Incorporating Novel Agents in the Transplant Setting

Transcription

1 Optimizing Therapeutic Sequencing in Myeloma Can Induction - Autologous SCT -Consolidation-Maintenance Lead to Improved Outcome? Paul G. Richardson, MD Jerome Lipper Multiple Myeloma Center Dana-Farber Cancer Institute, Harvard Medical School Boston, MA October 2010 Induction Incorporating Novel Agents in the Transplant Setting Preparative/Conditioning Regimen Consolidation Maintenance 1

2 What should be the Goal of Treatment in the Transplant Setting? Impact of achieving CR in transplant setting Meta-analysis of 21 studies 10 prospective 11 retrospective 4990 pts Highly significant association between maximal response following induction therapy and dlong-term outcome (P=0.0027) 0027) Highly significant association between maximal response (CR/nCR/VGPR) during or after HDT/SCT and long-term outcome (OS/EFS/PFS) (P< ) van de Velde et al. Haematologica 2007;92: Novel Agents as Part of Induction Regimens Prior to Stem Cell Transplantation 2

3 Summary of Novel Agent Induction Trials (Phase II/III Studies) VGPR rates post-induction and post- SCT Post-induction 80% Post-transplant transplant 71% 65% 54% 54% 45-55% 44-50% * * 61% 40% 42% 37% 37% 45% 30% 21% 15% VAD TD VD RD TAD CTD VCD PAD VTD Harousseau et al. J Clin Oncol 2010 Sep 7 [Epub] Rajkumar et al. Lancet Oncol 2010;11:29-37 Lokhorst et al. Blood 2010;115: *Post-transplant data not available CR only Morgan et al. ASH 2009 (Abstract 352), Sonneveld et al. ASH 2008 (abstract 653); IMW (abstract 152) Cavo et al. ASH 2009 (Abstract 351) Rosinol et al. ASH 2009 (Abstract 130) Phase 3: VTD vs TD GIMEMA Study Progression-free Survival VTD 24 mos 82% 30 mos 76% 58%* *significant difference between arms Superior PFS with VTD vs TD in pts with advanced age, ISS stage 2+3, high LDH, low albumin, del(13q), t(4;14) del(17p) In VTD, no difference in PFS for pts with or without high-risk cytogenetics Grade 3/4 PN during induction: VTD 9.7%, TD 2.1% Only 1% of pts in VTD had to discontinue treatment due to PN Cavo et al. ASH 2009 (Abstract 351) 3

4 Phase 3: VD vs vtd as Induction Prior to ASCT IFM Study n=205 Stratified by β2-m and del(13) by FISH R A N D O M I Z E VD vtd 4 x 21-day cycles Bortezomib 1.3 mg/m 2 d1, 4, 8, 11 Dex 40 mg d1-4 and 8-11 (c3+4 only) Bortezomib 1.0 mg/m 2 d1,4,8,11 Thal 100 mg daily Dex 40 mg d 1-4 and 8-11 (c3+4 only) Pts with <PR after cycle 2 could have bortezomib increased to 1.3 mg/m 2 and thal increased to 200 mg in the absence of PN Primary Objective: Induction CR rate Secondary Objectives: VGPR, PR, toxicity (including PN) Moreau et al. ASCO 2010 (abstract 8014) Harousseau et al. EHA 2010 (abstract 1097) Phase 3: VD vs vtd as Induction Prior to ASCT IFM Study Response rates VD vtd P Post-induction CR 12% 13% 0.74 ncr 22% 32% VGPR 35% 51% PR 81% 90% Post-transplant CR 33% 30% 0.65 ncr 54% 61% 0.35 VGPR 59% 73% PR 84% 90% 0.23 No difference regarding toxicity between two arms, except for Grade 2 PN Grade 2 PN : VD 28% vtd 15%, P=0.03 Grade 3 PN VD 6% vtd 3%, P=0.34 Moreau et al. ASCO 2010 (abstract 8014) Harousseau et al. EHA 2010 (abstract 1097) 4

