomodulatory agent
Tumoricidal activity
Immunomodulation
Lenalidomide
Dexamethasone
Dual mechanism of action
a b s t r a c t
New effective strategies are required that specifically address the challenges of multiple myeloma
(MM) treatment, namely, disease recurrence, immunosuppression, and treatment-related toxicities.
Recent preclinical and clinical findings suggest that the IMiDs® immunomodulatory compound
lenalidomide has a dual mechanism of action, involving both a direct tumoricidal activity and
immunomodulation, which may result in rapid and sustained control of MM, respectively. The
tumoricidal effect of lenalidomide occurs through several mechanisms, including disruption
of stromal support, induction of tumor suppressor genes, and activation of caspases. The
immunomodulatory effects of lenalidomide, including T-cell and natural killer (NK)-cell activation,
and increased expression of death effector molecules, lead to enhanced immune cell function and
may explain the beneficial effects of this agent in the maintenance setting. Lenalidomide appears to
be effective regardless of prior thalidomide treatment, which may reflect mechanistic differences –
lenalidomide has greater immunomodulatory properties than thalidomide, whereas thalidomide
has greater antiangiogenic activity. Recent studies also suggest that the concomitant use of
dexamethasone may influence lenalidomide’s direct and immunomodulatory effects. Lenalidomide
in combination with dexamethasone synergistically inhibits proliferation and induces apoptosis;
however, dexamethasone appears to antagonize the immune-enhancing effect of lenalidomide.
A study has demonstrated that a regimen of lenalidomide in combination with an optimal dose
and schedule of dexamethasone may increase survival by allowing synergistic antiproliferative
effects, without affecting immunomodulatory activity. As preclinical and clinical research continue,
additional insights into the dual mechanism of action of lenalidomide will help to further optimize
the use of lenalidomide in MM.
© 2010 Elsevier Ltd. All rights reserved.
1. Introduction
Multiple myeloma (MM) is a chronic disease characterized by the
presence of residual tumor and immune suppression.1–3 Although
newer chemotherapeutic agents have improved response rates
and survival outcomes, the median duration of response has not
exceeded 3 years and patients continue to experience disease
relapse.4 New effective strategies are required that specifically
address the challenges of MM, namely, disease recurrence,
immunosuppression, and treatment-related toxicities. Furthermore,
long-term treatment may be needed to prolong the duration of
response, reduce tumor proliferation rate, and delay or circumvent
drug resistance.
The IMiDs® immunomodulatory compounds lenalidomide and
pomalidomide are novel agents for the treatment of myeloma.
Although they are analogs of thalidomide, they have demonstrated
potent anticancer properties and better tolerability profiles than
*Corresponding author. The Institute of Cancer Research and Royal
Marsden Hospital, 15 Cotswold Road, Sutton, Surrey SM2 5NG, United
Kingdom. Tel.: +442073528133 (ext 4743); fax: +4402086429634.
E-mail address: [email protected] (F. Davies).
thalidomide (Table 1).5–11 Of the IMiDs® immunomodulatory
compounds, lenalidomide has been most extensively studied
and is approved for use in combination with dexamethasone
for the treatment of patients with MM who have received
at least one prior therapy.12 The mechanism of action of
IMiDs® immunomodulatory compounds has been the subject of
much recent research. Such investigations have highlighted that
lenalidomide has dual effects, involving both direct tumoricidal
properties and immunomodulatory activity (Fig. 1). This article will
focus on the dual actions of lenalidomide, describing preclinical
findings and relating these to recent clinical results in patients with
MM.
2. Tumoricidal effects of lenalidomide
2.1. Preclinical data
Lenalidomide exerts its tumoricidal effects through several mech-
anisms, including decreased production of cytokine and growth
factors leading to disruption of stromal support,9,13 induction of
tumor suppressor genes leading to cell cycle arrest, and activation
of caspases triggering tumor cell apoptosis (Fig. 2).14–18
0268-960X /$ – see front matter © 2010 Elsevier Ltd. All rights reserved.
S14 F. Davies, R. Baz / Blood Reviews 24 (2010) S13–S19
Table 1
Characteristics of thalidomide and the immunomodulatory compounds lenalidomide and pomalidomide.7–11
Characteristic Thalidomide Immunomodulatory compounds
Lenalidomide Pomalidomide
Structure N
N
O
O
O
O N
NH
O O
O
NH2
N
NH
O
O O
O
NH2
Plasma Cmax, mM7,8 5.4 2.2a 0.19
Tumoricidal properties
Inhibition of DNA synthesis in MM.1S cell line, IC50, mM9
>100 0.1–1 0.01–0.1
Immunomodulation
Interleukin-2 enhancement, EC50, mM10
>100 0.15 0.010
Antiangiogenesis
Inhibition of sprout formation from human umbilical artery ring explants, IC50, mM11
~0.1 ~1.0 0.1–1.0
a Cmax reported in ng/mL.
Reducesmultiple myeloma
cell burden
Tum
or
burd
en
Time
Improves immunefunction andtumor killing
Lenalidomide
NH2
O
O
ONH
IM MU
NO
MO
DU
LA
TO
RY
TU
MO
RIC
ID
AL
N
Fig. 1. Lenalidomide has a dual mechanism of action involving a direct tumoricidal
activity that leads to multiple myeloma cell death, and an immunomodulatory
effect that keeps the tumor in remission and improves immune function. These
dual effects make lenalidomide an optimal foundation therapy for the necessary
long-term treatment of multiple myeloma. © Celgene Corporation.
