the hematology iournal
`
`13'[1 Congress of
`the European Hematology Association
`Copenhagen, Denmark, June 12 - 15, 2008
`
`ABSTRACT BOOK
`
`baematologica
`
`
`
`2008|st
`
`ISSN 0390-6078
`
`Journal of the European Hematology Association
`Published by the Ferrata-Storti Foundation, Pavia, Italy
`Volume 93, supplement no. 1, June 2008
`www.haematologica.org
`
`ALVOGEN, Exh. 1042, p. 0001
`
`ALVOGEN, Exh. 1042, p. 0001
`
`

`

`13TH CONGRESS OF THE
`EUROPEAN HEMATOLOGY
`ASSOCIATION
`
`COPENHAGEN, DEMNARK,
`JUNE 12 - 15, 2008
`
`ABSTRACT BOOK
`
`ALVOGEN, Exh. 1042, p. 0002
`
`

`

`13th Congress of the European Hematology Association
`
`0440
`MELPHALAN + PREDNISONE vs MELPHALAN + PREDNISONE +
`THALIDOMIDE IN INDUCTION THERAPY FOR MULTIPLE MYELOMA
`IN ELDERLY PATIENTS: FIRST INTERIM RESULTS OF THE DUTCH
`COOPERATIVE GROUP HOVON
`P. Wijermans,1 M. Schaafsma,2 Y. Van Norden,3 R. Ammerlaan,4
`P. Sonneveld,5 S. Wittebol,6 H. Sinnige,7 P. Huijgens,8
`M. van Marwijk Kooy,9 R. van der Griend10
`1Haga Hospital, THE HAGUE; 2Mediasch Specrum Twente, ENSCHEDE;
`3HOVON datacentre, ROTTERDAM; 4Hovon datacenter, ROTTERDAM;
`5Erasmus MC, ROTTERDAM; 6Meander MC, AMERSFOORT; 7Jeroen
`Bosch Hospital, DEN BOSCH; 8Free University MC, AMSTERDAM; 9Sophia
`Hospital, ZWOLLE; 10Diakonessen Hospital, UTRECHT, Netherlands
`Background. The Dutch cooperative group HOVON started a ran-
`domised phase III study in elderly myeloma patients in September 2002
`comparing the standaard Melphalan and Prednisone treatment with the
`combination Melphalan, Prednison and Thalidomide (HOVON 49
`study). Patients with a multiple myeloma > 65 years of age with a stage
`IB or higher were candidates for this study. Methods. Melphalan was
`given in a dose of 0.25 mg/kg and prednisone 1 mg/kg for 5 days every
`4 weeks. Thalidomide was given daily with ina dose of 200 mg. A max-
`imum of 8 cycles was planned. If there was still a response further ther-
`apy was allowed till a plateau phase was reached. When a good response
`and a plateauphase was reached the patients who were randomised for
`Thalidomide received maintenance therapy with Thalidomide 50
`mg/day till progression of their disease. It was planned to enter 420
`patients in the study. However accrual decreased significantly due to
`positive outcome of other studies with Thalidomide. Therefor the study
`was stopped after the inclusion of 344 patients. This is the first analysis
`based upon the data of the first 320 patients. Results. 344 patients were
`entered. The first 320 patients were analysed for this report. 7 patients
`were non-eligible due to either being stage IA or not having a measura-
`ble tumor parameter. From one patient there was not a signed informed
`consent available. Eleven patients were excluded from this analysis
`because of insufficient data available at the time of evaluation. Thus
`data are presented of 301 patients; 149 in the M+P arm and 152 in the
`M+P+T arm. The median age was 72 years in both groups. The arms
`were well matched for age, sex, stage of the disease, performance sta-
`tus and type of M-protein. The best response on protocol was as folows
`M+P response rate 47% (with a CR 1%, VGPR 8% and PR 38% respec-
`tively) and for M+P+T arm a response rate of 63% (with a CR 1%,
`VGPR 28% and PR 34%) which was significantly better (p<0.001). There
`was a significant difference in the Event Free Survival in favour of the
`M+P+T arm (p< 0.001) but no difference was observed for the Progres-
`sion Free Survival (p=0.08) and Overall Survival (p=0.28). Toxicity. Only
`one third of all the patients received cycle 3 of Melphalan and Predni-
`son according the planned protocol. In all the other patients the doses
`had to be reduced and or delayed. Grade 2,3 and 4 toxicity of any type
`was seen in 59% of the patients in the M+P arm and in 87% of the
`M+P+T patients. This difference was mainly due to grade 2 and grade
`3 neurotoxicity. After three cycles only 36% of the patients used the full
`Thalidomide dose and after 6 cycles this was only 28%. No differences
`between the two arms were seen for other toxicities. Conclusions. In this
`randomised phase III study we did observe a significant improvement
`in the Resonse Rate, the quality of the responses and time to response
