Cancer Treatment Reviews (2008) 34, 283– 291
`
`a v a i l a b l e a t w w w . s c i e n c e d i r e c t . c o m
`
`j o u r n a l h o m e p a g e : w w w . e l s e v i e r h e a l t h . c o m / j o u r n a l s / c t r v
`
`NEW DRUGS
`
`Lenalidomide: A new therapy for multiple myeloma
`
`Antonio Palumbo a,*, Jesu´s San Miguel b,h, Pieter Sonneveld c,i,
`Philippe Moreau d,j, Johannes Drach e,k, Gareth Morgan f,l,
`Hermann Einsele g,m
`
`a Department of Hematology, University of Torino, Ospedale Molinette, Via Genova 3, 10126 Torino, Italy
`b Hematology Department, University Hospital of Salamanca, Paseo San Vicente 58-182, 37007 Salamanca, Spain
`c Department of Hematology, Erasmus Medical Center, P.O. Box 2040, 3000 CA Rotterdam, Netherlands
`d Hematology Department, University Hospital, Centre Hospitalier Universitaire Hoˆtel-Dieu, Place Alexis Ricordeau,
`44093 Nantes Cedex 01, France
`e Department of Medicine I, Clinical Division of Oncology, Medical University Vienna, Waehringer Guertel 18-20,
`A-1090 Vienna, Austria
`f Department of Haemato-oncology, The Royal Marsden Hospital, Down Road Sutton, Surrey SM2 5PT, UK
`g Medizinischen Klinik und Poliklinik II, Ha¨matologie und Onkologie, Universita¨t Wu¨rzburg, Klinikstraße 6-8,
`97070 Wu¨rzburg, Germany
`
`Received 24 October 2007; received in revised form 5 December 2007; accepted 11 December 2007
`
`KEYWORDS
`Lenalidomide;
`Multiple myeloma;
`Dexamethasone;
`Immunomodulatory
`drugs
`
`Summary The last decade has seen rapid evolution in the management of multiple myeloma.
`Cytogenetic, molecular, and proteomic techniques have led to a better understanding of the
`pathophysiology and prognostic markers of this heterogeneous malignancy. New immunomod-
`ulatory drugs, such as lenalidomide, which interrupt myeloma growth and survival pathways
`have entered into clinical usage. Combined with dexamethasone, oral lenalidomide has proved
`to be highly effective in patients whose disease has become resistant to conventional therapy.
`Currently, several clinical trials are ongoing in order to define the optimal use of this new agent
`and its combinations across the spectrum of patients with myeloma. Whether the ultimate out-
`come of future research will be a single-treatment solution for all patients, or whether
`
`* Corresponding author. Tel.: +39 (011) 6336107; fax: +39 (011) 6963737.
`E-mail addresses: appalumbo@yahoo.com (A. Palumbo), sanmigiz@aida.usal.es (J.S. Miguel), p.sonneveld@erasmusmc.nl (P. Sonneveld),
`philippe.moreau@chu-nantes.fr
`(P. Moreau),
`johannes.drach@meduniwien.ac.at (J. Drach), gareth.morgan@icr.ac.uk (G. Morgan),
`einsele_h@klinik.uni-wuerzburg.de (H. Einsele).
`h Tel.: +34 923 291384; fax: +34 923 294624.
`i Tel.: +31 10 463 3123; fax: +31 10 463 5814.
`j Tel.: +33 240083271; fax: +33 240083250.
`k Tel.: +43 1 40400 4429; fax: +43 1 40400 4461.
`l Tel.: +44 (020) 8722 4130; fax: +44 (020) 8722 4432.
`m Tel.: +49 (312) 0170011; fax: +49 (312) 01 70730.
`
`0305-7372/$ - see front matter c 2007 Elsevier Ltd. All rights reserved.
`
`doi:10.1016/j.ctrv.2007.12.005
`
`ALVOGEN, Exh. 1043, p. 0001
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`284
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`A. Palumbo et al.
`
`treatments will become better-tailored to the individual (based on prognostic markers and pre-
`existing co-morbidities) has yet to be determined.
`
`c 2007 Elsevier Ltd. All rights reserved.
`
`Introduction
`
`Multiple myeloma (MM) is a haematological malignancy
`characterised by proliferating plasma cells in the bone mar-
`row, with subsequent over-production of a monoclonal pro-
`tein in most patients.1,2 MM accounts for 1.5–2% of all
`cancer deaths and approximately 20% of deaths from hae-
`matological malignancies.3 Although MM is initially sensitive
`to conventional chemotherapy, it remains incurable with al-
`most all patients eventually relapsing. The median overall
`survival achieved with conventional approaches is approxi-
`mately 33 months.4,5 High-dose melphalan and autologous
`stem-cell transplantation (ASCT) increase the rate of com-
`plete remission, and extend event-free survival and overall
`survival in selected patients. However, relapse rates are
`high and, until recently, there were few salvage therapies.