The bone marrow microenvironment comprises a complex array
of physical and soluble factors that interact to promote MM cell
growth and survival, and may contribute to minimal residual
disease and the development of acquired drug resistance.19–21
Physical constituents of the bone marrow include extracellular
matrix glycoproteins and bone marrow stromal cells (BMSCs). The
extracellular matrix glycoprotein fibronectin has been shown to
control MM cell growth and survival, and plays a key role in cell-
adhesion-mediated drug resistance of MM cells.19,20 Fibronectin
adhesion activates a4b1 and a5b1 integrins, and signaling via
these integrin complexes confers resistance to several pro-apoptotic
effectors, including chemotherapeutic drugs and death receptor
activation.19,20 Adhesion of MM cells to BMSCs also induces secretion
of interleukin (IL)-6.21–23 IL-6 is known to mediate both MM cell
proliferation and the inhibition of Fas-induced apoptosis.22,24 In
a recent study using four MM cell lines, concomitant exposure
to IL-6 and fibronectin adhesion increased signal transducers
and activators of transcription (STAT) 3 phosphorylation, nuclear
translocation, and DNA binding – all of which are known to
lead to the transactivation of genes involved in proliferation,
differentiation, and survival.20 IL-6 also enhances the production
and secretion of vascular endothelial growth factor (VEGF) by MM
cells and vice versa.21–23 VEGF plays a role in tumor cell migration,
growth, and survival, and enhances microvascular density, which
correlates with disease progression and poor prognosis.13,21,22
Disruption of stromal support in myeloma is, therefore, an im-
portant treatment strategy. IMiDs® immunomodulatory compounds
have been shown to decrease the upregulation of IL-6 and VEGF
secretion induced by MM and BMSC interactions;9,23 this may
lead to disruption of stromal support and have subsequent effects
on MM cell migration, growth, and survival. A preclinical study
suggests that elotuzumab, a humanized antibody against CS1 (the
cell surface glycoprotein), can overcome cell-adhesion-mediated
drug resistance by altering extracellular-signal-regulated kinase
(ERK) 1/2 signaling of MM cells and osteoclasts.25 Furthermore,
in a recent phase I/II study, elotuzumab (5, 10, or 20mg/kg) in
combination with lenalidomide 25mg (days 1–21 of a 28-day cycle)
plus dexamethasone 40mg/week had an objective response rate
(defined as partial response [PR] and very good partial response
[VGPR]) of 82% and an overall response rate of 95% in lenalidomide-
naive patients,26 suggesting a combined beneficial effect on adverse
stromal interactions.
In addition to altering the bone marrow microenvironment,
IMiDs® immunomodulatory compounds have a direct effect on the
proliferation of MM cells via upregulation of tumor suppressor
genes.9,14,18 In a study by Gandhi et al., lenalidomide-mediated
growth inhibition was accompanied by induction of the cyclin-
dependent kinase (CDK) inhibitors p15, p16, p21, and p27, and
the early-response transcription factors Egr1, Egr2, and Egr3, in
cells derived from patients with MM.14 Lenalidomide also induced
p15, p21, Egr1, Egr2, and Egr3 expression in several MM cell
lines. Moreover, lenalidomide in combination with dexamethasone
synergistically upregulated these tumor suppressor genes, resulting
in inhibition of retinoblastoma protein phosphorylation, G0/G1 cell-
cycle arrest, and apoptosis.
Verhelle et al. investigated the effects of lenalidomide and
pomalidomide on proliferation of two myeloma cell lines (LP-1
and U266), the Namalwa lymphoma cell line, and normal
CD34+ progenitor cells.18 In cancer cell lines, both IMiDs®
immunomodulatory compounds inhibited proliferation, which was
associated with upregulation of p21 and inhibition of CDK activity,
leading to retinoblastoma hypophosphorylation and G0/G1 cell-
cycle arrest. In contrast, treatment of normal CD34+ cells with
these compounds led to p21 upregulation without CDK inhibition,
and there was significant expansion of normal CD34+ progenitor
cells. These findings may help explain the differential selective
effects of lenalidomide on malignant cells (tumoricidal effect) and
their normal counterparts (absence of suppression of bone marrow
progenitor cells). Such effects have been demonstrated in patients
with myelodysplastic syndrome where lenalidomide was shown
F. Davies, R. Baz / Blood Reviews 24 (2010) S13–S19 S15
G0/G1arrest
ChromatinHistone
M
G2
S
G1LENALIDOMIDE
IL-6
VEGF
Myeloma cell
Stromal
Cell
Integrin
Tumor suppressor
gene activation
Reduced
IL-6 and VEGF
expressionReduced MM cell migration,
growth, and survival
Inhibition of tumor cell proliferation
Cell-cycle arrest
Caspase activation
Tumor cell
apoptosis
+ DEXAMETHASONE
T
NK
NKTB
IgA
LENALIDOMIDE
IMMUNOMODULATORY
MM cells
Activated immune cells
release cytokines
and proliferate
Expansion of immunecells and improved function
T
NK
NKTNKT
TT
TNK
NKNK
NK
NKT
IFN-у
IL-2
Enhancement of humoral and
vaccine responses
Activated immune cells
target and trigger
MM cell apoptosis
B
TUMORICIDALA
NH2
N
o
o
oNH
NH2
N
o
o
oNH
NH2
N
o
o
oNH
Fig. 2. Overview of the mechanism of action of lenalidomide in MM, which leads to tumor cell death and increased immune response. IFN: interferon; Ig: immunoglobulin;
IL: interleukin; MM: multiple myeloma; NK: natural killer; VEGF: vascular endothelial growth factor. © Celgene Corporation.
to not only reduce the number of malignant cells, but also to
restore bone marrow function leading to improved hemopoiesis and
transfusion independence.27
A recent study demonstrated that IMiDs® immunomodulatory
compounds increase p21 expression by a novel epigenetic
mechanism.28 Lenalidomide and pomalidomide were found to
regulate p21 expression at the transcriptional level via Egr1
and Egr2, and other GC-rich DNA transcription factors, Sp1
and Sp3. Through activation of lysine-specific demethylase 1,
the immunomodulatory compounds increased p21 expression by
reducing histone methylation and increasing histone acetylation at
the p21 promoter, thus increasing transcription factor access to the
DNA. In addition to inducing cell-cycle arrest, these compounds
have been shown to activate caspases, directly triggering tumor
cell death.14,15 In the study by Gandhi et al., lenalidomide activated
caspases 3, 8, and 9 to varying degrees in different MM cell
lines. Furthermore, lenalidomide plus dexamethasone produced
synergistic activation of caspases and induction of apoptosis. In
another study, lenalidomide-induced apoptosis was attenuated by a
caspase-8 inhibitor in MM.1S cells,15 providing further evidence for
the role of immunomodulatory compounds in caspase activation.
