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Blood Reviews 23 (2009) 87–93
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Blood Reviews
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REVIEW
Lenalidomide in combination with dexamethasone for the treatment of relapsedor refractory multiple myeloma
Antonio Palumbo a,*, Meletios Dimopoulos b,k, Jesus San Miguel c,l, Jean-Luc Harousseau d,m, Michel Attal e,n,Mohamad Hussein f,o, Stefan Knop g,p, Heinz Ludwig h,q, Marie von Lilienfeld-Toal i,r, Pieter Sonneveld j,s
a Divisione di Ematologia dell’Università di Torino, Azienda Ospedaliera S. Giovanni Battista, Turin, Italyb Department of Clinical Therapeutics, University of Athens School of Medicine, Athens, Greecec Department of Hematology, University Hospital of Salamanca, Salamanca, Spaind Hôtel-Dieu Hospital, Nantes, Francee Division of Hematology, Centre Hospitalier Université de Purpan, Toulouse, Francef H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USAg Department of Hematology and Oncology, University Hospital, Würzburg, Germanyh Wilhelminenspital, Vienna, Austriai BMTU, Gledhow Wing, St. James’s University Hospital, Leeds Teaching Hospitals, Leeds, UKj Department of Hematology, Erasmus Medical Center, Rotterdam, The Netherlands
a r t i c l e i n f o s u m m a r y
Keywords:Dexamethasone
LenalidomideMultiple myelomaCytopeniaVenous thromboembolism0268-960X/$ - see front matter � 2008 Elsevier Ltd. Adoi:10.1016/j.blre.2008.07.003
* Corresponding author. Tel.: +39 0116336107; faxE-mail addresses: [email protected] (A. Pal
(M. Dimopoulos), [email protected] (J.S. Miguelnantes.fr (J.-L. Harousseau), [email protected] (Mmoffitt.org (M. Hussein), [email protected]@wienkav.at (H. Ludwig), Marie.v_Lilienfeld-ToaLilienfeld-Toal), [email protected] (P. Sonne
k Tel.: +30 210 3381541; fax: +30 210 3381511.l Tel.: +34 923291384.
m Tel.: +33 2 40 08 32 71; fax: +33 2 40 08 32 50.n Tel.: +33 (05) 61777784; fax: +33 (05) 61777541.o Tel.: +1 813 745 8090; fax: +1 813 979 3071.p Tel.: +49 931 201 0; fax: +49 931 201 70281.q Tel.: +43 1491502101; fax: +43 1491501009.r Tel.: +44 228 28715507; fax: +44 228 28714319.s Tel.: +31 10 463 3123; fax: +31 10 463 5814.
Recent studies have shown a clinical benefit of lenalidomide, an oral immunomodulatory drug, plus dexa-methasone in patients with relapsed/refractory multiple myeloma (MM). The most common grade 3–4adverse events were cytopenias, fatigue, muscle cramps, rash, infection, insomnia, and venous thrombo-embolism. Lenalidomide in combination with dexamethasone has been approved by the United StatesFood and Drug Administration and the European Medicines Agency for the treatment of patients withMM who have received at least one prior therapy. An expert panel reviewed the efficacy and toxicityof lenalidomide plus dexamethasone, and provided recommendations on the management of patientsreceiving this treatment. Patient selection is straightforward, as prognostic factors do not appear to heav-ily influence efficacy. In addition, the panel agreed on strategies for the management of side effects. Therecommendations presented here will aid the safe administration of lenalidomide, and avoid unnecessarydose reduction and discontinuation, thus assuring the best efficacy of treatment.
� 2008 Elsevier Ltd. All rights reserved.
Introduction
Multiple myeloma (MM) is a rather common hematologicalmalignancy accounting for approximately 10% of all hematological
ll rights reserved.
: +39 0116963737.umbo), [email protected]), jean-luc.harousseau@univ-
. Attal), [email protected] (S. Knop), [email protected] (M. vonveld).
cancers. MM is responsible for 1.5–2.0% of all cancer-relateddeaths, and 20% of all deaths from hematological malignancies.Despite significant advances in our understanding of the patholog-ical processes underlying the development of this devastating ill-ness, MM remains an incurable malignancy,1 with a mediansurvival of approximately 33 months.2
Conventional-dose chemotherapy and high-dose chemotherapywith stem cell support remain the current standard of care for MM,along with supportive care including bisphosphonates.3,4 The aimof current management strategies is to achieve and maintainhigh-quality remission for as long as possible, thus prolonging life,and to offer symptom control. Despite most MM patients respond-ing to current chemotherapeutic approaches, intensive chemother-apy relapse rates are almost 100%.
