R E V I E W
`
`A review of lenalidomide in combination
`with dexamethasone for the treatment
`of multiple myeloma
`
`Teru Hideshima1
`Noopur Raje1,2
`Paul G Richardson1
`Kenneth C Anderson1
`1Jerome Lipper Multiple Myeloma
`Center, Dana-Farber Cancer Institute;
`2Massachusetts General Hospital
`Cancer Center, Harvard Medical
`School, Boston, MA, USA
`
`Correspondence: Teru Hideshima
`Dana-Farber Cancer Institute, Mayer 549,
`44 Binney Street, Boston, MA 02115, USA
`Tel +1 617 632 2144
`Fax +1 617 632 2140
`Email teru_hideshima@dfci.harvard.edu
`
`Abstract: Lenalidomide (also known as Revlimid®, CC-5013) is an immunomodulatory
`derivative of thalidomide and has more potent anti-tumor and anti-infl ammatory effects than
`thalidomide. The molecular mechanisms of anti-tumor activity of lenalidomide have been
`extensively studied in multiple myeloma (MM) both preclinical models and in clinical trials.
`Lenalidomide: directly triggers growth arrest and/or apoptosis of drug resistant MM cells;
`inhibits binding of MM cells to bone marrow (BM) extracellular matrix proteins and stromal
`cells; modulates cytokine secretion and inhibits angiogenesis in the BM milieu; and augments
`host anti-tumor immunity. Lenalidomide achieved responses in patients with relapsed refractory
`MM. Moreover, lenalidomide with dexamethasone (Dex) demonstrates more potent anti-MM
`activities than Dex both in vitro and in randomized phase III clinical trials. Specifi cally, the
`combination improved overall and extent of response, as well as prolonged time to progression
`and overall survival, resulting in FDA approval of lenalidomide with Dex for therapy MM
`relapsing after prior therapy.
`Keywords: lenalidomide, dexamethasone, multiple myeloma
`
`Introduction
`Multiple myeloma (MM) is a B cell malignancy characterized by excess monotypic
`plasma cells in the BM in association with monoclonal protein in serum and/or urine,
`decreased normal immunoglobulin (Ig) levels, and lytic bone disease. The 2006
`estimate of multiple myeloma incidence in the United States is 16,570 cases, with an
`estimated number of 11,300 deaths. Conventional therapies with alkylating agents,
`anthracyclines, and corticosteroids can extend patient survival to a median of 3–4
`years (Gregory et al 1992; Group 1998), and high dose therapy followed by autolo-
`gous transplantation can modestly prolong median survival to 4–5 years (Fermand
`et al 1998; Lenhoff et al 2000). Attempts to improve autografting include repeated
`use of high dose therapies (Desikan et al 2000; Attal et al 2003), as well as immune
`strategies to treat minimal residual disease post-transplant (Massaia et al 1999) can
`improve outcome in some studies, few, if any, patients are cured. MM remains incur-
`able due to the development of tumor cell resistance to all therapies, highlighting the
`urgent need for novel treatment strategies.
`Thalidomide (Thal) has shown to be useful in various diseases including MM;
`however, it is a potent teratogen and causes side effects including peripheral neuropathy
`(Tseng et al 1996). Attempts were therefore made to develop Thal analogs which are
`more potent and have less adverse effects: lenalidomide (C13H13N3O3, MW = 259.26) is
`one such analog belonging to the class ofi mmunomodulatory drugs (IMiDs) developed
`by the drug discovery program.
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`Preclinical studies of lenalidomide
`Overview (Figure 1)
`The interaction of multiple myeloma (MM) cells with bone
`marrow (BM) extracellular matrix (ECM) proteins and BM
`accessory cells, BM stromal cells (BMSCs), osteoblasts,
`osteoclasts, endothelial cells, as well as other factors in
`the BM milieu (ie, cytokines, angiogenesis) plays a crucial
`role in MM pathogenesis and drug resistance (Damiano
`et al 1999; Akiyama et al 2002; Hideshima and Anderson
`2002; Hideshima et al 2003, 2004, 2006; Chauhan et al
`2004). These accessory cells not only physically interact
`with MM cells, but also secrete growth and/or anti-
`apoptotic factors such as interleukin (IL)-6, insulin-like
`growth factor (IGF)-1, vascular endothelial growth factor
`(VEGF), and tumor necrosis factor (TNF)-α (Akiyama
`et al 2002; Chauhan et al 1996, 2004, 2005; Catley et al
`2004; Hideshima et al 2006). Delineation of the mecha-
`nisms of BM stromal cell (SC)-mediated MM cell prolif-
`eration, survival, drug resistance, and migration therefore
`provides the framework for identifi cation and validation
`of novel therapeutic targets.