`With the advent of biologically-based treatment strategies
`such as bortezomib, thalidomide, and lenalidomide, treat-
`ments are now available which specifically target myeloma
`
`interactions within the bone marrow microenviron-
`cell
`ment. These interactions are key to the growth and survival
`of malignant cells, and have proved to be powerful tools in
`overcoming drug resistance and prolonging the duration of
`response in patients with MM.6,7
`Lenalidomide (RevlimidÒ; Celgene, NJ, USA) is an oral
`immunomodulatory derivative of thalidomide with potent
`activity, but a different toxicity profile to the parent
`compound. It possesses pleoyotropic (immunomodulatory,
`anti-angiogenic, and antineoplastic) activities, as well as
`anti-inflammatory effects.7,8 Lenalidomide induces apopto-
`sis, decreases the binding of MM cells to bone marrow
`stromal cells, and inhibits the production of cytokines
`(e.g. interleukin-6, vascular endothelial growth factor,
`tumour necrosis factor alpha) in the bone marrow milieu,
`which mediate angiogenesis and the growth and survival
`of resistant MM cells (Fig. 1).9 It also enhances dexametha-
`sone cytotoxicity, stimulates host anti-MM natural killer cell
`immunity, and inhibits osteoclast differentiation.10,11
`
`Antitumour activity of lenalidomide against multiple myeloma (MM) cells in the bone marrow microenvironment. A:
`Figure 1
`Direct cytotoxicity of MM cells by causing G1 growth arrest or apoptosis. B: Inhibiting adhesion of MM cells to bone marrow stromal
`cells. C: Inhibiting the expression or bioactivity of interleukin (IL)-6, and other cytokines (e.g. vascular endothelial growth factor
`[VEGF], insulin-like growth factor [IGF-1], stromal cell-derived factor 1 [SDF-1a]) necessary for cytokine-mediated growth, survival
`(proliferation, cell cycle progression), drug resistance (anti-apoptosis), and migration of MM cells within the bone marrow milieu. D:
`Inhibiting the production of VEGF and basic fibroblast growth factor (bFGF) necessary for angiogenesis. E: Providing co-stimulatory
`action on primary human T-cells, which enhance antitumour activity, mediated by T helper-1 cells, cytokines IL-2 and interferon-c,
`and increases the number and function of natural killer (NK) cells, cytotoxic T-cells (CTLs) and dentritic cells (DCs). Figure
`reproduced from Expert Rev Anticancer Ther 2006;6(9):1239–1247 with permission of Future Drugs Ltd.9
`
`ALVOGEN, Exh. 1043, p. 0002
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`Lenalidomide: A new therapy for multiple myeloma
`
`285
`
`aNeutrophilcountwasmanagedwithgranulocyte-colonystimulatingfactorin12patients,dosereductions/interruptionsofcyclophosphamidewereneededin10patients,andof
`
`dexamethasone;VTE=venousthromboembolism.
`OS=overallsurvival;PFS=progression-freesurvival;PR=partialresponse;RAD=lenalidomideplusadriamycinanddexamethasone;RCD=lenalidomidepluscyclophosphamideand
`Bort=bortezomib;CR=completeresponse;Dex=dexamethasone;DVd=pegylatedliposomaldoxorubicin,vincristineanddexamethasone;Len=lenalidomide;NR=notreached;
`
`lenalidomidein5patients.