Fortunately, biologically based treatments such as bortezomib,thalidomide, and lenalidomide are now available which specifi-cally target myeloma cell interactions within the bone marrowmicroenvironment. These interactions form the fundamental basisfor the growth and survival of malignant cells. Such treatments
Table 1FDA and EMEA approved indications for lenalidomide use.
FDA EMEA
Approved for use in combination withdexamethasone for the treatment ofmultiple myeloma patients who havereceived at least one prior therapy(June 29, 2006)
Approved for use in combination withdexamethasone for the treatment ofmultiple myeloma patients who havereceived at least one prior therapy(June 14, 2007)
Approved for the treatment of patientswith transfusion-dependent anemiadue to Low- or Intermediate-1-riskmyelodysplastic syndromesassociated with a deletion 5qcytogenetic abnormality with orwithout additional cytogeneticabnormalities (December 27, 2005)
EMEA: European Medicines Agency; FDA, Food and Drug Administration.
Table 2Efficacy and toxicity of lenalidomide plus dexamethasone in relapsed/refractorymultiple myeloma.
Efficacy (n = 353)15
Overall survival, months 35.0Time to progression, months 11.2Complete response, % 15.0Partial response, % 45.6Overall response, % 60.6
Toxicity (all grades) (n = 346)16
Hematological adverse events, %Neutropenia 27.7Anemia 24.3Thrombocytopenia 17.1
Non-hematological adverse events, %Constipation 38.7Fatigue 38.4Insomnia 32.1Muscle cramps 30.1Diarrhea 29.2Nausea 22.0Rash 15.9Infection 13.6Paresthesia 11.6DVT/PE 11.0
DVT: deep venous thrombosis; PE: pulmonary embolism.
88 A. Palumbo et al. / Blood Reviews 23 (2009) 87–93
have shown to be effective in overcoming drug resistance and pro-longing response duration in patients with MM.5,6
Lenalidomide (Revlimid�; Celgene, NJ, USA) is an oral immuno-modulatory analogue of thalidomide. It has greater potency thanits parent compound and a different toxicity profile.7 Several stud-ies have confirmed the efficacy and safety of lenalidomide inMM.8–13 However, although lenalidomide appears to act againstseveral key features of the disease, including the ability of myelo-ma cells to adhere to, and thereby invade, the bone marrow stro-ma,14 the precise mechanism by which lenalidomide exerts itsanti-neoplastic effect is unclear.
In June 2006 and June 2007, lenalidomide combined with dexa-methasone was approved by the United States Food and DrugAdministration and the European Medicines Agency, respectively,for the treatment of MM patients who have received at least oneprior therapy (Table 1). In January 2007, an international groupof MM specialists met to discuss the optimal management of lena-lidomide in combination with the corticosteroid dexamethasone,in the treatment of patients with relapsed/refractory MM, whohave received at least one prior therapy. Although lenalidomidehas been used in newly diagnosed patients and as a single-agent,the recommendations presented here are focusing on the currentlabel indication.
Efficacy
Clinical studies have shown that lenalidomide has single-agentactivity against relapsed/refractory MM, and synergistic effectswhen combined with dexamethasone.8–11 Two recent pivotalphase III studies (MM-009 and MM-010) have robustly demon-strated the clinical benefit of lenalidomide plus high-dose dexa-methasone, over dexamethasone alone in patients with relapsed/refractory MM.
In study MM-009, which included 354 patients with relapsed/refractory MM, lenalidomide plus high-dose dexamethasone ther-apy offered a significantly higher overall response (OR) comparedwith high-dose dexamethasone alone (61.0% versus 19.9%, respec-tively; p < 0.001), and a markedly higher proportion of patientsachieved a complete response (CR) with combination therapy(14.1% versus 0.6%). More importantly, lenalidomide plus high-dose dexamethasone resulted in a significantly longer median timeto progression (TTP) compared with dexamethasone alone (11.1versus 4.7 months, respectively; p < 0.001), and higher overallsurvival (OS) (29.6 versus 20.2 months; p < 0.001).12
Data from the second phase III trial (MM-010), in 351 patientswith relapsed/refractory MM have also revealed a significantlyhigher OR with combination lenalidomide plus high-dose dexa-methasone therapy, compared with dexamethasone alone (60.2%versus 24.0%, respectively; p < 0.001), with more patients
achieving a CR (15.9% versus 3.4%), as well as a longer TTP (11.3versus 4.7 months; p < 0.001), and higher OS (not reached versus20.6 months; p = 0.03).13
A combined analysis of the data from the two pivotal phase IIIstudies (described above) demonstrated that lenalidomide plushigh-dose dexamethasone achieved an OR in the region of 60%,including 15% of patients achieving CR, a median OS of 35 months,and a median TTP of 11 months (Table 2).15 Median time to firstresponse was approximately 2 months, and the median time toCR or near CR was approximately 5 months.13
Safety
Despite their structural similarity, lenalidomide appears to havea markedly different tolerability profile to that of thalidomide,including lower rates of neuropathy, sedation, and constipation.11
In clinical trials, among the most common grade 3–4 adverseevents according to the National Cancer Institute Common ToxicityCriteria associated with the use of lenalidomide plus dexametha-sone in patients with MM have been cytopenias, fatigue, musclecramps, rash, infection, insomnia, and venous thromboembolism(VTE) (Table 2).8,10,12,13,16,17 Such events are largely manageablethrough patient evaluation and monitoring, dose adjustment, orprophylactic intervention, recommendations for which are pro-vided below.
