27. April 2013 German-Speaking Myeloma Multicenter Group Hartmut Goldschmidt
Priv.-Doz. Serke, Professor Huhn Priv.-Doz. Martin, Professor Hoelzer Dr. Goldschmidt, Professor Haas HD1 1995 Dr. Cremer, Prof. Ho Triple MMM 2000
Front-Line Trials of the GMMG HD1 Trial: Tandem-Transplantation 1996 1998 (Phase II, n=151) HD2 Trial: Single- versus Double-Transplantation (Phase III, n=480) 1998 2001 HD3 Trial: Tandem-Transplantation (Germany) plus/minus Thalidomide (Phase III, GMMG n=550, HOVON n=500) 2001 2004 HO65/HD4 Trial: VAD vs. PAD, Transplantation, maintenance Thalidomide vs. Bortezomib (Phase III, GMMG n=399, HOVON=434) 2005-2008 MM5 Trial: VCD vs. Pad, Standard-intensification, consolidation / maintenance Lenalidomid, maintenance 2a vs. until CR (Phase III, n=504, Start II/2010; Extension n=100 Start 6/2013)
HD-1:Treatment Plan VA(I)D, until CR or plateau, max. 6 cycles Time 1996-1998 (n=151) HD-cyclophosphamide + G-CSF Melphalan 200 mg/m² cycle 1 PBSCT cycle 2 PBSCT Leukaphereses (CD34 + - selection) -interferon
HD-1: Improvement of Remission-Status 151 140 140 95 Interferon n=60
GMMG-HD2 Trial: Single versus Double Autologous Stem Cell Transplantation for Newly Diagnosed Multiple Myeloma 385 pts < 65 yrs (recruited 1998-2002), 358 pts evaluable Treatment 3-6 cycles of VAD-like induction Randomization: single ASCT versus double ASCT Results No significant difference for PFS between two treatment arms (P=0.36) Only ~ 51% of pts received intended double ASCT arm Conclusions Data do not support double HDT as standard frontline treatment in general Role of double HDT in the era of new drugs is under investigation Goldschmidt et al. IMW 2013 (Abstract P-216), poster presentation
GMMG-HD2 Trial
GMMG-HD2 Trial - Patient baseline characteristics
GMMG-HD2 Trial Consort Diagram
GMMG-HD2 Trial Progression Free Survival Intention to treat Per Protocol ITT Analysis 08/12
GMMG-HD2 Trial Overall Survival Intention to treat Per Protocol PP Analysis 08/12
HD3/HOVON50-Studie 2001-2004 MM Stage II oder III, Age 18-65 Randomisation 3 x VAD 3 x AD CAD MEL 200 + PBSCT MEL 200 + PBSCT -Interferon 9 Mio. U/Week Mobilisation & Leukapheresis Del13 / B2MG >3 mg/l, HLA-sib Donor Allogeneic Tx 2Gy + Fludara EBMT-study CAD MEL 200 + PBSCT MEL 200 + PBSCT Thalidomide
HOVON 50/GMMG-HD3: Safety analysis Cumulative percentage 25 20 15 10 5 N O VAD 201 11 AD+thal 211 19 Logrank P=.15 ArmA: DVT 8 (4%) Arm B: DVT 16 (8%) Arm B + LMWH: 12 (6%) AD+thal VAD 0 0 2 4 months 6 At risk: VAD 201 194 191 187 AD+thal 211 197 187 185 Minnema et al., Leukemia, 2004
