and high-dose melphalan, followed by thalidomide m

doi:10.1182/blood-2009-05-222539

Prepublished online October 30, 2009;2010 115: 1113-1120

Pieter Sonneveld and for Dutch-Belgian Hemato-Oncology Group (HOVON)Sinnige, Marinus van Marwijk-Kooy, Peter Joosten, Monique C. Minnema, Rianne van Ammerlaan, Shulamiet Wittebol, Michel Delforge, Henriëtte Berenschot, Gerard M. Bos, Kon-Siong G. Jie, Harm Marinus H. van Oers, Peter von dem Borne, Pierre Wijermans, Ron Schaafsma, Okke de Weerdt, Henk M. Lokhorst, Bronno van der Holt, Sonja Zweegman, Edo Vellenga, Sandra Croockewit,

thalidomide maintenance in patients with multiple myeloma

adriamycin, dexamethasone, and high-dose melphalan, followed by A randomized phase 3 study on the effect of thalidomide combined with http://bloodjournal.hematologylibrary.org/content/115/6/1113.full.html Updated information and services can be found at:

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by the American Society of Hematology, 2021 L St, NW, Suite 900, Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly

A randomized phase3study on the effect of thalidomide combined with adriamycin,dexamethasone,and high-dose melphalan,followed by thalidomide maintenance in patients with multiple myeloma

Henk M.Lokhorst,1Bronno van der Holt,2Sonja Zweegman,3Edo Vellenga,4Sandra Croockewit,5Marinus H.van Oers,6 Peter von dem Borne,7Pierre Wijermans,8Ron Schaafsma,9Okke de Weerdt,10Shulamiet Wittebol,11Michel Delforge,12 Henrie¨tte Berenschot,13Gerard M.Bos,14Kon-Siong G.Jie,15Harm Sinnige,16Marinus van Marwijk-Kooy,17Peter Joosten,18 Monique C.Minnema,1Rianne van Ammerlaan,2and Pieter Sonneveld,19for Dutch-Belgian Hemato-Oncology Group(HOVON)

1University Medical Center,Utrecht,The Netherlands;2Erasmus Medical Center-HOVON Data Center,Rotterdam,The Netherlands;3VU Medical Center, Amsterdam,The Netherlands;4Universital Medical Center,Groningen,The Netherlands;5Radboud Hospital,Nijmegen,The Netherlands;6Amsterdam Medical Center,Amsterdam,The Netherlands;7Leiden University Medical Center,Leiden,The Netherlands;8Haga Hospital,Den Haag,The Netherlands;9Medisch Spectrum Twente,Enschede,The Netherlands;10Antonius Hospital,Nieuwegein,The Netherlands;11Meander Medical Center,Amersfoort,The Netherlands; 12University of Leuven,Leuven,Belgium;13Albert Schweitzer Hospital,Dordrecht,The Netherlands;14Academisch Ziekenhuis,Maastricht,The Netherlands;

15Atrium MC,Heerlen,The Netherlands;16Jeroen Bosch Hospital,Den Bosch,The Netherlands;17Isala Kliniek,Zwolle,The Netherlands;18Medisch Centrum, Leeuwarden,The Netherlands;and19Erasmus Medical Center,Rotterdam,The Netherlands

The phase3trial HOVON-50was de-signed to evaluate the effect of thalido-mide during induction treatment and as maintenance in patients with multiple my-eloma who were transplant candidates.

A total of556patients was randomly assigned to arm A:3cycles of vincristine, adriamycin,and dexamethasone,or to arm B:thalidomide200mg orally,days1 to28plus adriamycin and dexametha-sone.After induction therapy and stem cell mobilization,patients were to receive high-dose melphalan,200mg/m2,fol-

lowed by maintenance with␣-interferon

(arm A)or thalidomide50mg daily(arm

B).Thalidomide significantly improved

overall response rate as well as quality of

the response before and after high dose

melphalan.Best overall response rate on

protocol was88%and79%(P؍.005),at

least very good partial remission66%and

54%(P؍.005),and complete remission

31%and23%(P؍.04),respectively,in

favor of the thalidomide arm.Thalidomide

also significantly improved event-free sur-

vival from median22months to34months

(P<.001),and prolonged progression

free from median25months to34months

(P<.001).Median survival was longer in

the thalidomide arm,73versus60months;

however,this difference was not significant

(P؍.77).Patients randomized to thalido-

mide had strongly reduced survival after

relapse.This trial was registered on www.

controlled-trials.com as ISRCTN013384.