Cytopenias
Thrombocytopenia and neutropenia were reported as the mostcommon reasons for dose reduction in the clinical studies.12,13
Grade 3–4 anemia and thrombocytopenia occurred in up to13.0% and 14.7% of patients with MM treated with lenalidomideplus dexamethasone, respectively; whereas grade 3–4 neutropeniahas been reported in up to 41.2% of patients with MM.12,13,17,18 Inthe phase III studies (MM-009 and MM-010), patients with renalinsufficiency (creatinine clearance < 0.835 ml/s) experienced moregrade 3–4 thrombocytopenia than those with normal renalfunction.19
Table 3Recommendations for patient selection.
Baselinefactor(s)
Recommendation(s)
Cytogeneticfactors, orpriortreatments
Not exclusion criteria
Age Not exclusion criterion. Close monitoring of patientsaged P65 years is recommendedIn elderly patients aged > 65 years, the reduction indexamethasone dose to 40 mg on days 1, 8, 15, and 22from the start of treatment is recommended. We furtherrecommend a dexamethasone dose reductionto 20 mg on days 1, 8, 15, and 22 in patients aged >75 years
Renalimpairment
Not exclusion criterion. Initial dose must follow instructionsfrom Table 4 with the option of dose escalation in moderaterenal insufficiency. It would be prudent to monitor renalfunctionDose reductions might be needed when toxicity occurs(see Table 4)
A. Palumbo et al. / Blood Reviews 23 (2009) 87–93 89
Venous thromboembolism
An increased risk of VTE has been associated with lenalido-mide use, especially when combined with high-dose dexametha-sone.20–22 Reported grade 3–4 VTE rates associated withlenalidomide plus dexamethasone treatment in patients withMM vary, from 11.4% to 14.7%.12,13 Importantly, concomitant useof erythropoietic agents may increase the VTE-risk in patients trea-ted with lenalidomide plus dexamethasone.20 In a trial of newlydiagnosed MM patients, treated with lenalidomide plus dexameth-asone, and aspirin as prophylaxis, the VTE rate was 3%.23 Also, thedose of dexamethasone appears to have a crucial influence on theincidence of VTE. In the study by Rajkumar et al. comparing high-dose dexamethasone plus lenalidomide, with low-dose dexameth-asone plus lenalidomide, grade 3–4 VTE occurred in 23.8% of pa-tients in the high-dose dexamethasone group, as opposed to 9.1%in the low-dose dexamethasone group.24
Other adverse events
The most common non-hematological adverse events of allgrades in the two pivotal phase III studies were fatigue, constipationor diarrhea, insomnia, nausea, and muscle cramps.12,13 These ad-verse events can be managed symptomatically, and they rarely re-quire lenalidomide dose interruption or dose reduction. Inaddition, rash is commonly reported (15.9%), among patients receiv-ing lenalidomide plus dexamethasone,8,18,23,25 but is typically self-limiting with a duration of several days or weeks.25 Atrial fibrillationappears to be more common in patients treated with lenalidomideplus dexamethasone, compared with dexamethasone alone (grade3–4: 2.9% versus 0.9%, respectively),16 especially if high-dose dexa-methasone is used (2.3% versus 0.5% with low-dose dexametha-sone),24 or if patients had previous atrial fibrillation. Also,dexamethasone therapy increases patient risk of infection;lenalidomide plus high-dose dexamethasone resulted in grade 3–4infection in 14.7% of patients, compared with 5.1% of patient withlow-dose dexamethasone.24
Prognostic factors
Pre-treatment
Prior treatment with the proteasome inhibitor bortezomib,thalidomide, or prior stem cell transplantation does not appear toreduce the efficacy of lenalidomide plus dexamethasone therapy.In a prospective subgroup analysis of data from the MM-009 andMM-010 trials, Stadtmauer et al. found that combination therapywith lenalidomide plus dexamethasone was more effective thandexamethasone alone, among relapsed MM patients who had re-ceived at least one prior line of therapy.26 Among patients who hadreceived a single prior therapy, lenalidomide plus dexamethasoneachieved a significantly longer TTP compared with those who had re-ceived more than two prior therapies (16.5 versus 10.2 months,respectively).
