I farmaci innovativi in Ematologia Bortezomib nel Mieloma Multiplo Elena Zamagni Istituto di Ematologia ed Oncologia Medica “Seràgnoli” Università degli Studi di Bologna

NOVEL AGENTS TARGETING MM CELLS AND THE BONE MARROW MILIEU Cytokine production Myeloma cells Adhesion - Angiogenesis A B D E C - Kyle RA, NEWJ 2004 (modificata)

MECHANISM OF ACTION OF BORTEZOMIB X Adapted from Adams J. Drug Discov Today 2003

BORTEZOMIB IN MULTIPLE MYELOMA AS….. Induction and consolidation therapy in the context of ASCT in young patients Up-front therapy in elderly patients Salvage treatment in relapsed/refractory patients Conditioning regimen and consolidation treatment in the context of allogeneic stem cell transplantation Therapy of MM bone disease Treatment of newly diagnosed and relapsed/refractory AL amyloidosis Other strategies have been used to improve the outcome of ASCT Among these strategies is double ASCT, which has been shown to be beneficial in patients not achieving a CR or VGPR following the first transplant In addition, the transplant protocol has been further intensified, which has led to improvements in response rates and survival Finally, novel agents are being introduced into the ASCT paradigm to further improve results

Current status: ASCT In patients <65 years old, ASCT is the standard of care - Superiority of a single ASCT over conventional chemotherapy - Superiority of double ASCT over a single autotransplantation Study n Age CR (%) EFS OS IFM 901 200 ≤65 5 vs 22* (7-year) 8% vs 16%* (7-year) 27% vs 43%* MRC VII2 401 8 vs 44* 19m vs 31m* 42m vs 54m* IFM 943 399  60 50 vs 42 (VGPR) 30m vs 25m* 58m vs 48* Bologna 964 321 47 vs 33 35m vs 23m* 71m vs 65m In patients <65 years old, ASCT is considered the standard of care, as randomized trials demonstrated the superiority of ASCT over conventional chemotherapy The table summarizes important studies that compared conventional chemotherapy with ASCT The first study comparing the two treatments was conducted by the French Myeloma Group and showed that high-dose therapy is superior to treatment with conventional chemotherapy It is important to note that although 3 of the 4 studies listed here demonstrated a statistically significant superiority of ASCT over conventional chemotherapy, a recent update of the large US Intergroup trial could not show a significant difference between ASCT and conventional chemotherapy 1 Attal M et al, N Engl J Med 1996 3 Attal M et al, N Engl J Med 2003 2 Child A et al, N Engl J Med 2003 4 Cavo M et al, J Clin Oncol 2007 *Significant difference

ASCT: new treatment paradigm with novel agents Introducing novel agents into ASCT As induction therapy • To maximize the speedy and degree of tumor reduction • To increase the CR rate before and after ASCT(s) • To apply ASCT(s) earlier and in a higher fraction of patients As consolidation/mainteinance therapy • To increase the final CR rate • To reduce the risk of relapse • To extend EFS and OS Other strategies have been used to improve the outcome of ASCT Among these strategies is double ASCT, which has been shown to be beneficial in patients not achieving a CR or VGPR following the first transplant In addition, the transplant protocol has been further intensified, which has led to improvements in response rates and survival Finally, novel agents are being introduced into the ASCT paradigm to further improve results

RESPONSE TO PRIMARY THERAPY EBMT criteria (with added nCR and VGPR categories) Cavo M. et al, ASH 2007

RESPONSE TO FIRST ASCT (MEL 200 mg/m2) EBMT criteria (with added nCR and VGPR categories) Cavo M. et al, ASH 2007

PBSC HARVEST Median values (range) Cavo M. et al, ASH 2007

RESPONSE (nCR) TO PRIMARY THERAPY ACCORDING TO GENETIC ABNORMALITIES VTD 43 47 4 8 10 20 30 40 50 60 13 pos t(4;14) pos P<0.001 P=0.002 VTD vs TD VTD TD 60 P=0.06 P=0.1 50 47 VTD 43 40 32 % 30 27 % 20 10 neg pos neg pos 13 t(4;14) Cavo M. et al, ASH 2007

