Journal of Clinical Pharmacy and Therapeutics (2008) 33, 219–226
`
`REVIEW ARTICLE
`
`Lenalidomide in the treatment of multiple myeloma:
`a review
`X. Armoiry*  PharmD PhD, G. Aulagner*  PharmD PhD and T. Faconà MD PhD
`*Pharmacy Department, Groupement Hospitalier Est, Hospices Civils de Lyon, Lyon,  Faculty of Pharmacy,
`Henri Poincare´ University, Nancy and àHematology Department, Hoˆpital Claude Huriez, Centre
`Hospitalier Universitaire Re´gional de Lille, Lille, France
`
`S U M M A R Y
`
`I N T R O D U C T I O N
`
`Lenalidomide is an immunomodulatory drug
`derived from thalidomide. It was developed to
`maximize the anti-inflammatory and anti-neo-
`plasic properties of thalidomide and to reduce its
`toxicity. The molecular mechanism of action of
`lenalidomide is unclear, but
`its therapeutic
`activity is mainly due to its well defined anti-
`inflammatory, immunomodulatory, anti-prolifer-
`ative and anti-angiogenic properties. In relapsed
`or refractory multiple myeloma (MM), lenalido-
`mide, combined with standard dose dexametha-
`sone,
`is superior to dexamethasone alone in
`terms of time to progression, response rate and
`overall survival. The most commonly reported
`adverse events include haematological toxicity
`with manageable neutropenia and thrombope-
`nia. Lenalidomide does not trigger the limiting
`toxicities of thalidomide: somnolence, neuropa-
`thy and constipation. Lenalidomide, in combi-
`nation with dexamethasone, is indicated for the
`treatment of MM patients who have received at
`least one prior therapy and is administered orally
`at the dose of 25 mg q.d. for 21 days of 28-day
`cycles. The drug is being investigated for the
`treatment of newly diagnosed MM.
`In this
`review, we summarize the pharmacokinetic,
`pharmacodynamic and clinical
`trial data on
`lenalidomide.
`
`Keywords: immunomodulatory drugs, lenalido-
`mide, myeloma
`
`Received 23 October 2007, Accepted 27 February 2008
`Correspondence: X. Armoiry, Pharmacy Department, Groupe-
`ment Hospitalier Est, Avenue de Doyen Le´pine, 69 500 Bron,
`France. Tel.: +33 472 357 245; fax: +33 472 357 331; e-mail:
`xavier.armoiry@chu-lyon.fr
`
`Multiple myeloma (MM), also called Kahler’s
`disease, is a rare progressive neoplastic disorder of
`unknown aetiology (1, 2) characterized by accu-
`mulation of a plasma cell clone in the bone mar-
`row. The diagnosis is mainly based on plasma cells
`infiltration in the bone marrow (more than 10% of
`nuclear cells), osteolytic lesions and the presence of
`monoclonal (M) immunoglobulin (or fragment) in
`serum or urine (3). MM represents about 10% of
`haematological malignancies and 1% of all cancers.
`The diagnosis of MM is made in about 21 000
`patients ⁄ year in Europe with approximately 16 000
`annual deaths from the disease (4). MM is pri-
`marily a disease of the elderly, with a median age
`at diagnosis of 68 years. Prior to the introduction of
`alkylating agents, the median survival for patients
`with MM was 12–17 months from time of diagnosis
`(5). The combination of melphalan plus prednisone
`(MP) has remained the gold standard therapy for
`decades, although complete remission (CR) was
`rare (<5%) and median survival did not exceed
`3 years (6). In the 1990s, high-dose therapy (HDT)
`with autologous stem cell
`transplantation was
`shown to prolong survival (about 12 months with
`an acceptable mortality rate of 1–2%), when com-
`pared with conventional
`therapy (7). Despite
`intensive therapy, MM remains an incurable
`disease.