Overall, the results of this subgroup analysis suggest that inter-vention with lenalidomide plus dexamethasone is more favorablewhen administered at first relapse, compared with its use later assalvage therapy.26 Also, patients who had received a high-dose ther-apy with stem cell support prior to lenalidomide treatment, wereequally likely to respond.27 Moreover, even patients refractory tothalidomide still respond well to lenalidomide plus dexametha-sone.8,26,28 In a subgroup analysis of combined data from theMM-009 and MM-010 studies, 50% of the patients previously resis-tant to thalidomide achieved a CR or a partial response with lenalid-omide plus dexamethasone, compared with 43% of the patients whohad previously demonstrated sensitivity to thalidomide (p > 0.05).28
Cytogenetics
Various cytogenetic factors, such as del(13) and t(4;14), havebeen associated with poor outcomes in patients with MM. Thispotential predictor of response to lenalidomide plus dexametha-sone treatment has been evaluated in the single-arm, open-labelexpanded access study MM-016.29 In this study, event-free survivalestimates at 6 months were comparable between groups, with andwithout these cytogenetic abnormalities (del(13): 81% versus 73%,p = 0.61; t(4;14): 71.4% versus 72.4%, p = 0.66, respectively).29 Fromthese data it appears that the treatment of patients with relapsed/refractory MM with lenalidomide plus dexamethasone has thecapacity to overcome the poor prognosis conferred by del(13) andt(4;14), relative to event-free survival and response rate.29
Elderly patients
MM is most commonly diagnosed in adults aged over 50 yearswith a mean age at diagnosis of 65 years. Advancing age, and theassociated physical frailties, is often a barrier to the implementa-tion of the more effective high-dose chemotherapy regimens andstem cell transplantation. The availability of new treatments possi-bly resulted in advances in 5-year survival in patients younger than70 years, whereas only a 1-year survival benefit was observed inpatients aged over 70 years.30 Notably, advancing age does not ap-pear to reduce the clinical efficacy of lenalidomide because the po-sitive effects of lenalidomide plus dexamethasone treatment areseen in both elderly (> 65 years) and younger patients withMM.31,32 A subgroup analysis of the two pivotal phase III clinicaltrials for lenalidomide (MM-009 and MM-010) revealed compara-ble OR, progression-free survival, and TTP between elderly andyounger patients.31,32
In conclusion, with the exception of pregnancy and knownhypersensitivity to lenalidomide or its components, there are nospecific exclusion criteria for therapy with this agent (Table 3).
Duration of treatment
In the international phase III MM-010 trial, the median time tofirst response after lenalidomide plus dexamethasone treatmentwas 2.1 months, and median time to CR or near CR was 5.1 months;13
however, the optimal duration of lenalidomide plus dexamethasonetreatment has not yet been defined. The panel recommends contin-uing treatment in case the obtained response is less than a CR, untildisease progression, or intolerable toxicity occurs.
90 A. Palumbo et al. / Blood Reviews 23 (2009) 87–93
Management of patient groups
Renal insufficiency
As lenalidomide is mainly renally excreted, and renal functionmay be impaired in patients with MM by immunoglobulin lightchains, amyloidosis, or drugs, the potential effect of renal insuffi-ciency in lenalidomide plus dexamethasone therapy has been eval-uated in a subgroup analysis of the MM-009 and MM-010studies.19 In this study only patients with moderate renal insuffi-ciency were included (serum creatinine <221 lmol/l). With theselimitations, the lenalidomide plus dexamethasone combinationoffered improved OR, TTP, and OS in patients with relapsed/refrac-tory MM compared with dexamethasone alone, regardless of creat-inine clearance.19 A higher rate of grade 3–4 thrombocytopeniawas reported in patients with creatinine clearance of less than0.835 ml/s compared with patients with clearance of more than0.835 ml/s (13.8% versus 4.6%; p < 0.01), however, there was nodifference in grade 3–4 neutropenia.19 A pharmacokinetic studyin patients with renal insufficiency, who did not have MM, wasconducted to determine the area under the curve for lenalidomidein the setting of various glomerular filtration rates (GFRs).33 Fromthese observations, dose reductions depending on the GFR, andtherefore the creatinine clearance rate, have been deduced (Table4).33 These ensure sufficient dosing to achieve a therapeutic areaunder the curve, whilst avoiding toxic levels.33 Unfortunately, allpatients in the MM-009 and MM-010 trials had a serum creatininelevel of less than 221 lmol/l therefore, conclusions about MMpatients with renal insufficiency are still weak. When using therecommended dose adjustments (Table 4) and monitoring for ormanaging the occurrence of cytopenias (Table 6), particularlythrombocytopenia, no problems are expected with the use of lena-lidomide in patients with renal insufficiency.