2.2. Clinical data
The tumoricidal actions of lenalidomide are thought to lead to
the initial high-quality clinical responses observed in patients with
MM.29–37 Table 2 summarizes data from recent studies of different
regimens for the treatment of newly diagnosed or relapsed/
refractory MM, and highlights the short time to response and high
response rates of patients treated with lenalidomide-containing
S16 F. Davies, R. Baz / Blood Reviews 24 (2010) S13–S19
Table 2
Response data for regimens investigated for the treatment of newly diagnosed or relapsed/refractory MM.
Regimen Newly diagnosed patients with MM
BiRD31 RD32 Rd32 MPR30 MP30 MPV38
Relapsed/refractory patients with MM
RD39 RAD35 V36 VPLD40
Median time to first response, months 1.8a − − 1.9 2.8 1.4 1.9 1 1.4 1.4
Median time to best response, months 7a − − − − 4.2 − − − −
CR+VGPR/nCR, % 74 50 40 33 12 41 32.3 60 13 27
a Mean values.
BiRD: clarithromycin, lenalidomide, and dexamethasone; CR: complete response; MM: multiple myeloma; MP: melphalan and prednisone; MPR: melphalan,
prednisone, and lenalidomide; MPV: melphalan, prednisone, and bortezomib; nCR: near CR; −: not reported; RAD: lenalidomide, adriamycin, and dexamethasone;
Rd: lenalidomide and low-dose dexamethasone; RD: lenalidomide and high-dose dexamethasone; V: bortezomib; VGPR: very good partial response;
VPLD: bortezomib and pegylated liposomal doxorubicin.
regimens.30–32,35,36,38–40 In 72 patients with newly diagnosed MM
receiving lenalidomide in combination with clarithromycin and
dexamethasone (BiRD) as first-line therapy for MM, the response
rate (VGPR plus complete response [CR] plus stringent CR) was
74%.31 Moreover, mean time to first response, defined as greater
than 50% decrease of M-protein, was 53.9 days (range 21–816)
and mean time to maximum response was 209 days (range 27–
850). Furthermore, a recent study by Rajkumar et al. compared
lenalidomide in combination with either low-dose dexamethasone
(160mg per 28-day cycle) or high-dose dexamethasone (480mg
per 28-day cycle) in 445 patients with newly diagnosed MM.
This study demonstrated a CR-plus-VGPR rate of 40% and 50% in
lenalidomide plus low-dose dexamethasone and lenalidomide plus
high-dose dexamethasone, respectively.32 As part of a phase III
study by Palumbo et al., the combination of melphalan and
prednisone (MP) (n =154) versus MP plus lenalidomide (MPR)
(n =153) was investigated in the initial treatment of elderly patients
with newly diagnosed MM.30 In an interim analysis, the CR-plus-
VGPR rate was significantly higher in the MPR arm versus the
MP arm (33% versus 12%, respectively; p < 0.001). Similarly, median
time to first response was significantly shorter in the MPR arm
compared with the MP arm (1.9 versus 2.8 months; p < 0.001).30
This study also investigated the effect of continuous lenalidomide
treatment on efficacy outcomes, which will be discussed in a
separate section.
In the relapsed/refractory MM setting, two large, multicenter, ran-
domized, double-blind, placebo-controlled phase III trials (MM-009
and MM-010) compared the efficacy of lenalidomide 25mg (days
1–21 of each 28-day cycle) plus dexamethasone 40mg (days 1–4,
9–12, and 17–20 of the first four cycles, then days 1–4 only
of subsequent cycles) versus placebo plus dexamethasone 40mg
continued until disease progression.33,41 In a recent pooled analysis
of these studies (n = 704), patients treated with lenalidomide plus
dexamethasone had a significantly improved overall response rate
(ORR; 60.6% versus 21.9%; p < 0.001) and CR rate (15.0% versus
2.0%; p < 0.001) compared with patients who received placebo
plus dexamethasone (Fig. 3).39 The time to first response was
similar in patients treated with lenalidomide plus dexamethasone
and those treated with placebo plus dexamethasone (median
1.9 versus 2.0 months, respectively). However, lenalidomide
treatment was associated with significant improvements in time
to progression (median 13.4 versus 4.6 months; p < 0.001) and
duration of response (median 15.8 versus 7.0 months; p < 0.001).
At a median follow-up of 48 months for surviving patients, a
significant benefit in overall survival (OS; median 38.0 versus
31.6 months; p =0.045) was observed despite 47.6% of placebo-
plus-dexamethasone patients crossing over to lenalidomide-based
therapy after disease progression or study unblinding.
Also in the relapsed/refractory MM setting, the speed of
response to lenalidomide was evaluated using a similar regimen
of lenalidomide plus dexamethasone in an open-label phase IIIb
Fig. 3. Pooled analysis of responses from two phase III trials of lenalidomide
plus dexamethasone versus placebo plus dexamethasone in patients with
relapsed/refractory multiple myeloma.39 CR: complete response; ORR: overall
response rate; PR: partial response; VGPR: very good PR.
study in 150 patients with MM who had received at least one
previous therapy.34 Preliminary results indicate that a 50% reduction
in M-protein or serum free light chain levels was reached by half
of the patients within 28 days, and by 72% of the patients within
32 days. Furthermore, a PR or better was observed in 74% of
patients.