5 Phase 2: VTD versus VTDC for Induction Efficacy, % VTD VTDC Post-induction n=49 n=48 ORR VGPR Combined CR* Post-ASCT n=38 n=27 ORR VGPR Combined CR* *M-protein confirmation Median follow up: 9.8 mos Median TTP, PFS, OS not reached Estimated 1-yr survival rate: 94% Safety, % VTD VTDC Any AE SAE Grade 3 AE Lymphocytopenia Anemia 8 18 Neutropenia Thrombocytopenia 6 6 Fatigue 2 8 Constipation 6 2 PN All grades Grade 3/ Ludwig et al. EHA 2010 (Abstract 371) Rationale for Combination Therapy in Multiple Myeloma IMiDs, Bortezomib Dex Bortezomib Alkylators Anthracyclines Mitochondria NF-κB Cytochrome-c Smac Caspase-8 Caspase 9 Caspase-3 PARP Tumor cell death Tumor cell death From Richardson PG, Mitsiades CS, Hideshima T, Anderson KC: Expert Review of AntiCancer Therapy. 2008;8:

6 RVD Phase I/II Lenalidomide, Bortezomib, and Dexamethasone: Up to 8 cycles intially, followed by maintenance, SCT optional: Day Bz Bz Bz Bz Dex Dex Dex Dex Len MTD based on phase I: Lenalidomide, 25 mg/day; Bortezomib, 1.3 mg/m 2; Dexamethasone, 20 mg/day, cycles 1-4, 10 mg/day, cycles 5-8. Antithrombotic therapy: Aspirin mg daily. Acyclovir or equivalent for HZV prophylaxis. With a median follow-up of 27.3 mos TTP, PFS, and OS have not been reached. 18-month PFS: 75%; 24-month OS: 97% Richardson et al. Blood 2010;116: Best Response to RVD Response, n (%) All pts (N=66) Phase II (N=35) CR 19 (29) 13 (37) ncr 7 (11) 7 (20) VGPR 18 (27) 6 (17) PR 22 (33) 9 (26) CR+nCR 26 (39) 20 (57) (90% CI) (29, 50) (42, 71) CR+nCR+VGPR 44 (67) 26 (74) (90% CI) (56, 76) (59, 86) At least PR 66 (100) 35 (100) (90% CI) (96, 100) (92, 100) Response improvement seen in 42/56 pts (75%) from C4 8 and 20/38 pts (53%) beyond C8 Median (range time to best overall response) was 2.1(0.6,20) mos Richardson et al. Blood 2010;116:

7 Lenalidomide / Bortezomib-Based Rx Response RVD 2 N = 66 RVDD 3 N = 70 VDCR 4 N = 41 CR + ncr 39% 33% 32% > VGPR 67% 59% 59% > PR 100% 97% 93% RVD: lenalidomide, bortezomib, dexamethasone; RVDD: RVD with pegylated liposomal doxorubicin; VDCR: RVD plus cyclophosphamide; VTD: bortezomib, thalidomide, dexamethasone Hematologic toxicity more severe with addition of chemo but not cumulative Risk of DVT does not appear to be increased over Lenalidomide alone Risk of PN does not appear to be increased over Bortezomib alone Generally well tolerated, although TRM with VDCR (2 pts in Evolution Study) 2 Richardson PG, et al. Blood Jakubowiak AJ, et al. Blood. 29;114(22). Abstract Kumar S, et al. Blood. 2009:114(22). Abstract 127. Weekly Bortezomib, CyBorD Modified CyBorD: Cyclophosphamide, weekly bortezomib, and reduced-dose dexamethasone CyBorD Modified CyBorD Response ITT n = 33 n = 30 ORR ( PR) 88% 93% VGPR 61% 60% CR/nCR 39% 40% Toxicity Grade 3 AE 48% 37% Grade 4 AE 12% 3% PN Grades 1/2 64% 56% PN Grade 3 6% 0% Reeder CB, et al. Blood. 2009;114(122). Abstract 616 7