Hepatic insufficiency/drug interactions
Lenalidomide is mainly excreted renally and does not appear tointerfere with the major metabolic pathways of the liver. However,clinical trials have thus far excluded patients with severe hepaticdysfunction, mostly when transaminases were 1.5-times the upperlimit of normal, which is why there is little information about thesafety of lenalidomide in hepatic impairment. In vitro studies sug-gest that lenalidomide is not extensively metabolized by the P450-enzyme system, and that it did not inhibit or induce any of thoseenzymes.16 Clinical studies did not show any significant interactionbetween lenalidomide and warfarin or digoxin, suggesting that it issafe to use these drugs in combination. However, it must be notedthat liver enzyme levels might be elevated as a result of lenalido-mide treatment.23
Table 4Recommended dose adjustments for patients with impaired renal function.a
Renal impairment Dose
Mild (CLcr P 0.835 ml/s) 25 mg every day (full dose)Moderate (0.501 6 CLcr < 0.835 ml/s) 10 mg every dayb
Severe (CLcr < 0.501 ml/s, not requiringdialysis)
15 mg every 48 h
End-stage renal disease (CLcr < 0.501 ml/s,requiring dialysis)
15 mg three-times a week followingeach dialysis
CLcr: creatinine clearance.Table adapted from Chen et al. (2007) J Clin Pharmacol 47:1466–1415 � 2007 SAGEPublications. Adapted by permission of SAGE Publications, Inc.33
a Recommendations based on a pharmacokinetic study.33
b The dose may be escalated to 15 mg everyday after two cycles if the patient isnot responding to treatment.
Elderly patients aged over 65 years
As lenalidomide and dexamethasone are effective and welltolerated in elderly patients, this combination represents an idealoption for frail, elderly patients who are not eligible for conven-tional chemotherapy. It seems that the most dangerous adverse ef-fects depend on the dose of dexamethasone, rather than on thedose of lenalidomide. In a recent study of patients with previouslyuntreated MM, the Eastern Cooperative Oncology Group (ECOG)compared lenalidomide plus high-dose dexamethasone (40 mgon days 1–4 and 15–18, every 28 days) with lenalidomide pluslow-dose dexamethasone (40 mg on days 1, 8, 15, and 22, every28 days). In the low-dose dexamethasone group less frequentthromboembolism (22% versus 6%), infection/pneumonia (16% ver-sus 8%), or hyperglycemia (10% versus 7%) occurred. Also, 1-yearOS was improved with low-dose dexamethasone (96.5% versus86%; p < 0.001).24 The benefit of the combination with low-dosedexamethasone was observed regardless of age. As these findingsare from a single study, they need to be validated. Nevertheless,in light of these findings, if indicated, a lower dose of dexametha-sone could be used in patients more sensitive to toxicities, such aselderly patients, to avoid toxicity whilst maintaining efficacy(Table 3).
Management of side effects
Cytopenias
Monitoring of full blood count and, in some cases, interruptionof treatment or dose reductions (see Table 5 for dosing levels), isrecommended (Table 6). Moreover, in some patients with neutro-penia additional treatment with granulocyte colony-stimulatingfactor is recommended. Some patients with anemia may requiretreatment with erythropoiesis-stimulating agents (ESAs). Notably,the FDA recently added a ‘‘black box” warning to the packageinserts for the ESAs epoetin alfa and darbepoetin alfa. This warningrecommends that treatment should be stopped if the patient’shemoglobin level rises above 120 g/l.34 Furthermore, until furtherdata become available, the anemia itself should not be treated withESAs unless the patient is severely symptomatic or at risk of need-ing a transfusion (e.g. hemoglobin <100 g/l) (Table 6). In addition,the FDA warns of an increased risk of mortality, cardiovascularevents, and tumor progression with the use of ESAs.34
Venous thromboembolism
All cancer patients have an increased risk of VTE, with the inci-dence varying according to the type of cancer.35,36 This latterobservation suggests an underlying process associated with thedisease itself.35 The hypercoagulability associated with MM mayplace these patients at especially increased risk for VTE, regardlessof therapy,36,37 and as such the incidence, risk for, and manage-ment of VTE in patients with MM warrant careful clinicalevaluation.