`
`8
`
`13
`10
`22
`
`Grade4:38a
`Neutropenia/thrombocytopenia:13
`32
`30
`41
`
`13
`11
`15
`
`9
`
`2
`
`11
`15
`
`3–4,%
`Infectiongrade
`
`grade3–4,%
`Thrombocytopenia
`
`3–4,%
`Neutropeniagrade
`
`3–4,%
`VTEgrade
`
`2
`
`5
`
`0
`
`grade3–4,%
`neuropathy
`Peripheral
`
`NR
`NR
`30
`
`months
`
`12
`
`8
`
`5
`
`3
`
`15
`16
`14
`
`39
`65
`82
`75
`60
`61
`
`60(37–79)
`59(34–76)
`64(44–77)
`62
`63(33–84)
`64(36–86)
`
`38
`21
`61
`62
`176
`177
`
`Len+Bort44
`RCD43
`RAD42
`Len+DVd41
`Len+Dex16
`Len+Dex15
`
`PPR,%CR,%MedianPFS,monthsMedianOS,
`
`years(range)
`Medianage,
`
`n
`
`Therapy
`
`Table1Summaryofclinicaltrialswithlenalidomidecombinationtreatmentinthemanagementofrelapsed/refractorymultiplemyeloma
`
`Recently, lenalidomide has been found to have a direct anti-
`proliferative effect on MM cell lines (via p21WAF-1 up-regu-
`lation), while protecting normal B-cells from apoptosis,
`suggesting a potential role in bone marrow regeneration.12
`This paper reviews the recent clinical findings with lena-
`lidomide, an agent which has demonstrated remarkable
`activity against resistant MM cells.6,7 Lenalidomide has been
`approved by the Food and Drug Administration (FDA) in the
`USA, and the European Medicines Agency for use in combi-
`nation with dexamethasone in patients with MM who have
`received at least one prior therapy.
`
`Relapsed/refractory MM
`
`Lenalidomide as a single agent
`
`Two phase I dose-escalation trials of oral lenalidomide in
`advanced MM defined 25 mg/day as the maximum tolerated
`dose.10,13 These studies revealed the favourable pharmaco-
`kinetic profile and the acceptable toxicity profile of lenalid-
`omide in patients with relapsed/refractory disease. In a
`subsequent phase II study, 25% of patients with relapsed/
`refractory MM responded to lenalidomide (complete re-
`sponse [CR], partial response [PR], or minor response). In
`patients who failed to respond to lenalidomide mono-
`therapy, after the addition of oral dexamethasone 29% re-
`sponded. In this study, the efficacy of lenalidomide was
`observed in heavily pre-treated patients, including those
`who had received prior treatment with thalidomide.14
`
`Lenalidomide plus dexamethasone
`
`Recently, two phase III randomized clinical trials (MM-009
`and MM-010) have demonstrated the superiority of lenalido-
`mide plus dexamethasone, compared with dexamethasone
`alone in previously treated patients with relapsed/refrac-
`tory MM (Table 1).15,16
`In the first of these two trials (MM-009), researchers in
`the USA and Canada enrolled 354 patients.15 Two-thirds of
`the patients had previously had a stem cell transplant,
`and nearly half had previously been treated with thalido-
`mide. Patients received either oral lenalidomide (25 mg/
`day on Days 1–21, of every 28-day cycle) plus dexametha-
`sone (40 mg/day on Days 1–4, 9–12, and 17–20, of every
`cycle), or placebo plus dexamethasone (same dose and reg-
`imen as in the lenalidomide group) (Table 1). At the start of
`cycle 5, the dose of dexamethasone was reduced to 40 mg/
`day on Days 1–4 only, of every cycle. The study found that
`the time-to-progression (TTP) of disease was delayed in pa-
`tients who had received lenalidomide plus dexamethasone,
`compared with those treated with dexamethasone alone
`(median
`11.1 months
`vs
`4.7 months,
`respectively;
`p < 0.001). Also improved in patients treated with lenalido-
`mide plus dexamethasone, compared with those treated
`with dexamethasone alone, were overall response rate
`(61.0% vs 19.9%, respectively; p < 0.001) and median overall
`survival
`(29.6 months
`vs
`20.2 months,
`respectively;
`p < 0.001).15
`In a second study (MM-010), paralleling the findings from
`the North American trial, researchers from Europe, Israel,
`and Australia enrolled 351 patients.16 In this study, the
`
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`

`286
`
`A. Palumbo et al.