`
`Within the BM microenvironment, several proliferative/
`antiapoptotic signaling cascades are activated in MM cells:
`phosphatidylinositol-3 kinase (PI3K)/Akt (also known as
`protein kinase B); I κ B kinase (IKK)/nuclear factor κ-B
`(NFκB); Ras/Raf/mitogen-activated protein kinase (MAPK)
`kinase (MEK)/extracellular signal-related kinase (ERK); and
`Janus kinase (JAK) 2/signal transducers and activators of
`transcription (STAT)-3 (Figure 1, Table 1). These signaling
`cascades mediate: cytoplasmic sequestration of many tran-
`scription factors; upregulation of cyclin D and anti-apoptotic
`Bcl-2 family members; as well as augmentation of telom-
`erase activity (Hideshima et al 2001a; Akiyama et al 2002).
`Importantly, these molecular events are triggered by both
`MM cell adherence to BMSCs and by cytokines secreted
`from BMSCs (Dankbar et al 2000; Hideshima et al 2004;
`Mitsiades et al 2004). Cytokines secreted from MM cells
`and BMSCs and other cells may in turn further augment
`cytokine secretion.
`Novel biologically based agents target not only the
`MM cell, but also MM cell–host interactions, cytokines,
`and their sequelae in the BM milieu. Thalidomide and
`
`Figure 1 Potential mechanisms of action of anti-MM activity of lenalidomide. Lenalidomide: directly induces tumor cell apoptosis and/or growth arrest (A); enhances NK
`and/or NK cell activity via activation of CD28/NF-AT2 pathway (B); inhibits MM cell adhesion to host microenvironment (C); inhibits angiogenesis (D); inhibits osteoclasto-
`genesis (E); as well as inhibits cytokine secretion (F).
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`its immunomodulatory derivative (IMiD) lenalidomide
`(Revlimid®; Celgene Corp., Summit, NJ, USA) are examples
`of such agents targeting the tumor cell in its BM milieu
`which can achieve responses even in refractory relapsed MM.
`Lenalidomide may inhibit MM cell growth by several differ-
`ent mechanisms (Figure 1). First, lenalidomide has a direct
`effect on MM cells to induce G1 growth arrest or apoptosis
`even of drug resistant cells (Hideshima et al 2000; Mitsiades
`et al 2002). Second, lenalidomide inhibits adhesion of MM
`cells to BMSCs, and thereby can overcome cell adhesion
`mediated drug resistance (CAM-DR); third, lenalidomide
`inhibits bioactivity and/or secretion in MM cells and/or BM
`stromal cells of cytokines [eg, interleukin (IL)-6, IL-1β,
`IL-10, and tumor necrosis factor (TNF)α] which augment
`MM cell growth, survival, drug resistance, migration, and
`expression of adhesion molecules. Importantly, lenalidomide
`is several thousand fold more potent than Thal at inhibiting
`TNFα/IL-1β secretion from mononuclear cells stimulated
`with lipopolysaccharide (LPS) in vitro (Corral et al 1999;
`Muller et al 1999). Fourth, vascular endothelial growth fac-
`tor (VEGF) and basic fi broblast growth factor (bFGF) are
`secreted by MM cells and/or BMSCs, and lenalidomide may
`inhibit activity of VEGF, bFGF, and angiogenesis in MM.
`Lenalidomide also acts against MM through immunomodu-
`latory effects such as augmentation of activity of cytotoxic
`T-cells and natural killer (NK) cells, associated with secretion
`of IL-2 and interferon-γ (Davies et al 2001; LeBlanc et al
`2004; Hayashi et al 2005).
`Bone destruction is a hallmark of MM, with 70%–80% of
`patients manifesting bone involvement. Recently, Anderson
`et al demonstrated that an IMiD CC-4047 (Actimid®; Celgene
`Corp., Summit, NJ, USA) inhibits osteoclastgenesis via
`downregulation of transcription factor PU.1 (Anderson et al
`2006). Lenalidomide also has inhibitory effect on osteoclas-
`togenesis (Terpos et al 2007).
