Treatment results with Bortezomib in multiple myeloma

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

Circulating proteasome levels are an independent prognostic factor in MM 1.0 Probability of overall survival 0.8 0.6 0.4 0.2 Log-rank P <.001 0.0 0 20 40 60 80 Months Patients with low proteasome levels Patients with high proteasome levels Jakob et al., Blood 2007

Bortezomib vs. HD-Dex for Relapsed MM APEX Trial 78% improvement in median TTP with bortezomib (p< 0.001) Percent of patients without progression 100 90 80 70 60 50 40 30 20 10 0 0 Bortezomib Dexamethasone Median TTP: Bortezomib 6.2 months Dexamethasone 3.5 months 1 2 3 4 5 6 7 8 9 10 11 12 13 14 14.8 Richardson et al, NEJM 2005 Time (months)

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

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, 15-18 in 1 st cycle, afterwards d 1-4 only q 3 weeks Remission rate 95% Oakervee et al., Br J Haematol 2005

Bortezomib ± DOXIL: MMY-3001 Trial Time to Progression Percent of Patients Progression-Free 0 20 40 60 80 100 Bortezomib 6.5 months Statistical analysis: HR (95% CI) 1.82 (1.41-2.35) p = 0.000004 Bortezomib + PLD 9.3 months 0 100 200 300 400 500 Time (days) Orlowski et al., J Clin Oncol 2007

Bortezomib ± DOXIL: MMY-3001 Trial Overall Survival Percent of Subjects Alive 0 20 40 60 80 100 Censored Died B+PLD 82% 18% Bortezomib B 75% 25% HR (95% CI) 1.41 (1.002;1.97) P < 0.05 Bortezomib +PLD 0 50 100 150 200 250 300 350 400 450 500 550 600 650 700 Time (days) Orlowski et al., J Clin Oncol 2007

Phase I/II Study LBH589 + Bortezomib Number of Patients 9 8 7 6 5 4 3 2 1 0 Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 5 CR VGPR PR MR SD PD NE 80 70 60 72.2% 61.5% % of Patients 50 40 30 20 10 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

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 1 4 9 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)

VISTA Trial: Overall Survival Percentage of subjects w/o event (%) 100 90 80 70 60 50 40 30 20 10 0 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 = 0.0032 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 Time (months) 36% Risk reduction San Miguel et al., NEJM 2008

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

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 2005-02, CALGB Convent. CT No benefit

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

Bortezomib-Dex vs VAD: Remission rates Patients (%) 100 90 80 70 60 50 40 30 20 10 0 7 Response after induction All p<0.0005 VD vs VAD 15 16 39 65 82 100 90 80 70 60 50 40 30 20 10 Response after 1st HDCT 22 44 40 61 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 (%) 100 90 80 70 60 50 40 30 20 10 47 68 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

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

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

Phase 3 Trial VTD vs TD: Efficacy Efficacy VTD TD P Induction ncr 31% 11% <0.0001 After first ASCT ncr 52% 31% <0.0001 After double ASCT ncr 55% 41% 0.002 After consolidation ncr 62% 45% 0.0002 Best confirmed overall ncr and VGPR ncr 71% 54% <0.0001 VGPR 89% 74% <0.0001 Cavo et al. Lancet 2010

Phase 3 Trial VTD vs TD: Outcome Median follow-up: 36 months Progression-free survival Percent P=0.0057 TD VTD Estimated 3-year PFS VTD 68% TD 56% Estimated 3-year OS VTD 86% TD 84% Cavo et al. Lancet 2010

Phase III: PAD vs VAD induction HOVON 65 MM / GMMG-HD4 study MM Stage II or III, Age 18 65 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 200 + PBSCT MEL 200 + PBSCT Depending on local policy for patients PR MEL 200 + PBSCT Allogeneic Tx Depending on local policy for patients PR MEL 200 + 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

Outcome Progression-free survival Overall survival Progression free survival Overall survival 100 100 B: PAD Cumulative percentage 75 50 25 B: PAD A: VAD Cumulative percentage 75 50 25 A: VAD A: VAD B: PAD At risk: A: VAD 373 B: PAD 371 10 Nov 2010-15:14:01 N 373 371 F 243 215 0 0 12 24 36 months48 289 321 199 237 110 118 30 39 A: VAD B: PAD At risk: A: VAD 373 B: PAD 371 10 Nov 2010-15:14:34 N 373 371 D 120 93 0 0 12 24 36 months 48 320 336 290 306 174 191 63 79 HR = 0.79 (0.66-0.95), P=0.01 HR = 0.73 (0.56-0.96), P=0.02 Sonneveld et al., ASH 2010 (Abstract 344), oral presentation

Subgroup analysis VAD/HDM/ thalidomide PAD/HDM/ bortezomib N PFS at 36m % OS at 36m % N PFS at 36m % OS at 36m % All 373 40 70 371 48 78 ISS 1 ISS 2 ISS 3 168 65 101 50 32 29 81 70 50 167 93 73 55 45 37 86 71 68 Creatinin 0-2 mg/dl > 2 mg/dl 328 44 44 12 75 32 336 34 48 49 78 72 P<0.01 in univariate analysis Sonneveld et al., ASH 2010

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 86 61 45 31 (n=553) PAD 88 67 48 33 2-5 VAD 47 30 13 NR (n-46) PAD 89 78 56 47 > 5 VAD 75 25 25 25 (n=13) PAD 60 40 40 NR Scheid et al., ASH 2010

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 93 86 77 70 PAD 93 86 78 73 VAD 59 44 16 16 PAD 89 89 83 83 VAD 75 50 50 17 PAD 60 60 60 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

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)

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

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.