`In the last 10 years,
`thalidomide and
`bortezomib have been shown to be effective in the
`treatment of relapsed or refractory MM (8–10) and
`promising in newly diagnosed MM (11–13). More
`recently,
`lenalidomide has been developed and
`evaluated, not only for relapsed or refractory MM
`but also for newly diagnosed MM (14–17). Lena-
`lidomide (CC-5013 trade name REVLIMIDÒ) is the
`leading drug among the immunomodulatory
`
`Ó 2008 Blackwell Publishing Ltd
`
`219
`
`ALVOGEN, Exh. 1041, p. 0001
`
`

`

`lenalidomide
`As an immunomodulatory drug,
`inhibits the secretion of pro-inflammatory cyto-
`kines including TNF-a, interleukin (IL)-1b, IL-6 and
`IL-12 from lipopolysaccharide (LPS)-stimulated
`peripheral blood mononuclear
`cells
`(PBMC)
`(18, 19). It also increases production of the anti-
`inflammatory cytokine IL-10 by LPS-stimulated
`PBMC and consequently inhibits the expression,
`but not the enzymatic activity, of cyclooxygenase-2
`(20). Lenalidomide induces T-cell proliferation and
`IL-2 and interferon (IFN)-c production (19, 21) and
`it augments cytotoxic activity of natural killer cells
`(22).
`Lenalidomide has anti-angiogenic properties as
`it suppresses vascular endothelial growth factor
`and basic fibroblast growth factor production by
`the endothelium and bone marrow stroma, with
`consequent inhibition of angiogenesis (23).
`The activity profile of lenalidomide is similar to
`that of thalidomide but, in vitro, lenalidomide is 50
`to 2000 times more potent in inhibiting cytokines
`production by LPS-stimulated PBMC, such as
`TNF-a, IL-1b or IL-6 (24).
`
`P H A R M A C O K I N E T I C P R O F I L E
`
`Single-dose lenalidomide pharmacokinetics was
`assessed in a phase I, single-blind, placebo-con-
`trolled, ascending study in 19 healthy volunteers
`(25). Lenalidomide was rapidly absorbed following
`oral administration with maximum plasma con-
`centrations (Tmax) occurring between 0Æ6 and 1Æ5 h
`post-dose. Maximal plasma concentration (Cmax)
`and area under the curve (AUC) increased in a
`dose-proportional manner over the single dose
`range of 5–400 mg. Co-administration with food
`did not alter the extent of absorption (AUC) but did
`reduce Cmax by 36%. The pharmacokinetic dispo-
`sition of lenalidomide is linear. In vitro (14C)-le-
`nalidomide
`binding
`to plasma proteins
`is
`approximately 30%. The metabolic profile of lena-
`lidomide in humans has not been studied.
`In
`healthy volunteers, approximately two-thirds of
`lenalidomide is eliminated unchanged through
`urinary excretion. The process exceeds the glo-
`merular filtration rate and is therefore partially or
`entirely active. Half-life of elimination is approxi-
`mately 3 h. In patients with MM, maximum plasma
`concentrations occurred between 0Æ5 and 4Æ0 h
`post-dose both on days 1 and 28. AUC and Cmax
`
`O
`
`NH
`
`O
`
`O
`
`N
`
`O
`
`220 X. Armoiry et al.
`
`Fig. 1. Chemical structure of thalidomide.
`
`NH
`
`O O
`
`N
`
`O
`
`NH2
`
`Fig. 2. Chemical structure of lenalidomide.
`
`compounds derived from thalidomide aimed at
`maximizing its anti-inflammatory and anti-neo-
`plasic properties and improve its tolerability. This
`new drug is a synthetic glutamic acid derivative
`obtained from thalidomide by the removal of an
`oxy group from the phthalyl ring and by the
`addition of an amino group (Figs 1 and 2). This
`review focuses on the efficacy and tolerability of
`lenalidomide in the treatment of MM.
`
`P H A R M A C O D Y N A M I C P R O P E R T I E S
`
`Lenalidomide is a small molecule analogue of
`thalidomide that was originally identified based on
`its ability to potently inhibit tumour necrosis factor
`(TNF)-a production. It is now known that
`the
`therapeutic activity of lenalidomide is likely due to
`multiple mechanisms of action: anti-inflammatory,
`immunomodulatory, anti-proliferative and anti-angio-
`genic (Fig. 3).
`Lenalidomide exerts direct anti-proliferative and
`pro-apoptotic effects on MM cells grown in vitro.
`
`Inhibits stromal
`cell adhesion
`
`Stimulates T cells
`
`Inhibits
`cytokines
`
`IL-6
`TNF
`IL-1
`
`MM cells
`
`Stimulates
`NK cells
`
`Induces
`aptoptosis
`
`Inhibits
`angiogenisis
`
`Fig. 3. Mechanisms of action of lenalidomide in multiple
`myeloma (from Celgene Corporation, France).
`
`Ó 2008 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 33, 219–226
`
`ALVOGEN, Exh. 1041, p. 0002
`
`

`

`values increase proportionally with dose following
`single and multiple doses. Exposure (AUC) in MM
`patients is 57% higher than in healthy male vol-
`unteers.