3. Immunodulatory effects of lenalidomide
3.1. Preclinical data
In addition to the rapid tumoricidal effects, lenalidomide provides
sustained disease control by improving immune function, resulting
in continued tumor killing (Fig. 2).42–50 One mechanism by
which lenalidomide exerts immunomodulatory effects is via
enhanced antigen-specific CD8+ T-cell cytolysis.43 The effects
of lenalidomide and thalidomide on CD8+ T-cell activity in
response to viruses were investigated in an in vitro dendritic cell/
CD8+ T-cell co-culture system.43 Thalidomide, and to a greater
extent lenalidomide, enhanced the lysis of influenza virus matrix
peptide-pulsed dendritic-cell targets, with lenalidomide also
stimulating a detectable cytomegalovirus-specific lytic response.
The enhancement of antiviral response was thought to be due
to IL-2-stimulated expansion of antigen-specific memory-effector
CD8+ T cells.
Another important mechanism by which lenalidomide induces
immunomodulation is by increasing NK-cell expression of death
effector molecules.44 In a recent study, NK cells were cultured
in the presence of immobilized immunoglobulin G, IL-2, and
increasing concentrations of lenalidomide.44 Lenalidomide was
found to stimulate NK-cell activity by enhancing Fc-g receptor
signaling, which, in turn, led to increased production of granzyme
B and increased Fas-ligand expression on NK cells. Lenalidomide
has also been shown to have beneficial effects on NKT cells.45
Lenalidomide enhanced antigen-specific expansion of NKT cells in
response to the NKT ligand a-galactosylceramide in both healthy
F. Davies, R. Baz / Blood Reviews 24 (2010) S13–S19 S17
donors and in patients with MM. Moreover, NKT cells activated
by lenalidomide were found to have greater ability to secrete
interferon (IFN)-g. These findings are important given that the
antitumor activity of NKT cells is associated with their ability to
secrete IFN-g.
3.2. Clinical data
A recent study assessed the effect of lenalidomide combination
therapy on NK/NKT cell numbers and receptor expression.51 Ten
patients with newly diagnosed or relapsed/refractory MM received
lenalidomide 25mg (days 1–21), dexamethasone 40mg (days
1, 8, 15, and 22) and cyclophosphamide (500mg on day 1 in
cycle 1, and subsequently on days 1 and 8 of each cycle).
Despite the concomitant administration of immunosuppressive
drugs, lenalidomide treatment increased the number of NK and
NKT cells by 73% and 45% versus baseline, respectively, very early
in the course of treatment (at the end of cycle 1). In addition, there
was increased expression of the activating receptors NKG2D, NKp30,
and NKp44 on NK cells, and NKG2D on NKT cells.
The immunomodulatory effects of lenalidomide have been
demonstrated in other clinical studies.46,47,52,53 In a study by Lioznov
et al., the effects of lenalidomide salvage therapy (15–25mg/day
on days 1–21 of each 28-day cycle) were assessed on T and NK
cells after allogeneic stem cell transplantation (SCT).46 Significant
increases in the levels of activated T cells (p=0.005), regulatory
T cells (p =0.0036), and activated NK cells (p =0.0008) were
observed in patients after starting lenalidomide therapy (n =8).
Maximum levels of activated T and NK cells were achieved
approximately 3 months after starting lenalidomide therapy,
and maximum levels of regulatory T cells were reached after
approximately 6 months. Moreover, in a phase I study of heavily
treated patients with metastatic malignant melanoma and other
advanced cancers, evidence of T-cell activation was indicated
by significantly increased serum levels of soluble IL-2 receptor,
granulocyte-macrophage colony-stimulating factor, IL-12, tumor
necrosis factor-a, and IL-8 in 9 patients who received lenalidomide
5–50mg for 28 days.47
There is also evidence that lenalidomide improves the humoral
immune system. The use of lenalidomide before pneumococcal
vaccination in patients with advanced/relapsed MM was found
to increase antigen-specific antibodies and T-cell responses
compared with patients who were vaccinated prior to receiving
lenalidomide.54 The immunomodulatory effects of lenalidomide
observed in preclinical and clinical studies may be the main
contributors to the beneficial effects of this agent in the
maintenance setting.30,55–58 In a retrospective pooled analysis of
trials MM-009 and MM-010, over half of patients with an initial
documented PR subsequently achieved CR/VGPR, and patients who
achieved a PR by cycle 6 still had a substantial probability (38%)
of achieving a CR/VGPR with continued treatment.55 Continued
treatment was not associated with increased toxicity, although the
tolerability of the regimen may be further improved by reducing
the dose of dexamethasone.59
Findings from studies in MM patients after autologous SCT also
suggest that lenalidomide may be a highly effective maintenance
treatment.57,58 In one recent study, 614 patients were randomized
to receive consolidation therapy with lenalidomide (25mg/day for
21 days of each 28-day cycle for 2 months) followed by maintenance
with either placebo or lenalidomide (10–15mg/day) until relapse.
Maintenance with lenalidomide significantly improved 3-year
progression-free survival (PFS) rates versus consolidation therapy
alone (68% versus 35%; hazard ratio [HR] = 0.46; p < 0.000001).
This benefit was observed irrespective of achieving a CR after
SCT, indicating a true maintenance effect.57 In a phase III study
from the Cancer and Leukemia Group B (CALGB), patients with
newly diagnosed MM received (at day 100–110 after autologous
SCT) either lenalidomide (starting dose 10mg/day, escalated to
15mg/day after 3 months) or placebo maintenance therapy until
disease progression.58 During an interim analysis based on 28% PFS
at a median follow-up of 12 months, progression was noted in
13.8% of patients (29 of 210) receiving maintenance lenalidomide
treatment compared with 27.9% (58 of 208) for patients who
received placebo (p < 0.0001), representing a 58% risk reduction for
disease progression. The estimated median time to progression was
25.5 months in the placebo arm, but it had not been reached in the
lenalidomide arm.