(Blood.2010;115:1113-1120)

Introduction

High-dose melphalan(HDM),followed by autologous stem cell support,has become standard of care for younger multiple my-eloma(MM)patients.Impressive response rates including high percentages of complete remission(CR)and very good partial remissions(VGPR)after HDM have resulted in prolonged progression-free survival(PFS)and overall survival(OS)of high quality compared with conventional treatment.1-4The achievement of CR plus VGPR after conventional and intensive therapy is an important prognostic factor for prolonged PFS and OS,5,6so it is likely that more effective tumor reduction before HDM should translate into better quality of the response and improved survival after HDM.We recently published that the combination of thalidomide,adriamycin,and dexamethasone(TAD)compared with vincristine,adriamycin,and dexamethasone(V AD)induced a better response before HDM,which was maintained after intensifi-cation.7However,the long-term effects on survival were not determined.Posttransplant therapy like thalidomide maintenance may further improve the quality of response rate after HDM.It is not clear whether this should be applied in all patients and for which period of time.It was shown that the beneficial effect on PFS and OS of maintenance thalidomide after HDM was mainly due to improved response in patients not already in CR and VGPR both in patients given thalidomide continuously and for a limited period.8 In our study,thalidomide as part of induction before and as maintenance after HDM improved response,event-free survival (EFS),and PFS,but not OS due to strongly reduced survival from relapse.These results may have implications for posttransplant therapies with thalidomide as well as for other novel agents like bortezomib and lenalidomide.

Methods

Patients with newly diagnosed MM,Salmon and Durie stage II or III, aged18to65years inclusive,were eligible for inclusion in the HOVON-50study.The protocol was approved by the Research Ethics

Submitted May28,2009;accepted September30,2009.Prepublished online as Blood First Edition paper,October30,2009;DOI10.1182/blood-2009-05-222539.

An Inside Blood analysis of this article appears at the front of this issue.

The online version of this article contains a data supplement.Presented in part at the50th Annual Meeting of the American Society of Hematology,San Francisco,CA,December7,2008.

The publication costs of this article were defrayed in part by page charge payment.Therefore,and solely to indicate this fact,this article is hereby marked‘‘advertisement’’in accordance with18USC section1734.

©2010by The American Society of Hematology

1113

BLOOD,11FEBRUARY2010⅐VOLUME115,NUMBER6Board of each participating hospital,and the study was conducted in accordance with the Declaration of Helsinki(registered on www. controlled-trials.com as ISRCTN013384).Patients underwent routine staging,including bone marrow investigations,to perform conventional karyotyping andfluorescence in situ hybridization(FISH)analysis of 13q abnormalities,as previously described,9before start of therapy. After written informed consent was obtained,patients were randomly assigned to3cycles of VAD,10vincristine(0.4mg,intravenous[IV] rapid infusion on days1-4),doxorubicin(9mg/m2,IV rapid infusion on days1-4),and dexamethasone(40mg orally,days1-4,9-12,and 17-20),arm A,or to200to400mg of thalidomide orally daily, doxorubicin(9mg/m2,IV rapid infusion on days1-4),and dexametha-sone(40mg orally,days1-4,9-12,and17-20;TAD),arm B.Thalido-mide was continued from day1until2weeks before stem cell mobiliza-tion.Cycle2should start at day29,and cycle3at day57.The thalidomide dose could be escalated to maximally400mg in case of good tolerability.Patients randomized to thalidomide received thrombo-sis prophylaxis consisting of subcutaneously low-molecular-weight heparin nadroparine2850IE anti-Xa or5700anti-Xa in case of weight above90kg.11Stem cells were mobilized using1000mg/m2cyclophos-phamide IV on day1,15mg/m2adriamycin IV rapid infusion on days1 to4,40mg of dexamethasone orally on days1to4(CAD),given at4to 6weeks after induction treatment,plus5␮g/kg granulocyte–colony-stimulating factor twice daily until collection.After stem cell harvest, patients received1or2courses of200mg/m2HDM with autologous stem cell rescue.Centers committed to single or double HDM before start of the study.Patients achieving at least partial remission(PR)after HDM were eligible for maintenance.Patients randomized to arm A received maintenance therapy with␣-interferon(3ϫ106IU,thrice weekly)starting between2and3months after HDM,and patients randomized to arm B received50mg of thalidomide daily starting between2and3months after HDM without venous thrombus embolism prophylaxis until relapse or progression.Patients with an human histocompatibility leukocyte antigen–identical sibling donor could proceed to nonmyeloablative allogeneic stem cell transplantation between2and6months after HDM,in the context of a separate HOVON-54MM trial,evaluating a tandem autologous allogeneic approach.