`In a phase I trial in patients with MM (26), the
`mean terminal elimination half-lives were 3Æ1–4Æ2 h
`on both day 1 and day 28. There was little or no
`accumulation of CC-5013. Intersubject variability
`was generally low to moderate for AUC and Cmax,
`with values ranging from 10Æ6% to 51Æ8% and 3%
`to 33% on day 1 and day 28, respectively.
`Multiple myeloma patients with mild renal
`impairment had an AUC 56% greater than those
`with normal renal function. Pharmacokinetic dif-
`ferences due to race, gender, age or hepatic
`impairment have not been studied.
`
`T H E R A P E U T I C T R I A L S
`
`Main studies for the approval in relapsed or
`refractory MM
`
`Phase I and phase II trials. The clinical programme of
`lenalidomide in MM started in April 2000 with the
`initiation of two phase I studies in heavily pre-
`treated patients with relapsed or refractory MM.
`Both trials were designed to identify the maximum
`tolerated dose (MTD) and to evaluate the safety of
`lenalidomide monotherapy in this population.
`Cytopenias were the dose-limiting toxicity in both
`studies and the MTD of lenalidomide was deter-
`mined to be 25 mg ⁄ day for 21 days ⁄ month.
`No significant somnolence, constipation or neu-
`ropathy was observed with continued lenalido-
`mide therapy. However,
`reversible cytopenias
`were observed during the second cycle of treat-
`ment in subjects who received 25 mg ⁄ day. In the
`first study of the 24 evaluable patients treated
`according to this schedule, 29% had an M para-
`protein reduction superior to 50%;
`in 71% of
`patients, the M component decreased to at least
`25% (26). In the second study, 20% of the subjects
`achieved a reduction of M paraprotein superior to
`50% at doses of 25–50 mg ⁄ day (27).
`The results of two phase II trials are also avail-
`able (28, 29).
`The first one was a multicentre, single-arm,
`open-label study conducted to evaluate the efficacy
`and safety of single-agent lenalidomide, adminis-
`tered at a dose of 30 mg q.d. for 21 days every
`
`Lenalidomide in the treatment of multiple myeloma
`
`221
`
`28 days (28-day cycle) in patients (n = 222) with
`relapsed or refractory MM (28). Twenty-five per
`cent of patients achieved partial reference or
`complete response (PR + CR) and 71% achieved
`stable disease or better and the median time
`to progression (TTP) was approximately 6 months.
`The second study was an open-label, random-
`ized trial to evaluate two dose-regimens of lena-
`lidomide for patients (n = 102) with relapsed or
`refractory MM (29). Patients were randomized to
`receive either 30 mg q.d. or 15 mg b.i.d.,
`for
`21 days of every 28-day cycle. With progressive or
`stable disease after two cycles, patients received,
`additionally, 40 mg dexamethasone for 4 days
`every 14 days. Patients receiving 15 mg twice daily
`showed an increased rate of grade 3 ⁄ 4 myelo-
`suppression (41% vs. 13%, P = 0Æ03). The overall
`response (OR) rate was 25% and the median
`overall survival (OS) in the 30 mg once-daily and
`twice-daily groups was 28 and 27 months, respec-
`tively. Dexamethasone was added in 68 patients
`and 29% responded.
`The preliminary results of this study were the
`basis for the once-daily regimen of lenalidomide,
`combined with dexamethasone, used in the sub-
`sequent phase III trials.
`
`Phase III trials. The approval of lenalidomide for
`the treatment of relapsed or refractory MM was
`mainly based on the results of pivotal studies
`(MM-009 and MM-010) initiated in 2003. The FDA
`agreed that
`the best comparator was standard
`dose dexamethasone. The studies were multicen-
`tre, multinational,
`randomized, double-blind,
`placebo-controlled trials to evaluate and compare
`the
`efficacy of
`lenalidomide plus high-dose
`dexamethasone
`(Rev-Dex) vs. dexamethasone
`alone (Dex).
`MM-009 trial was undertaken in North America
`and MM-010 in Europe,
`Israel and Australia.
`A total of 354 and 351 patients were recruited
`respectively.
`Lenalidomide was given at the dose of 25 mg
`q.d. for 21 days of every 28-day cycle and dexa-
`methasone at the dose of 40 mg from days 1 to 4, 9
`to 12 and 17 to 20 every 28-day cycle for four cycles
`then from days 1 to 4 for subsequent cycles.
