Improving Outcomes in Myeloma How many and in

Improving Outcomes in Myeloma How many and in which order should we use novel agents? Antonio Palumbo, MD Myeloma Unit, Division of Haematology, University of Turin, Italy 45 m

Treatment strategies

Sensitive vs Resistant Disease Diagnosis 2° Relapse 30 months 15 months 7 months 3 months Combination regimen c 1° Relapse Single agent Sensitive disease c Resistant disease Low-risk SAE High-risk SAE Single agent

Combination Therapy vs Single Agent Progression 2 nd-line treatment Combination therapy 3 rd-line treatment 4 th-line treatment Progression Single agent 2 nd-line treatment • Combination could improve PFS only – quality of life • Combination could improve OS – evidence needed

OLD Therapeutic Algorithm Patients < 65 years Patients > 65 years Diagnosis Autologous transplant (high-dose melphalan) Oral melphalan (low-dose melphalan) 1° Relapse Dexamethasone 2° Relapse Doxorubicin 3° Relapse Cyclophosphamide

NEW Therapeutic Algorithm < 65 years 65 -75 years > 75 years Diagnosis Induction (VD-VCD-VTD) ASCT Mainenance (Len) Full-dose Combination MPV (MPT-Rd) Reduced-dose Combination mpt-rd (mpv) 1° Relapse Bort- Dex Len-Dex Bort-Dex 2° Relapse Len-Dex Bort-Dex Len-Dex 3° Relapse Carfilzomib Pomalidomide HADAC inhib Elontuzumab 4° Relapse Thal-Dex Bort-Dex-Cyclo (Doxo – Thal –Len) Len-Dex-Cyclo (Doxo – Thal –Len) PFS > median expected time repeat previous regimen PFS < median expected time change previous regimen

Clinical Impact of VTD Consolidation in VGPR Patients After ASCT Responses after ASCT VGPR 85% CR 15% Responses after VTD VGPR 49% CR 49% 15% 49% 85% VGPR 49% CR Ladetto M, et al. J Clin Oncol. 2010; 28: 2077 -2084.

Complete Response are all the same? Response Criteria Tumor gene copy number Diagnosis 25, 000 - 500, 000 PR 5, 000 – 100, 000 VGPR 1, 500 – 20, 000 Immunofixation-negative CR 1, 000 – 10, 000 Immunophenotypic CR* 10 – 100 Molecular CR^ 5 – 20 *Paiva et al Blood 2009: 114; 4369 -72; ^Ladetto et al. J Clin Oncol. 2010; 28(12): 2077 -84

Clinical Impact of Minimal Residual Disease PFS in PCR-negative patients months Ladetto M, et al. ASH 2009. Abstract 960.

Treatment strategy Tumour burden Continuous therapy Prolongs PFS Combinational therapy Increases CR rate Time

CR predicts long term outcome Analysis of 1175 elderly patients PFS OS 100 CR 75 75 CR VGPR PR 50 50 VGPR PR 25 0 0 10 20 30 40 months 50 60 70 0 10 20 30 40 50 60 70 80 months Gay F et al. Haematologica 2010; 95[suppl. 2]: 236, abs. 0570.

Outcome and continuous treatment Lenalidomide maintenance Revlimid Placebo P < 10 -7 Attal et al. ASCO 2010 Mc. Carthy et al. ASCO 2010 Palumbo et al. EHA 2010 Bortezomib maintenance 1. 00 PFS 1, 0 0, 8 0. 75 0, 6 VMPT VT 0. 50 VT 0, 4 VP 0. 25 0, 2 VMP P = 0. 006 0. 00 0 10 VT: median not reached VP: 23 months HR: 1. 7; p=0. 05 0, 0 20 30 40 50 Palumbo et al. ASH 2009 60 0 5 10 15 20 25 30 Mateos et al. ASH 2009 35

VTD vs TD GIMEMA experience velcade (bortezomib)-thalidomidedexamethasone thalidomide-dexamethasone

Phase 3: VTD vs TD Efficacy VTD TD P 31% 11% <0. 0001 52% 31% <0. 0001 55% 41% 0. 002 45% 0. 0002 Induction ≥ n. CR After first ASCT ≥ n. CR After double ASCT ≥ n. CR After consolidation ≥ n. CR 62% Best confirmed overall ≥ n. CR and ≥ VGPR ≥ n. CR 71% 54% <0. 0001 ≥ VGPR 89% 74% <0. 0001 Cavo et al. ASH 2010 (Abstract 42), oral presentation Cavo et al. Lancet 2010; 376: 2075 -85