Furthermore, in an interim analysis of the study of elderly
patients with newly diagnosed MM by Palumbo et al., PFS was
13.0 months in patients who received MP alone, 13.2 months
in patients who received MPR followed by placebo, and not
reached in patients who received MPR followed by maintenance
lenalidomide therapy (MPR-R) (p < 0.001 for MPR-R versus MP).30
A landmark analysis of PFS in patients remaining on therapy
following cycle 9 demonstrated that maintenance treatment with
lenalidomide versus placebo resulted in a 75% reduced risk of
disease progression (HR=0.245; 95% confidence interval [CI] 0.126–
0.476; p < 0.001). Taken together, these findings indicate that
continuous lenalidomide therapy may provide sustained disease
control. To date no benefit in OS has been observed in the
maintenance setting.
4. Differences in the mode of action of thalidomide and
IMiDs® immunomodulatory compounds
Table 1 provides an overview of pharmacokinetic and pharmacody-
namic characteristics of thalidomide and the IMiDs® immunomod-
ulatory compounds. Of note, lenalidomide and pomalidomide
have greater tumoricidal effects than thalidomide. In an in vitro
study in MM.1S cells, DNA synthesis was inhibited by 50%
with pomalidomide 0.01–0.1mM and lenalidomide 0.1–1.0mM;
however, only 15% inhibition was noted with thalidomide 100mM.9
Lenalidomide also has a more potent effect on the immune system,
specifically by increased stimulation of T-cell proliferation and
cytokine production.60 Indeed, lenalidomide has been found to be
100–1000 times more potent in stimulating T-cell proliferation
and IFN-g and IL-2 production than thalidomide.6 In contrast, both
thalidomide and pomalidomide were found to be more potent at
inhibiting sprout formation than lenalidomide when antiangiogenic
properties were assessed in a human umbilical explant model
(Table 1).11
Lenalidomide has a more favorable nonhematologic-toxicity
profile than thalidomide, exhibiting reduced somnolence, constipa-
tion, and peripheral neuropathy.60 Myelosuppression occurs more
frequently with lenalidomide than with thalidomide,60 but may
be overcome through the use of granulocyte colony-stimulating
factor or other agents.61–64 As lenalidomide is an analog of
thalidomide, there could be a question of possible resistance to
lenalidomide in patients who had relapsed after, or who were
refractory to, treatment with thalidomide.60 However, evidence now
indicates that clinical benefit from lenalidomide can be achieved
in thalidomide-treated and -refractory patients.60,65 In a post hoc
pooled analysis of trials MM-009 and MM-010, lenalidomide
plus dexamethasone was more effective than dexamethasone
alone, irrespective of prior thalidomide exposure.60 Furthermore,
lenalidomide plus dexamethasone showed considerable activity
in patients who had relapsed while on thalidomide (ORR 41.9%;
CR 6.5%) or had never previously responded to thalidomide
(ORR 50.0%; CR 5.0%). This apparent lack of resistance observed
between lenalidomide and thalidomide may reflect their different
mechanisms of action.
S18 F. Davies, R. Baz / Blood Reviews 24 (2010) S13–S19
5. Influence of dexamethasone on the dual effects of
lenalidomide
Recent evidence suggests that coadministration of dexamethasone
may alter the dual effects of lenalidomide.9,14,16,17 As mentioned,
lenalidomide in combination with dexamethasone synergistically
inhibits myeloma cell growth, activates caspases, and induces
apoptosis,14 enhancing the tumoricidal effects of lenalidomide.
However, dexamethasone appears to antagonize the immune-
enhancing effect of lenalidomide by inhibiting the T- and NK-cell
costimulatory effects of lenalidomide.14 Specifically, dexamethasone
inhibited lenalidomide-enhanced IL-2 production in primary
human T cells, and inhibited lenalidomide-mediated IFN-g and
granzyme B production in primary human NK cells in a dose-
dependent manner in vitro.14
These findings may help to explain the results of the recent
phase III trial in patients with newly diagnosed MM by
Rajkumar et al., where low-dose dexamethasone plus lenalidomide
demonstrated a benefit in early OS compared with patients who
received lenalidomide plus high-dose dexamethasone.32 One-year
OS was 96% (95%CI 94–99) in the low-dose group compared with
87% (95%CI 82–92) in the high-dose group, and 2-year OS was 87%
(95%CI 81–93) and 75% (95%CI 68–93), respectively. Taken together,
results from the preclinical studies and clinical trial suggest that a
regimen of lenalidomide plus low-dose dexamethasone may result
in the best clinical activity by providing synergistic antiproliferative
effects, but without affecting the immunomodulatory effects of
lenalidomide.14 An alternative explanation for the prolonged OS
with the lower dose of dexamethasone could be related to the
tolerability profile. A lower dose would be associated with a better
safety profile, which may allow longer treatment exposure.
Alternatively, patients may benefit from receiving lenalidomide
alone or independent of corticosteroids. A recent retrospective
study evaluated the activity of lenalidomide monotherapy in newly
diagnosed MM.66 In 17 patients treated with lenalidomide without
corticosteroids, the ORR was 47% at a median follow-up of 7 months
(range 1–26). The median time to first response was 50 days (range
28–98) and median time to best response was 69 days (range 30–
591). Based on these positive findings, a phase II trial has been
initiated to investigate the role of a response-adapted approach
using single-agent lenalidomide as primary therapy for older
patients with newly diagnosed standard-risk MM (ClinicalTrials.gov
identifier: NCT00772915).