8 Combinations in the Upfront Treatment of MM Stewart AK, Richardson PG, San Miguel JF Blood 2009 Impact of Novel Agents in the Post-ASCT Setting 8

9 Aims of Consolidation or Maintenance Therapy Consolidation Improve response/induce deeper response following therapy by administration of highly effective therapy for limited period of time Maintenance Maintain response achieved following therapy by administration of low-dose treatment for prolonged period Thalidomide Maintenance Studies Treatment n Induction with thal ASCT Maintenance duration Reference R R R R R Thal+pred Pred Thal+pamidronate pamidronate None Thal None Thal IFN Thal None 243 No Single ASCT 12 mos Spencer No Double ASCT until PD 668 Yes Double ASCT until PD 556 Yes 820 Yes Single or double ASCT Single ASCT/ Non-intensive Tx Attal 2006, Barlogie 2010 Barlogie 2006, 2008, 2010 until PD Lokhorst 2010 until PD Child 2010 Spencer et al. J Clin Oncol 2009;27: ; Attal et al. Blood 2006;108: ; Barlogie et al. N Engl J Med 2006;354: ; Blood 2008;112: ; J Clin Oncol 2010;28: ; Lokhorst et al. Blood 2010;115: ; Child et al. EHA 2010 (Abstract 1095) 9

10 Thalidomide Maintenance Studies Significant improvement in PFS with maintenance therapy Significant improvement in OS with maintenance therapy Survival after relapse Spencer Yes Yes Similar in all groups Attal Yes Yes Similar in all groups Barlogie Yes Yes, in pts with cytogenetic abnormalities Reduced OS after Thal exposure Lokhorst Yes No Reduced OS after Thal exposure Child Yes No Reduced OS after Thal exposure Attal et al. Blood 2006;108: ; Spencer et al. J Clin Oncol 2009;27: ; Barlogie et al. N Engl J Med 2006;354: ; Blood 2008;112: ; J Clin Oncol 2010;28: ; Child et al. EHA 2010 (Abstract 1095); Lokhorst et al. Blood 2010;115: Phase 3: Lenalidomide after ASCT (IFM ) (n=307) (n=307) Primary endpoint: PFS Attal et al. ASCO 2010 (Abstract 8018) 10

11 Phase 3: Lenalidomide after ASCT (IFM ) Median follow up from randomization: 12 mos P < 10-7 p<10-7 Lenalidomide Placebo PFS advantage for lenalidomide maintenance regardless of Level of response achieved pre-consolidation Level of β 2 M Attal et al. ASCO 2010 (Abstract 8018) Presence of del13 Induction regimen (VAD or VD) CALGB : Lenalidomide as Maintenance Therapy after ASCT n=208 n=210 Primary endpoint: TTP McCarthy et al. ASCO 2010 (Abstract 8017) 11

12 CALGB : Lenalidomide as Maintenance Therapy after ASCT Median follow up from ASCT: 12 mos P= TTP advantage for lenalidomide maintenance regardless of Level of β 2 M Exposure to thal or len during induction McCarthy et al. ASCO 2010 (Abstract 8017) Conclusion Novel agents are having a significant impact in transplant setting Induction setting Improving CR rates Associated with improved long-term outcome Three-drug regimens appear superior to two-drug regimens Bortezomib/dex could be considered a backbone of induction regimens before high-dose therapy Post-ASCT setting Novel agents able to upgrade response Lenalidomide significantly improves PFS Long-term follow-up needed to assess effects on OS Moreau et al. Leukemia 2010;24:

13 What is the Role for Transplantation in MM in the Era of Novel Agents? Multicenter, Sequential, Randomized Trial to assess Optimal Timing of HDT and ASCT Pre-novel Agent Era Pts (n=202) early HDT group (n=91): HDT-ASCT upfront late HDT group (n=94) conventional chemotherapy, ASCT at relapse Median follow-up: 58 mos Median OS Early HDT group: 64.6 mos Late HDT group: 64 mos (P=0.92) Fermand et al. Blood 1998;92:

