27. April German-Speaking Myeloma Multicenter Group. Hartmut Goldschmidt

Transkript

1 27. April 2013 German-Speaking Myeloma Multicenter Group Hartmut Goldschmidt

2 Priv.-Doz. Serke, Professor Huhn Priv.-Doz. Martin, Professor Hoelzer Dr. Goldschmidt, Professor Haas HD Dr. Cremer, Prof. Ho Triple MMM 2000

3 Front-Line Trials of the GMMG HD1 Trial: Tandem-Transplantation (Phase II, n=151) HD2 Trial: Single- versus Double-Transplantation (Phase III, n=480) HD3 Trial: Tandem-Transplantation (Germany) plus/minus Thalidomide (Phase III, GMMG n=550, HOVON n=500) HO65/HD4 Trial: VAD vs. PAD, Transplantation, maintenance Thalidomide vs. Bortezomib (Phase III, GMMG n=399, HOVON=434) 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)

4 HD-1:Treatment Plan VA(I)D, until CR or plateau, max. 6 cycles Time (n=151) HD-cyclophosphamide + G-CSF Melphalan 200 mg/m² cycle 1 PBSCT cycle 2 PBSCT Leukaphereses (CD selection) -interferon

5 HD-1: Improvement of Remission-Status Interferon n=60

6 GMMG-HD2 Trial: Single versus Double Autologous Stem Cell Transplantation for Newly Diagnosed Multiple Myeloma 385 pts < 65 yrs (recruited ), 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

7 GMMG-HD2 Trial

8 GMMG-HD2 Trial - Patient baseline characteristics

9 GMMG-HD2 Trial Consort Diagram

10 GMMG-HD2 Trial Progression Free Survival Intention to treat Per Protocol ITT Analysis 08/12

11 GMMG-HD2 Trial Overall Survival Intention to treat Per Protocol PP Analysis 08/12

12 HD3/HOVON50-Studie MM Stage II oder III, Age Randomisation 3 x VAD 3 x AD CAD MEL PBSCT MEL PBSCT -Interferon 9 Mio. U/Week Mobilisation & Leukapheresis Del13 / B2MG >3 mg/l, HLA-sib Donor Allogeneic Tx 2Gy + Fludara EBMT-study CAD MEL PBSCT MEL PBSCT Thalidomide

13 HOVON 50/GMMG-HD3: Safety analysis Cumulative percentage N O VAD AD+thal Logrank P=.15 ArmA: DVT 8 (4%) Arm B: DVT 16 (8%) Arm B + LMWH: 12 (6%) AD+thal VAD months 6 At risk: VAD AD+thal Minnema et al., Leukemia, 2004

14 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 VAD TAD VAD TAD GMMG HOVON Breitkreutz et al., Leukemia, 2007

15 EFS Gesamtpopulation p = 0.73 p = 0.012

16 OS Gesamtpopulation p = 0.42 p = 0.70

17 HOVON 65 MM / GMMG-HD4 Trial MM Stage II or III, Age 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 PBSCT MEL PBSCT In GMMG 2 nd MEL PBSCT Thalidomide 50 mg/day for 2 years maintenance Allogeneic Tx In GMMG 2 nd MEL PBSCT Bortezomib 1.3 mg/m 2 / 2 weeks for 2 years maintenance

18 Progression-free survival with censoring at allo-sct: primary endpoint PFS with censoring at allo-sct 100 HR = 0.75 ( ), P=0.004 Cumulative percentage B: PAD A: VAD A: VAD B: PAD 10 Nov :13:13 0 N A: VAD 373 B: PAD 371 Cox LR Stratified At risk: F P = months

19 Multivariate Cox regression analysis PFS (allo censored) OS t HR p t HR p Arm Arm WHO WHO 1.49 <.001 IgA IgA IgG IgG LDH LDH ISS ISS 1.47 < q q SG SG

20 HO65/HD4: Impact of kidney function Cumulative percentage A;cr<=176 A;cr>176 B;cr<=176 B;cr> Nov :21:42 A;cr<=176 A;cr>176 B;cr<=176 B;cr>176 Logrank At risk: N D P < Overall survival B;cr<=176 A;cr<=176 B;cr>176 A;cr> months C. Scheid et al., ASH 2010 / EBMT 2011

21 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.

22 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

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24 PFS according to B-based and non-b-based ASCT(s) within subgroups with or without cytogenetic abnormalities Del(17p) and t(4;14) negative* B-based ASCT(s) Non-B-based ASCT(s) P= P= Del(17p) and/or t(4;14) positive* B-based ASCT(s) Non-B-based ASCT(s) Number at risk Non-B-based ASCT(s) B-based ASCT(s) Months HR 0.79 ( ) p=0.010 Number at risk Non-B-based ASCT(s) B-based ASCT(s) Months HR 0.58 ( ) p=0.000 * Regardless of presence or absence of del(13q)

25 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

26 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 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: Rosiñol L, et al. Blood 2012;120: Sonneveld P, et al. J Clin Oncol 2012;30: Cavo M, et al. Lancet 2010;376:

27 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-HD (1.46, 2.79) (20) (33) < IFM (1.34, 2.96) (24) (38) PETHEMA GEM05MENOS (1.40, 3.83) (35) (55) Pooled (fixed effect) 2.05 (1.64, 2.56) (24) (39) < Heterogeneity I 2 = 0% Q = 0.25 with df = 2 GIMEMA MM-BO (1.22, 2.52) (41) (55) Pooled (fixed effect) 1.96 (1.62, 2.37) (28) (42) < Heterogeneity I 2 = 0% Q = 0.82 with df = 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

28 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

29 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

30 Scoring system Score GIMEMA IFM Pethema HOVON / Total GMMG N = 399 N = 405 N = 381 N = 416 N = (58%) (58%) (62%) (48%) (56%) (34%) (32%) (29%) (34%) (32%) (2%) (6%) (4%) (5%) (4%) (6%) (5%) (5%) (12%) (7%)

31 2-year Overall survival (OS) according to «scoring system» in 850 patients receiving bortezomib-based induction 1,0 OS 1, ,6 0.4,4 P < % 86% 73% 52% 3, , months

32 Cereblon Expression in HOVON-65/GMMG-HD4 A Progression free survival C Progression free survival > median < median Months > median < median p = Months A-B: thal-treated, C-D: bort-treated p = B Overall survival D Overall survival > median < median Months > median < median Months p = p = Broyl A, et al. Blood. 2013;121:

33 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

34 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

35 GMMG-ReLApsE study relapsed Multiple Myeloma (1.-3. relapse) age 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

36 OS GMMG-HD2 vs HD3/HD4 Overall Survival ITT OS Probability HD2 HD3/HD years since first HDM

37 GMMG-HD2, -HD3, -HD4 Beteiligte Kliniken und Praxen

38 Assoziierte Prüfzentren in hämatologischen Studien Hinweis auf Publikation im Ärzteblatt Schurich, B., Bertsch, U., Hügle-Dörr, B.: Deutsches Ärzteblatt, Jg. 110, Heft 5, Seite , 01. Februar 2013

39 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

40 MM5 Rekrutierung ( ) First patient in: Rekrutierung MM Last patient in: geplant registriert n=504 Patienten Soll: ca. 15 Pat./Monat (ab Monat 7) Soll: ca. 7 Pat./Monat (erste 6 Monate)

41 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)

42 GMMG - Study group meeting