6. Conclusions
Current available data suggest MM requires continuous therapy
to reduce tumor burden and prolong survival. Lenalidomide
has the attributes of an agent that targets both tumor growth
and concomitant immunosuppression, while being well tolerated
and convenient for long-term use. Lenalidomide has potent
tumoricidal and immunomodulatory effects on myeloma cells and
their microenvironment, which are thought to result in both
rapid and sustained control of MM in the clinic. Lenalidomide,
in combination with dexamethasone, is active and generally
well tolerated in the relapsed/refractory MM setting and there
is evidence that continuous treatment with lenalidomide may
improve clinical response. Furthermore, lenalidomide appears to
be effective regardless of prior thalidomide treatment, which may
reflect the different mechanisms of the two agents – lenalidomide
has greater immunostimulatory properties and tolerability than
thalidomide, whereas thalidomide has more potent antiangiogenic
activity. Combined findings from preclinical and clinical studies
also provide insights into how the use of concomitant lenalidomide
and dexamethasone can be further optimized. The use of low-dose
dexamethasone may provide synergistic antiproliferative effects
without antagonizing lenalidomide-mediated immune effects,
which may explain the early survival benefit observed compared
with high-dose dexamethasone. As preclinical and clinical research
continues, additional insights into the dual mechanism of action of
lenalidomide will be obtained, which may help to further maximize
the use of lenalidomide in the treatment of MM.
7. Conflict of interest
Dr Davies has served on the Speakers Bureau for Celgene
Corporation and Ortho Biotech and has participated in Advisory
Boards for Celgene, Ortho Biotech, and Novartis. Dr Baz has
participated in Advisory Boards for, and has received research
funding from, Celgene Corporation.
Acknowledgements
The authors received editorial support from Excerpta Medica in the
preparation of this manuscript, funded by Celgene Corporation. The
authors are fully responsible for content and editorial decisions for
this manuscript.
References
1. Matsui W, Wang Q, Barber JP, et al. Clonogenic multiple myeloma progenitors,
stem cell properties, and drug resistance. Cancer Res 2008;68:190–7.
2. Cook G, Campbell JD. Immune regulation in multiple myeloma: the host-tumour
conflict. Blood Rev 1999;13:151–62.
3. Schutt P, Brandhorst D, Stellberg W, et al. Immune parameters in multiple
myeloma patients: influence of treatment and correlation with opportunistic
infections. Leuk Lymphoma 2006;47:1570–82.
4. Attal M, Harousseau JL, Leyvraz S, et al. Maintenance therapy with
thalidomide improves survival in patients with multiple myeloma. Blood
2006;108:3289–94.
5. Chanan-Khan AA, Cheson BD. Lenalidomide for the treatment of B-cell
malignancies. J Clin Oncol 2008;26:1544–52.
6. Kotla V, Goel S, Nischal S, et al. Mechanism of action of lenalidomide in
hematological malignancies. J Hematol Oncol 2009;2:36.
7. Chung F, Lu J, Palmer BD, et al. Thalidomide pharmacokinetics and metabolite
formation in mice, rabbits, and multiple myeloma patients. Clin Cancer Res
2004;10:5949–56.
8. Chen N, Lau H, Kong L, et al. Pharmacokinetics of lenalidomide in subjects with
various degrees of renal impairment and in subjects on hemodialysis. J Clin
Pharmacol 2007;47:1466–75.
9. Hideshima T, Chauhan D, Shima Y, et al. Thalidomide and its analogs overcome
drug resistance of human multiple myeloma cells to conventional therapy. Blood
2000;96:2943–50.
10. Corral LG, Haslett PA, Muller GW, et al. Differential cytokine modulation and
T cell activation by two distinct classes of thalidomide analogues that are potent
inhibitors of TNF-alpha. J Immunol 1999;163:380–6.
11. Lu L, Payvandi F, Wu L, et al. The anti-cancer drug lenalidomide inhibits
angiogenesis and metastasis via multiple inhibitory effects on endothelial cell
function in normoxic and hypoxic conditions. Microvasc Res 2009;77:78–86.
12. Revlimid® (lenalidomide). Prescribing information. Celgene Corporation,
Summit, NJ. http://www.revlimid.com/pdf/REVLIMID_PI.pdf.
13. Hideshima T, Chauhan D, Podar K, Schlossman RL, Richardson P, Anderson KC.
Novel therapies targeting the myeloma cell and its bone marrow microenviron-
ment. Semin Oncol 2001;28:607–12.
14. Gandhi AK, Kang J, Capone L, et al. Dexamethasone synergizes with lenalidomide
to inhibit multiple myeloma tumor growth, but reduces lenalidomide-induced
immunomodulation of T and NK cell function. Curr Cancer Drug Targets 2010;
10:155–67.
15. Mitsiades N, Mitsiades CS, Poulaki V, et al. Apoptotic signaling induced by
immunomodulatory thalidomide analogs in human multiple myeloma cells:
therapeutic implications. Blood 2002;99:4525–30.
16. Schafer PH, Gandhi AK, Zhang LH, et al. Opposing effects of dexamethasone
on lenalidomide activity in multiple myeloma: additive/synergistic effects on
anti-proliferative activity on myeloma cells and antagonistic effects on immune
function [abstract]. Blood 2008;112: Abstract 2761.
17. Schafer PH, Gandhi AK, Zhang LH, et al. Opposing effects of dexamethasone
on lenalidomide activity in multiple myeloma [abstract]. Clin Lymph Myeloma
Suppl 2009;9(Suppl 1): Abstract B444.
18. Verhelle D, Corral LG, Wong K, et al. Lenalidomide and CC-4047 inhibit the
proliferation of malignant B cells while expanding normal CD34+ progenitor
cells. Cancer Res 2007;67:746–55.
19. Damiano JS, Cress AE, Hazlehurst LA, Shtil AA, Dalton WS. Cell adhesion
mediated drug resistance (CAM-DR): role of integrins and resistance to apoptosis
in human myeloma cell lines. Blood 1999;93:1658–67.
F. Davies, R. Baz / Blood Reviews 24 (2010) S13–S19 S19
20. Shain KH, Yarde DN, Meads MB, et al. Beta1 integrin adhesion enhances IL-6-
mediated STAT3 signaling in myeloma cells: implications for microenvironment
influence on tumor survival and proliferation. Cancer Res 2009;69:1009–15.