`
`Table 1 Selected ongoing clinical trials of lenalidomide based
`combination treatment in multiple myeloma
`Agent
`Phase
`Perifoine + Dex
`I
`Hepatitis B vaccine
`I
`Doxorubicin + Dex
`I/II
`Bortezomib + Dex
`I/II
`Bortezomib + Dex
`II
`Bevacizumab + Dex
`II
`Clarithromycin + Dex
`II
`Dex
`III
`Dex
`III
`Dex
`IV
`
`Patient
`Rel/ref
`Rel/ref
`Rel/ref
`Newly diagnosed
`Rel/ref
`Rel/ref
`Newly diagnosed
`Newly diagnosed
`Previously treated
`Previously treated
`
`Lenalidomide plus dexamethasone in multiple myeloma
`
`Direct anti-tumor activities
`of lenalidomide
`Although the targets of whereby lelalidomide mediates anti-
`tumor activity of lenalidomide have not been fully delineated,
`several studies have examined the molecular mechanisms
`mediating sequelae of lenalidomide. Our previous studies
`demonstrated that lenalidomide induces G0/G1 growth arrest
`associated with p21Cip1 upregulation and/or apoptosis which
`is mediated via caspase-8 activation (Hideshima et al 2000;
`Mitsiades et al 2002). Lenalidomide inhibits LPS-mediated
`induction of Cox-2 and prostaglandin E2 (PGE2) production by
`a post-transcriptional mechanism in RAW 364.7 cells (Fujita
`et al 2001), suggesting that the anti-tumor activity induced
`by lenalidomide may also be due to inhibition of Cox-2 and
`PGE2. Lenalidomide inhibits nuclear factor (NF)-κB subunit
`activity in MM cell lines (Mitsiades et al 2002), which is
`consistent with reports that Thal inhibits DNA binding activ-
`ity of the p50/p65 NF-κB triggered by TNFα and IL-1β in
`Jurkat cell line (Keifer et al 2001) and in PBMCs (Rowland
`et al 2001). Since NF-κB plays an essential role in cell cycle
`regulation, cell survival, anti-apoptosis, and cytokine produc-
`tion in MM cells (Hideshima et al 2001b, 2002), inhibition of
`NF-κB activity by lenalidomide may also enhance or restore
`sensitivity to other chemotherapeutic agents. Specifi cally, we
`have demonstrated that MM cell adhesion-mediated upregula-
`tion of IL-6 is mediated via NF-κB activation (Chauhan et al
`1996; Hideshima et al 2002). Recently, Stewart et al (2004)
`reported pharmacogenomic studies suggesting that hyperac-
`tivation of the Wnt signaling antagonist DKK-1 is associated
`with response to the immunomodulators Thal and lenalido-
`mide. Furthermore, β-catenin expression is downregulated
`by lenalidomide in MM cell lines.
`Lenalidomide in combination with Dex is one of the most
`promissing MM novel treatment options. It induces at least
`additive direct cytotoxicity in MM cells (Hideshima et al
`2000), associated with activation of dual apoptotic signal-
`ing cascades: Dex induces caspase-9 (Chauhan et al 2001;
`Hideshima et al 2001a) and lenalidomide triggers caspase-8
`activation (Mitsiades et al 2002) (Figure 2). Most recently,
`enhanced anti-MM activity of rapamycin, a specifi c mTOR
`inhibitor, in combination with lenalidomide has been reported
`(Raje et al 2004). In this study, the combination of rapamycin
`plus lenalidomide overcomes drug resistance in MM cell
`lines resistant to conventional chemotherapy. Interestingly,
`differential signaling cascades, including the ERK and PI3-
`K/Akt pathways, are targeted by these drugs individually
`and in combination, suggesting the molecular mechanism
`by which they inhibits MM growth and survival.
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`Figure 2 Potential mechanisms of synergistic cytotoxicity by lenalidomide plus
`Dex treatment in MM cells. Lenalidomide triggers caspase-8 dependent apoptosis,
`whereas Dex induces caspase-9 dependent apoptosis. The combination therefore
`triggers dual apoptotic signaling cascades.