`Investigational treatment had to be stopped at the
`time of disease progression or in case of unac-
`ceptable adverse events.
`
`Ó 2008 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 33, 219–226
`
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`

`222 X. Armoiry et al.
`
`The primary endpoint was TTP according to
`Blade et al.’s criteria (30) and secondary endpoint
`included OS, OR rate and safety. A preplanned
`interim analysis of TTP, response rate and safety
`was performed by an Independent Data Monitor-
`ing Committee (IDMC).
`The results presented below relate to analyses of
`data encompassing the whole double-blind period
`(2003 to summer 2005).
`In the MM-009 North American Phase III trial
`(31, 32), the median TTP with Rev-Dex was supe-
`rior to the one in the Dex arm (48Æ1 weeks vs.
`20Æ1 weeks, P < 0Æ01). The hazard ratio for TTP was
`2Æ82 (95% CI, 2Æ14–3Æ7, P < 0Æ001). The OR rate was
`61% in the Rev-Dex arm and 19Æ9% in Dex arm
`including 14Æ1% and 0Æ6% of CR, respectively. OS
`time was longer for patients treated in the Rev-Dex
`arm (29Æ6 vs. 20Æ2 months) with a hazard ratio of
`1Æ52 (95% CI, 1Æ04–2Æ24, P = 0Æ03).
`The MM-010 trial reported very similar results
`with TTP of 48Æ7 weeks in the Rev-Dex arm vs.
`20Æ1 weeks in the Dex arm (33, 34). The hazard ratio
`for TTP was 2Æ85 (95% CI, 2Æ16–3Æ76, P < 0Æ001). OR
`rate was greater with Rev-Dex regimen (60Æ2% vs.
`24% including 15Æ9% and 3Æ4% of CR respectively).
`The OS was also superior for patients in the Rev-
`Dex arm (not estimable as of May 2006 in this arm
`vs. 20Æ6 months in the Dex arm, P < 0Æ01) with a
`hazard ratio of 2Æ10.
`The interim analysis of TTP and response rate
`was performed at the start of 2005. Since the results
`already surpassed the preplanned significance
`threshold, the IDMC decided in early 2005 to lift
`the blind and recommended that all patients in the
`Dex arm should be offered the choice of treatment
`with lenalidomide–dexamethasone combination.
`The impact of prior therapy with thalidomide on
`sensitivity of MM to subsequent lenalidomide was
`evaluated in a prospective subgroup analysis of
`MM-009 and MM-010 (35). In patients who had
`received prior thalidomide, the major response rate
`(CR + PR) was significantly higher in the group
`assigned to receive Rev-Dex than in those who
`received Dex alone (53Æ2% vs. 15Æ2%, P < 0Æ001). In
`this subgroup, the CR rate was also significantly
`higher for the Rev-Dex vs. Dex alone group (8Æ1%
`vs. 1Æ4%, P < 0Æ05).
`treatments was also
`Influence of previous
`assessed (36). Median TTP for patients with one
`prior regimen was 16Æ5 months in Rev-Dex patients
`
`vs. 4Æ6 months in Dex alone patients (HR, 2Æ86). For
`patients with two or more prior regimens, median
`TTP was also significantly higher in Rev-Dex group
`(10Æ2 months vs. 4Æ7 months; HR, 2Æ66).
`There was also a significant difference between
`the patients with one prior regimen vs. two or more
`regimens within the Rev-Dex group (P < 0Æ05).
`
`Ongoing clinical development in MM
`
`Newly diagnosed MM. Patients eligible for HDT:
`A first non-comparative phase II trial assessed the
`efficacy of lenalidomide plus dexamethasone for
`newly diagnosed MM (14). Results showed a 91%
`OR rate including 38% of CR ⁄ near complete
`response (nCR). The 2-year progression-free sur-
`vival rates for patients proceeding to HDT and
`patients remaining on Rev-Dex were 83% and
`59%, respectively; the OS rates were 92% and 90%
`at 2 years and 92% and 85% at 3 years, respec-
`tively. The 3-year OS rate for the whole cohort was
`88% (15). On this encouraging basis, phase III trials
`are being conducted in order to evaluate lenalido-
`mide plus dexamethasone as frontline therapy.
`The Eastern Cooperative Oncology Group
`conducted a
`randomized study
`comparing
`lenalidomide plus standard-dose dexamethasone
`(L-highD: 12 days of dexamethasone per month)
`with lenalidomide plus low-dose dexamethasone
`(L-lowD: 4 days of dexamethasone per month) (16).