21. Raab MS, Podar K, Breitkreutz I, Richardson PG, Anderson KC. Multiple myeloma.
Lancet 2009;374:324–39.
22. Dankbar B, Padro T, Leo R, et al. Vascular endothelial growth factor and
interleukin-6 in paracrine tumor-stromal cell interactions in multiple myeloma.
Blood 2000;95:2630–6.
23. Gupta D, Treon SP, Shima Y, et al. Adherence of multiple myeloma cells to bone
marrow stromal cells upregulates vascular endothelial growth factor secretion:
therapeutic applications. Leukemia 2001;15:1950–61.
24. Chauhan D, Kharbanda S, Ogata A, et al. Interleukin-6 inhibits Fas-induced
apoptosis and stress-activated protein kinase activation in multiple myeloma
cells. Blood 1997;89:227–34.
25. Tai YT, Fulciniti M, Hideshima T, et al. Targeting MEK induces myeloma-cell
cytotoxicity and inhibits osteoclastogenesis. Blood 2007;110:1656–63.
26. Lonial S, Vij R, Harousseau J, et al. Elotuzumab in combination with lenalidomide
and low-dose dexamethasone in relapsed or refractory multiple myeloma:
a phase I/II study [abstract]. J Clin Oncol 2010;28(15s): Abstract 8020.
27. List A, Dewald G, Bennett J, et al. Lenalidomide in the myelodysplastic syndrome
with chromosome 5q deletion. N Engl J Med 2006;355:1456–65.
28. Escoubet-Lozach L, Lin IL, Jensen-Pergakes K, et al. Pomalidomide and
lenalidomide induce p21 WAF-1 expression in both lymphoma and multiple
myeloma through a LSD1-mediated epigenetic mechanism. Cancer Res
2009;69:7347–56.
29. Palumbo A, Falco P, Corradini P, et al. Melphalan, prednisone, and lenalidomide
treatment for newly diagnosed myeloma: a report from the GIMEMA-Italian
Multiple Myeloma Network. J Clin Oncol 2007;25:4459–65.
30. Palumbo A, Dimopoulos MA, Delforge M, et al. A phase 3 study to determine the
efficacy and safety of lenalidomide combined with melphalan and prednisone in
patients ≥65 years with newly diagnosed multiple myeloma (NDMM) [abstract].
Haematologica 2010;95(Suppl 2): Abstract 0566.
31. Niesvizky R, Jayabalan DS, Christos PJ, et al. BiRD (Biaxin [clarithromycin]/
Revlimid [lenalidomide]/dexamethasone) combination therapy results in high
complete- and overall-response rates in treatment-naive symptomatic multiple
myeloma. Blood 2008;111:1101–9.
32. Rajkumar SV, Jacobus S, Callander NS, et al. Lenalidomide plus high-dose
dexamethasone versus lenalidomide plus low-dose dexamethasone as initial
therapy for newly diagnosed multiple myeloma: an open-label randomised
controlled trial. Lancet Oncol 2010;11:29–37.
33. Dimopoulos M, Spencer A, Attal M, et al. Lenalidomide plus dexamethasone for
relapsed or refractory multiple myeloma. N Engl J Med 2007;357:2123–32.
34. Weisel KC, Hanel M, Niederwieser D, et al. Speed of response with lenalidomide
and dexamethasone in patients with relapsed or refractory multiple myeloma:
first results of the MM-019 German compassionate use protocol [abstract].
Haematologica 2009;94(Suppl 2): Abstract 0397.
35. Knop S, Gerecke C, Liebisch P, et al. Lenalidomide, adriamycin, and
dexamethasone (RAD) in patients with relapsed and refractory multiple
myeloma: a report from the German Myeloma Study Group DSMM (Deutsche
Studiengruppe Multiples Myelom). Blood 2009;113:4137–43.
36. Richardson PG, Sonneveld P, Schuster MW, et al. Bortezomib or high-dose
dexamethasone for relapsed multiple myeloma. N Engl J Med 2005;352:
2487–98.
37. Morgan GJ, Schey SA, Wu P, et al. Lenalidomide (Revlimid), in combination
with cyclophosphamide and dexamethasone (RCD), is an effective and tolerated
regimen for myeloma patients. Br J Haematol 2007;137:268–9.
38. San Miguel JF, Schlag R, Khuageva NK, et al. Bortezomib plus melphalan and
prednisone for initial treatment of multiple myeloma. N Engl J Med 2008;359:
906–17.
39. Dimopoulos MA, Chen C, Spencer A, et al. Long-term follow-up on overall
survival from the MM-009 and MM-010 phase III trials of lenalidomide plus
dexamethasone in patients with relapsed or refractory multiple myeloma.
Leukemia 2009;23:2147–52.
40. Orlowski RZ, Nagler A, Sonneveld P, et al. Randomized phase III study of
pegylated liposomal doxorubicin plus bortezomib compared with bortezomib
alone in relapsed or refractory multiple myeloma: combination therapy
improves time to progression. J Clin Oncol 2007;25:3892–901.
41. Weber DM, Chen C, Niesvizky R, et al. Lenalidomide plus dexamethasone for
relapsed multiple myeloma in North America. N Engl J Med 2007;357:2133–42.
42. Davies FE, Raje N, Hideshima T, et al. Thalidomide and immunomodulatory
derivatives augment natural killer cell cytotoxicity in multiple myeloma. Blood
2001;98:210–6.
43. Haslett PA, Hanekom WA, Muller G, Kaplan G. Thalidomide and a thalidomide
analogue drug costimulate virus-specific CD8+ T cells in vitro. J Infect Dis 2003;
187:946–55.
44. Wu L, Adams M, Carter T, et al. Lenalidomide enhances natural killer cell
and monocyte-mediated antibody-dependent cellular cytotoxicity of rituximab-
treated CD20+ tumor cells. Clin Cancer Res 2008;14:4650–7.
45. Chang DH, Liu N, Klimek V, et al. Enhancement of ligand-dependent activation
of human natural killer T cells by lenalidomide: therapeutic implications. Blood
2006;108:618–21.