`
`Anti-angiogenic activity
`Previous studies have shown that oral administration of
`lenalidomide attenuates growth factor-induced angiogenesis
`in vivo. This effect is correlated with the inhibitory effect
`of lenalidomide on growth factor-induced Akt phosphoryla-
`tion, thereby providing a potential mechanism for its anti-
`migratory and subsequent anti-angiogenic effects (Dredge
`et al 2005). In MM, an anti-angiogenic effect of Thal in
`vitro has been demonstrated (D’Amato et al 1004; Singhal
`et al 1999; Lentzsch et al 2002; Fujita et al 2004); however,
`to date no strong evidence of an anti-angiogenic effect of
`lenalidomide in vivo has been demonstrated. Moreover,
`Singhal et al (1999) reported no correlation of BM angiogen-
`esis with response to Thal in patients with relapsed refractory
`MM, suggesting that lenalidomide may mediate its anti-MM
`activity via mechanisms other than anti-angiogenesis.
`
`Immunomodulatory activities
`A unique feature of the anti-tumor effect of Thal and lenalido-
`mide is their ability to modulate and potentiate host immune
`responses against MM. Several studies have demonstrated
`the effects of lenalidomide on peripheral blood lymphocytes
`(Davies et al 2001; Haslett et al 2003; LeBlanc et al 2004;
`Hayashi et al 2005). Co-culture of naive splenocytes with
`
`anti-CD3 monoclonal antibody and IMiD1 (Actimid®)
`directly costimulates T cells and increases Th-1-type cyto-
`kines. Most excitingly, IMiDs augment CTL and NK cell
`activity against MM cell lines and autologous MM cells,
`associated with increased IL-2 levels in serum (Davies et al
`2001). Although Thal/IMiDs induce IL-2 secretion from
`T cells (Corral et al 1999; Shannon et al 2000), the mecha-
`nisms whereby these compounds induce IL-2 production
`from T cells has not totally been defi ned. Importantly, our
`recent studies demonstrated that lenalidomide signifi cantly
`costimulates proliferation of CD3+ T cells induced by CD3
`ligation, immature dendritic cells (DCs; SI, 2.1), or mature
`DCs (SI, 2.6). T-cell proliferation triggered by DCs is abro-
`gated by cytotoxic T lymphocyte antigen 4-immunoglobulin
`(CTLA-4-Ig). Lenalidomide also overcomes the inhibitory
`effects of CTLA-4-Ig on Epstein-Barr virus and infl uenza-
`specifi c CD4 and CD8 T-cell responses, as measured by
`cytokine capture and enzyme-linked immunosorbent spot
`(ELISPOT) assays. Importantly, lenalidomide triggers
`tyrosine phosphorylation of CD28 on T cells, followed by
`activation of NF-κB (LeBlanc et al 2004). Furthermore, we
`have demonstrated that IMiDs facilitate the nuclear translo-
`cation of nuclear factor of activated T cells (NF-AT)-2 and
`activator protein-1 via activation of PI3-K/Akt signaling,
`with resultant IL-2 secretion. IMiDs enhance both NK cell
`cytotoxicity and ADCC induced by triggering IL-2 produc-
`tion from T cells (Hayashi et al 2005). These studies therefore
`defi ne the molecular mechanisms whereby lenalidomide trig-
`gers NK cell-mediated cytotoxicity against MM cells, further
`supporting their therapeutic use in MM. More recently, we
`have shown that lenalidomide enhances ADCC induced by
`SGN-40, a humanized IgG1 anti-CD40 monoclonal antibody
`(Tai et al 2005).
`
`Clinical studies of lenalidomide
`Pharmacokinetics
`Pharmacokinetics (PK) of lenalidomide in MM patients
`has been reported by Wu and Scheffl er (2004) at American
`Society of Clinical Oncology in 2004. In this single-center,
`open-label, non-randomized, phase I dose escalation study
`in relapsed and refractory MM, the doses of lenalidomide
`used were 5, 10, 25 or 50 mg/day orally for 28 days. Blood
`samples were collected before and at 15 min, 30 min, 45 min,
`1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 6 h, 8 h, 10 h, 12 h, 18 h, 24 h,
`48 h, and 72 h after administration on both days 1 and 28. No
`lenalidomide dose-limiting toxicity was observed at any dose
`level within the fi rst 28 days. Absorption of lenalidomide was
`rapid on both day 1 and 28, with tmax ranging from 0.7 to 2.0 h
`
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`at all dose levels. Plasma levels of lenalidomide declined in a
`monophasic manner, with elimination half-life ranging from
`2.8 to 6.1 h on both days 1 and 28 at all four doses. No plasma
`accumulation was observed upon multiple dosing. Importantly,
`daily oral doses of lenalidomide up to 50 mg produced no
`dose-limiting toxicity within the fi rst 28 days.