HOVON 50/GMMG-HD3: Interim analysis Median CD34 + yield GMMG VAD (n=105) TAD (n=93) P-value Chi² HOVON VAD (n=100) TAD (n=100) P- valuechi ² 12 x 10 6 /kg Med. total CD34 + cells collected 10.9 9.8 0.02 9.4 7.4 0.009 10 8 6 4 2 0 VAD TAD VAD TAD GMMG HOVON Breitkreutz et al., Leukemia, 2007
EFS Gesamtpopulation p = 0.73 p = 0.012
OS Gesamtpopulation p = 0.42 p = 0.70
HOVON 65 MM / GMMG-HD4 Trial MM Stage II or III, Age 18 65 Randomization Bortezomib 1.3 mg/m 2 Doxorubicin 9 mg/m 2 3 x VAD 3 x PAD Dexamethasone 40 mg HDD CAD + GCSF CAD + GCSF MEL 200 + PBSCT MEL 200 + PBSCT In GMMG 2 nd MEL 200 + PBSCT Thalidomide 50 mg/day for 2 years maintenance Allogeneic Tx In GMMG 2 nd MEL 200 + PBSCT Bortezomib 1.3 mg/m 2 / 2 weeks for 2 years maintenance
Progression-free survival with censoring at allo-sct: primary endpoint PFS with censoring at allo-sct 100 HR = 0.75 (0.62-0.91), P=0.004 Cumulative percentage 75 50 25 B: PAD A: VAD A: VAD B: PAD 10 Nov 2010-15:13:13 0 N A: VAD 373 B: PAD 371 Cox LR Stratified At risk: 373 371 F 225 197 P =0.005 0 12 24 36 months 48 258 295 176 218 97 112 26 36
Multivariate Cox regression analysis PFS (allo censored) OS t HR p t HR p Arm 0.74.002 Arm 0.70.013 WHO 1.22.005 WHO 1.49 <.001 IgA 1.62.002 IgA 1.82.01 IgG 1.33.041 IgG 1.71.008 LDH 1.25.10 LDH 1.59.006 ISS 1.25.001 ISS 1.47 <.001 13q- 1.43.001 13q- 1.62.002 SG 0.81.039 SG 0.73.031
HO65/HD4: Impact of kidney function Cumulative percentage 100 75 50 25 0 A;cr<=176 A;cr>176 B;cr<=176 B;cr>176 24 Nov 2010-11:21:42 A;cr<=176 A;cr>176 B;cr<=176 B;cr>176 Logrank At risk: 328 44 336 34 N 328 44 336 34 D 89 31 83 10 P <.001 291 28 307 28 Overall survival B;cr<=176 A;cr<=176 B;cr>176 A;cr>176 0 12 24 months 36 269 20 280 25 163 10 176 15 C. Scheid et al., ASH 2010 / EBMT 2011
Impact of intensive therapy in high-risk disease Analysis of HOVON/GMMG trial (German centres) PFS OS Neben et al. Blood 2012;119(4):940-8.
PAD (Vel/Dex) zur Erstlinienbehandlung von Patienten mit multiplen Myelom Standard für die Induktionstherapie war bislang VAD, so dass der Ersatz der ohnehin nicht sehr wirksamen Substanz Vincristin durch Bortezomib entsprechend dem GMMG/HOVON-Protokoll als neuer Standard für die Induktionstherapie anzusehen ist. Dies entspricht auch der Bewertung der deutschen Studien-gruppe GMMG. MDK Gutachten Prof. Heyll, August 2009