Bortezomib + CHT prior to ASCT: phase II studies PR /  VGPR prior to ASCT (%) CR + nCR after ASCT (%) Regimen Reference n Bortezomib (1.3 or 1.0 mg/m2) + adriamycin + dexamethasone (PAD) 41 PAD 1: 95 / 29 PAD 2: 89 / 16 PAD1: 57 PAD 2: 42 Popat et al. IMW 2007 Bortezomib + DOXIL® 63 58 / 16 - Orlowski et al. ASH 2006 Bortezomib + DOXIL® + dexamethasone 50 95 / 20 - Belch et al. IMW 2007 Bortezomib + DOXIL® + dexamethasone 40 92.5 /42.5 ≥ VGPR 75 65 Jakubowiak et al. IMW 2007 Bortezomib + DT-PACE Barlogie et al. BJH 2007 303 84* - 92 / 35 Bortezomib + Cyclo-dex Reeder et al. ASH 2007 33 * At 24 months

Toxicities with front line Bortezomib containing regimens Neutropenia (Gr 3-4) DVT and PE prophylaxis required PE Gastrointestinal toxicity Toxicity in presence of renal failure Thrombocytopenia (Gr 3-4) DVT PN Uncommon 0-2% Not reported Yes No Rare Mostly reversible with dose modification Bortezomib www.velcade.info

Bortezomib dose modification for the management of PN Severity of PN signs/symptoms Modification of dose and regimen Grade 1 (paresthesia and/or loss of reflexes without pain or loss of function) No action Grade 1 with pain or Grade 2 (interfering with function but not with ADLs) Reduce bortezomib to 1.0 mg/m2 Grade 2 with pain or Grade 3 (interfering with ADL) Withhold bortezomib until toxicity resolves then reinitiate at 0.7 mg/m2 and administer once per week Grade 4 (permanent sensory loss interfering with function) Discontinue bortezomib SmPC Janssen-Cilag 2007 www.emea.europa.eu ADL, activities of daily living

Updated survival analysis of CREST Overall survival Bortezomib 1.3 mg/m2 Bortezomib 1.0 mg/m2 Jagannath et al. ASH 2007 (abstract 2717)

The role of bortezomib in the context of high-dose therapy with stem cell transplantation CONCLUSIONS Significantly higher response rate and CR+nCR rate after induction therapy with bortezomib containing regimens Superior nCR rate with VTD is not adversely affected by t(4;14) or chromosome 13 deletion Higher good-quality response with bortezomib containing regimens translates into a significantly higher probability of nCR or VGPR after the first ASCT Primary therapy with bortezomib containing regimens does not adversely impair the efficiency of PBSC harvest Relatively low toxicity profile, reflected by low discontinuation rate and absence of early deaths Other strategies have been used to improve the outcome of ASCT Among these strategies is double ASCT, which has been shown to be beneficial in patients not achieving a CR or VGPR following the first transplant In addition, the transplant protocol has been further intensified, which has led to improvements in response rates and survival Finally, novel agents are being introduced into the ASCT paradigm to further improve results

Median age at diagnosis: 68 yo EPIDEMIOLOGY OF MM 2% <40 yrs 38% 70 yrs 60% 40-69 yrs more than 50% occur in people over the age of 71 more than 50% occur in people over the age of 71 Median age at diagnosis: 68 yo Kyle et al. Best Pract Res Clin Haematol 2007;20(4):637-64

Melphalan/Prednisone vs poli-CHT and Dex containing regimens Progression-free survival Overall survival 27 studies 6633 patients Survival (%) Facon et al. Blood 2006;107(4):12921298 Myeloma Trialists‘ Collaborative Group. J Clin Oncol 1998;16:3832–3842

MPV: phase I-II study Four 6-week cycles Bortezomib Rest period Pazienti (n=60): età mediana 75aa Four 6-week cycles Day 1 2 3 4 8 11 22 25 29 32 33–42 Bortezomib Melphalan 9 mg/m2 Prednisone 60 mg/m2 Rest period Five 5-week cycles Day 1 2 3 4 8 15 22 23–35 Bortezomib 1.0 mg/m2: 6 patients (Phase I) Bortezomib 1.3 mg/m2: 6 patients (Phase I) + 48 patients (Phase II) Total = 49 weeks of treatment Mateos et al. Blood 2006;108:2165–2172

MPV: response rates e overall survival OS Best response: median 7 cycles (2–9) Median follow-up: 26 months Survival rate at 38 months: 1.0 89% ORR MPV: 85% 70% 0.8 60% 50% 45% 0.6 43% CR + nCR 40% MP*: 49% 32% 0.4 * MP: Historical control 30% 20% 0.2 11% 11% P<0.0001 10% 0.0 0% CR IF- CR IF+ PR SD 10 20 30 40 Mateos et al. Blood 2006;108:2165–2172 Mateos et al. Haematologica 2008;93(4):560-565