`The other PK study has been reported by Richardson et al
`(2006). In this study, plasma concentration of lenalidomide
`was determined in 39 patients during the fi rst and second
`cycles in both 15 mg and 30 mg dose groups, and when Dex
`was added due to progressive disease (PD) or stable disease
`(SD) on lenalidomide alone. The mean minimum (Cmin)
`plasma lenalidomide concentrations on days 1, 2, 3, 4, and
`21 during the fi rst and second 21-day cycles of lenalidomide
`alone and with the addition of Dex are shown for the 30 mg
`once-daily and 15 mg twice-daily cohorts. The average Cmin
`plasma levels were less in the twice-daily compared with
`daily dosing regimens. No obvious effect on lenalidomide
`plasma concentrations was seen with addition of Dex in either
`once- or twice-daily treatment.
`
`Clinical trials of lenalidomide
`Only a limited number of reports are available for clini-
`cal studies of lenalidomide (Bartlett et al 2004). A phase I
`clinical study of lenalidomide was completed at Dana-Farber
`Cancer Institute (Richardson et al 2002a). In this study,
`dose-escalation (5 mg/day, 10 mg/day, 25 mg/day, and
`50 mg/day) of lenalidomide was evaluated in 27 patients
`(median age 57 years; range, 40–71 years) with relapsed
`and refractory relapsed MM (Richardson et al 2002b). These
`patients received a median of 3 (range, 2–6) prior regimens,
`including autologous stem cell transplantation and Thal in
`15 and 16 patients, respectively. In 24 evaluable patients,
`no dose-limiting toxicity (DLT) was observed in patients
`treated at any dose level within the fi rst 28 days; however,
`grade 3 myelosuppression developed after day 28 in all 13
`patients treated with 50 mg/day lenalidomide. Dose reduction
`to 25 mg/day was well tolerated in 12 patients and therefore
`considered to be the maximal tolerated dose (MTD). Most
`importantly, no signifi cant somnolence, constipation, or
`neuropathy, the most common toxicities of Thal, have been
`seen in any cohort. Best responses of at least 25% reduction
`in paraprotein occurred in 17 of 24 (71%) patients (90%
`confi dence interval [CI], 52%–85%), including 11 (46%)
`patients who had received prior Thal; stable disease (less
`than 25% reduction in paraprotein) was observed in an addi-
`tional 2 (8%) patients. This study therefore demonstrates that
`lenalidomide can overcome conventional drug resistance,
`
`Lenalidomide plus dexamethasone in multiple myeloma
`
`even resistance to Thal. Given that lenalidomide is an oral
`agent, it is currently being evaluated in a randomized trial
`post autografting in an attempt to prolong progression free
`and overall survival.
`A multicenter, open-label, randomized phase II study
`to evaluate 2 dose regimens of lenalidomide for relapsed,
`refractory MM has been performed. In this study, 70 patients
`were randomized to receive either 30 mg once-daily or 15 mg
`twice-daily oral lenalidomide for 21 days of every 28-day
`cycle. An additional 32 patients received 30 mg once daily.
`Patients with progressive or stable disease after 2 cycles
`received additional Dex. Responses were evaluated according
`to European Group for Blood and Marrow Transplantation
`(EBMT) criteria. Overall response rate (CR+PR+MR) to
`lenalidomide alone was 25%; 24% for 30 mg once-daily and
`29% for 15 mg twice-daily cohort. Median overall survival in
`30-mg once-daily and 15 mg twice-daily groups was 28 and 27
`months, respectively. However, median progression-free sur-
`vival was 7.7 months on 30 mg once-daily versus 3.9 months
`on 15 mg twice-daily lenalidomide. Dex was added in 68
`patients and 29% responded. Importantly, time to fi rst occur-
`rence of clinically signifi cant grade 3/4 myelosuppression
`was shorter in the 15 mg twice-daily group (1.8 months) than
`30 mg once-daily (5.5 months, p = 0.05) group. Moreover,
`analysis of the fi rst 70 patients showed increased grade 3/4
`myelosuppression in patients receiving 15 mg twice-daily
`(41% vs 13%, p = 0.03). This study indicate that lenalidomide
`is active and well tolerated in relapsed, refractory myeloma,
`with the 30-mg once-daily regimen providing the basis for
`future studies as monotherapy and with Dex (Richardson
`et al 2006).