`
`researchers found a similar response with lenalidomide plus
`high-dose dexamethasone compared with dexamethasone
`alone: the median TTP was 11.3 months vs 4.7 months,
`respectively (p < 0.001), the overall response rate was
`60.2% vs 24.0% (p < 0.001), and the median overall survival
`was not reached in the lenalidomide plus dexamethasone
`arm vs 20.6 months in the dexamethasone alone arm
`(p = 0.03).16
`Subgroup analyses of patients from these two phase III
`studies found that when lenalidomide plus dexamethasone
`was administered at the first relapse, the treatment re-
`sponse rate was higher (65% vs 58%) and the TTP longer
`(18 months vs 10 months), than when treatment was used
`later as salvage therapy.17 Thus, earlier treatment with
`lenalidomide may further improve the length of response
`duration. Another subgroup analysis has shown that regard-
`less of prior thalidomide exposure, the TTP and overall re-
`sponse were consistently higher with lenalidomide plus
`dexamethasone treatment, compared with dexamethasone
`alone (prior thalidomide: 36 weeks and 54% vs 20 weeks
`and 14%, no prior thalidomide: 60 weeks and 65% vs
`20 weeks and 28%).18 Even among those patients who were
`resistant to prior treatment with thalidomide, lenalidomide
`plus dexamethasone led to a high overall response rate
`(50%) and a longer TTP (31 weeks).18 A multivariate analysis
`found that previous exposure to thalidomide, the duration
`of MM disease, and the number of prior therapies were all
`predictors of a shorter TTP.19
`At the start of treatment, several patient characteristics
`can predict poor survival
`including: thrombocytopenia
`(platelet count <150 · 109/L); serum albumin P3 mg/dL;
`serum calcium P11 mg/dL; and serum creatinine P2 mg/
`dL.4 Lenalidomide was shown to be predominantly elimi-
`nated via urinary excretion, and effects of lenalidomide
`are therefore dependent on renal function.20 In patients
`with severe renal dysfunction (creatinine clearance
`<30 mL/min), TTP and overall survival after lenalidomide
`plus dexamethasone treatment tended to be shorter, com-
`pared with patients with a better creatinine clearance
`(>30 mL/min); these results were still significantly higher
`than for patients treated with dexamethasone alone.21 In
`patients with impaired renal function dose adjustments
`are required. Recently, recommendations for initial starting
`doses in these patients have been provided.20
`Recently recognised chromosomal changes, such as dele-
`tion of chromosome 13 (del 13), deletion of chromosome
`17, and translocation of 4;14 (t[4;14]), have been found to
`be prognostic for a more unfavourable clinical course, and
`these findings are likely to find application in future risk-
`adaptive treatment strategies.22 A recent study from the
`University of Calgary, Canada, has found that patients with
`and without chromosomal changes (del 13 or t[4;14]) re-
`sponded equally well to lenalidomide plus dexamethasone
`treatment, with little difference between the patient
`groups in either the response rate (CR + PR) or event-free
`survival.23
`Notably, neither advancing age (>65 years) nor the inclu-
`sion of patients ineligible for ASCT had a significant impact
`on the treatment response with lenalidomide plus dexa-
`methasone.24–27 Subgroup analysis from the phase III stud-
`ies found that the same clinical benefit was achieved in
`both elderly (>65 years) and younger (665 years) patients
`
`in terms of the overall response (58.9% vs 60.9%, respec-
`tively). However, TTP and overall survival were slightly
`shorter in the young (11.0 months and 29.8 months, respec-
`tively) compared with the elderly (14.0 months and overall
`survival not reached, respectively);24 similar results were
`also obtained in patients aged P75 years.26 These findings
`are reflected in data from the Canadian Expanded Access
`Programme, which found that among the elderly and the
`young, there was little difference in PR (58% vs 56%, respec-
`tively; p = 0.15), progression-free survival (PFS; 43% vs 43%,
`respectively), or overall survival (74% vs 76%, respectively)
`following a median of 4 cycles (range 1–8) of treatment
`with lenalidomide plus dexamethasone, with or without
`prednisone.27
`Evidence from the phase III studies found that both pre-
`viously-transplanted
`and
`non-transplanted
`patients
`achieved comparable rates of overall response (63% vs
`55%, respectively) and CR (13% vs 16%, respectively) with
`lenalidomide plus dexamethasone treatment. However,
`there was a trend towards a slightly longer TTP in those