Thalidomide for the trial was obtained from Gru¨nenthal GmbH.

Assessments

Response was evaluated on an intention-to-treat basis according to the European Group for Blood and Marrow Transplant criteria and required a negative immunefixation for CR12and a90%or greater reduction in the serum M-protein plus urinary M-protein level less than100mg/24hours for a VGPR.6

Definition of end points

EFS was determined from the date of randomization until induction failure, progression,or death,whichever camefirst.Patients with an induction failure,that is,not at least a PR on protocol treatment,were considered a failure at1day after randomization.PFS was calculated from randomiza-tion until progression or relapse,whichever camefirst.OS was measured from randomization until death from any cause.Patients still alive at the date of last contact were censored.

Statistical considerations

The primary objective of the study was to compare EFS between the 2treatment arms on an intention-to-treat basis,that is,patients were analyzed according to assignment to treatment arm A(no thalidomide) or B(with thalidomide).Patients who received an allogeneic transplan-tation(allogeneic stem cell transplantation[allo-SCT])after HDM were censored for the primary end point EFS,at the date of allo-SCT.To stress the censoring,we will denote this end point as EFS cens.To detect with a power of80%a hazard ratio(HR)of0.70,which corresponds to an increase of3-year EFS cens from28%to41%,and assuming approximately10%allo-SCT,450patients had to be randomized and 252events had to be observed.

Secondary end points were response(overall response rate,VGPR,and CR rate),PFS,and OS between the2treatment arms.Patient characteristics between the2treatment arms were compared using the Fisher exact test or the Pearson␹2test in case of discrete variables,or the Wilcoxon rank sum test in case of continuous variables.The response end points were compared between the2treatment arms using logistic regression.Odds ratios(ORs) were calculated with a95%confidence interval(CI).

EFS cens,PFS,and OS were estimated by the Kaplan-Meier method,and 95%CIs were constructed.Survival analysis was performed using Cox regression to see whether there was a difference in survival between the 2treatment arms.The HRs and corresponding95%CIs were determined for all survival end points.Kaplan-Meier curves were generated to illustrate differences between the2treatment arms and compared using the log-rank test.

Logistic and Cox regression analysis were also used to evaluate the impact of treatment arm on response and survival when adjusted for other prognostic factors.The following baseline characteristics were included in the regression analyses:age,sex,World Health Organization performance status(0vs1vs2-3),stage according to Salmon and Durie(II vs III), immunoglobulin(Ig)isotype(IgA,IgG,other),lactate dehydrogenase (normal vs elevated),and international scoring system(ISS;1vs2vs3).13 The MICE method of multiple imputations was used to cope with missing data on some of the baseline covariates14to obtain20complete datasets. Each of those datasets was then analyzed separately,and estimates of the parameters of interest were averaged across the20copies to give a single estimate for the ORs and HRs with95%CIs(see Carlin et al15and references therein).

The impact of response at1year on outcome was analyzed using forest plots.16Safety was analyzed using descriptive statistics to summarize the incidence of adverse events(AEs)and laboratoryfindings.Toxicity of the 2regimens was assessed by laboratory evaluation,physical examination, vital signs,and AE assessments.AEs were scored using the National Cancer Institute common toxicity criteria,version2.0.

All reported P values are2-sided,and a significance level of␣ϭ.05 was used.

Results

Between November27,2001and May31,2005,556patients were randomized for study treatment.Twenty patients were not eligible because of stage I disease(nϭ12),other cancer (nϭ4),or other reasons(nϭ4),and were excluded from the analysis.Of the remaining536patients,268were randomized to arm A(control arm)and268were randomized to arm B (treatment with thalidomide).Median age was56years(range, 30-65years),20%of patients were in Salmon and Durie stage II,and80%of patients in stage III.Important patient character-istics and prognostic factors were equally divided in both arms (Table1).Figure1shows theflow of the patients through the protocol,including reasons for going off treatment.A total of 82%of patients randomized to arm A and82%of patients randomized to arm B received HDM and stem cell rescue. Further protocol treatment was administered in149of 219patients(68%)in arm A(27%allo-SCT;34%interferon maintenance)versus191of221patients(86%)in arm B(16% allo-SCT;58%thalidomide maintenance).