MPV: cytogenetic abnormalities No influence of del13, del17p and IgH translocation on PFS e OS Mateos et al. Haematologica 2008;93(4):560-565

9 x 6-week cycles (54 weeks) in both arms VISTA: VELCADE as Initial Standard Therapy in multiple myeloma: Assessment with melphalan and prednisone Randomized, international, phase III trial of VMP vs MP in previously untreated MM patients who were not candidates for HDT-ASCT Patients: Symptomatic multiple myeloma/end organ damage with measurable disease ≥65 yrs or <65 yrs and not transplant-eligible; KPS ≥60% 682 pz VMP Cycles 1-4 Bortezomib 1.3 mg/m2 IV: days 1,4,8,11,22,25,29,32 Melphalan 9 mg/m2 and prednisone 60 mg/m2 days 1-4 Cycles 5-9 Bortezomib 1.3 mg/m2 IV: days 1,8,22,29 R A N D O M I Z E Primary Endpoint: TTP Secondary Endpoints: CR rate, ORR, TTR, DOR, PFS, TNT, OS, QoL (PRO) 9 x 6-week cycles (54 weeks) in both arms Response and progression assessed q3 weeks per EBMT1 using central laboratory for M-protein quantification; results reported in real time to investigator for evaluation MP Cycles 1-9 Melphalan 9 mg/m2 and prednisone 60 mg/m2 days 1-4 1. Bladé et al. Br J Haematol 1998;102:1115-23. San Miguel et al. Blood 2007;110:Abstract 76 24

VISTA: response to therapy High CR with VMP VMP, N=336 MP, N=331 p-value M-protein* M-protein ORR (CR+PR) 82% 50% <0.000001 CR (IF-) 35% 5% PR 46% 45% VGPR (≥90% M-protein) 10% EBMT1 71% 35% 30% 4% 40% 31% N/A *measured in serum or urine by centralized laboratory 1. Bladé et al. Br J Haematol 1998;102:1115-23. San Miguel et al. Blood 2007;110:Abstract 76 25

VISTA: time to progression ~52% reduced risk of progression on VMP VMP: 24.0 months (83 events) MP: 16.6 months (146 events) HR = 0.483, p < 0.000001 VMP MP Number of patients at risk MP: 338 296 241 206 152 86 53 22 5 VMP: 344 295 272 245 185 111 65 31 17 San Miguel et al. Blood 2007;110:Abstract 76 26

VISTA: overall survival ~ 40% reduced risk of death on VMP Median follow-up 16.3 months VMP: not reached (45 deaths) MP: not reached (76 deaths) HR = 0.607, p = 0.0078 VMP MP Number of patients at risk MP: 338 320 301 280 220 157 116 69 29 7 VMP: 344 315 300 290 235 168 115 72 36 4 OS 2-years 82.6% in VMP vs 69.5% in MP <75 years OS 2-years  84% in VMP vs 74% in MP ≥75 years OS 2-years  79% in VMP vs 60% in MP Treatment related deaths on each arm: VMP 1%; MP 2% San Miguel et al. Blood 2007;110:Abstract 76 27

VISTA: subgroup analysis efficacy of VMP not influenced by age, renal function and cytogenetic abnormalities Impact of age Best M-protein response Total (N=336) Age<75 Yrs (N=230) Age≥75 Yrs (N=106) CR (IF-) 35% 36% 33% ≥PR 82% 85% 74% Impact of CrCl Best M-protein response Total (N=336) CrCl<60 (N=182) CrCl≥60 (N=154) CR (IF-) 35% 34% ≥PR 82% 81% Impact of cytogeneticsFISH: any (t4-14, t14-16, -17p) vs None Best M-protein response Total (N=165) High Risk (N=26) Std Risk (N=139) CR (IF-) 32% 35% ≥PR 82% 81% San Miguel et al. Blood 2007;110:Abstract 76

VMP: grade 3/4 (%) adverse events VMP (n=340) MP (n=337) Gr 3 Gr 4 Neutropenia 30 10 23 15 Thrombocytopenia 20 17 16 14 Anaemia 3 8 GI 19 1 5 <1 Peripheral neuropathy 13 Fatigue 6 Pneumonia 2 4 Herpes Zoster Risolution or improvement of PN in 75% of pts within a median time of 64 days Low percentage of DVT in both arms of treatment (1%) Serious adverse events: 45% for VMP vs 36% for MP San Miguel et al. Blood 2007;110:Abstract 76 29