14 Retrospective Analysis: Delayed Transplantation at Relapse versus Early Transplantation Review of 410 pts treated with Thal/dex or Len/dex at Mayo Clinic n=292 transplant eligible Initial therapy: Thal/dex n=125, Len/dex n=167 n=292 Transplant eligible n=174 early SCT n=118 delayed SCT (n=46 transplanted to date) Median estimated time to SCT: 5.3 mos early SCT 39 mos delayed SCT Early SCT: Pts undergoing SCT within 12 mos of diagnosis; SCT performed within 2 mos of SC harvest Delayed SCT: remaining pts irrespective of whether SCT was actually done Kumar et al. ASH 2009 (abstract 956) Retrospective Analysis: Delayed Transplantation at Relapse versus Early Transplantation Median OS from diagnosis Early SCT: 86 mos Late SCT: not reached, P=0.3 Conclusions Continued initial therapy and delayed transplant at the time of first relapse appears comparable to upfront transplant Findings need to be confirmed in prospective randomized trials Kumar et al. ASH 2009 (abstract 956) 14

15 The image cannot be displayed. Your computer may not have enough memory to open the image, or the image may have been corrupted. Restart your computer, and then open the file again. If the red x still appears, you may have to delete the image and then insert it again. 12/16/2010 Timing of Transplant RVD Phase I/II: PFS by ASCT Status from 1-yr Landmark Risk of progression decreased markedly after 12 mos Post-hoc landmark analysis from 1-yrpost-treatment treatment initiation in 53 pts who had not progressed at 1-yr follow-up No difference detected (log-rank p=0.84) in PFS by whether pts received ASCT or not (pts not censored at time of ASCT) Richardson et al. Blood 2010;116: Phase 3 study: MPR versus Tandem ASCT Interim Analysis Induction Consolidation Maintenance n=402 Rd (four 28-day cycles) Lenalidomide 25 mg/d, days1-21 Low-dose dex 40mg/d, days 1,8,15,22 R A N D O M I Z n=202 MPR (six 28-day cycles) Melphalan 0.18 mg/kg/d, days 1-4 Prednisone 2 mg/kg/d, days 1-4 Len 10 mg/d, days 1-21 n=200 E MEL 200 Tandem Mel 200mg /m 2 plus stem cell support R A N D O M I Z E No maintenance Maintenance Len 10 mg/d, days day course until relapse Primary end point: PFS Palumbo et al. ASCO 2010 (abstract 8015) 15

16 Phase 3 study: MPR versus Tandem ASCT Interim Analysis Results (median follow up: mos) Rd induction: PR 86%, VGPR 37%, CR 6% Pts who completed at least 3 cycles MPR or 1 cycle MEL200 were evaluated MPR (n=117) MEL 200 (n=122) CR 13% 16% 0.82 VGPR 55% 53% 0.63 PR 91% 91% 12 mos 91% 91% mos 97% 98% 0.27 Grade 3/4 hematologic toxicity it Neutropenia 48% 84% <0.001 Thrombocytopenia 8% 84% <0.001 Grade 3/4 non-hematologic toxicity Infections 0 16% Gastrointestinal 0 22% Palumbo et al. ASCO 2010 (abstract 8015) P Future Directions? ASCT upfront Novel agent combo upfront + ASCT at relapse? Tailored approach to therapy? Identify groups of pts in whom early transplant is required versus pts in whom transplant could be delayed to relapse 16

17 IFM/DFCI 2009 Study Newly Diagnosed MM Pts (SCT candidates) Randomize, stratification ISS & FISH RVD x 3 CY (3g/m 2 ) MOBILIZATION Goal: 5 x10 6 cells/kg Induction Collection RVD x 3 CY (3g/m 2 ) MOBILIZATION Goal: 5 x10 6 cells/kg Melphalan 200mg/m 2 * + ASCT RVD x 2 Lenalidomide Consolidation Maintenance RVD x 5 Lenalidomide SCT at relapse MEL 200 mg/m2 if <65 yrs, >65 yrs 140mg/m 2 Novel Agents Alone versus Intensive Therapy + Novel Agents: European Intergroup Trial 3 x CVD + Registration Stem cell apheresis Induction Stem cell mobilization in all pts R1 4 x VMP HDM 1/2 R2 2 x VRD none Consolidation Lenalidomide Lenalidomide Maintenance until relapse HDM/ASCT at relapse 17