`without prior ASCT (median 10.3 months vs 14.3 months;
`p = 0.13).25
`
`Adverse events
`
`While the phase III studies found that combining lenalido-
`mide with high-dose dexamethasone was associated with
`more side effects than dexamethasone alone (19.8% vs
`10.2%, respectively, of patients dropped out of the study
`because of side effects), this has to be considered in the
`context of the improved overall response rate. Only 38.4%
`of patients in the lenalidomide plus dexamethasone group
`withdrew from the study because of disease progression,
`compared with 71.6% of those taking dexamethasone
`alone.15
`Lenalidomide is not associated with the same frequency
`or severity of side effects commonly seen with thalidomide,
`such as neuropathy, constipation, or somnolence. Myelosup-
`pression (grade 3–4 neutropenia and thrombocytopenia),
`which was the dose-limiting side effect from phase I studies
`of lenalidomide, is the most frequent adverse event and can
`be effectively managed by dose reductions and interrup-
`tions. The incidence of grade 3–4 neutropenia (41.2% in
`the MM-009 study and 29.5% in the MM-010 study) was
`three-times higher than that of thrombocytopenia (14.7%
`in MM-009 and 11.4% in MM-010).15,16
`Notably, Richardson et al. observed that the proportion
`of patients who experienced grade 3–4 myelosuppression
`was significantly higher in patients who had received prior
`treatment with ASCT.14 This finding was confirmed by the
`phase III studies which found that the incidence of grade
`3–4 neutropenia with lenalidomide plus dexamethasone
`was significantly higher in patients who had received prior
`ASCT (38.1% vs 27.3%; p < 0.05).25 The risk of grade 3–4
`myelosuppression, and thrombocytopenia in particular, fol-
`lowing treatment with lenalidomide is also significantly in-
`creased in patients with impaired renal function21,28,29
`emphasizing the need for appropriate dose reduction. Evi-
`dence from the Canadian Expanded Access Programme
`shows that treatment with lenalidomide plus dexametha-
`sone (with or without prednisone) was equally well-toler-
`
`ALVOGEN, Exh. 1043, p. 0004
`
`

`

`Lenalidomide: A new therapy for multiple myeloma
`ated in both elderly (>65 years) and young (665 years) pa-
`tients with 46% and 49%, respectively, remaining on therapy
`after a median of 4 cycles (range 1–8) of treatment.27
`Regardless of age, among the elderly and young a similar
`incidence of grade 3–4 neutropenia (46% vs 44%, respec-
`tively), grade 3–4 thrombocytopenia (38% vs 24%), febrile
`neutropenia (12% vs 9%), infection (25% vs 16%), and grade
`3–4 fatigue (13% vs 11%) was recorded, with no significant
`differences between the groups.27
`Since myelosuppression is common with lenalidomide
`treatment a group of experts have provided some clinical
`guidance for the management of cytopenias. In general, pa-
`tients’ blood count should be monitored on a biweekly basis
`during lenalidomide treatment, but weekly monitoring is
`recommended in patients with cytopenias at baseline.30 In
`case cytopenias occur, granulocyte-colony stimulating fac-
`tor (G-CSF) or erythropoietin stimulating agents might be
`needed, and in more severe cases dose reductions or inter-
`ruptions might are required.30 In addition, the group recom-
`mends the consideration of routine antibiotic prophylaxis
`for all patients upon initiation of lenalidomide treatment.31
`While there is a benefit of the combination of lenalido-
`mide and dexamethasone for the treatment of MM com-
`pared with lenalidomide as monotherapy,14 studies also
`show that the addition of dexamethasone increases the risk
`of deep-vein thrombosis. In the North American study (MM-
`009), grade 3–4 thromboembolic events occurred in 14.7%
`of patients treated with lenalidomide plus dexamethasone,
`and 3.4% of patients in the dexamethasone alone group.15 In
`the other study (MM-010), grade 3–4 thromboembolic
`events occurred in 11.4% of patients treated with lenalido-
`mide plus dexamethasone and 4.5% of patients in the dexa-
`methasone alone group.16 Additional studies have shown
`that the risk of a thrombotic event further increased in pa-
`tients treated with lenalidomide, who had a history of prior
`thalidomide treatment, or concomitant erythropoietin
`use.18,32
`Also, both lenalidomide and thalidomide are associated
`with an increased risk of venous thromboembolism, particu-
`larly when used with high-dose dexamethasone. Across a
`number of studies in MM patients treated with lenalidomide
`plus dexamethasone, venous thromboembolism rates vary
`widely (3–75%).14,32–35 As a result, safety concerns persist