Bortezomib alone or Dexamethasone for relapsed MM Bortezomib alone (n = 333) APEX 8 cycles 1.3 mg/mq Days 1, 4, 8, 11 Every 21 days High-dose Dexamethasone (n = 336) 4 cycles 40 mg Days 1-4, 9-12, 17-20 Every 35 days 5 cycles 3 cycles 3 cycles 1.3 mg/mq Days 1, 8, 15, 22 Every 28 days 5 cycles 40 mg Days 1-4 Every 28 days International, randomized study in relapsed or refractory MM (N = 669) comparing single agent bortezomib to HD dexamethasone Endpoints Primary: TTP Secondary: survival, response rate (RR), grade ≥ 3 infection, safety Richardson P et al. NEJM 2005

78% improvement in median TTP with bortezomib OS 1 0.8 0.4 0.2 Bortezomib Dexamethasone 0.6 30 90 210 330 0.9 0.7 0.5 0.3 0.1 60 150 270 420 120 180 240 300 360 390 Time (days) P < 0.001 1 0.8 0.4 0.2 0.6 0.9 0.7 0.5 0.3 0.1 Bortezomib Dexamethasone 90 270 630 990 180 450 810 360 540 720 900 1080 1170 Time (days) P = 0.0272 29.8 mos 23.7 mos 78% improvement in median TTP with bortezomib Superior survival despite > 62% of HD dex pts crossing over to bortezomib 1-yr survival rate: 80% vs 67%; P = 0.0002 Richardson P et al. NEJM 2005

Del(13) in Multiple Myeloma APEX: Matched-Pairs Analysis Proportion of patients 1.0 0.8 0.2 0.5 120 240 HR (95% CI) = 9.31 (1.88, 46.06); P = 0.0020 0.7 0.3 0.6 0.9 0.4 0.1 60 180 300 360 420 480 540 Del(13) (n = 12) No deletion (n = 24) Del(13) (n = 9) No deletion (n = 17) Time (days) HR (95% CI) = 1.61 (0.35, 7.46); P = 0.79 Del(13) associated with poor survival in Dex-treated patients Del(13) has no impact on survival in Bortezomib-treated patients 74/333 bortezomib patients had metaphase cytogenetics available – 11 del(13); 63 no del(13) 94/336 dex pateitns had metaphase cytogenetics available – 13 del(13); 81 no del(13) Del(13) patients matched 1:2 with no del(13) patients Of the 24 del(13) patients, only 21 were identified to have at least one corresponding match to the no del(13) patient population Reference: Jagannath S, Richardson PG, Sonneveld P, et al. Bortezomib appears to overcome poor prognosis conferred by chromosome 13 deletion in phase 2 and 3 trials. ASCO 2005, Orlando FL. Abstract 6501. Jagannath et al. Leukemia 2006

Treatment with Bortezomib of patients with renal failure NF-KB activation related to impaired renal function Half-life independent of renal clearance1 Short time to response (1.2 months)2,5 Reduces inflammation in myeloma kidney Toxicity profile similar to that of patients with normal renal function3,5 Flexible even in dyalisis-dependent patients4,5 Apex trial: trend towards shorter TTP/OS in patients with renal failure as compared with others but p NS (OS significantly shorter in dex treated pts) 5 1. Mulkerin et al. ASCO 2006 (Abstract 2032) 2. Richardson P et al. Blood 2005;106: (Abstract 2547) 3. Jagannath S et al. Cancer 2005;103:1195–2000 4. Chanan-Khan et al. Blood 2007; 109:2604–2606 5. San Miguel J et al. Leukemia 2008

Bortezomib + DOXIL vs Bortezomib Randomization 646 pts: relapsed and/or refractory MM Stratifications: 1. B2M (≤2.5, >2.5 but ≤5.5, >5.5) 2. Response vs. PD on initial therapy BZ 1.3 mg/m2 D 1, 4, 8, 11 every 21d for up to 8 cycles Treated until: PD Unacceptable toxicity 8 cycles administered (continued if MM still responding) Primary endpoint: TTP Secondary endpoint: OS, ORR, safety BZ as above + Pegylated liposomal doxorubicin 30 mg/m2 on D4 Orlowski et al. J Clin Oncol 2007

Bortezomib + DOXIL vs Bortezomib Time to progression Overall survival Orlowski et al. J Clin Oncol 2007