PFS according to B-based and non-b-based ASCT(s) within subgroups with or without cytogenetic abnormalities 0 25 50 75 100 Del(17p) and t(4;14) negative* B-based ASCT(s) 50 41 Non-B-based ASCT(s) P=0.0101 0 25 50 75 100 P=0.0002 Del(17p) and/or t(4;14) positive* 35 23 B-based ASCT(s) Non-B-based ASCT(s) Number at risk Non-B-based ASCT(s) B-based ASCT(s) 0 12 24 36 48 60 Months 534 441 364 206 101 36 611 540 441 272 135 43 HR 0.79 (0.67-0.95) p=0.010 Number at risk Non-B-based ASCT(s) B-based ASCT(s) 0 12 24 36 48 60 Months 150 112 71 33 15 5 172 144 112 59 28 9 HR 0.58 (0.44-0.76) p=0.000 * Regardless of presence or absence of del(13q)
Bortezomib-based versus non-bortezomib-based induction prior to ASCT in multiple myeloma: meta-analysis of phase 3 trials Pieter Sonneveld, 1 Hartmut Goldschmidt, 2 Laura Rosiñol, 3 Joan Bladé, 3 Juan José Lahuerta, 4 Michele Cavo, 5 Paola Tacchetti, 5 Elena Zamagni, 5 Michel Attal, 6 Henk M. Lokhorst, 7 Avinash Desai, 8 Andrew Cakana, 9 Kevin Liu, 10 Helgi van de Velde, 11 Dixie-Lee Esseltine, 12 Philippe Moreau 13 1 Department of Hematology, Erasmus Medical Center, Rotterdam, the Netherlands; 2 University Hospital of Heidelberg, Heidelberg, Germany; 3 Hematology Department, Hospital Clinic de Barcelona, IDIBAPS, Barcelona, Spain; 4 Servicio de Hematología, Hospital Universitario 12 de Octubre, Madrid, Spain; 5 Istituto di Ematologia Seràgnoli, Università degli Studi di Bologna, Bologna, Italy; 6 Department of Hematology, Hopital Purpan, Toulouse, France; 7 Utrecht Medical Center, Utrecht, the Netherlands; 8 Janssen Global Services, Raritan, NJ, USA; 9 Janssen Research & Development, High Wycombe, UK; 10 Janssen Research & Development, Raritan, NJ, USA; 11 Janssen Research & Development, Beerse, Belgium; 12 Millennium: The Takeda Oncology Company, Cambridge, MA, USA; 13 University Hospital, Nantes, France
Background Bortezomib-based regimens compared to non-bortezomib-based previous standards of care as induction therapy prior to ASCT in a total of 4 multicenter, cooperative group phase 3 studies 1 4 Study 1º endpoint Bortezomib-based regimen Non-bortezomib-based regimen IFM 2005-01 HOVON-65/ GMMG- HD4 PETHEMA GEM05MENOS65* GIMEMA MM-BO2005 Post-induction CR+nCR rate PFS Post-induction and post-asct CR rate Post-induction CR+nCR rate Bortezomib-dexamethasone (N=240) Bortezomib-doxorubicindexamethasone (PAD, N=413) Bortezomib-thalidomidedexamethasone (VTD, N=130) VTD (N=241) *Study included a third induction arm, comprising VBMCP/VBAD followed by bortezomib Vincristine-doxorubicindexamethasone (VAD, N=242) VAD (N=414) Thalidomide-dexamethasone (TD, N=127) TD (N=239) 1. Harousseau JL, et al. J Clin Oncol 2010;28:4621-9. 3. Rosiñol L, et al. Blood 2012;120:1589-96. 2. Sonneveld P, et al. J Clin Oncol 2012;30:2946-55. 4. Cavo M, et al. Lancet 2010;376:2075-85.