Toxicity and compliance to the protocol

During TAD,62%of patients were able to take the full dose of 200mg of thalidomide daily during all cycles.Although allowed

1114LOKHORST et al BLOOD,11FEBRUARY2010⅐VOLUME115,NUMBER6according to the study protocol,in none of the patient’s dose was escalation beyond200mg of thalidomide daily performed.In 19%of patients,thalidomide was reduced;in10%thalidomide was stopped,mainly due to(neuro)toxicity;and in8%of patients randomized to TAD,thalidomide was not started.After 12,24,and36months of maintenance,68%,47%,and30%of patients were still taking thalidomide,whereas these percent-ages for interferon were50%,26%,and20%,respectively.In 26%of patients,thalidomide was stopped due to progression. Thalidomide maintenance was stopped in33%of patients due to toxicity.During follow-up,54%of these patients showed progression.Side effects of common toxicity criteria grades 3and4are summarized in Table2.Neurologic side effects, mainly polyneuropathy(PNP),were significantly higher during induction in the thalidomide arm(grades3-4,15%vs8%, Pϭ.01;grades2-4,48%vs29%,Pϭ.007).During thali-domide maintenance(nϭ156),neuropathy grade1was re-corded in21%,grade2in33%,grade3in9%,and grade4in1% of patients,respectively.Deep venous thrombosis(DVT)occurred in 8%of patients during V AD and in10%of patients during TAD.The cumulative incidence of DVT was12%at1year.11

Response

Thalidomide induced a significantly higher response rate during induction before HDM,as well as a significantly higher response after HDM and“best”response on protocol.At least PR was achieved in88%of patients randomized to arm B compared with 79%of patients randomized to arm A(ORϭ1.92,95%CIϭ1.21-3.07,Pϭ.005).Thalidomide also improved the quality of the response as determined by VGPR and CR percentages.At least VGPR on protocol was achieved in54%of patients randomized to arm A compared with66%of patients randomized to arm B (Pϭ.005;Table3).When adjusted for covariates,the differences of PR,VGPR,and CR rate remained statistically significant between the arms(Table4).

EFS,PFS,and OS

The survival end points are based on follow-up data available as of May2009.The median follow-up of309patients still alive is 52months(range,2-86).

Patients randomized to thalidomide had a significantly pro-longed EFS cens(34months vs22months;HRϭ0.60,95% CIϭ0.48-0.75;PϽ.001)and PFS(34months vs25months; HRϭ0.67,95%CIϭ0.55-0.82;PϽ.001);see Table4and Figure 2.OS curves in both arms were comparable:median 60months for the patients in the control arm and73months for the patients randomized to thalidomide,HRϭ0.96,95%CIϭ0.74-1.25,Pϭ.77(Table4and Figure2).

The HRs remained very similar when the analyses were adjusted for covariates,as can been seen in Table4.

Median overall survival from progression/relapse was shorter for the patients randomized to thalidomide.Median OS was 20months versus31months in arm A(HRϭ1.50,95%CIϭ1.11-2.02,Pϭ.009).

According to the protocol,PFS and OS have not been censored at allo-SCT.However,afterward,it was decided also to compare PFS and OS between the2arms with censoring at allo-SCT (PFS cens and OS cens).PFS cens remained significantly improved in the thalidomide arm(HRϭ0.59,95%CIϭ0.47-0.74,PϽ.001), whereas there was no significant impact on OS cens(HRϭ0.86, 95%CIϭ0.-1.14,Pϭ.29).

Landmark analysis to determine impact of response

We have chosen for the landmark analysis to evaluate the prognos-tic impact of an early VGPR or CR,as maintenance was started very early after HDM,which excludes determining the response induced by HDM alone.Based on the best response achieved within12months,373patients were classified as CR(nϭ60), VGPR(nϭ176),or PR(nϭ137).PFS and OS were calculated from12months.Patients achieving a CR within12months had improved PFS and OS,although this was not statistically signifi-cant;68%of patients who were in CR at12months were still alive at6years.

Effect of thalidomide in different response categories

In a previous report,the prolonged PFS and OS induced by thalidomide maintenance was only apparent in patients who had not(yet)achieved a VGPR or CR after HDM.8Also in our study, thalidomide treatment resulted in a prolonged PFS in the group of373patients with at least a PR at12months.However,in neither response category did the PFS prolongation result in an improved OS.

