Multiple Myeloma in the Non-transplant Setting Antonio Palumbo, MD University of Torino, Torino, I, EU

Standard of Care for Elderly Patients 2

Meta-Analysis: MPT vs MP Meta-analysis of randomized clinical trials (GIMEMA, IFM, HOVON, NMSG and TMSG) N = 1,682 (MP, n = 868 vs MPT, n = 814) Median overall survival (OS), 32.7 mo vs 39.3 mo Overall hazard ratio for OS = 0.82 Median progression-free survival (PFS), 14.9 mo vs 20.4 mo Overall hazard ratio for PFS = 0.67 Test of heterogeneity between studies was statistically significant for OS (p = 0.26) and for PFS (p = 0.23). MPT: melphalan-prednisone-thalidomide; MP: melphalan-prednisone Waage A et al. EHA 2010. Abstract 0567.

LMWH vs Warfarin vs Aspirin for Lenalidomide and Thalidomide Standard Risk of VTE Lenalidomide Thalidomide LMWH WAR ASA 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; PE: pulmonary embolism 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 Progression-free survival 3-year overall survival* VMP MP 24.0 mos (83 events) 16.6 mos (146 events) HR = 0.483 p < .000001 VMP MP 72% 59% HR = 0.644 p = .0032 * Median follow-up 25.9 months, median OS not reached San Miguel JF et al. ASH 2008. Abstract 650. 5 5

Bortezomib: Once Weekly VMP (VISTA) twice-weekly once-weekly CR 30% 27% 23% 2-year PFS 48% 56% 58% Sensory PN Any grade 44% 22% Grade 3/4 13% 14% 2% Discontinuation due to PN na 16% 4% Total planned dose 67.6 mg/m2 46.8 mg/m2 Total delivered dose 40.1 mg/m2 39.4 mg/m2 Bringhen S et al. Blood 2010;116(23):4745-53.

New Treatment Options 7

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/dL VMP Cycles 1-9 Bortezomib 1.3 mg/m2 IV Days 1,8,15,22* Melphalan 9 mg/m2 and prednisone 60 mg/m2 Days 1-4 VMPT Thalidomide 50 mg/day continuously R A N D O M I Z E 9 x 5-week cycles in both arms MAINTENANCE Bortezomib 1.3 mg/m2 IV Days 1,15 Thalidomide 50 mg/day continuously NO MAINTENANCE Until relapse *66 VMP patients and 73 VMPT-VT patients were treated with twice weekly infusions of bortezomib Palumbo A et al. J Clin Oncol 2010;28(34):5101-9.

Bortezomib-Melphalan-Prednisone-Thalidomide Time to First Response and Time to CR VMP VMPT  VT 100 80 60 40 20 PR: VMPTVT PR: VMP % of patients CR: VMPTVT CR: VMP 0 5 10 15 20 25 30 Months Palumbo A et al. Proc ASH 2010;Abstract 620.

Bortezomib-Melphalan-Prednisone-Thalidomide Median follow-up 32 months Progression-free survival 41% Reduced Risk of Progression Time to next therapy 48% Reduced Risk of Progression 3-year PFS Median PFS VMP VMPT 32% 27.4 months 51% 37.2 months 3-year TNT Median TTNT VMP VMPT 51% 37.6 months 70% Not reached HR 0.52 p < 0.0001 HR 0.59 p < 0.0001 Palumbo A et al. J Clin Oncol 2010;28(34):5101-9.

Prognostic Factors PFS According to ISS and Cytogenetics ISS 1 or 2 Absence of t(4;14) or t(14;16) or del17 0.00 0.25 0.50 0.75 1.00 10 20 30 40 50 60 Time (months) Patients (%) 1.00 0.75 VMPT-VT VMPT-VT Patients (%) 0.50 VMP VMP 0.25 P<0.0001 P=0.003 0.00 10 20 30 40 50 60 Time (months) ISS 3 Presence of t(4;14) or t(14;16) or del17 0.00 0.25 0.50 0.75 1.00 10 20 30 40 50 60 1.00 VMPT-VT 0.75 VMPT-VT Patients (%) Patients (%) VMP 0.50 VMP P=0.51 0.25 P=0.49 0.00 10 20 30 40 50 60 Time (months) Time (months) Palumbo A et al. Proc ASH 2010;Abstract 620.