`
`Clinical studies of lenalidomide
`in combination with Dex
`As described above, preclinical studies have demonstrated
`the effi cacy of combination treatment of lenalidomide with
`Dex in MM and several clinical trials of this combination
`treatment have been completed.
`In two double blind, multicenter, international phase
`III clinical trials (MM-009, North American, 353 patients;
`MM-010, Europe, Australia, and Israel, 351 patients),
`patients with relapsed or refractory MM not resistant to Dex
`were treated with Dex 40 mg daily on days 1–4, 9–12, and
`17–20 every 28 days and were randomized to receive either
`lenalidomide 25 mg daily orally on days 1–21 every 28 days
`or placebo. At a median follow-up from randomization of
`17.1 months (MM-009) and 16.5 months (MM-010), both
`studies show signifi cant improvement with lenalidomide
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`plus Dex compared to Dex in overall response (OR)
`(MM-009: 1% vs 20.5%, p ⬍ 0.001; MM-010: 59.1%
`vs 24%, p ⬍ 0.001, respectively), time to progression
`(TTP) (MM-009: 11.1 months vs 4.7 months, p ⬍ 0.001;
`MM-010: 11.3 months vs 4.7 months, p ⬍ 0.001, respec-
`tively), and overall survival (OS) (MM-009: 29.6 months
`vs 20.5 months, p ⬍ 0.001; MM-010: not estimable vs 20.6
`months, p ⬍ 0.001, respectively). In a subgroup analysis on
`patients with impaired creatinine clearance, no signifi cant
`difference in response rate, TTP, or OS was observed in
`patients with creatinine clearance above or below 50 mL/
`min who were treated with lenalidomide plus Dex; however,
`for 16 patients with creatinine clearance ⬍30 mL/min,
`median TTP and OS was shorter than for those with creati-
`nine clearance ⬎30 mL/min, but still signifi cantly longer
`than for patients treated with Dex (Weber et al 2006).
`Treatment with lenalidomide plus Dex in newly diagnosed
`MM patients has also reported by Rajkumar et al (2005). In
`this study, lenalidomide was given orally 25 mg daily on days
`1–21 of a 28-day cycle. Dex was given orally 40 mg daily
`on days 1–4, 9–12, and 17–20 of each cycle. Thirty-one of
`34 patients achieved an objective response, including 2 (6%)
`achieving complete response (CR) and 11 (32%) meeting
`criteria for both very good partial response and near complete
`response, resulting in an overall objective response rate of
`91%. This study indicated that lenalidomide plus Dex is a
`highly active regimen with manageable side effects in the
`treatment of newly diagnosed MM.
`A number of studies demonstrated that MM is character-
`ized by cytogenetic abnormalities causing dysregulation of
`the genes at the breakpoints, and by point mutations (Kuehl
`et al 2002; Fonseca et al 2004; Carrasco et al 2006). Spe-
`cifi cally, chromosome 13 deletions are present in over 50%
`of MM patients and considered to be associated with poor
`prognosis. In addition, t(4; 14) in MM also predicts poor
`response to conventional and high dose treatment and short-
`ened survival. A recent study has shown that lenalidomide
`overcomes the poor prognosis conferred by chromosome 13
`deletion and t(4; 14) in MM patients, evidenced by event free
`survival and response rate (Bahlis et al 2006).
`Recently, a phase I/II 3 combination treatment of
`lenalidomide, Dex and adriamycin (RAD therapy) for
`relapsed MM patient has been reported. In this study, 31
`patients were evaluated for response and toxicity: 26 patients
`achieved reduction of paraprotein levels of at least 50% for
`a response rate of 84%, including one confi rmed CR and
`14 PRs according to the EBMT criteria. Importantly, 8 of
`10 patients who displayed del (13) on cytogenetic analysis
`
`responded, including 6 confi rmed PRs. One patient each
`experienced acute renal failure due to emesis and hypo-
`volemia, pneumocystis pneumonitis, and catheter related
`infection. Somnolence, constipation, thromboembolism,
`or neuropathy was not observed. This study showed that
`RAD induces substantial responses with an acceptable
`toxicity profi le, and thus signifi cantly contributes to the
`therapeutic armamentarium even in heavily pretreated MM
`patients (Knop et al 2006). Most recently, a phase I study of
`lenalidomide and dexamethasone in combination with Akt
`inhibitor perifosine for patients with relapsed or refractory
`MM, and a phase I/II study of lenalidomide, dexamethasone
`and bortezomib combination therapy for newly diagnosed
`MM patients are ongoing.