46. Lioznov M, El-Cheikh J Jr, Hoffmann F, et al. Lenalidomide as salvage therapy
after allo-SCT for multiple myeloma is effective and leads to an increase of
activated NK (NKp44(+)) and T (HLA-DR(+)) cells. Bone Marrow Transplant 2010;
45:349–53.
47. Bartlett JB, Michael A, Clarke IA, et al. Phase I study to determine the safety,
tolerability and immunostimulatory activity of thalidomide analogue CC-5013
in patients with metastatic malignant melanoma and other advanced cancers.
Br J Cancer 2004;90:955–61.
48. Reddy N, Hernandez-Ilizaliturri FJ, Deeb G, et al. Immunomodulatory drugs
stimulate natural killer-cell function, alter cytokine production by dendritic cells,
and inhibit angiogenesis enhancing the anti-tumour activity of rituximab in vivo.
Br J Haematol 2008;140:36–45.
49. Tai YT, Li XF, Catley L, et al. Immunomodulatory drug lenalidomide (CC-5013,
IMiD3) augments anti-CD40 SGN-40-induced cytotoxicity in human multiple
myeloma: clinical implications. Cancer Res 2005;65:11712–20.
50. Chiarenza A, Parrinello N, La Cava P, et al. Lenalidomide is able to restore
immune system in multiple myeloma patients [abstract]. Blood 2009;114:
Abstract 4909.
51. van Heteren P, Renz O, Hahn-Ast C, et al. Activation of innate immunity
in patients receiving combination therapy with lenalidomide (Revlimid),
cyclophosphamide and low-dose dexamethasone (RCD) for newly diagnosed
or relapsed/refractory myeloma [abstract]. Haematologica 2010;95(Suppl 2):
Abstract 0352.
52. Noonan KA, Ferguson A, Huff CA, et al. The immunomodulatory role of
lenalidomide on Prevnar® responses in patients with relapsed multiple
meyloma: a comprehensive analysis of the immune response [abstract]. Blood
2008;112: Abstract 2772.
53. Baz R, Dimopoulos M, Richardson P, Yu Z, Hussein M, Chanan-Khan A.
Lenalidomide-based therapy leads to improvement of humoral immune system
in relapsed or refractory multiple myeloma patients who respond to the therapy
[abstract]. Haematologica 2009;94(Suppl 2): Abstract 0395.
54. Noonan KA, Ferguson A, Emerling A, et al. Lenalidomide augments immune
responses to Prevnar vaccination in relapsed myeloma patients: implications
for cancer and infectious vaccines [abstract]. Blood 2009;114: Abstract 1864.
55. Harousseau JL, Dimopoulos MA, Wang M, et al. Better quality of response
to lenalidomide plus dexamethasone is associated with improved clinical
outcomes in patients with relapsed or refractory multiple myeloma.
Haematologica 2010;95:1738–44.
56. San Miguel JF, Dimopoulos MA, Stadtmauer EA, et al. Longer duration
of treatment and maintenance of best response with lenalidomide and
dexamethasone prolongs overall survival in patients with relapsed or refractory
multiple myeloma [abstract]. Blood 2008;112: Abstract 3702.
57. Attal M, Cristini C, Marit G, et al. Lenalidomide maintenance after transplanta-
tion for myeloma [abstract]. J Clin Oncol 2010;28(15s): Abstract 8018.
58. McCarthy PL, Owzar K, Anderson KC, et al. Phase III intergroup study of
lenalidomide versus placebo maintenance therapy following single autologous
stem cell transplant (ASCT) for multiple myeloma (MM): CALGB 100104
[abstract]. J Clin Oncol 2010;28(15s): Abstract 8017.
59. San Miguel JF, Dimopoulos M, Weber D, et al. Dexamethasone dose
adjustments seem to result in better efficacy and improved tolerability
in patients with relapsed/refractory multiple myeloma who are treated
with lenalidomide/dexamethasone (MM009/010 sub-analysis) [abstract]. Blood
2007;110: Abstract 2712.
60. Wang M, Dimopoulos MA, Chen C, et al. Lenalidomide plus dexamethasone is
more effective than dexamethasone alone in patients with relapsed or refractory
multiple myeloma regardless of prior thalidomide exposure. Blood 2008;112:
4445–51.
61. Mark T, Stern J, Furst JR, et al. Stem cell mobilization with cyclophosphamide
overcomes the suppressive effect of lenalidomide therapy on stem cell collection
in multiple myeloma. Biol Blood Marrow Transplant 2008;14:795–8.
62. Palumbo A, Ben Yehuda D, Cavallo F, et al. Adequate mobilization of CD34 in
newly diagnosed multiple myeloma patients receiving lenalidomide induction
therapy [abstract]. Haematologica 2009;94(Suppl 2): Abstract 0707.
63. Talamo G, Claxton DF, Ehmann WC, Mierski J, Rybka W, Ibrahin S. Effect of
mobilization chemotherapy with cyclophosphamide and etoposide on stem cell
collection by lenalidomide [abstract]. J Clin Oncol 2009;27(15s): Abstract 7096.
64. Tarantolo SR, McSweeney PA, Micallef IN, Klein LM, Calandra G, Huebner D.
Plerixafor can predictably mobilize hematopoietic stem cells in patients with
multiple myeloma previously treated with lenalidomide [abstract]. Biol Blood
Marrow Transplant 2009;15(Suppl 1): Abstract 91.
65. Guglielmelli T, Bringhen S, Berruti A, et al. Sequential therapy with IMiD’s
in relapsed-refractory multiple myeloma patients [abstract]. Blood 2009;114:
Abstract 2888.
66. Baz R, Patel M, Finley-Oliver E, et al. Single agent lenalidomide in newly
diagnosed multiple myeloma: a retrospective analysis. Leuk Lymphoma
2010;51:1015–9.