Impact of chromosome13abnormalities

Conventional karyotyping data were available in421(79%) patients.A chromosome13abnormality,defined asϪ13q or

VAD indicates vincristine,adriamycin,and dexamethasone;TAD,thalidomide, adriamycin,and dexamethasone;and LCD,light chain disease.

*Data not included when calculating percentages.MYELOMA,THALIDOMIDE,HIGH-DOSE MELPHALAN1115

BLOOD,11FEBRUARY2010⅐VOLUME115,NUMBER6

Figure1.Flow diagram of536adult patients with MM included in the HOVON-50study by treatment arm.*One patient died2days after registration without any protocol treatment;†1patient received interferon maintenance without prior HDM.

Table2.Number(%)of patients with adverse events CTC grade3to

Only adverse events with an incidenceϾ5%(except coagulation)are reported.

Expected events such as diarrhea and mucositis were not recorded on the CRFs.

VAD indicates vincristine,adriamycin,and dexamethasone;TAD,thalidomide,

adriamycin,and dexamethasone;and CTC,common toxicity criteria.

Table3.Number(%)of patients with response during protocol

VAD indicates vincristine,adriamycin,and dexamethasone;TAD,thalidomide,

adriamycin,and dexamethasone;PR,partial remission;VGPR,very good partial

remission;and CR,complete remission.

1116LOKHORST et al BLOOD,11FEBRUARY2010⅐VOLUME115,NUMBER6

–13,was present in 79(19%)patients,18.5%in patients randomized to nonthalidomide,and 19.4%patients randomized to thalidomide.In univariate analysis,abnormalcy of chromo-some 13[abn (13)]had no statistically significant impact on PR,VGPR,CR,EFS cens ,PFS,or OS.There was also no statistically significant interaction between abn (13)and treatment arm,indicating that the effect of thalidomide was not significantly different in patients with or without abn (13).

FISH data regarding chromosome 13abnormality were available for 294(55%)patients.A chromosome 13abnormality was present in 101(34%)patients,33.3%in patients random-ized to nonthalidomide,and 34.8%of patients randomized to thalidomide.The presence of a FISH abn (13)had no significant impact on response and survival,except for PFS.Univariate analysis showed that patients with abn (13)had worse PFS (HR ϭ1.38,95%CI ϭ1.04-1.84,P ϭ.03).FISH analysis was not centralized and was performed on unpurified bone marrow samples.8This may explain the rather low incidence of chromo-some 13abnormalities in our population.

Discussion

Our study was designed to evaluate whether thalidomide added to induction before and during maintenance after intensive therapy would result in a better outcome for newly diagnosed myeloma.17We hypothesized that more effective tumor reduction before autologous stem cell transplantation using HDM should result into a higher and better quality of the response after intensification,which is probably the best situation to sustain the response by maintenance treatment.

Although thalidomide improved the response before and after HDM,prolonged EFS,and PFS,this benefit was not translated into a statistically significant lengthened survival.One explanation might be that %of relapsed patients from the nonthalidomide arm received thalidomide during salvage therapy compared with 38%of patients with relapse in the thalidomide arm.Alternatively,the reduced postrelapsed survival could be due to generation of aggressive drug-resistant clones that generate relapses after pro-longed thalidomide exposure.Median survival from relapse was

EFS indicates event-free survival;PFS,progression-free survival;OS,overall survival;WHO,World Health Organization;S&D,Salmon and Durie;ISS,International Scoring System;LDH,lactate dehydrogenase;ULN,upper limit of normal;␤2m,␤2-microglobulin;and n.i.,not included in multivariate analysis (already used for ISS).

*The subscript “cens”indicates that patients are censored at allo-SCT.

MYELOMA,THALIDOMIDE,HIGH-DOSE MELPHALAN

1117

BLOOD,11FEBRUARY 2010⅐VOLUME 115,NUMBER 6

only 20months for the patients randomized to thalidomide,al-though 51%of patients received bortezomib during salvage therapy compared with 39%of patients from the nonthalidomide arm.For lenalidomide,these percentages were 18%and 16%,and for a second autologous stem cell transplantation,9%and 5%,respectively.

