XI th International Myeloma Workshop, Kos, June 28 th, 2007 Single vs. Double HDT in Multiple Myeloma Hartmut Goldschmidt Medizinische Klinik V, Universität Heidelberg Nationales Centrum für Tumorerkrankungen Heidelberg
Single vs. double HDT in MM Trial Comparsion: HDT vs. CT Number Patients CR Rate (%) (ASCT vs CC) EFS (months) (ASCT vs CC) OS (months) (ASCT vs CC) Attal et al. 1996 (IFM90) Fermand et al. 1999 (MAG91) Child et al. 2003 (MRC7) 200 22 vs 5** 28 vs 18 ** 57 vs 44** 190 n.d. 25 vs 19** 42 vs 45 401 44 vs 8** 31 vs 19** 54 vs 42** Palumbo et al, 2003 195 26 vs 7 ** 28 vs 16** 58+ vs 43** (IMMSG) Bladé et al. 2003 (PETHEMA) Barlogie et al. 2006 (USIG) 164 30 vs 11** 42 vs 34** 65 vs 67 516 11 vs 11 17* vs 14* 38* vs 38* [Abr.: ASCT, autologous stem cell transplantation; CC, conventionel Chemotherapy; IFM, Inter Groupe Francophone du Myelome; MRC, Medical Research Council; MAG, Myelome Auto Greffe; ÜETHEMA, Spanish Cooperative Group; USIG, US Inter Group; IMMSG, Italian Multiple Myeloma Study Group; CR, complete Remission; EFS, event free survival; OS, over all survival; n.d., not done; *, 7 y EFS/OS, ** significant difference]
High-dose therapy in MM ASCT: Current status Single HDT ASCT is the standard of care for younger (< 60-75 years) myeloma patients due to: Improved CR, VGPR, PR Improved EFS Improved OS, if VGPR or CR is achieved Low treatment related mortality (1-5%) Debate B. Barlogie vs. J.F. Fermand: ASCT as an part of primary therapy in myeloma
Single vs. double HDT in MM ASCT: Current status Double HDT Double HDT was evaluated in many prospective trials (IFM, MAG, HOVON, Bologna, GMMG, DSMM) and is considered the standard in several transplant centers and study groups because of: Further improvement of CR, VGPR, PR Improvement of EFS (IFM, MAG, HOVON, Bologna) MEL 200-based tandem transplant is the backbone of the Arkansas Total Therapy regimens with potential cure But: Prolonged OS only in two (IFM, MAG) trials Is Double HDT standard of care?
High-dose therapy in MM Single versus Double HDT: Results EFS/OS Author n median Results Follow-up IFM 94 399 60 Better EFS* and OS* HOVON 303 50 Better EFS**, OS = Bologna 220 60 Better EFS*, OS = MAG 95 227 73 Better EFS and OS GMMG HD2 261 24 Better EFS*** * F Pt ith VGPR ( CR) d CR * For Pts. with VGPR (ncr) and CR ** For Pts. with CR ***3 rd Analysis presented at Sydney
Single vs. double HDT in MM Improvement of Remission-Status: HD1- Trial 1996-1999 ncr n n
High-dose therapy in MM ASCT: Double HDT Critical Points Type of high dose therapy (e.g. including TBI?) Time between first and second HDT Maintenance versus no maintenance Relapse therapy (second/third TPX), new drugs
High-dose therapy in MM IFM 95 : SURVIVAL Arm B : Mel-200 Arm A : TBI Moreau et al. Blood 1999
High-dose therapy in MM IFM 94 : Overall Survival All Patients P<0.01 DT ST Attal et al. NEJM 2003
High-dose therapy in MM IFM 94 : Overall Survival if response to 1 st graft < 90% DT p<0.001 ST Attal et al. NEJM 2003
High-dose therapy in MM IFM 94 : Overall Survival if response to 1st graft 90 % DT ST p= n.s. Attal et al. NEJM 2003