`for lenalidomide in MM despite FDA approval.36 It should
`be remembered, however, that patients with MM are at rel-
`atively high baseline-risk of developing thromboembolic
`events, especially deep-vein thrombosis. Upfront combina-
`tions, including thalidomide plus low-dose dexamethasone
`and/or alkylating agents, are associated with intermediate
`risk, whereas the same regimens for relapsed/refractory
`MM seem to be associated with lower risk.37 The risk of
`thromboembolic events may be particularly high when spe-
`cific risk factors increase the thrombogenic potential of the
`immunomodulatory agents. These risk factors are: combina-
`tional regimen including doxorubicin or high-dose dexa-
`methasone; newly diagnosed disease;
`immobilization;
`infection; and history of thromboembolism.32,37,38 National
`Comprehensive Cancer Network Guidelines recommend
`prophylactic anticoagulation in patients treated with lena-
`lidomide plus dexamethasone.5 Several different thrombo-
`prophylaxis strategies have been effective in lowering the
`risk of developing clots: daily aspirin (81–325 mg/day);
`
`287
`
`full-intensity warfarin (International Normalized Ratio 2–
`3); and prophylactic subcutaneous enoxaparin (40 mg/
`day). However, none of these prevention strategies has
`been prospectively compared, so the choice often reflects
`physician and/or patient preference.34,37,36,39 A panel of ex-
`perts recommend a 4- to 6-month course of prophylaxis in
`patients with risk factors, with low-dose aspirin (81–
`100 mg) or prophylactic doses of low-molecular-weight
`heparin.40
`
`Other lenalidomide combinations
`
`The clinical safety and efficacy of lenalidomide in combina-
`tion with other agents for the management of patients with
`relapsed/refractory MM has been evaluated in a number of
`clinical trials (Table 1). In a phase I/II clinical trial at the
`Cleveland Clinic Cancer Center, the combination of lenalid-
`omide (10 mg/day, on Days 1–21) plus DVd, which com-
`prised
`intravenous
`pegylated
`liposomal
`doxorubicin
`(40 mg/m2), intravenous vincristine (2 mg on Day 1), and
`oral dexamethasone (40 mg/day on Days 1–4) every 28-
`day cycle was evaluated. Overall, 41 of 62 patients included
`in the trial had failed a previous thalidomide-containing reg-
`imen. The lenalidomide plus DVd regimen was found to be
`well tolerated with a PR or better, recorded in 75% of pa-
`tients (29% achieving a CR or near-CR) and a median PFS
`of 12 months.41 Myelosuppression was acceptable, with a
`7% incidence of
`febrile neutropenia. Thromboembolic
`events were recorded in 9% of patients and grade 3 periph-
`eral neuropathy in 5%.
`Data of a phase I/II study evaluating the efficacy and
`safety of lenalidomide (15 mg for 21 days) used in combina-
`tion with adriamycin (9 mg/m2 for Days 1–4 as a continuous
`infusion) and dexamethasone (40 mg/day on Days 1–4 and
`17–20) have also been presented. After two unexpected
`events of non-febrile neutropenia,
`the protocol was
`amended to include G-CSF support (6 mg of pegfilgrastim
`on Day 6), resulting in an uneventful course in all patients
`treated subsequently at the two highest dose levels of lena-
`lidomide.42 Of the 22 patients evaluable for a response, a
`response (at least PR) was achieved in 18 patients (82%).
`These data provide evidence for the efficacy and acceptable
`toxicity profile of lenalidomide plus adriamycin and dexa-
`methasone in the treatment of relapsed MM.18
`In a second study, heavily pre-treated patients (median
`of previous lines of therapy 4 [range 1–8]) were treated
`with oral daily doses of lenalidomide (25 mg for 21 days of
`a 28-day cycle)
`in combination with dexamethasone
`(40 mg/day on Days 1–4 and 12–15) and cyclophosphamide
`(500 mg/day on Days 1, 8, 15, and 28) of for a maximum of 6
`cycles. The study found that this combination was effective,
`and had a manageable toxicity profile. Of the 20 patients as-
`sessed, 15 patients achieved a response, including 1 CR and
`3 very good partial responses (VGPR).43 Only 2 patients dis-
`continued treatment due to a failure to respond, and an-
`other patient discontinued due to liver toxicity. Neutrophil
`counts were maintained and managed by administration of
`G-CSF in 12 patients, a dose reduction or interruption of
`cyclophosphamide in 10 patients, and a dose reduction or
`interruption of lenalidomide in 5 patients. A further study
`is now ongoing to investigate this treatment regimen with
`cyclophosphamide on Days 1 and 8 only.
`
`ALVOGEN, Exh. 1043, p. 0005
`
`

`

`288
`
`A. Palumbo et al.