In the past, an increased risk of VTE was associated with tha-lidomide treatment, particularly if combined with dexametha-
Table 5Dosing levels for dose reductions.
Level Dose
1 25 mg every day for 21 days, every 28 days2 15 mg every day for 21 days, every 28 days3 10 mg every day for 21 days, every 28 days4 5 mg every daya for 21 days, every 28 days
a Do not dose below 5 mg daily.
Table 6Recommendations for the management of cytopenias.
Recommendations
Monitoring of FBC In case of a normal baseline FBC, biweekly monitoring isrecommendedIf baseline FBC is abnormal because of multiple myelomainfiltration, treatment should still be pursued with a full dose,and weekly monitoring at a minimumDose reduction strategies (see Table 5 for dosing levels) shouldbe followed for all other causes of abnormal baseline, andfollow-up FBCs
CytopeniasNeutropenia If the ANC is <1.5 � 109/l on the first day of a new cycle,
withhold lenalidomide treatment until grade 1 toxicity isreached. Reinitiate treatment at a lower dose (see Table 5 fordosing levels)If the ANC is <0.5 � 109/l during the cycle, start granulocytecolony-stimulating factor until the ANC is >1.5 � 109/l, thenwithhold lenalidomide treatment until grade 1 toxicity isreached. Reinitiate treatment at the next cycle at a lower dose(see Table 5 for dosing levels)
Febrileneutropenia
Antibiotic prophylaxis should be applied if patients receivelenalidomide with high-dose dexamethasone. Patients shouldreceive clear instructions to seek medical care within 3 h iffebrile while neutropenic. After an occurrence of a priorepisode of febrile neutropenia, the use of antibioticprophylaxis is recommended
Thrombocytopenia If the platelet count is <75 � 109/l on the first day of a newcycle, withhold treatment with lenalidomide until grade 1toxicity is reached. Reinitiate treatment at a lower dose (seeTable 5 for dosing levels)If the platelet count is <25 � 109–50 � 109/l during the cycle,withhold anticoagulation. Reinitiate treatment at the nextcycle at a lower dose (see Table 5 for dosing levels)
Anemia Erythropoiesis-stimulating agents should be used in patientswith Hb counts of <100 g/l, and in symptomatic patients whopresent with Hb counts of <120 g/l. The target level oftreatment is a Hb count of 120 g/l, and this should not beexceeded
ANC: absolute neutrophil count; FBC: full blood count; Hb: hemoglobin.
Table 7Recommendations for the management of venous thromboembolism.
Recommendations
Screening Neither baseline coagulation studies, nor screening for VTE inasymptomatic patients are recommendedIn symptomatic patients, sonography for the diagnosis of VTEis recommended
VTE prophylaxis A 4–6 month course of prophylaxis is recommended inpatients with risk factorsAt present there is no evidence for the best prophylaxisThe use of low-dose aspirin (81–100 mg) when the risk of VTEis low or prophylactic doses of LMWH when the risk of VTE ishigh, are recommendedLow-dose warfarin is not recommended; therapeutic-dosewarfarin seems to be associated with an increased risk ofsevere hemorrhage
VTE treatment The patient can be continued on treatment with lenalidomideplus dexamethasone or re-treated after stabilizationdepending on the severity of VTEFor therapeutic anticoagulation, patients previously on aspirinshould be switched to LMWH; and patients already onprophylactic doses of LMWH should receive therapeutic doses.We recommend 6 months of therapeutic-dose LMWH, afterwhich prophylaxis can be restarted
LMWH: low-molecular-weight heparin; VTE: venous thromboembolism.