High-dose therapy in MM HOVON 24 : Event Free Survival (A) 100 ulative percenta age Cum 75 logrank p=0.014 50 logrank p=0.014 25 0 N E Single 148 139 Double 155 134 Double Single 0 24 48 72 96 months 120 At risk: Single 148 60 21 11 4 1 Double 155 74 44 23 12 2 Sonneveld et al. 2007 in press
High-dose therapy in MM (C) HOVON 24 : Overall Survival 100 Cum mulative percen ntage 75 50 25 Single Double logrank p=0.81 0 N D Single 148 105 Double 155 108 0 24 48 72 96 months 120 At risk: Single 148 117 82 51 21 5 Double 155 109 81 57 23 3 Sonneveld et al. 2007 in press
High-dose therapy in MM GMMG-HD2 trial 1999-2002 Randomisation I: VID vs. VAD until CR or plateau, max. 6 cycles HD-cyclophosphamide (ifosfamide) + G-CSF Cycle 1 >/= SD VAD/VID Randomisation II Leukapheresis CD34 + -selection optional One cycle Melphalan 200 mg/m² Cycle 2 + PBSCT Interferon-αα Interferon-α
Single vs. double HDT in MM GMMG-HD2: Patient characteristics Single Double Number of Patients 178 180 Median Age [years] 55 56 Beta-2 MG [mg/l] 2.5 2.8 ALB [g/l] 40 39 HB [g/dl] 11.5 11.8 CRP [mg/dl] 6 5 Database 6/2007
Single vs. double HDT in MM GMMG-HD2: Number of Patients Single TPX Double TPX Randomization n=188 n= 197 N=385 Evaluable n=178 n=180-10 -17-27 N=358-12 -6-18 Stem Cell Mob. n=166 n=174 N=340-10 -6-16 TPX I n=156 n=168-75 N=324 Refusal of 2nd TPX by 47 patients TPX II n=93
High-dose therapy in MM ASCT: HD2 Points to consider 2 nd TPX only in 52% of evaluable pts., 26% of pts in Double TPX-Arm refused 2 nd TPX, therefore ITT and per protocol analyses TRM Single HDT (2%) vs. Double TPX (2%/3%) Time between Single HDT and Double HDT: Median of 141d Relapse therapy second/third TPX >20% Treatment with new drugs > 40%
GMMG Single vs. Double HDT: EFS ITT double single
GMMG Single vs. Double HDT: EFS per protocol double single
GMMG Single vs. Double HDT: OS ITT double single
GMMG Single vs. Double HDT: OS per protocol double single
Single vs. double HDT in MM GMMG HD2: Conclusions The final analysis of the GMMG-HD2 study does not show a benefit in terms of EFS or OS for pts. treated with Double HDT compared to pts. treated with Single HDT CR after HDT correlated with good prognosis, there is no difference in CR in both treatment arms (p=0.5) We have to identify Pts. who significantly benefit y g y from Double HDT
Single vs. double HDT in MM EFS after HDT TT 2: 70 genes high risk model Shaughnessy et al., Blood 2007
Single vs. double HDT in MM EFS after HDT in predicted EC-groups HD and MPL data, n=100 EFS rate 0.0 0.2 0.4 0.6 0.8 1.0 22 21 12 EC1.1: 11 EC1 1: 11q13+, CCND1 EC1.2: t(11;x), CCND1 EC2.1: CCND2 EC2.2: t(4;14), CCND2, FGFR3 p.lr = 0.00081700081 p.cph = 0.0029 0 3 6 9 12 15 18 21 24 27 30 33 36 Months p.cph(1.1 vs. 2.2) = 0.00106 44 41 32 32 24 19 12 8 7 5 3 1 25 18 16 15 10 7 5 4 1 18 18 13 12 9 9 7 3 3 3 13 9 5 4 2 2 2 Hose et al., abstr. 74, ASH2004
Single vs. double HDT in MM Dynamic magnetic resonance imaging (DMRI) in MM before after
Conclusion I: HDT in MM ASCT: HDT is the current standard of care TBI (12Gy) or BU 16 should be avoided and Mel 200 should be used TRM is relatively low Follow up for patients treated with HDT is partly longer than 10 years late effects are known Treatment time (Induction, SC-Mob, TPX) is mostly shorter than one year