Melphalan-Prednisone-Lenalidomide N = 459, 82 centers in Europe, Australia, and Israel Double-Blind Treatment Phase Open-Label Extension Phase Cycles (28-day) 1-9 Cycles 10+ RANDOMIZATION 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 Continuous lenalidomide treatment 10 mg/day days 1-21 Lenalidomide (25 mg/day) ± Dexamethasone MPR M: 0.18 mg/kg Days 1-4 P: 2 mg/kg Days 1-4 R: 10 mg/day po Days 1-21 Disease Progression Placebo MP M: 0.18 mg/kg Days 1-4 P: 2 mg/kg Days 1-4 PBO: Days 1-21 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 65-75 Years of Age 2 2 - - Year PFS Year PFS Median PFS Median PFS 2 2 - - Year PFS Year PFS Median PFS Median PFS 100 5 10 15 20 25 30 35 40 50 75 100 100 100 100 100 MPR MPR - - R R 55% 55% Not reached Not reached MPR MPR - - R R 61% 61% Not reached Not reached MPR MPR 27% 27% 14.7 months 14.7 months 75 75 75 75 75 MP MP 16% 16% 13.0 months 13.0 months MP MP 10% 10% 12.4 months 12.4 months HR 0.315 HR 0.423 50 50 50 50 50 Log rank P < .001 Log rank P < .001 Patients (%) Patients (%) Patients (%) Patients (%) 25 25 25 25 25 HR 0.675 Log rank P = .031 5 5 10 10 15 15 20 20 25 25 30 30 35 35 40 40 5 5 5 10 10 10 15 15 15 20 20 20 25 25 25 30 30 30 35 35 35 40 40 40 Time (months) Time (months) MPR-R: melphalan-prednisone-lenalidomide/lenalidomide continuous treatment; MPR: melphalan-prednisone-lenalidomide; MP: melphalan-prednisone Palumbo A et al. EHA 2010. Abstract 0566.

Lenalidomide Continuous Therapy Melphalan-Prednisone-Lenalidomide Landmark Analysis 69% Reduced Risk of Progression MPR Lenalidomide Continuous Therapy 5 10 15 20 25 30 50 75 100 Time (months) Patients (%) MPR-R MPR HR 0.314 Log rank P < .001 MPR-R: melphalan-prednisone-lenalidomide/lenalidomide continuous treatment; MPR: melphalan-prednisone-lenalidomide Palumbo A et al. EHA 2010. Abstract 0566.

Age-Adjusted Therapies 15

Impact of AEs on Outcome Safety meta-analysis of 6 MPT trials1 Median OS, MP vs MPT: 32.7 mo vs 39.3 mo HR = 0.83 p = 0.004 Median PFS, MP vs MPT: 14.9 mo vs 20.3 mo Estimated HR = 0.68 p < 0.0001 – In practice, clinicians would vary the actual dose according to patient's status, evidence of response or relapse and occurrence of side effects or toxicity. – A substantial proportion of patients in all studies either stopped thalidomide prematurely or dose reduced. MPT, melphalan-prednisone-thalidomide; AE, adverse event 1 Fayers P et al Blood 2011, in press

Frail Patients: Treatment Algorithm RISK FACTORS - Age over 75 years - Mild, moderate or severe frailty: Help needed for household and personal care - Comorbidities and organ dysfunction: Cardiac Pulmonary Hepatic Renal Dose level 0 Dose level -1 Dose level -2 No risk factors At least one risk factor + any G 3-4 non-hematologic AE Go-go Moderate-go Slow-go Palumbo personal communication

Frail Patients: Treatment Algorithm Dose Reductions Agent Dose level 0 Dose level -1 Dose level -2 Bortezomib 1.3 mg/m2 twice / wk d 1,4,8,11 / 3 wks 1.3 mg/m2 once / wk d 1,8,15,22 / 5 wks 1.0 mg/m2 once / wk Thalidomide 100 mg/d 50 mg/d 50 mg qod Lenalidomide 25 mg/d d 1-21 / 4 wks 15 mg/d 10 mg/d Dexamethasone 40 mg/d d 1,8,15,22 / 4 wks 20 mg/d Melphalan 0.25 mg/kg d 1-4 / 4-6 wks 0.18 mg/kg 0.13 mg/kg Prednisone 25 mg qod 12.5 mg qod Cyclophosphamide Wk, week; d, day; qod, every other day Palumbo & Anderson, New Engl J Med 2011

For how many patients with MM have you used subcutaneous (SQ) bortezomib? 19 19

What Clinicians Want to Know A Live CME Event Addressing the Most Common Questions and Controversies in the Current Clinical Management of Select Hematologic Cancers Sunday, June 5, 2011 7:00 PM – 9:30 PM Chicago, Illinois Moderator Neil Love, MD Faculty Sergio Giralt, MD John P Leonard, MD Lauren C Pinter-Brown, MD Antonio Palumbo, MD Susan M O’Brien, MD Professor Michael Hallek 20 20