A. Palumbo et al. / Blood Reviews 23 (2009) 87–93 91
sone or chemotherapy. Not surprisingly, this has also been foundfor lenalidomide, especially when combined with dexametha-sone.20–22 The reported variation in the incidence of VTE amongpatients with MM treated with lenalidomide plus dexametha-sone could be as a result of differences between the studiesregarding factors that increase VTE-risk. The major risk factorsthat increased the risk of VTE are duration of disease,36 high tu-mor mass,38,39 concomitant chemotherapy including doxorubi-cin,35,36,38 high-dose dexamethasone,24 erythropoietin,21
advanced age,35,40 immobilization,35 central venous line,35 ongo-ing infection/inflammation,39 and previous VTE or pre-existingcoagulation disorders.35,40 If patients present with VTE symp-toms, they should be screened for VTE before using lenalidomideplus dexamethasone (Table 7). If any of these risk factors arepresent in a patient who is symptomatic or asymptomatic, VTEprophylaxis is recommended (Table 7).
Several studies indicate that the addition of aspirin appears toameliorate the increased risk of developing VTE. Baz et al.showed that daily low-dose aspirin (81 mg) reduced the inci-dence of VTE in patients who were treated with a thalido-mide-based regimen, without an increase in the occurrence ofbleeding complications.41 Accordingly, low-dose aspirin wasshown to bring the VTE-risk in patients with MM patients trea-ted with a similar lenalidomide-based regimen, to a level com-parable to the institutional background rate of VTE in patientswith MM.42 In a study in which a VTE rate of 75% (9/12 patients)was reported,43 the addition of aspirin (325 mg/day) reduced theVTE rate to 15% (4/26 patients) a statistically significant reduc-tion (p = 0.0002).44
Warfarin has been considered as an alternative to aspirin in VTErisk-reduction strategies. However, therapeutic-dose warfarin isassociated with an increased risk of severe hemorrhage, as wellas reduced effectiveness in cancer patients receiving chemother-apy.35,45,46 In contrast, low-dose warfarin may not be efficaciousin this setting.
In a general population of cancer patients, standard dose low-molecular-weight heparin (LMWH) was shown to be at least aseffective as, and safer than warfarin.46,47 Meyer et al. reported asignificantly reduced risk of VTE and death due to bleeding in 71patients with a variety of solid and hematological malignancies,when LMWH was used as prophylaxis versus warfarin. Indeed all6 deaths due to bleeding that occurred in this study, occurredamong patients treated with warfarin.46
In the absence of controlled randomized studies it is impossibleto suggest a definitive recommendation. At present, the evidencerelies on small uncontrolled trials. With these limitations, aspirinmay be considered a suitable option in patients at low risk ofVTE. By contrast, prophylactic doses of LMWH may be suggestedin patients at high risk of VTE.
If VTE develops, treatment should be provided (Table 7). In astudy in which patients with cancer who had already developeda VTE were assigned to either LMWH or a coumarin (warfarin oracenocoumarol), the risk of recurrence was significantly loweramong those randomized to LMWH therapy.47 However, amongpatients with severe renal impairment (creatinine clearance rate60.501 ml/s), the use of LMWH has been associated with anincreased risk of bleeding.48
The prior occurrence of a VTE, including a pulmonary embolism,is not an exclusion criterion for treatment with lenalidomide plusdexamethasone. In this situation patients should be instructed tofully adhere to antithrombotic prophylaxis.
Rash
Rash is commonly reported among patients receiving lenalido-mide plus dexamethasone.8,16,18,23,25 Although rash is mostly self-limiting with a duration of several days or weeks,25 some physi-cians have successfully applied antihistamines or a short courseof low-dose prednisone (Table 8).
Table 8Recommendations for the management of non-hematological adverse events.
NHAE Recommendation(s)
Atrial fibrillation Monitor on a regular basisConstipation Does not require additional prophylaxis or therapyRash In case of rash, treat the patient with antihistamines. If rash is
persistent, continuous low-dose prednisone (10–20 mg/day,for 14 days) should be added. Rash is mostly self-limitingwith a duration of several days or weeks, but in some casesdose reduction/discontinuation of lenalidomide is necessary(see Table 5 for dosing levels)
Fatigue Other causes such as anemia, infection, depression, orhypothyroidism should be ruled out. Patients benefit fromcounseling, and support in identifying and implementingappropriate coping strategies, such as energy conservationand distraction.53 Dose reduction may be considered forsevere fatigue (see Table 5 for dosing levels)
Infection Routine antibiotic prophylaxis, for 3 months upon initiation oftreatment, should be considered in all patients, but is deemedmandatory in all patients on high-dose dexamethasone,elderly patients, and in those with a history of increasedinfection rate. In addition, vaccination against pneumococci,meningococci, and Haemophilus influenzae type b should beconsidered
NHAE: non-hematological adverse events.
