Überführung von Studiendaten in die klinische Praxis Hartmut Goldschmidt

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1 Überführung von Studiendaten in die klinische Praxis Hartmut Goldschmidt

2 - academic study group - founded in specialized in multiple myeloma - investigator initiated trials (IITs) - about 40 stem cell transplantation centers - about 100 NIO-praxisis/ hospitals without ASCT unit (associated sites) - leading group: 15 members - investigator meetings twice per year

3 Transplantation and Associated Trial Sites

4 Previous First Line Trials 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)

5 Treatment Schedule of HOVON 65 MM / GMMG-HD4 Trial MM Stage II or III, Age x VAD Randomization 3 x PAD Bortezomib 1.3 mg/m 2 Doxorubici n 9 mg/m 2 CAD + GCSF CAD + GCSF Dexametha sone 40 mg HDD MEL PBSCT MEL PBSCT In GMMG if <PR 2 nd MEL PBSCT Allogeneic Tx In GMMG if < PR 2 nd MEL PBSCT Thalidomide 50 mg/day for 2 years maintenance Bortezomib 1.3 mg/m 2 / 2 weeks for 2 years maintenance

6 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

7 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

8 Cumulative percentage Kidney function HOVON 65 MM / GMMG-HD4 Trial 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

9 Current First Line Trial MM5 Trial VCD vs. PAd, standard intensification (high dose therapy and ASCT) consolidation/maintenance with Lenalidomide, maintenance 2a vs. until CR Phase III, randomized, 4 treatment arms Start 07/2010, last patient in: 11/ transplantation sites 78 associated sites n= additional patients after amendment 07/2013

10 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

11 Recruitment MM5 Trial First patient in: Last patient in (n=504): Rekrutierung MM geplant registriert Amendment +100 pat.: Last patient in (n=604): geplant: ca. 15 Pat./Monat (ab Monat 7) geplant: ca. 7 Pat./Monat (in den ersten 6 Monaten) 11

12 Amendment 02/2012 (after inclusion of 314 patients) subcutaneous administration of Bortezomib Moreau et al., Lancet Oncol., 2011: superior safety data (PNP ) and comparable response rates Amendment 07/2013 additional 100 patients Next interim analysis 07/2014 Comparison of bortezomib application i.v. versus s.c. in respect to toxicity (especially PNP)

13 MM5-scientific programme (central diagnostics) => depth of remission? => risk assessment? => pathogenic mechanism? sflc (Freelite ), Heavy Chain Test (Hevylite) Interphase in situ hybridazition (ifish), at least 14 probes Gene Expression Profiling (GEP) Multicolour Flow Cytometry MRD diagnostics => depth of remission

14 ReLApsE-Studie 282 Patienten Multiples Myelom, Rezidiv Jahre Randomisation 167 Patienten rekrutiert Stand Zyklen Rd 3 Zyklen Rd 1) Cyclophosphamid + G-CSF + Stammzellsammlung 1) Cyclophosphamid + G-CSF + Stammzellsammlung Rd bis Progress HD Mel 200mg/m² + autologe Transplantation bei Progress Hochdosistherapie + Auto Tx empfohlen (außerhalb dieser Studie) 2) R-Erhaltungstherapie bis Progress 1) Stammzellmobilisierung und -sammlung wenn kein geeignetes Transplantat von früheren Mobilisierungen vorhanden 2) Lenalidomid-Erhaltungstherapie 10mg/d kontinuierlich R-Revlimid (Lenalidomid), d-dexamethason, HD Mel-Hochdosis Melphalan

15 Primäre Fragestellung progressionsfreies Überleben Sekundäre Fragestellungen Gesamtüberleben Ansprechraten Toxizitätsanalyse

16 GMMG Trials in Preparation BPV Trial: -First line therapy for patients not eligible for stem cell transplantation: Bendamustine, Prednisone and Bortezomib -Primary endpoint: therapeutic efficacy of BPV regimen: overall response defined as partial response (PR) or better -96 patients in 15 centers (mainly local established hematologists) -Phase IIB Start: September 2014

17 BIRMA trial -Refractory or relapsed myeloma patients with mutation in BRAF-V600 gene -Primary endpoint: therapeutic efficacy of LGX818/MEK162 (both kinase inhibitors) to reduce tumor burden -Phase II, 15 patients -Start: End of 2014 => new GMMG study generation with focus on personalized therapy

18 GMMG HD 6 Trial A randomized phase III trial on the effect of elotuzumab in VRD induction/ consolidation and in lenalidomide maintenance in patients with newly diagnosed myeloma

19 HD6-Trial - proposal symptomatic MM 1st line treatment 18-70a N 500 patients 3 years recruitment Randomization 4 x VRD A-I + A-II 4 x VRD + Elotuzumab 1) 1) Cy + G-CSF + leukapheresis HDM + TPL 2. HDM + TPL (if no ncr/cr) B-I + B-II GMMG standard intensificat ion A-I A-II B-I B-II 2 x VRD consolidation 2 x VRD + Elo. consolidation 2 x VRD consolidation 2 x VRD + Elo. consolidation Rev. MT Rev. MT + Elotuzumab Rev. MT Rev. MT + Elotuzumab 1) high risk patients, optional in phase II trial Flowsheet 06/2013 VRD= Bortezomib/Lenalidomid/Dexamethasone; Elo=Elotuzumab; Rev.MT= Lenalidomid maintenance

20 GMMG Trials: Summary (1) nicht behandlungsbedürftig behandlungsbedürftig Erstbehandlung Rezidiv BPV Symptomatisches MM BIRMA Refraktär Myelomlast MGUS Stadium I HD6 MM5 ReLApsE PERSPECTIVE Zeit

21 Members of the GMMG Study Group at the Investigator Meeting 2012 in Heidelberg Thank you for your attention!