`
`10
`
`8
`
`4
`
`14
`24
`18
`
`43
`52
`17
`
`21
`
`14
`
`6
`
`13
`
`3
`
`6
`
`100%at1year
`NR
`97%at1year
`88%at3years
`
`3–4,%
`grade
`Infection
`
`grade3–4,%
`Thrombocytopenia
`
`3–4,%
`grade
`Neutropenia
`
`3–4,%
`VTEgrade
`
`grade3–4,%
`Peripheralneuropathy
`
`months
`MedianOS,
`
`NR
`
`months
`
`14
`24
`31
`
`18
`
`71
`81
`88
`
`91
`
`PPR,%CR,%MedianPFS,
`
`years(range)
`Medianage,
`
`n
`
`Therapy
`
`Table2Summaryofclinicaltrialswithlenalidomidecombinationtreatmentinthemanagementofnewlydiagnosedmultiplemyeloma
`
`At the 2006 annual American Society of Hematology
`Meeting, Richardson et al. presented the results of the first
`study combining lenalidomide (5–15 mg/day) with bortezo-
`mib (1.0 or 1.3 mg/m2). The study, conducted in heavily
`pre-treated relapsed/refractory patients with MM (median
`prior therapies 5 [range 1–13]), found that the combination
`of lenalidomide plus bortezomib with or without dexameth-
`asone achieved at least a minimal response rate of 58%,
`including a CR/near-CR in 6% of patients.44 Responses were
`long-lasting (median 6 months, range 1–26) and 11 patients
`remained on therapy for more than 1 year. Additionally,
`preliminary data from a phase II trial of lenalidomide
`(15 mg/day) plus bortezomib (1.0 mg/m2) and dexametha-
`sone (40 mg/day) demonstrated a 50% overall response rate.
`However, although dexamethasone dose reductions were
`needed in the majority of patients, the combination was
`otherwise well tolerated.45
`
`Newly diagnosed MM
`
`Lenalidomide plus dexamethasone
`
`A phase II trial was conducted to evaluate the efficacy and
`safety of lenalidomide plus dexamethasone as initial ther-
`apy for MM (Table 2). A total of 34 patients were enrolled
`and were treated with oral daily doses of lenalidomide
`(25 mg on Days 1–21 of each 28-day cycle) and dexametha-
`sone (40 mg/day on Days 1–4, 9–12, and 17–20).46,47 For
`patients who continued therapy beyond 4 months, the dose
`of dexamethasone was reduced to 40 mg/day on Days 1–4
`of each cycle only. Patients also received once-daily aspirin
`(81 mg or 325 mg, at the discretion of the physician) as
`thromboprophylaxis. Overall, 13 patients proceeded to
`ASCT after a median of 4 cycles of lenalidomide plus dexa-
`methasone treatment (and were evaluated at that time),
`while 21 patients stayed on treatment for a median of 19 cy-
`cles (range 2–30).46 The combination was found to be highly
`effective: the overall response rate was 91%; the CR or
`VGPR rate was 56%. Among the patients staying on the com-
`bination treatment as primary therapy without stem cell
`transplantation, the CR or VGPR rate was 67%.46 Two-year
`PFS and the 3-year overall survival were 59% and 85%,
`respectively.46 In the 13 patients who received ASCT the
`2-year PFS was 83%, and the 3-year overall survival was
`92% (Table 2).46 Half of the patients had grade 3 or greater
`non-haematological toxicities (mostly fatigue).46 Only 1 pa-
`tient developed a pulmonary embolism (grade 4 toxicity)
`and recovered with therapy; no other thromboembolic
`events were recorded.47 Overall, myelosuppression was
`minimal in this trial, probably reflecting the better bone
`marrow reserves in patients who had previously been un-
`treated.47 Furthermore, the researchers found no adverse
`effect on stem-cell mobilization, indicating that lenalido-
`mide plus dexamethasone treatment would be useful as a
`pre-transplantation conditioning regimen.46,47 However,
`Kumar et al. reported a trend towards a lower CD34+ stem
`cell yield within 12 months of diagnosis in patients who re-
`ceived lenalidomide plus dexamethasone, and hence recom-
`mended that CD34+ stem cells be collected within 6 months
`of initiation of lenalidomide containing treatments.48 It
`must be noted that this was a retrospective study, and that
`
`NR=notreached;OS=overallsurvival;PFS=progression-freesurvival;PR=partialresponse;VTE=venousthromboembolism.