`The interim analysis reported a 1 year survival rate
`of 96Æ5% in the R-lowD arm vs. 86% in the R-highD
`arm (17). Major grade 3 or higher toxicities were
`significantly higher in the R-highD arm: thrombo-
`embolism (22Æ1% vs. 6Æ1%), infection ⁄ pneumonia
`(15Æ7% vs. 7Æ5%) and hyperglycaemia (9Æ7% vs.
`6Æ6%).
`Patients not eligible for HDT: With the same
`therapeutic approach taken with bortezomib and
`thalidomide (11–13), lenalidomide is being evalu-
`ated in combination with the MP standard (R-MP)
`for the treatment of newly diagnosed MM in
`patients not eligible for HDT (elderly patients).
`Recently, a phase I ⁄ II trial conducted in 54 patients
`estimated that the MTD was 0Æ18 mg ⁄ kg melphalan
`and 10 mg lenalidomide (37). With these doses,
`81% of patients achieved at least a partial response,
`47Æ6% achieved a very good partial response and
`23Æ8% achieved a CR. A phase III trial comparing
`R-MP to MP (MM-015) is ongoing (38).
`
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`Maintenance therapy. The use of maintenance ther-
`apy is mainly discussed in younger patients in
`order to improve the quality of response or to
`maintain it. Lenalidomide is being evaluated in two
`phase III placebo-controlled trials conducted by
`two cooperative groups (the Intergroupe Franco-
`phone du Mye´lome and the Cancer and Leukemia
`Group B), to assess its efficacy at prolonging the
`duration of the response after autologous stem cell
`transplantation in patients under the age of 65 (39,
`40). In elderly patients, the MM-015 study com-
`paring R-MP to MP will also investigate the role of
`lenalidomide maintenance (38).
`
`Other lenalidomide-based combinations for relapsed or
`refractory MM. Other lenalidomide-based regimens
`are under investigation for the treatment of relapsed
`or refractory MM such as lenalidomide plus doxo-
`rubicin and dexamethasone (RAD) or lenalidomide
`plus pegylated liposomal doxorubicin–vincristin–
`dexamethasone (R-Dvd) (41). In a phase I ⁄ II trial
`evaluating RAD regimen, 26 patients out of 31
`(84%) achieved a partial response including one
`confirmed CR with an acceptable toxicity profile
`(42). Another phase I ⁄ II
`trial reported an OR
`response rate of 75%, with 29% of CR ⁄ nCR in
`patients treated with R-Dvd regimen (43).
`
`S A F E T Y A N D T O L E R A B I L I T Y
`
`Neutropenia were reported more frequently in the
`Rev-Dex arm than in the Dex arm (39Æ4% vs. 6Æ3%)
`including grade 3 (30% vs. 2Æ9%) and grade 4
`(5Æ4% vs. 0Æ6%) severities (44). Grade 4 febrile
`neutropenia episodes were observed infrequently
`(0Æ6% in the Rev-Dex group compared with 0Æ0%
`in the placebo ⁄ dexamethasone group). In case of
`neutropenia, the physician should consider the use
`of growth factors in patient management. Throm-
`bocytopenia and anaemia were also more frequent
`in the Rev-Dex arm as compared with the pla-
`cebo ⁄ Dex arm (18Æ4% vs. 5Æ7% and 17Æ0% vs. 6Æ3%,
`respectively).
`The non-haematological adverse reactions which
`occurred significantly more frequently in the Rev-
`Dex arm group compared with the Dex arm were
`fatigue (27Æ2% vs. 18%), asthenia (17Æ6% vs.
`10Æ9%), constipation (23Æ5% vs. 8Æ9%), muscle
`cramp (20Æ1% vs. 10Æ6%), diarrhoea (14Æ2% vs.
`7Æ1%) and rash (10Æ2% vs. 3Æ4%).
`
`Lenalidomide in the treatment of multiple myeloma
`
`223
`
`Lenalidomide has almost no sedative effects and
`neuropathic effect is minimal.
`Other adverse events, such as nausea, vertigo,
`dyspnoea, occurred less frequently.
`As with thalidomide, thrombotic or thrombo-
`embolic events, including deep venous thrombosis,
`pulmonary
`embolism, were
`reported more
`frequently in the Rev-Dex arm (11Æ3%) than in the
`Dex arm (3Æ8%) (45). Furthermore, a combined
`review of studies MM-009 and MM-010 showed
`that the incidence of deep venous thrombosis was
`significantly higher among the Rev-Dex patients
`who received erythropoietic agents concomitantly
`(19Æ2% vs. 6Æ8%, P = 0Æ001). Therefore, antithrom-
`botic prophylaxis using low-molecular-weight
`heparin, aspirin or warfarin, should be given to all
`patients receiving lenalidomide plus dexametha-
`sone and low-molecular-weight heparin should be
`recommended for patients with additional throm-
`botic risk-factors.