Phase 3: VTD vs TD Outcome • Median follow-up: 36 months Progression-free survival VTD Percent TD P=0. 0057 • Estimated 3 -year PFS • VTD 68% • TD 56% • Estimated 3 -year OS • VTD 86% • TD 84% Cavo et al. ASH 2010 (Abstract 42), oral presentation Cavo et al. Lancet 2010; 376: 2075 -85

Outcome in 590 patients according to chromosomal abnormalities Overall survival Overall Survival Progression-Free Survival Progression-free survival t(4; 14) del(17 p) both % at 34 mos 60* 49 24* *P=0. 0008 months % at 40 mos 89* no abnorm. 81 del(13 q) alone 77* t(4; 14)±del(17 p) *P=0. 003 months Cavo et al ASH 2010

Phase 2: VRD induction, ASCT, VRD consolidation, lenalidomide maintenance IFM 2008 Patients (n=31), median age 58 years Post induction Post ASCT Post consolidation s. CR 13% 26% 38% CR 10% 10% ≥ VGPR 62% 68% 84% ≥PR 94% 91% 94% Neutropenia grade 3/4 39% During induction 26% During consolidation 20% During maintenance 20% Lenalidomide dose reduction 26% Thrombocytop. grade 3 Anemia grade 3 Sensory PN all grades Grade 1 Grade 2 13% During induction 3% During consolidation 10% 6% During induction 3% During consolidation 3% 68% During induction 55% During consolidation 13% 45% 23% Bortezomib dose reduction 23% Roussel et al. ASH 2010 (Abstract 624), oral presentation

PAD-V vs VAD-T HOVON experience velcade-doxorubicin-dexamethasone bortezomib maintenance vincristine-doxorubicin-dexamethasone thalidomide maintenance

Outcome Progression-free survival Overall survival HR = 0. 79 (0. 66 -0. 95), P=0. 01 HR = 0. 73 (0. 56 -0. 96), P=0. 02

MPR vs MEL 200

CRD vs MEL 200

Treatment schedule l 402 patients (younger than 65 years) randomized from 62 centers l Patients: Symptomatic disease, organ damage, measurable disease Rd* four 28 -day courses R: 25 mg/d, days 1 -21 d: 40 mg/d, days 1, 8, 15, 22 1° R A N D O M I Z A T I O N CRD six 28 -day courses C: 300 mg/sqm, days 1, 8, 15 D: 40 mg, days 1, 8, 15, 22 R: 25 mg/d, days 1 -21 MEL 200 Two courses M: 200 mg/m 2 day -2 Stem cell support day 0 2° R A N D O M I Z A T I O N *Thromboprophylaxis randomization: aspirin vs low molecular weight heparin R, lenalidomide; M, melphalan; d, dexamethasone; P, prednisone MAINTENANCE 28 -day courses until relapse R: 10 mg/day, days 1 -21 PDN: 50 mg every other day

VMP with MEL-200 VRD consolidation Len maintenance

A randomized phase III study to compare bortezomib, melphalan, prednisone (VMP) with high-dose melphalan followed by bortezomib, lenalidomide, dexamethasone (VRD) consolidation and lenalidomide maintenance in patients with newly diagnosed multiple myeloma INDUCTION 1500 pts 3 VCD + CY 4 VMP (500 pts) NONE VRD Maintenance HDM at 1° relapse 1 HDM (500 pts) NONE VRD Maintenance 2 HDM (500 pts) NONE VRD Maintenance

Standard of Care for Elderly Patients

Meta-Analysis: MPT vs MP Progression-free survival MPT better MP better Overall survival MPT better MPT: melphalan-prednisone-thalidomide; MP: melphalan-prednisone Waage A, et al. EHA 2010. Abstract 0567.

LMWH vs Warfarin vs Aspirin for Lenalidomide and Thalidomide Lenalidomide Standard Risk of VTE Thalidomide LMWH WAR ASA 0 1 2 3 4 5 6 7 8 Patients (%) High Risk of VTE • Previous VTE, infection, immobilization, CVC, doxorubicin • LMWH is suggested ASA: Acetylsalicylic acid; LMWH: low molecular weight heparin; VTE: venous thromboembolism; CVC: central venous catheter Palumbo A, et al. EHA 2009. Abstract 0214.

VMP (Bortezomib/Melphalan/Prednisone) Current Standard of Care ~52% reduced risk of progression ~36% reduced risk of death 100 VMP 80 MP MP 70 60 50 40 30 20 Median TTP VMP: 24. 0 months (83 events) MP: 16. 6 months (146 events) HR=0. 483, P <. 000001 10 0 0 3 6 9 12 15 80 70 60 50 40 30 20 10 0 18 21 24 VMP 90 Percentage of Subjects Without Event Percentage of Patients Without Event 90 27 Median follow-up 25. 9 months Median OS not reached VMP: 3 -year OS rate = 72% MP: 3 -year OS rate = 59% HR = 0. 644, P =. 0032 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 Time (Months) San Miguel JF, et al. ASH 2008. Abstract 650.

