Treatment results with Bortezomib in multiple myeloma

Transcription

1 Treatment results with Bortezomib in multiple myeloma Prof. Dr. Orhan Sezer Hamburg University Medical Center

2 Circulating proteasome levels are an independent prognostic factor in MM 1.0 Probability of overall survival Log-rank P < Months Patients with low proteasome levels Patients with high proteasome levels Jakob et al., Blood 2007

3 Bortezomib vs. HD-Dex for Relapsed MM APEX Trial 78% improvement in median TTP with bortezomib (p< 0.001) Percent of patients without progression Bortezomib Dexamethasone Median TTP: Bortezomib 6.2 months Dexamethasone 3.5 months Richardson et al, NEJM 2005 Time (months)

4 VCD: Velcade Cyclo Dexa q 3 weeks. DSMM VI Trial RR: 82% CR: 16% DSMM, Br J Haematol 2007

5 Bortezomib + Adriamycin + Dexa Bortezomib 1,3 mg/m², d 1, 4, 8, 11 Adriamycin 9 mg/m²/d, d 1-4 Dexamethasone 40 mg/d, d 1-4, 8-11, in 1 st cycle, afterwards d 1-4 only q 3 weeks Remission rate 95% Oakervee et al., Br J Haematol 2005

6 Bortezomib ± DOXIL: MMY-3001 Trial Time to Progression Percent of Patients Progression-Free Bortezomib 6.5 months Statistical analysis: HR (95% CI) 1.82 ( ) p = Bortezomib + PLD 9.3 months Time (days) Orlowski et al., J Clin Oncol 2007

7 Bortezomib ± DOXIL: MMY-3001 Trial Overall Survival Percent of Subjects Alive Censored Died B+PLD 82% 18% Bortezomib B 75% 25% HR (95% CI) 1.41 (1.002;1.97) P < 0.05 Bortezomib +PLD Time (days) Orlowski et al., J Clin Oncol 2007

8 Phase I/II Study LBH589 + Bortezomib Number of Patients Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 5 CR VGPR PR MR SD PD NE % 61.5% % of Patients MR PR VGPR CR 0 All (n=36) BTZ refractory (n=13) Sezer et al., Phase I/II study of bortezomib and LBH589 in multiple myeloma International Multiple Myeloma Workshop 2009

9 VISTA: VELCADE as Initial Standard Therapy in multiple myeloma: Assessment with melphalan and prednisone Randomized Phase III Study VMP vs MP in previously untreated patients with symptomatic MM, who are not candidades for HDCT (age 65 yrs. or comorbidity) R A N D O M I Z E VMP Cycles 1 4 Bortezomib 1.3 mg/m 2 IV: d 1,4,8,11,22,25,29,32 Melphalan 9 mg/m 2 and prednisone 60 mg/m 2 : d 1 4 Cycles 5 9 Bortezomib 1.3 mg/m 2 IV: d 1,8,22,29 Melphalan 9 mg/m 2 and prednisone 60 mg/m 2 : d x 6-week cycles (54 weeks) in both arms MP Cycles 1 9 Melphalan 9 mg/m 2 and prednisone 60 mg/m 2 : d 1 4 Primary end point: TTP Secondary end points: CR rate, ORR, time to response, DOR, time to next therapy (TNT), OS, QoL (PRO)

10 VISTA Trial: Overall Survival Percentage of subjects w/o event (%) VMP MP Median follow-up 25.9 months VMP: median OS not reached (75 deaths); 3-year OS rate = 72% MP: median OS not reached (111 deaths); 3-year OS rate = 59% HR = 0.644, p = Time (months) 36% Risk reduction San Miguel et al., NEJM 2008

11 VISTA - Trial CR RR TRM Time to response Remission duration Remission duration (CR) Survival rate at 2 yrs VMP 30% 71% 1% 1.4 mo 20 mo 24 mo 82% MP 4% 35% 1% 4.2 mo 13 mo 13 mo 69% San Miguel et al., NEJM 2008

12 Optimising HDCT + ASCT Induction Bortezomib-Dex Vel-Cyclo-Dex Vel-ADM-Dex Vel-Thal-Dex Thal-Dex Thal-Cyclo-Dex Len-Dex RAD Mel 200 Mel 200 Consolidation/ Maintenance Thalidomide IMF 99/02 Bortezomib DSMM XI Lenalidomide IMF , CALGB Convent. CT No benefit