`In MM-009 and MM-010 phase trials, atrial
`fibrillation occurred more frequently in the Rev-
`Dex arm (4Æ0% vs. 0%).
`
`T E R A T O G E N I C P O T E N T I A L
`
`There is no reported data on foetal exposure to
`lenalidomide in humans.
`in rats
`studies
`Embryo-foetal development
`revealed no teratogenic effects at the highest dose
`of 500 mg ⁄ kg (approximately 600 times the human
`dose of 10 mg based on body surface area). A pre
`and post-natal development study in rats revealed
`few adverse effects on the offspring of female rats
`treated with lenalidomide
`at doses up to
`500 mg ⁄ kg. The male offspring exhibited slightly
`delayed sexual maturation and the female off-
`spring had slightly lower body weight gain during
`gestation when bred to male offspring (25).
`As lenalidomide is chemically related to thalid-
`omide, and thalidomide is one of the most terato-
`genic drugs, there is a strict contra-indication to the
`use of lenalidomide during pregnancy. Therefore,
`lenalidomide is available in Europe under the
`conditions described in a specific risk management
`programme for female patients with childbearing
`potential. Prior
`to the start of
`treatment, a
`medically supervised pregnancy test should be
`performed during the consultation, when lenalid-
`omide is prescribed or in the 3 days prior to the
`
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`224 X. Armoiry et al.
`
`Table 1. Dose adjustments recommended at the start of the therapy for patients with impaired renal function
`
`Renal function (CLcr)
`
`Mild renal impairment (CLcr ‡ 50 mL ⁄ min)
`Moderate renal impairment (30 £ CLcr <50 mL ⁄ min)
`Severe renal impairment (CLcr < 30 mL ⁄ min, not requiring dialysis)
`End-stage renal disease (CLcr < 30 mL ⁄ min, requiring dialysis)
`
`Dose adjustment
`
`25 mg once daily (full dose)
`10 mg once dailya
`15 mg every other day
`15 mg, thrice a week following
`each dialysis
`
`aThe dose may be escalated to 15 mg once daily after two cycles if patient is not responding to treatment and is tolerating the treatment.
`
`visit to the prescriber once the patient had been
`using effective contraception for at least 4 weeks.
`Then, the pregnancy test should be repeated every
`4 weeks, including 4 weeks after the end of treat-
`ment, except in the case of confirmed tubal sterili-
`zation. These pregnancy tests should be performed
`on the day of the prescribing visit or in the 3 days
`prior to the visit to the prescriber.
`
`D O S A G E A N D A D M I N I S T R A T I O N
`Lenalidomide (REVLIMIDÒ) is available in 5, 10, 15
`and 25 mg capsules. Based on European Union
`approval,
`the recommended starting dose of
`REVLIMIDÒ is 25 mg ⁄ day with water orally
`administered as a single 25 mg capsule on days
`1–21 of repeated 28-day cycles. The recommended
`dose of dexamethasone is 40 mg ⁄ day on days 1–4,
`9–12 and 17–20 of each 28-day cycle for the first
`four cycles of therapy and then 40 mg ⁄ day orally
`on days 1–4 every 28 days. Dosing is modified, if
`necessary, based upon clinical and laboratory
`findings, in particular in the presence of grade 3 or
`4 neutropenia, thrombocytopenia or other grade 3
`or 4 toxicity judged to be related to lenalidomide.
`Because of its urinary excretion, REVLIMIDÒ must
`be used with caution and dose adapted as shown in
`Table 1 for patients with renal impairment.
`
`C O N C L U S I O N
`
`On the basis of MM-009 and MM-010 phase III
`trials, REVLIMIDÒ is approved in the European
`Union since June 2007, for the treatment of MM
`patients who have received at
`least one prior
`therapy, in combination with dexamethasone.
`Because of its possible teratogenicity, lenalido-
`mide must be used according to a restricted
`
`the
`distribution programme, which requires
`participation of physician, pharmacist and patients.
`This new drug will most likely play an important
`role as frontline therapy for patients with MM. The
`drug is being evaluated for the treatment of other
`haematological malignancies and solid tumours.
`
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