Conclusion II: HDT in MM ASCT: CR and VGPR correlate with better quality of life CR and VGPR achievement correlates with longer survival Combination of new drugs with HDT induces more and deeper CR => Cure? Outside clinical trials, double transplantation should be proposed to patients failing to achieve a CR or VGPR after the first transplant
Single vs. double HDT in MM Participating centers (n = 66) Caritas-Krankenhaus Bad Mergentheim HUMAINE-Klinikum Bad Saarow Med. Universitätsklinik ität ik Virchow-Klinikum ik Berlin Krankenhaus Berlin-Neukölln Krankenanstalten Gilead Bielefeld Med. Universitätsklinik Bochum Med. Univ.-Klinik Bonn Med.Univ.-Poliklinik Bonn Zentralkrankenhaus St. Jürgen Straße Bremen Knappschaftskrankenhaus Bottrop Med. Klinik Klinikum Chemnitz Karl-Thiem-Klinikum Cottbus Städt. Kliniken Darmstadt Städt. Klinikum Dessau Knappschaftskrankenhaus Dortmund Med. Klinik und Poliklinik I, Tech. Univ. Dresden St. Johannes-Hospital Duisburg Werdau Kliniken Duisburg Med. Klinik Universitätsklinikum Essen Malteserkrankenhaus Flensburg Med. Klinik III, Universität Frankfurt Krankenhaus Nordwest Frankfurt Klinikum Fulda Städt. Krankenhaus Gütersloh Kath. Krankenhaus Hagen Allg. Krankenhaus Hamburg-Altona Universitätskrankenhaus Hamburg-Eppendorf Ev. Krankenhaus Hamm St. Marien-Hospital Hamm Städt. Krankenhaus Siloah Hannover PD Dr. Rohrberg/Dr. Hurtz Halle Med. Klinik und Poliklinik V, Univ. Heidelberg Klinik für KMT Idar-Oberstein PD Dr. Ruffert/Dr. Hoffmann Jena Med. Klinik Westpfalz-Klinikum Kaiserslautern Med. Klinik St. Vincentius-Krankenhäuser Karlsruhe Städtisches Klinikum Karlsruhe Klinikum Kassel Klinik für Innere Medizin Universität Köln Klinikum Krefeld Städt. Krankenhaus Süd Lübeck Klinikum der Stadt Ludwigshafen Medizinische Fakultät der Universität Magdeburg Krankenhaus Altstadt Magdeburg Med. Klinik und Poliklinik Universität Mainz III. Med. Klinik Univ. Mannheim Universitätsklinik Marburg Marinen Hospital Marl Kreiskrankenhaus Meißen Medizinische Klinik Minden/Westf. Krankenhaus Maria Hilf Mönchengladbach Dr.Grabenhorst Mönchengladbach Städtische Kliniken Offenbach Dr. Baldus Rüsselsheim Akad. Lehrkrankenhaus Saarbrücken Nordwest-Krankenhaus Sande Evang. Diakoniewerk Schwäbisch Hall Mutterhaus d. Borromäerinnen Trier KH der Barmherzigen Brüder Trier Klinikum ik der Stadt Villingen-Schwenningen i Hanusch Krankenhaus Wien Zentrum für KMT Wiesbaden Med. Poliklinik Univ. Würzburg Med. Klinik, Kliniken St. Antonius Wuppertal Universitätsspital Zürich Stadtspital Triemli Zürich
Vielen Dank! Thank You! UK Heidelberg Montpellier Gerlinde Egerer Thomas Möhler Ute Hegenbart Ulrike Klein Michael Hundemer Marc Raab Jens Hillengaß Dirk Hose Anthony D. Ho Lutz Edler Axel Benner Biostatistics Bioinformaticsi K. Mahtouk J. Moreaux M. Condomines T. Rème B. Klein J. DeVos J.F. Rossi Our patients Montpellier Hans Salwender Axel Glasmacher Christof Scheid Ralph Naumann Annette Hänel Dieter Huhn Andreas Neubauer Hans Martin Uta Imbach Sarah Pignotti Iris Breitkreutz Uta Bertsch