`The common side effects of lenalidomide treatment in
`phase 2 clinical trials of relapsed refractory MM are sum-
`marized in Table 1. The most common toxicities associated
`with Thal (eg, constipation, neuropathy, tremors) were not
`observed. Toxicities associated with lenalidomide were
`primarily hematologic and reversible. The most common
`grade 3 or higher adverse events during lenalidomide therapy
`were neutropenia and thrombocytopenia. Grade 4 neutro-
`penia occurred in 2 of 34 (5.8%) patients treated at 15 mg
`twice daily vs 4 of 68 (5.9%) patients treated with 30 mg
`daily. Grade 4 thrombocytopenia occurred in 2 (5.8%) of
`34 patients on 15 mg twice daily vs 2 of 68 patients (2.9%)
`treated with 30 mg daily. Deep vein thrombosis (DVT)
`was reported in 1 patient on the 30 mg daily and 2 patients
`(5.8%) on the 15 mg twice-daily treated regimen. Sedation
`or neurologic toxicities were not observed in most of these
`studies (Richardson et al 2006). The differences in the side
`effect profi le between Thal and lenalidomide may refl ect
`distinct patterns of antiangiogenic, cytokine-related, micro-
`environmental, and immunomodulatory activity, rather than
`distinct separate mechanisms of action.
`In phase III trials of lenalidomide plus Dex for newly
`diagnosed MM patients, 47% of patients experienced grade
`III or higher nonhematologic toxicity. The most common
`adverse effects were fatigue (15%), muscle weakness (6%),
`anxiety (6%), pneumonitis (6%), and rash (6%) (Rajkumar
`et al 2006a). Recently, a randomized phase III trial of
`lenalidomide plus high-dose Dex versus lenalidomide plus
`low-dose Dex in newly diagnosed MM has also reported
`by Rajkumar et al (2006b). In this study, patients in both
`arms received lenalidomide 25 mg/day orally on days 1–21
`every 28 days. In addition, patients in the high-dose Dex
`arm received Dex 40 mg on days 1–4, 9–12, and 17–20
`orally every 28 days, while patients in the low-dose Dex
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`IPR2018-01714
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`arm received Dex 40 mg on days 1, 8, 15, and 22 orally
`every 28 days. Although response rate (RR) has not yet
`been reported, toxicity rates are higher in the high-dose
`Dex arm than low-dose Dex arm. For example, Grade 3
`and above toxicities in cardiac ischemia (2.7% vs 0.5%),
`hypercalcemia (5.8% vs 1.8%), infection (18.8% vs 9%),
`thromboembolism (18.4% vs 5.4%), and non-hematologic
`toxicities (22% vs 12.6%) are higher in high-dose Dex arm
`than low-dose Dex arm. If RR is similar in both arms, dos-
`age of Dex can be reduced to 25 mg.
`
`Conclusion
`Lenalidomide plus Dex treatment is highly effective in
`both preclinical and clinical studies. It is one of the prom-
`ising treatment options against both relapsed/refractory
`and newly diagnosed MM patients. Adverse effects of this
`combination can be markedly reduced by lowering the
`Dex dosage.
`
`Future directions
`Lenalidomide plus Dex treatment can be further combined
`with other novel or conventional agents to improve patient
`outcome in MM. Indeed, potent Akt inhibitor Perifosine,
`proteasome inhibitor bortezomib (Velcade®; Millennium
`Pharmaceuticals Inc.), and anti-angiogenic agent bevaci-
`zumab (Avastin®; Genentech) are already under evaluation
`in combination clinical trials.
`
`Acknowledgments
`Supported by National Institutes of Health Grant PO-1
`78378 and RO-1 CA 50947; the Doris Duke Distinguished
`Clinical Research Scientist Award (KCA); the Multiple
`Myeloma Research Foundation (TH, NR, KCA); and the
`Myeloma Research Fund (KCA).
`
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