`in favour of the M+P+T arm. This did translate in an improvement of
`the Event Free Survival but not in the Overall Survival. The toxicity of
`the five days schedule with 0.25 mg/kg/day Melphalan led to a sub-
`stantial number of patients who did not received the planned therapy.
`Thalidomide added significantly to the toxicity (mainly neurotoxicity)
`of the treatment. We were unable to confirm the positive effect with
`Thalidomide as part of front-line therapy on Overall Survival as it was
`seen in other studies
`
`0441
`OVERALL SURVIVAL WITH DEXAMETHASONE IN PHASE III MULTIPLE
`MYELOMA TRIALS AFTER ADJUSTMENT FOR CROSS-OVER TO
`LENALIDOMIDE
`J. Morgan,1 K. Ishak,2 B. Deniz,2 T. Drayson,3 M. Dimopoulos,4
`M. Weber,5 M. Augustson,6 J. Child,7 R. Knight,8 G. Begum,9
`A. Dunn,9 A. Shearer,10 J. Caro2
`1The Royal Marsden NHS Foundation Trust & The Institute of Cancer Research,
`SURREY, UK; 2United BioSource Corporation, MONTREAL, Canada; 3Uni-
`versity of Birmingham, BIRMINGHAM, UK; 4University of Athens School of
`Medicine, ATHENS, Greece; 5Anderson Cancer Center, HOUSTON, TX,
`USA; 6Sir Charles Gairdner Hospital, NEDLANDS, Australia; 7University of
`Leeds, LEEDS, UK; 8Celgene, SUMMIT, NJ, USA; 9Warwick Medical School,
`COVENTRY, UK; 10Celgene UK, LONDON, UK
`Background. In pivotal trials (MM-009/010) evaluating lenalidomide
`plus high dose dexamethasone (Len+Dex) vs Dex alone, 47% of the lat-
`ter switched to Len±Dex at disease progression or following ethical
`study unblinding. Given the significantly better efficacy of Len+Dex, sur-
`vival with Dex alone is overestimated. Aims. Use external data on sur-
`vival to adjust Dex survival for the cross-over to Len±Dex. Methods.
`Pooled data from the UK Medical Research Council (MRC) MM IV, V,
`VI, and VIII trials enrolled between 1980 and 1997 were used to derive
`an equation predicting survival with second-line conventional therapies
`(including VAD, ABCM, Melphalan and cyclophosphamide), according
`to patient and disease characteristics. Applying this equation to MM-
`009/010 Dex patients yielded their expected survival without cross-over
`to Len±Dex. This was used to estimate survival for this subgroup in a
`lifetime simulation by adjusting the scale parameter of the post-progres-
`sion survival equation estimated from MM-009/010. Since survival pat-
`terns change with additional lines of treatment, further calibration was
`necessary for multiple prior therapies. As patient-level data for this sub-
`group were not available from MRC, published Mayo clinic data on
`median survival with conventional therapies for patients with two pri-
`or therapies (12.6 months) was used to adjust the predicted median from
`the trial-based, MRC-calibrated equation. The simulation model was
`then used to compare long-term survival with Len+Dex vs Dex alone
`without cross-over. Results. Of 873 MRC patients who initiated second-
`line conventional treatment, 826 had died, with 17.6 months median sur-
`vival from starting second-line treatment. Survival did not differ signif-
`icantly between Dex- and non-Dex-containing regimens (p-value=0.79).
`Exponential survival with age, performance status, M-protein, B2M and
`time to progression as predictors provided best fit to the data. Applica-
`tion using this equation to predict survival for MM-009/010 Dex patients
`with one prior therapy yielded a median survival of 16.2 months
`(95%CI: 13.1-20.1) compared to 33.6 months (95%CI: 27.1-NE)
`observed with cross-over to Len±Dex. The median survival for patients
`with multiple prior therapies was 12.6 months (95%CI: 10.2 - 15.6),
`compared to 27.3 months (95%CI: 23.3-33.3) with cross-over to
`Len±Dex. The calibrated lifetime simulation yielded estimated mean
`survival of 2.2 life-years with Dex alone compared with 5.6 life-years
`with Len+Dex for patients with one prior therapy, and 1.5 life-years for
`Dex alone compared with 4.2 life-years for Len+Dex for patients with
`multiple prior therapies. Conclusions. Lenalidomide delivers significant-
`ly larger survival gains in this life-limiting orphan disease when appro-
`priate adjustment has been made for the cross-over that occurred in the
`trials.
`
`117788 | haematologica | 2008; 93(s1)
`
`ALVOGEN, Exh. 1042, p. 0003
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`