Our results are quite comparable with Total Therapy II,in which,as in our trial,in the thalidomide arm thalidomide was given both before and after HDM.18The first results of this study,initially reported in 2006,also showed improved response and PFS,but no benefit in OS because of significantly shorter survival after relapse in the thalidomide group.Median overall survival from relapses was only 1.1years for patients random-ized to thalidomide versus 2.7years for the nonthalidomide patients.Only after prolonged follow-up of median 72months did a favorable effect of thalidomide survival become apparent for the one-third of patients with cytogenetic abnormalities.19This might also become obvious with longer follow-up of our study,as we can observe a divergence in the OS curves at 5years (Figure 2C),resulting in a prolongation of survival from 60to 73months for the thalidomide group.Although this difference is not (yet)statistically significant,this may still be of high clinical relevance from a patient’s perspective.

The role,including positioning and duration of application,of thalidomide in combination with intensive therapy seems not yet defined.In the Intergroupe Francophone du Mye ´lome (IFM)study with low risk patients defined by normal ␤2-microglobulin levels and no chromosome 13abnormalities as determined by FISH,thalidomide maintenance 200mg/daily after HDM pro-longed EFS,PFS,and OS.8In this study,thalidomide was not used before HDM.In the IFM trial,only patients not in VGPR and CR had a survival advantage from thalidomide,indicating that the beneficial effect of thalidomide was due to further tumor reduction rather than maintaining the achieved response.Most recent data are from an Australian study showing thalidomide consolidation for 12months after autologous stem cell transplan-tation improved response,PFS,and OS.20This improvement was not restricted to patients failing to achieve CR/VGPR.In this study,initial induction therapy was free and was mostly VAD-like,and thalidomide was combined with prednisone maintenance.The authors state that the positive outcome of their study is most likely due to the use of a sequential noncross-resistant antimyeloma approach.

These results seem to be in contrast with our study and the initial results of Total Therapy II.The HOVON and the Total Therapy II studies cannot be compared,as in the IFM and in the Australian studies,the only question was the role of thalidomide as maintenance after transplant.It is remarkable,however,that as well as in the HOVON-50and Total II,survival from relapse was significantly shorter,HOVON-50survival at 1year 66%versus 77%and Total II 52%versus 76%,whereas 1-year survival from relapse was identical irrespective of thalidomide in the IFM study,73%versus 78%,and in the Australian study,79%and 77%,respectively.

Conflicting results have also been obtained with thalidomide in combination with melphalan and prednisone (MP)in elderly patients.In both IFM studies,21,22the Italian 23and in the HOVON study,24MP-thalidomide improved response and PFS compared with MP.A survival benefit,however,for MP-thalidomide was only observed in the IFM studies.An important difference in design between the studies was that thalidomide in the IFM studies was

A

C u m u l a t i v e p e r c e n t a g e

25

50

75100

months A:noThal

B:+Thal At risk:

A:noThal 268 128 81 48 27 9 0 B:+Thal 268

163

124

91

53

24

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Logrank P<.001

A:noThal 268 175 B:+Thal

268 141

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A:noThal 268 201 138 88 45 14 2 B:+Thal 268

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B:+Thal At risk:

A:noThal 268 229 210 185 114 47 8 B:+Thal 268

233

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55

18

Logrank P=0.77

A:noThal

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C u m u l a t i v e p e r c e n t a g e

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months A:noThal

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A:noThal 184 121 71 33

8

1 B:+Thal 138

79

38

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Logrank P=0.008

A:noThal 184 B:+Thal 138 84

N

d

Figure 2.Kaplan-Meier estimates of EFS cens ,PFS,and OS from randomization,and OS from progression/relapse for patients who were randomized to TAD for induction to and thalidomide maintenance after HDM (solid line)or to VAD for induction to,and ␣-interferon maintenance after HDM (dotted line).For EFS cens ,estimate patients who received an allogeneic transplantation (allo-SCT)after HDM were censored and excluded at the date of allo-SCT.(A)EFS cens ,(B)PFS,(C)OS,and (D)OS from progression/relapse.

1118

LOKHORST et al

BLOOD,11FEBRUARY 2010⅐VOLUME 115,NUMBER 6

given for a limited period,and in the Italian and HOVON studies until relapse.

The impact of prior exposure and response to thalidomide (induction)therapy on its use as maintenance treatment is currently unknown.Taking all data together,a cautious conclusion might be that limited duration of postinduction/intensification therapy until maximal response is preferable to avoid resistant relapse and to minimize the side effects of prolonged thalidomide exposure.However,with the advent of many novel treatment options in relapsed multiple myeloma,PFS and EFS are probably better end points than OS,to assess the impact of a particular treatment regimen.