V-MPT at 1°Relapse/ MPT at diagnosis Bortezomib day 1,4,15,22 Melphalan 0.18 mg/kg (4 days) 50 mg/month Prednisone 2 mg/kg (4 days) 6 cycles Thalidomide 50 mg/daily continuously 1°Relapse Diagnosis 50 45 V-MPT (N = 14) 39% MPT (N = 129)^ RR 79% RR 80% 40 34% 35 43% 30 25 24% 36% % 21% 20 15 13% 26% 15% 17% 10 10 5% 5 0% CR- VGPR PR MR PD CR- VGPR PR MR PD Palumbo A et al. Blood 2007 ^Historical controls Lancet 2006;367:825

Bortezomib combinations for relapsed/ refractory MM ASH 2007 Bortezomib regimen Phase n CR + PR CR + nCR Abstract* + low-dose melphalan, dex 1/2 53 78% 34% Popat et al. (abstract 2713) + mel, prednisone, thal, defibrotide 24 42% (16% VGPR) not stated Palumbo et al. (abstract 2715) + bendamustine, prednisone 2 46 61% 15% Poenisch et al. (abstract 2723) + doxorubicin, dex + thal/dex 35 93% 68% Lee et al. (abstract 2731) + thal, DOXIL, dex + thal maintenance 20 80% 40% Offidani et al. (abstract 2729) + lenalidomide, dex 27 79% (includes MR) 33% (includes VGPR) Richardson et al. (abstract 2714) *Abstracts from Blood 2007;110

Davies & Morgan et al. Haematologica 2007 Bortezomib combinations for relapsed/ refractory MM selection of studies published in 2007-2008 Bortezomib regimen Phase n CR + PR CR + nCR Reference + cyclophosphamide, dex Retrosp 16 75% 31% Davies & Morgan et al. Haematologica 2007 + intermediate-dose dex, cyclophosphamide 2 54 82% 16% Kropff et al. BJH 2007 + melphalan, prednisone, thalidomide 1/2 30 67% 17% (43% CR + VGPR) Palumbo et al. Blood 2007 + Doxil 3 646 44% 18% Orlowski et al. JCO 2007 + thal-dex 85 63% 22% Pineda-Roman et al. Leukemia 2008 + doxil, thal,dex 42 81% nr Ciolli et al. BJH 2008

Novel therapy combinations with bortezomib Drug class Abstract* Tanespimycin Hsp90 inhibitor Richardson et al. ASH 2007 Suberoylanilide hydroxamic acid (SAHA) Histone deacetylase (HDAC) inhibitor Weber et al. ASH 2007 Badros et al. ASH 2007 Romidepsin HDAC inhibitor Prince et al. ASH 2007 Tipifarnib (R115777) David et al. ASH 2007 LBH (Panobinostat) Sezer et al. EHA 2008 CNTO 328 Anti-Interleukin (IL-6) monoclonal antibody Manges et al. ASH 2007 Perifosine (KRX-0401) Alkyphospholipid Dasatinib Tyr kinase inhibitor Wildes et al. ASH 2007

Bortezomib retreatment in relapsed MM: a retrospective multicenter survey Retrospective survey of 49 patients in 15 centers Median of 4 therapies prior to first bortezomib treatment Safety profile in line with first treatment Initial treatment Retreatment ORR 100% 63% CR 12% 10% Time to response (median) 3.2 months 3.0 months Dex added 39% 62% Treatment-free interval (median) 6.6 months 4.1 months TTP 10.9 months 6.7 months Hrusovsky et al, ASH 2007

BORTEZOMIB IN MULTIPLE MYELOMA CONCLUSIONS Rapidity of action, no renal and cardiac toxicity Peripheral neuropathy mostly reversible with dose modification Response not influenced by high risk cytogenetic abnormalities Other strategies have been used to improve the outcome of ASCT Among these strategies is double ASCT, which has been shown to be beneficial in patients not achieving a CR or VGPR following the first transplant In addition, the transplant protocol has been further intensified, which has led to improvements in response rates and survival Finally, novel agents are being introduced into the ASCT paradigm to further improve results Optimal use as induction regimen in young and elderly patients and as salvage treatment

BORTEZOMIB IN MULTIPLE MYELOMA OPEN ISSUES Duration of response Role and schedule of maintenance treatment-efficacy of retrieve Combination with new drugs/chemotherapy Long term results in patients with poor prognosis In combination or in alternative to ASCT in young patients? Role of double ASCT? Other strategies have been used to improve the outcome of ASCT Among these strategies is double ASCT, which has been shown to be beneficial in patients not achieving a CR or VGPR following the first transplant In addition, the transplant protocol has been further intensified, which has led to improvements in response rates and survival Finally, novel agents are being introduced into the ASCT paradigm to further improve results