OR for post-transplant CR+nCR rate similar across studies Non-bortezomib-basedBortezomib-based Study Odds ratio (95% CI) N CR/nCR (%) N CR/nCR (%) P-value HOVON-65/GMMG-HD4 2.02 (1.46, 2.79) 408 82 (20) 409 136 (33) <0.0001 IFM 2005-01 1.99 (1.34, 2.96) 238 56 (24) 236 90 (38) 0.0006 PETHEMA GEM05MENOS65 2.31 (1.40, 3.83) 126 44 (35) 130 72 (55) 0.0010 Pooled (fixed effect) 2.05 (1.64, 2.56) 772 182 (24) 775 298 (39) <0.0001 Heterogeneity I 2 = 0% Q = 0.25 with df = 2 GIMEMA MM-BO2005 1.75 (1.22, 2.52) 238 98 (41) 236 130 (55) 0.0025 Pooled (fixed effect) 1.96 (1.62, 2.37) 1010 280 (28) 1011 428 (42) <0.0001 Heterogeneity I 2 = 0% Q = 0.82 with df = 3 0.2 0.5 1 2 5 Favor non-bortezomib-based treatment Favor bortezomib-based treatment Odds ratio and 95% CI (log scale) With inclusion of study-level data from GIMEMA MM-BO2005, the pooled OR remained similar (1.96) to that for the integrated analysis
ISS 3, high LDH and t(4;14) and/or del(17p) as a prognostic index for OS Score Definition % of overall population Outcome 0 Absence of adverse factors (neither high LDH, nor ISS 3, nor t(4;14) and /or del(17p)) 57% 3-year OS: 89% 1 Presence of only 1 adverse factor (either high LDH or ISS 3 or t(4;14) and/or del(17p)) 32% 3-year OS: 73% 2 Presence of high LDH plus ISS 3 in the absence of t(4;14) and /or del(17p) 6% 3-year OS: 68% 3 Presence of t(4;14) and/or del(17p) in addition to either ISS 3 or high LDH 5% Median OS: 19 mos 3-year OS: 24% Moreau et al. ASH 2012 (Abstract 598), oral presentation
ISS 3, high LDH and t(4;14) and/or del(17p) as a prognostic index for OS Score: 2 Score: 0 Score: 1 Score: 3 Moreau et al. ASH 2012 (Abstract 598), oral presentation
Scoring system Score GIMEMA IFM Pethema HOVON / Total GMMG N = 399 N = 405 N = 381 N = 416 N = 1601 0 232 234 236 201 903 (58%) (58%) (62%) (48%) (56%) 1 134 128 110 143 515 (34%) (32%) (29%) (34%) (32%) 2 8 23 16 21 68 (2%) (6%) (4%) (5%) (4%) 3 25 20 19 51 115 (6%) (5%) (5%) (12%) (7%)
2-year Overall survival (OS) according to «scoring system» in 850 patients receiving bortezomib-based induction 1,0 OS 1,8 0.8 0.6,6 0.4,4 P < 0.0001 93% 86% 73% 52% 3,2 0.2 2 1 0 0,0 0 6 12 6 12 18 24 months 18 24 0
Cereblon Expression in HOVON-65/GMMG-HD4 A Progression free survival C Progression free survival 1.0 0.8 0.6 0.4 0.2 > median < median 0.0 0 12 24 36 Months 1.0 0.8 0.6 0.4 0.2 > median < median p = 0.009 42 31 13 4 30 19 4 0 0.0 0 12 24 36 Months A-B: thal-treated, C-D: bort-treated p = 0.18 48 38 19 3 2 39 33 10 4 48 B Overall survival D Overall survival 1.0 0.8 0.6 0.4 0.2 1.0 0.8 0.6 0.4 0.2 > median 48 38 18 9 < median 40 31 16 6 0.0 0 12 24 36 Months > median 42 35 15 8 < median 47 43 25 10 0.0 0 12 24 36 Months p = 0.13 48 p = 0.81 48 Broyl A, et al. Blood. 2013;121:624-7. 1 1 60 2 60
MM5-Trial symptomatic MM 1st line treatment 18-70a Randomization 3 x PAd A1 + B1 3 x VCD A2 + B2 1) 1) CAD + leukapheresis HDM + TPL 2. HDM + TPL (if no ncr/cr) Standard intensification according to local protocol (GMMG standard) 2 x Lenalidomide A1 B1 A2 B2 Lenalidomide for 2 years Lenalidomide if no CR Lenalidomide for 2 years Lenalidomide if no CR 1) High Risk Patients, optional in Phase II trial Flowsheet 31.03.2011