Elevated lactate dehydrogenase,the presence of IgA,Salmon and Durie stage III,and a higher ISS score predicted for inferior outcome on one or more end points (Table 4).It is important to notice how well the ISS stage differentiated between the different risk groups,which confirms the importance of this new prognostic staging system (Figure 3).Chromosome 13abnormali-ties as determined by conventional karyotyping and FISH had no prognostic significance.Unfortunately,current well-known prognostic factors like 17p-and t(4;14)were not determined.Thalidomide did not reverse the impact of other unfavorable prognostic factors.

Neurotoxicity of thalidomide was high,although relatively low dosages during induction and during maintenance were used and recommendations for dose adjustments were given.PNP grades 2to 4developed in nearly 50%of patients,and in 58%of patients thalidomide was stopped or dose reduced.In the Total Therapy II trial,30%of patients had to stop with thalidomide due to side effects in the first 2years,also mainly because of PNP.The incidence of DVT was not higher in the thalidomide arm,probably as a result of the preventive effect of low-molecular-weight heparin for thalidomide-induced DVT.11The number of patients who started maintenance with interferon was low,probably due to fear of patients and doctors for expected side effects.As there seemed to be also no favorable effect on PFS and EFS,our results also indicate that there is probably no role for interferon maintenance anymore.

The achievement of VGPR and CR has been shown to be a major prognostic factor for survival.This was partially con-firmed by our landmark analysis for best response achieved within 12months,which showed patients in CR had an impres-sive 68%survival at 6years.It has already been shown that the application of the novel antimyeloma agents bortezomib and lenalidomide into front-line therapy may be even more effective with regard to improving the response before and after autolo-gous stem cell transplantation.25-29The combination of bor-tezomib with dexamethasone explored by the IFM in newly diagnosed patients induced at least PR in 80%of patients,including 47%of patients with at least VGPR and 21%of patients with CR/non-CR (near CR [nCR]).25After HDM,the quality of response further improved to at least 62%VGPR,including 35%of patients with a CR/nCR.Even better results were obtained with the combination bortezomib/thalidomide/dexamethasone as induction therapy,resulting in at least 77%VGPR,including 54%of patients with a CR/nCR.26In addition,lenalidomide combined with dexamethasone is highly effective,as shown by an overall response of more than 90%,including 57%of patients with CR/nCR.27However,the long-term effect on PFS and OS of such (expensive)combination therapies as induction must be established before these can be recommended outside clinical trials.What also remains is how to implement the best maintenance strategy posttransplant,that is,which response category should receive maintenance,the duration of

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At risk: I 207 124 96 69 34 18 II 91 52 36 25 18 6 III 97 43 28 19 10 2

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N e C u m u l a t i v e p e r c e n t a g e

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At risk: I 207 175 139 103 49 23 II 91 71 48 32 21 7 III 97 65 42 29 17 3

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At risk: I 207 194 177 163 104 50 II 91 78 67 61 40 14 III 97 74 60 52 34 10

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Figure 3.EFS cens ,PFS,and OS from randomization by ISS score.(A)EFS cens ,(B)PFS,and (C)OS.

MYELOMA,THALIDOMIDE,HIGH-DOSE MELPHALAN

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BLOOD,11FEBRUARY 2010⅐VOLUME 115,NUMBER 6

Contribution:H.M.L.and P.S.designed and directed the study and edited the manuscript;S.Z.,E.V.,S.C.,M.H.v.O.,P.v.d.B, P.W.,R.S.,O.d.W.,S.W.,M.D.,H.B.,G.M.B.,K.-S.G.J.,H.S., M.v.M.-K.,P.J.,and M.C.M.and contributed patients to the study and reviewed the manuscript;B.v.d.H.participated in designing the research protocol,performed statistical analyses, and reviewed data and the manuscript;and R.v.A.reviewed data and the manuscript.

Conflict-of-interest disclosure:The authors declare no compet-ingfinancial interests.

For a complete list of Dutch-Belgian HOVON participants,see the supplemental Appendix(available on the Blood website;see the Supplemental Materials link at the top of the online article).

Correspondence:Henk M.Lokhorst,Department of Hematol-ogy,University Medical Center Utrecht,Heidelberglaan100, 3584CX Utrecht,The Netherlands;e-mail:h.lokhorst@ umcutrecht.nl.

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