18 Phase 3: Bortezomib/dex vs VAD IFM 2005/01 Progression-free Survival VAD VD P PFS in all pts 30 mos 36 mos PFS in pts with ISS 2 & 3 23 mos 33 mos PFS in pts with t(4;14) +/- del17 24 mos 33 mos Harousseau et al. ASH 2009 (Abstract 353) Impact of Thalidomide in Presence of High Risk Cytogenetic Abnormalities: Front-line Studies Reference Regimen Results (ASH 2009 abstract #) Thal/dex Thal/dex upfront does not overcome del13, t(4;14) or del17 Zamagni 349 CTD Adverse FISH [t(4;14), t(14;16), 16) t(14;20), 1p-, 1q+, 17p-] associated with reduced PFS and OS Morgan

19 Len/dex in Pts with Cytogenetic Abnormalities Study details Newly diagnosed MM (n=100) 1 Relapsed/ refractory MM (n=207) 2 Relapsed/ refractory MM (n=130) (expanded access program) 3 Relapsed/refractory MM (n=83) 4 Cytogenetic abnormalities del (13), del (17p), t(4;14), t(14;16), hypodiploidy del(13), t(4;14) del(13), t(4;14), del (17p) t(4;14), add1q21, del17p Results PFS significantly shorter in pts with high-risk disease OS comparable in pts with and without highrisk disease Significant difference in ORR, PFS, OS between pts with and without cytogenetic abnormalities del(13) and t(4;14) did not adversely affect ORR, TTP and OS del(17): lower ORR, significantly reduced TTP and OS Addition of bortezomib to len/dex may overcome adverse prognosis of t(4;14) and add1q21, but not del17p 1. Kapoor, P. et al. Blood 2009;114: Avet Loiseau et al. Leukemia 2010;24: Reece et al. Blood 2009;114: Dimopoulos et al. ASH 2009 (Abstract 958) Bortezomib Induction Regimens: High-risk Disease VD (Harousseau, ASH 2009, abstract 353; Avet-Loiseau et al. JCO 2010, Epub) VTD (Cavo, ASH 2009, abstract 351) VTD (Rosinol, ASH 2009, abstract 130) PAD (Sonneveld, EHA 2009, abstract 473) VCD (Einsele, ASH 2009, abstract 131) PFS longer for VD vs VAD in pts with ISS 2 3 VD is superior to VAD in terms of PFS and OS for t(4;14), but not for del(17) Superior PFS with VTD vs TD in pts with advanced age, ISS stage 2 and 3, high LDH, low albumin, del(13q), t(4;14) del(17p) In VTD, no difference in PFS for pts with or without high-risk cytogenetics Similar CR and VGPR rates in pts with and without t(4;14), t(14;15), del(17) No significant impact of del(13) or t(4;14) on VGPR or CR/nCR rates No significant impact of del(13) or t(4;14) on ORR; trend to lower ORR with del(17) 19

20 Impact of t(4;14) in Pts Receiving Vel/dex or VAD Induction Therapy OS comparison of VAD vs Vel/Dex for t(4;14) pts OS of 507 pts treated with Vel/Dex induction t(4;14) neg Vel/Dex t(4;14) pos VAD P = P = Avet-Loiseau et al J Clin Oncol 2010 Impact of del(17p) in Pts Receiving Vel/dex or VAD Induction Therapy OS comparison VAD vs Vel/Dex for del(17p) pts OS of 531 pts treated with Vel/Dex induction No del(17p) Vel/Dex VAD P = 0.49 P < Del(17p) pos Avet-Loiseau et al J Clin Oncol