Bortezomib: Once Weekly VMP (VISTA) VMP twice-weekly VMP once-weekly CR 30% 27% 23% 2 -year PFS 48% 56% 58% Any grade 44% 22% Grade 3/4 13% 14% 2% na 16% 4% Total planned dose 67. 6 mg/m 2 46. 8 mg/m 2 Total delivered dose na 40. 1 mg/m 2 39. 4 mg/m 2 Sensory PN Discontinuation due to PN Bringhen S, et al. Blood. 2010 Aug 31. [Epub ahead of print]

New treatment options

Bortezomib-Melphalan-Prednisone-Thalidomide VMPT-VT vs VMP • 511 patients (older than 65 years) randomized from 61 Italian centers • Patients: Symptomatic multiple myeloma/end-organ damage with measurable disease • ≥ 65 yrs or < 65 yrs and not transplant-eligible; creatinine < 2. 5 mg/d. L R A N D O M I Z E VMP Cycles 1 -9 Bortezomib 1. 3 mg/m 2 IV Days 1, 8, 15, 22* Melphalan 9 mg/m 2 and prednisone 60 mg/m 2 Days 1 -4 9 x 5 -week cycles in both arms VMPT Cycles 1 -9 Bortezomib 1. 3 mg/m 2 IV Days 1, 8, 15, 22* Melphalan 9 mg/m 2 and prednisone 60 mg/m 2 Days 1 -4 Thalidomide 50 mg/day continuously NO MAINTENANCE Until relapse MAINTENANCE Bortezomib 1. 3 mg/m 2 IV Days 1, 15 Thalidomide 50 mg/day continuously *66 VMP patients and 73 VMPT-VT patients were treated with twice weekly infusions of bortezomib Palumbo A, et al. J Clin Oncol. 2010; Oct 12: [E-pub ahead of print]. 33

Bortezomib-Melphalan-Prednisone-Thalidomide Response Rate VMP (N=253) VMPT VT (N=250) P Value CR 24% 38% . 0008 ≥ VGPR 50% 59% . 03 ≥ PR 81% 89% . 01 VMPT VT % of patients VMP CR VGPR PR SD PD Palumbo A, et al. J Clin Oncol. 2010; Oct 12: [E-pub ahead of print]. 34

Bortezomib-Melphalan-Prednisone-Thalidomide Time to first response and time to CR VMPT VT VMP 100 PR: VMPT VT % of patients 80 PR: VMP 60 CR: VMPT VT 40 CR: VMP 20 0 0 5 10 15 20 25 30 Months Palumbo et al. JCO. 2010; [Epub ahead of print]

Bortezomib-Melphalan-Prednisone-Thalidomide Median follow-up 32 months Progression-Free survival Time to next therapy 41% Reduced Risk of Progression 48% Reduced Risk of Progression 3 -years PFS Median PFS VMPT 51% 37. 2 months VMP 32% 3 -years TNT 27. 4 months VMPT Not reached 51% 37. 6 months 1. 00 0. 75 0. 50 HR 0. 59 P < 0. 0001 0. 25 Patients (%) 70% VMP 1. 00 Median TTNT HR 0. 52 0. 50 P < 0. 0001 0. 25 0. 00 0 10 20 30 40 Time (months) 50 60 0 10 20 30 Time (months) 40 50 60

Melphalan-Prednisone-Lenalidomide N = 459, 82 centers in Europe, Australia, and Israel Open-Label Extension Phase Double-Blind Treatment Phase RANDOMIZATION Cycles (28 -day) 1 -9 MPR-R M: 0. 18 mg/kg Days 1 -4 P: 2 mg/kg Days 1 -4 R: 10 mg/day po Days 1 -21 MP M: 0. 18 mg/kg Days 1 -4 P: 2 mg/kg Days 1 -4 PBO: Days 1 -21 Cycles 10+ Continuous lenalidomide treatment 10 mg/day days 1 -21 Placebo Disease Progression Lenalidomide (25 mg/day) ± Dexamethasone Placebo Stratified by age (≤ 75 vs > 75 years) and stage (ISS I/II vs III) M, melphalan; P, prednisone; R, lenalidomide; PBO, placebo; po, orally; ISS, International Staging System. Palumbo A, et al. EHA 2010. Abstract 0566.