13 IFM2005/01 Study: Bortezomib-Dex vs VAD Primary Endpoint: Remission rate after induction with VAD vs Bortezomib-Dex Randomisation A1 A2 B1 B2 VAD x 4 VAD x 4 Induction Bortezomib- Dex x 4 Bortezomib- Dex x 4 DCEP x 2 Consolidation DCEP x 2 Melphalan 200mg/m 2 + ASCT Melphalan 200mg/m 2 + ASCT Transplant 1 Melphalan 200mg/m 2 + ASCT 2nd ASCT or RIC allo, if <VGPR Melphalan 200mg/m 2 + ASCT VAD: Vincristine, Adriamycin, Dexamethasone DCEP: Dexamethasone, Cyclophosphamide, Etoposide, Platin Harousseau et al., J Clin Oncol 2010

14 Bortezomib-Dex vs VAD: Remission rates Patients (%) Response after induction All p< VD vs VAD Response after 1st HDCT Response after 2nd HDCT 0 0 CR + ncr VGPR PR CR + ncr VGPR VGPR VAD (n=219) VD (n=223) Patients (%) All p<0.01 VD vs VAD VAD (n=219) VD (n=223) Patients (%) VAD (n=87) VD (n=55) CR + ncr: Complete response + near complete response VGPR: Very good partial response Harousseau et al., J Clin Oncol 2010

15 Summary of bortezomib induction regimen Harousseau VD vs VAD (n=223 vs 219) Cavo VTD vs TD (n=199 vs 200) (abstract 158) Sonneveld PAD vs VAD (n=75 vs 75) (abstract 653) Rosinol VTD vs VBCMP/VBAD+V vs TD (n=61 vs 54 vs 58) (abstract 654) Knop VCD (n=100) (abstract 2776) Results post-induction CR n/a 21%vs 6% n/a 31%vs 22% vs 6% 11% CR + ncr 15% vs 7% 33% vs 12% 5% vs 1% n/a n/a VGPR 39% vs 16% 61% vs 30% 42% vs 15% n/a 50% CR + PR 82% vs 65% 92% vs 78.5% 83% vs 59% 77% vs 70% vs62% 79% Results post-asct CR n/a 41% vs 20% n/a 50% vs 39% vs 26% n/a CR + ncr 40% vs 22% 54% vs 29% 23% vs 9% n/a n/a VGPR 61% vs 44% 75% vs 53% 80% vs 50% n/a n/a CR + PR n/a n/a 93% vs 80% n/a n/a n/a: not available

16 Phase III: VTD vs TD (GIMEMA study) n=236 n=238 Randomization Induction (three 21-day cycles) Bortezomib-Thal-Dex (VTD) V 1.3 mg/m 2 d1, 4, 8, 11 T 200 mg daily D 320 mg/cycle Induction (three 21-day cycles) Thal-Dex (TD) T 200 mg daily D 320 mg/cycle Double ASCT Consolidation (two 35-day cycles) Bortezomib-Thal-Dex (VTD) V 1.3 mg/m 2 once-weekly T 100 mg/d through d 1 to 70 D 320 mg/cycle Consolidation (two 35-day cycles) Thal-Dex T 100 mg/d through d 1 to 70 D 320 mg/cycle Maintenance: Dex Cavo et al., ASH 2010

17 Phase 3 Trial VTD vs TD: Efficacy Efficacy VTD TD P Induction ncr 31% 11% < After first ASCT ncr 52% 31% < After double ASCT ncr 55% 41% After consolidation ncr 62% 45% Best confirmed overall ncr and VGPR ncr 71% 54% < VGPR 89% 74% < Cavo et al. Lancet 2010

18 Phase 3 Trial VTD vs TD: Outcome Median follow-up: 36 months Progression-free survival Percent P= TD VTD Estimated 3-year PFS VTD 68% TD 56% Estimated 3-year OS VTD 86% TD 84% Cavo et al. Lancet 2010