21 Retrospective Analysis of 2 GIMEMA Trials: Impact of Upfront Bortezomib-based Regimens on Clinical Outcomes According to Cytogenetic Abnormalities by FISH Analysis Progression-free Survival For pts with high-risk cytogenetic abnormalities randomized to different treatments 33 mos in pts with t(4;14) +/- del(17p) VTD 68% TD 40% P For pts randomized to different treatments and stratified according to cytogenetic abnormalities 33 mos in pts with t(4;14) +/- P del(17p) VTD 68% VMPT 46% 0.03 VMPT 46% VMP 39% ns 33 mos in pts with no abnorm. / del(13q) VTD 77% VMPT 58% Cavo et al. EHA 2009 (abstract 1096) RVD Upfront: Impact of Cytogenetic Abnormalities on Response and PFS n VGPR (%) 18 m (%) Abnormal metaphase Yes cytogenetics No Del13 by FISH Yes No Del17p by FISH Yes No t(4;14) by FISH Yes No t(11;14) by FISH Yes No Del17p and/or t(4;14) by FISH Yes No Richardson et al. Blood 2010;116:

22 Conclusions Role of ASCT in era of novel agents is undergoing investigation SCT may not be needed in all transplant-eligible pts as initial therapy Aim: offer tailored treatment approach based on individual risk factors Open questions Optimal novel agent combination during induction Duration of therapy: should all pts receive maintenance therapy? Which cytogenetic abnormalities remain poor prognostic factors and how can these be overcome? Clinical Investigators in MM - A Global Network: Leadership, including Anderson KC., Harousseau JL., San Miguel J., W Dalton, Kyle R. APEX/ SUMMIT/CREST/ VISTA/ Combination Studies Investigators: Sponsors including Millenium; Celgene; J & J; Novartis; BMS; Keryx; Merck ECOG, CALGB, Multiple Myeloma Research Consortium (MMRC) Abubakr Y. Agura E. Alexanian R. Alsina M. Andre M. Attal M. Avigan D. Barlogie B. Baccarani M. Bahlis N. Barbui T. Barton, K. Belch A. Beksac M Bensinger W. Ben-YehudD. Berdeja J. Berenson, J. Bjorkstrand Bladé J. Boccadoro, M. Boue F. Bourhis J. Bron D. Catlett J. Moreau P. Coleman M. Cavenagh J. Cavet J. Chanan-Khan A. Coiffier B. Comenzo, R. Craddock, C. Dearden C. Delforge M. Densmore J. Dispienzeri, A Dimopoulos, T Doyen C. Durk H. Durie, B Ehninger G. Einsele H. Engelhardt M. Facon T. Fay J. FehrenbacheL Feremans W. Fermand JP. Fernandez H. Fonseca, R Giguere J. Glasmacher A. Rossi JF. Advocacy/Support MMRF; IMF ; FDA; EMEA Glass J. Goldschmidt H. Gordon P. Gramatzki M. Gruber A. Gyan E. Hamm J. Hegewisch-Becker Hideshima T. Huber C. Hulin C. Hussein M. Ifthikharuddin J. Irwin D. Jackson G. Jagannath S. Jagasia M. Jakubowiak A. Joshua D Klein A. Kobbe G. Kovacs M. Krishnan A. Kropff M. Kuter D Lacy M. Lenhoff S. Limentani S. Lokhorst H. Lonial S. Ludwig H. Mandelli F. Marie J.P. Marsden G.J. Martin T. Mason J. Mateos S. Mavromatis B. Mitsiades, C. Morris C. Morrison V. Niesviesky R. Nowrousian M. Orlowski R. Pecora A. Phelan J. Posada J. Prince M Rahemtulla A. Rai K. Rajkumar V. Reece D. Richardson P. Rowe J.M. Schilder R. Schmidt W. Schuster M. Sezer O. Shadduck R. Shustik C. Siegel D. Singhal S. Sonneveld P. Sotto J.J. Stadtmauer E. Stewart, K Tarantolo S. Van Droogenbroeck Van Oers M.H. Vellenga E. Vesole D. Vij R. Wang M. Zachee P. Zangari M. Zeldenrust, S Zonder, J 22