Melphalan-Prednisone-Lenalidomide Progression-Free Survival 58% Reduced Risk of Progression 2 -Year PFS Median PFS 55% 65 -75 Years of Age Not reached 100 16% MP HR 0. 423 50 Log rank P <. 001 25 61% Not reached 27% 14. 7 months MP 75 13. 0 months 10% 12. 4 months HR 0. 315 Patients (%) 75 MPR-R Log rank. P <. 001 50 25 HR 0. 675 Log rank. P =. 031 0 0 0 5 10 15 20 25 Time (Months) 30 35 40 0 5 10 15 20 25 30 35 40 Time (Months) MPR-R: melphalan-prednisone-lenalidomide continuous treatment; MPR-R: melphalan-prednisone-lenalidomide; MP: melphalan-prednisone Palumbo A, et al. EHA 2010. Abstract 0566.

Melphalan-Prednisone-Lenalidomide Treatment – Initial 9 Cycles MPRa MP 65 -75 years of age 17 10 > 75 years of age 34 16 65 -75 years of age 88 97 > 75 years of age 56 97 Discontinuation rateb, % Cumulative dose intensityc, % MPR includes MPR-R and MPR for the initial 9 cycles. Discontinuation due to AEs or withdrawal of consent c Cumulative dose intensity of melphalan and lenalidomide/placebo a b Palumbo A, et al. EHA 2010. Abstract 0566.

Melphalan-Prednisone-Lenalidomide Landmark Analysis 69% Reduced Risk of Progression MPR Lenalidomide Continuous Therapy 100 MPR-R MPR Patients (%) 75 HR 0. 314 50 Log rank P <. 001 25 0 0 5 10 15 20 Time (Months) 25 30 MPR-R: melphalan-prednisone-lenalidomide continuous treatment; MPR-R: melphalan-prednisone-lenalidomide Palumbo A, et al. EHA 2010. Abstract 0566.

Lenalidomide-Prednisone Melphalan-Prednisone-Lenalidomide Cycles (28 -day) 1 -4 Cycles (28 -day) 5 -10 RP R: 25 mg/d, days 1 -21 P: 50 mg 3 times/week MPR M: 2 mg 3 times/week P: 50 mg 3 times/week R: 10 mg/d, days 1 -21 M, melphalan; P, prednisone; R, lenalidomide; Falco P. et al. SIES 2010 (abstract 102

Melphalan-prednisone-lenalidomide (melphalan 0. 18 0. 13 mg/kg) RP Age MPR 1 0. 13 mg/kg MPR 2 0. 18 mg/kg MM 015 75(65 -88) 75 (65 -86) 71 (65 -87) Neutropenia 6 11 36 Thrombocytopenia 0 0 13 G-CSF Administration 14 26 66 18 33 32 GR 4 Adverse events % Response Rates VGPR M, melphalan; P, prednisone; R, lenalidomide; 1 Falco 2 Palumbo P. et al. SIES 2010 (abstract 102) A. et al. EHA 2010 (abstract 0566)

Age-adjusted therapies

Are all the same?

Age-Adjusted Therapy INCIDENCE: 2002 8. 9/100. 000 Full-dose chemotherapy Autologous transplant 65 -74 years 25 -64 years 36% 31% 33% 75 -101 years Reduced-dose chemotherapy Regione Piemonte, Assessorato Sanità 2006

Age - Comorbidities Full dose chemotherapy Reduced dose chemotherapy 65 -75 years >75 years Normal: • Cardiac • Pulmonary • Liver • Renal function <65 years Abnormal: • Cardiac • Pulmonary • Liver • Renal function Normal: • Cardiac • Pulmonary • Liver • Renal function 65 -75 years Abnormal: • Cardiac • Pulmonary • Liver • Renal function Recommendations by A. Palumbo

Age-Adjusted Doses 65 -75 Years > 75 Years Further Dose Redcution Dexamethasone weekly 40 mg 20 mg 10 mg Melphalan Days 1 -4 0. 25 mg/kg 0. 18 mg/kg 0. 13 mg/kg Thalidomide per day 200 mg 100 mg 50 mg Lenalidomide* Days 1 -21 25 mg 10 mg 1. 3 mg/m 2 1. 0 mg/m 2 biweekly Bortezomib If a grade 3 -4 AE occurs: 1. discontinue therapy; 2. wait for grade 1 AE; 3. restart at a lower dose *Lenalidomide plus melphalan starting dose 10 mg/d Recommendations by A. Palumbo.

SWEDEN AUSTRALIA FINLAND NORWAY DENMARK UNITED KINGDOM NETHERLANDS ISRAEL POLAND GERMANY CZECH REPUBLIC AUSTRIA SWITZERLAND PORTUGAL SPAIN ITALY GREECE TURKEY