92 A. Palumbo et al. / Blood Reviews 23 (2009) 87–93
Infection
Prophylactic antibiotics are effective in preventing infection inpatients with MM.49 As dexamethasone therapy increases thepatient’s risk of infection,24 it is recommended that routine antibi-otic prophylaxis is given to all patients on high-dose dexametha-sone, elderly patients, and in those with a history of increasedinfection rate, for 3 months upon initiation of treatment with lena-lidomide plus dexamethasone (Table 8). This should include pro-phylaxis against encapsulated organisms, as well as Pneumocystiscarinii pneumonia. At present there is no clear evidence to supporta need for vaccination in these patients, yet the panel believes thatvaccinations against pneumococci, meningococci, and Haemophilusinfluenzae type b should be considered. If pneumonitis-like symp-toms develop that do not respond to antibiotic treatment, physi-cians should be aware of a possible lenalidomide-inducedhypersensitivity pneumonitis-like syndrome.50 Notably, eventhough neutropenia is common with lenalidomide in the treat-ment of MM, it does not generally translate into neutropenic fever,which is different from observations in myelodysplasticsyndromes. Nevertheless, neutropenic fever may occur, and willrequire medical attention. After an occurrence of a prior episodeof febrile neutropenia, the use of antibiotic prophylaxis is recom-mended (Table 6).
Other adverse events
If fatigue occurs, other causes such as anemia, infection, depres-sion, or hypothyroidism should be ruled out (Table 8). In the expe-rience of the panel, constipation is usually of grades 1–2, and doesnot require additional treatment (Table 8). In addition, the panelrecommends regular monitoring for cardiac side effects (Table 8).
Effect on stem cells
Melphalan (Alkeran�; Celgene, NJ, USA), to date the most po-tent cytotoxic agent in MM, has a deleterious effect on hemato-poietic stem cells.51 Therefore, it is commonly not applied priorto mobilization and collection of CD34+ stem cells, and thus is ex-cluded from induction-therapy regimens. A study by Rajkumaret al. in newly diagnosed patients receiving at least four cyclesof lenalidomide plus dexamethasone treatment, prior to high-
dose therapy and stem cell transplantation, did not reveal any ad-verse effects of lenalidomide on the mobilization of CD34+ stemcells.23 All patients who were scheduled to receive a stem celltransplant achieved adequate stem cell collection and engraft-ment as expected. However, a study by Kumar et al. showed atrend towards lower CD34+ stem cells yield within 12 monthsof diagnosis in patients who received lenalidomide plus dexa-methasone. As a result, they recommend CD34+ stem cells be col-lected within 6 months of initiation of lenalidomide containingtreatments.52
Conclusion
The combination of lenalidomide and dexamethasone repre-sents a significant step forward in the management of MM, partic-ularly for those patients with relapsed/refractory disease, forwhom treatment options are currently limited. Patient selectionis straightforward, as efficacy does not appear to be influencedappreciably by relevant prognostic factors including age, cytoge-netics, or prior lines of therapy. Side effects are generally predict-able and manageable, and a range of simple, prophylacticinterventions are recommended to address the more commonand more serious associated adverse events. The recommendationson the use of lenalidomide plus dexamethasone presented herewill aid the safe administration of lenalidomide, and avoid unnec-essary dose reduction and discontinuation, thus assuring the bestefficacy of treatment.
Conflict of interest statement
Antonio Palumbo: Speaker and advisory board member, forCelgene and Pharmion, plus research grant from Celgene.
Meletios Dimopoulos: Member of advisory board for Celgene,honorarium Celgene.
Jesus San Miguel: Member of advisory board for Pharmion, Cel-gene, and Janssen-Cilag.
Jean-Luc Harousseau: Member of advisory board for CelgeneFrance and Pharmion, and on the speaker’s bureau for Orthobio-tech and Pharmion.
Michel Attal: Member of advisory boards for Celgene, Orthobio-tec and Pharmion.
Mohamad Hussein: Member of advisory board for Celgene, andresearch grants from Novartis, Celgene, OrthoBiotech, Kyphon, Am-gen, and Bayer.
Stefan Knop: Member of advisory board for Celgene, researchfunding and honoraria by Celgene Germany.
Heinz Ludwig: Member of advisory board for Celgene.Marie von Lilienfeld-Toal: Member of advisory board for
Celgene, honoraria from Celgene.Pieter Sonneveld: Member of advisory board for Celgene, con-
sultant for Celgene, and received honoraria from Celgene.
Acknowledgements
The authors received editorial support in the preparation of thismanuscript, funded by Celgene. The authors, however, were fullyresponsible for content and editorial decisions for this manuscript.
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