`BiRD=lenalidomideplusdexamethasoneandclarithromycin;CR=completeresponse;Dex=dexamethasone;Len=lenalidomide;MPR=lenalidomideplusmelphalanandprednisone;
`
`74(72–85)
`71(57–77)
`63(36–83)
`
`64(32–78)
`
`54
`72
`44565
`
`MPR51
`MPR50
`BiRD49
`Len+Dexlow-dose35
`Len+Dexhigh-dose4634
`
`7
`
`ALVOGEN, Exh. 1043, p. 0006
`
`

`

`Lenalidomide: A new therapy for multiple myeloma
`
`289
`
`only 3 of the 43 patients failed to mobilize. These patients
`were all older than 67 years of age, and had received 7–
`11 months of therapy before the attempt at stem cell mobi-
`lization was made.48
`In a randomized phase III study (E4A03) the efficacy and
`safety of lenalidomide plus low-dose dexamethasone was
`compared with lenalidomide plus high-dose dexametha-
`sone. The study enrolled 445 patients who were treated
`with lenalidomide (25 mg/day on Days 1–21 of each 28-
`day cycle) plus high-dose dexamethasone (40 mg/day on
`Days 1–4, 9–12, and 17–20 of every cycle), or lenalidomide
`plus low-dose dexamethasone (40 mg/day on Days 1, 8, 15,
`and 22 of every cycle). The study showed that overall sur-
`vival at first interim analysis was significantly superior with
`lenalidomide plus low-dose dexamethasone, compared with
`lenalidomide plus high-dose dexamethasone (97% vs 86%,
`respectively; p < 0.001). Moreover, toxicities were higher
`with lenalidomide plus high-dose dexamethasone, com-
`pared with lenalidomide plus low-dose dexamethasone:
`the incidence of grade P3 thromboembolism (22.1% vs
`6.1%); infection/pneumonia (15.7% vs 7.5%); and hyper-
`glycaemia (9.7% vs 6.6%) (Table 2).35
`A second phase II trial evaluated the safety and efficacy of
`once-daily oral dosing with lenalidomide (25 mg on Days 1–21
`of each 28-day cycle) in combination with dexamethasone
`(40 mg once weekly) and clarithromycin (500 mg twice daily)
`(Table 2).29,49 A total of 72 patients (54% of whom had Inter-
`national Staging System disease classification stage >2) were
`followed up for a mean of 10 months. Once again, the
`combination yielded a high overall response rate (88%)
`with 31% (achieving a CR or near-CR).49 The study found
`that both myelosuppression and a baseline serum creatinine
`level of >1.4 mg/dL were highly predictive of a dose
`reduction.29
`
`Melphalan, prednisone, and lenalidomide
`
`Based on the encouraging results from trials with lenalido-
`mide plus dexamethasone combination therapy, phase I/II
`dose-finding studies were conducted to evaluate the safety
`and efficacy of lenalidomide used in combination with mel-
`phalan and prednisone, in newly diagnosed elderly patients
`who were not candidates for stem cell transplantation
`(Table 2).50,51 In the first of these studies, Palumbo et al.
`investigated 9 courses of treatment with oral lenalidomide
`(5–10 mg/day for 21 days every 4–6 weeks) used in combi-
`nation with melphalan (0.18–0.25 mg/kg) and prednisone
`(2 mg/kg for 4 days every 4–6 weeks), followed by mainte-
`nance therapy with once-daily oral lenalidomide (10 mg/day
`for 21 days every 4–6 weeks).50 Aspirin (100 mg/day) was
`used to prevent deep-vein thrombosis. The study found that
`this combination was well tolerated and effective in newly
`diagnosed elderly patients.50 In all patients, a 1-year
`event-free survival of 92% and a 1-year overall survival of
`100% was reported. At
`the maximum tolerated dose
`(0.18 mg/kg melphalan and 10 mg/day lenalidomide),
`47.6% of patients achieved at least a VGPR and 23.8% a
`CR. Grade 3–4 adverse events were mainly related to hae-
`matological toxicities such as neutropenia (52.4%) and
`thrombocytopenia (23.8%). Severe non-haematological side
`effects were less frequent, and included febrile neutropenia
`(9.5%), cutaneous
`rash (9.5%), and thromboembolism
`
`(5.8%). The addition of aspirin markedly reduced the risk
`of thromboembolic events in this study.50
`These findings were confirmed in a subsequent study which
`defined the maximum tolerated doses: as 5 mg/m2 for mel-
`phalan, 60 mg/m2 for prednisone, and 10 mg for lenalido-
`mide.51 Notably, the results from Palumbo et al. showed
`that combination treatment with lenalidomide appeared to
`overcome the poor prognosis conferred by del 13 with
`event-free survival not significantly different between those
`who did and did not have this abnormality.50 These results
`have been corroborated by Bahlis et al. who found that nei-
`ther the presence of del 13 nor t(4;14) impacted on the re-
`sponse rates (71.5% vs 86.0%, respectively) or the event-
`free survival (71.4% vs 72.4%, respectively; p = 0.66) at
`6 months.23
`
`Amyloidosis
`
`Based on the encouraging results seen with lenalidomide in
`MM patients, a phase II trial was conducted in order to evalu-
`ate the haematological response rate and toxicity of lenalid-
`omide monotherapy and lenalidomide plus dexamethasone
`combination