Amendment seit 02/2012 subkutane Applikation von Bortezomib Moreau et al., Lancet Oncol., 2011: - Bessere Verträglichkeit (PNP-Rate ) - Vergleichbare Response-Raten Umstellung in MM5 von i.v. zu s.c.-applikation - Gleiche Dosis, Injektionsvolumen
GMMG-ReLApsE study relapsed Multiple Myeloma (1.-3. relapse) age 18-70 years relapse 12 months after high dose therapy Randomization 3x RD 3x RD Cyclophosphamide + G-CSF + stem cell collection 1) Cyclophosphamide + G-CSF + stem cell collection 1) RD until progression/ relapse HD Mel 200mg/m² + autologous transplantation R-maintenance 2) until progression/ relapse 1) stem cell collection only if no useable stem cells are available from earlier mobilization 2) Lenalidomide maintenance therapy 10mg/day R-Lenalidomide, D-Dexamethasone, HD Mel-high dose Melphalan
OS GMMG-HD2 vs HD3/HD4 Overall Survival ITT OS Probability HD2 HD3/HD4 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 5 6 7 8 years since first HDM
GMMG-HD2, -HD3, -HD4 Beteiligte Kliniken und Praxen
Assoziierte Prüfzentren in hämatologischen Studien Hinweis auf Publikation im Ärzteblatt Schurich, B., Bertsch, U., Hügle-Dörr, B.: Deutsches Ärzteblatt, Jg. 110, Heft 5, Seite 176-177, 01. Februar 2013
Altenkirchen / Strehl Aschaffenburg/Welslau Baden-Baden / Staiger Bad Honnef / Forstbauer Bad Kreuznach / Schulz Bad Mergentheim / Hartung Berlin / Kiewe Berlin / Ilona Blau Berlin Seestraße/ Schmittel Bochum / Nückel Bonn / Ko Bonn / Verbeek Bonn-Beuel / Forstbauer Braunschweig / Pies Buchholz / Schieder Celle / Marquard Coburg / Lamberti Darmstadt / Kojouharoff Dortmund / Lathan Duisburg / Selbach, Anhuf Erfurt / Weniger Eschweiler / Staib Frankfurt / Bolling Frankf.NW-KH / Weidmann Frankfurt Maingau KH/ Böck Frankfurt / Prof. Chow Frechen / Schulz Gießen / Schließer Hamburg / Engel (HOPA) HH-Schnelsen /Müller-Hagen HH-Lerchenfeld / Wolff Hanau / Fauth Hanau Klinikum / Immenschuh Heidelberg / Karcher/Fuxius Heilbronn / Koniczek Heilbronn / Martens (SLK) Hennigsdorf/Speidel Idar-Oberstein / Roemer Kaiserslautern / Reeb Karlsruhe / Procaccianti Koblenz / Thomalla (InVO) Köln / Reiser Köln / Schmitz Köln-Holweide / Schulte Köln / MVZ Weihrauch Kronach / Stauch Landshut / Vehling-Kaiser Lebach / Kremers Lüneburg / Goldmann Mainz / Papesch Mannheim / Hensel Marburg / Balser Neunkirchen / Schmidt Nürtingen / Golf Oberhausen / Steiniger Offenbach / Böck Ostfildern Paracelsus / Abele Pforzheim / Dencausse Pinneberg / Leonhard Pirmasens / Scheuer Siegburg / Fronhoffs Siegen / Klump Singen / Fietz Speyer / Franz-Werner Stuttgart / Denzlinger Trier / Grundheber Trier / Kirchen (Brüder-KH) Trier / Rendenbach Trier / Mahlberg (Mutterh.) Troisdorf / Forstbauer Viersen / Reiter Wendlingen / Eckert Westerstede / Janssen Wolfsburg / Gabrysiak
MM5 Rekrutierung (11.10.2012) First patient in: Rekrutierung MM5 26.07.2010 Last patient in: geplant registriert 11.10.2012 n=504 Patienten Soll: ca. 15 Pat./Monat (ab Monat 7) Soll: ca. 7 Pat./Monat (erste 6 Monate)
To do 2013 Fokus auf Relapse Extension MM 5 (LKP Goldschmidt) Benda-Borte-Pred. (LKP Knauf) Poma responseadaptiert plus Cyclo (LKP Weisel) MM6 Protokoll (Start 2/14) Tumorzell-Mob (Start multizentrisch 4/14)
GMMG - Study group meeting