19 Phase III: PAD vs VAD induction HOVON 65 MM / GMMG-HD4 study MM Stage II or III, Age n=744, median age 57 n=373 3 x VAD Randomization 3 x PAD n=371 PAD: Bortezomib 1.3 mg/m 2 Doxorubicin 9 mg/m 2 Dex 40 mg CAD + GCSF CAD + GCSF MEL PBSCT MEL PBSCT Depending on local policy for patients PR MEL PBSCT Allogeneic Tx Depending on local policy for patients PR MEL PBSCT Thalidomide 50 mg/day for 2 years maintenance Bortezomib 1.3 mg/m 2 / 2 weeks for 2 years maintenance Sonneveld et al., ASH 2010

20 Outcome Progression-free survival Overall survival Progression free survival Overall survival B: PAD Cumulative percentage B: PAD A: VAD Cumulative percentage A: VAD A: VAD B: PAD At risk: A: VAD 373 B: PAD Nov :14:01 N F months A: VAD B: PAD At risk: A: VAD 373 B: PAD Nov :14:34 N D months HR = 0.79 ( ), P=0.01 HR = 0.73 ( ), P=0.02 Sonneveld et al., ASH 2010 (Abstract 344), oral presentation

21 Subgroup analysis VAD/HDM/ thalidomide PAD/HDM/ bortezomib N PFS at 36m % OS at 36m % N PFS at 36m % OS at 36m % All ISS 1 ISS 2 ISS Creatinin 0-2 mg/dl > 2 mg/dl P<0.01 in univariate analysis Sonneveld et al., ASH 2010

22 Subgroup analysis of HOVON-65/GMMG-HD4: Influence of Renal Function on Outcome Progression-free survival (%) Creatinine (mg/dl) Treatment PFS 12 mo PFS 24 mo PFS 36 mo PFS 48 mo < 2 VAD (n=553) PAD VAD NR (n-46) PAD > 5 VAD (n=13) PAD NR Scheid et al., ASH 2010

23 Subgroup analysis of HOVON-65/GMMG-HD4: Influence of Renal Function on Outcome Creatinine (mg/dl) Treatment OS 12 mo OS 24 mo OS 36 mo OS 48 mo < 2 (n=553) 2-5 (n-46) > 5 (n=13) Overall survival (%) VAD PAD VAD PAD VAD PAD NR Comparison of results in patients with elevated creatinine (2-5 mg/dl) and creatinine < 2 mg/dl Inferior response, PFS and OS with VAD and thal maintenance Similar results for both groups for bortezomib-containing treatment Combining HDM with a bortezomib-containing induction- and maintenance regimen is able to overcome the negative prognostic impact of an impaired renal function in patients with newly diagnosed MM Scheid et al., ASH 2010

24 Bortezomib regimens in presence of high-risk disease in transplant setting VD (Avet-Loiseau et al. JCO 2010;28:4630-4) VTD (Cavo, ASH 2010, abstract 42) VTD (Rosinol, ASH 2010, abstract 307) PAD (Sonneveld, ASH 2010, abstract 40) VCD (Einsele, ASH 2009, abstract 131) 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 patients with t(4;14) del(17p) In VTD, no difference in PFS for patients with or without t(4;14) Superior CR rate for VTD versus TD in patients with t(4;14) and del(17) Bortezomib partly overcomes poor risk caused by t(4;14) and del(17p) No significant impact of del(13) or t(4;14) on ORR; trend to lower ORR with del(17)

25 Suggestions for treatment of ultra highrisk patients Patients with t(4;14) Patients with renal insufficiency Patients with del(17p) or poorrisk GEP Plasma cell leukemia Bortezomib-based chemotherapy Bortezomib-based chemotherapy Dose-dense chemotherapy (prospective trials) Role of consolidation and/or maintenance? Avet-Loiseau H, ASH 2010

26 Conclusions Induction treatment with bortezomib containing protocols before HDCT improve progression-free and/or overall survival. In patients not eligible for HDCT, MPV results in superior PFS and overall survival in comparison to MP. Proteasome inhibition represents a major treatment form in relapsed or refractory multiple myeloma. Dexamethasone adds to the efficacy of bortezomib. Combination with alkylating agents, anthracyclines or novel drugs further improve both remission rates and remission quality.