Strategies for front-line treatment of Multiple Myeloma Thierry FACON Lille University Hospital, Lille, France On behalf of IFM 1

Historical Perspective of Multiple Myeloma Proteasome inhibitors (Bortezomib) Other immuno-modulatory agents (Lenalidomide) High-dose therapy with autologous stem cell support ABMT VAD Bisphosphonates High-dose melphalan High-dose dexamethasone Thalidomide Oral melphalan and prednisone Slide 6. Historical Perspective: MM The first successful use of chemotherapy for MM was reported in 1958; a racemic mixture of D- and L-phenylalanine called “sarcolysine” was used. Tests of the 2 isomers demonstrated that the L-isomer was responsible for the anti-myeloma activity. In 1962, Bergsagel et al from SWOG reported that L-phenylalanine mustard (melphalan) produced remissions in about one-third of patients with MM In 1967, Salmon et al reported that high doses of glucocorticoids could induce remissions in patients with refractory or relapsing MM. Subsequently, combination therapy with melphalan and prednisone was extensively studied, and in 1972 Alexanian et al reported on its efficacy In 1983, McElwain and Powles reported that high-dose melphalan was effective for patients with MM and plasma cell leukemia. In 1984, Barlogie et al reported on the successful treatment of advanced MM with VAD. In 1986, the group described the efficacy of high-dose glucocorticosteroid therapy for the treatment of patients with resistant disease In 1996, Berenson et al described the efficacy of bisphosphonate pamidronate in reducing skeletal events in patients with advanced MM High-dose therapy with autologous stem cell support and thalidomide and arsenic trioxide treatment for patients with relapsed and refractory disease were introduced in 1999 At the beginning of the 21st century, other major advances included MAbs, proteosome inhibitors, and other IMiDs for treating patients with MM 1962 1983 1984 1986 1996 1999 2000+ Barlogie B et al. N Engl J Med. 1984;310:1353 Berenson JR et al. N Engl J Med. 1996;334:488 Alexanian R et al. Ann Intern Med. 1986;105:8 Bergsagel D. Cancer Chemother Rep. 1962;21:87 Salmon SE et al. Cancer Chemother Rep. 1967;51:179 Rousselot P et al. Cancer Res. 1999;59:1041 McElwain TJ, Powles RL. Lancet. 1983;2:822 2

Period estimates of 10-year survival of patients with MM by major age groups in defined calendar periods from 1984-1986 to 2002-2004 Brenner et al; Blood 2008; 111:2521-26 3

Front-line treatment in multiple myeloma patients not eligible for stem cell transplantation 4

Age- and Sex- Incidence Rates per 100 000/year for MM in the South Thames Area (1999-2000) 60.00 50.00 40.00 30.00 20.00 10.00 0.00 Males Females Females and Males combined Rate per 100,000 16-24 25-34 35-44 45-54 55-64 65-74 75-84 85+ Age (years) Phekoo et al; BJH 2004; 127: 299-304

Median 39.3 months (35.6-44.6) Median 32.7 months (30.5-36.6) HR=0.83 in favour of MPT, P=.005 Cox model for treatment, with analysis sratified by study using a random effects (frailty) model

MRC Myeloma IX non intensive pathway Older less fit patients (approximately > 65 y) Morgan et al. Blood 2007; 110:1051a(abs 3593) Morgan et al. Blood 2008; 112:245 (abs 656) 7 7

9 x 6-week cycles (54 weeks) in both arms VISTA: VELCADE as Initial Standard Therapy in multiple myeloma: Assessment with MP Randomized, international, phase III trial of VMP vs MP in 682 previously untreated patients with symptomatic MM who were not candidates for HDT-ASCT due to age (≥65 yrs) or co-morbid conditions Stratification: β2-microglobulin, albumin, region VMP Cycles 1–4 Bortezomib 1.3 mg/m2 IV: d 1,4,8,11,22,25,29,32 Melphalan 9 mg/m2 and prednisone 60 mg/m2: d 1–4 Cycles 5–9 Bortezomib 1.3 mg/m2 IV: d 1,8,22,29 R A N D O M I Z E Primary end point: TTP Secondary end points: CR rate, ORR, time to response, DOR, time to next therapy (TNT), OS, QoL (PRO) 9 x 6-week cycles (54 weeks) in both arms MP Cycles 1–9 Melphalan 9 mg/m2 and prednisone 60 mg/m2: d 1–4 San Miguel et al. N Engl J Med 2008;359:906–17 8 8

VISTA:Efficacy data ORR: VMP 71%, MP 35% CR: VMP 30%, MP 4% Time to progression Overall survival 100 100 VMP MP VMP MP 80 80 60 60 Patients without event (%) Median follow-up: 25.9 months 3-year OS: VMP: 72% MP: 59% P = .0032 40 40 VMP: 24.0 months MP: 16.6 months P < .000001 20 20 3 6 9 12 15 18 21 24 27 4 8 12 16 20 24 28 32 36 40 Time (months) Time (months) Only 5% “true” non-responders 43% of MP patients received bortezomib upon progression 3-y OS VMP 68.5% vs MP 54%, median OS VMP not reached vs MP 43.1 mo. after a median FU 36.7 mo. Mateos et al.JCO,2010;28:2259-2266

Spanish MPV; Mateos et al.Lancet Oncology 2010 Epub August 24. MPV, an evolving standard of care From twice weekly to once weekly regimens Spanish MPV; Mateos et al.Lancet Oncology 2010 Epub August 24. Induction 6 cycles; one 6-week cycle, bortezomib 2x weekly, five 5-week cycles, bortezomib 1x weekly. Maintenance VT or VP Italian MPV; Palumbo et al.JCO 2010 Epub October 12.Bringhen et al.Blood 2010 Epub August 31. Induction Nine 5-week cycles, bortezomib 1x weekly.No maintenance in MPV but VT maintenance in VMPT One-weekly schedule reduces the incidence of PN and decreases the rate of discontinuation without any reduction in efficacy

not eligible for a transplant MM-015: phase III trial of MPR vs MP for long-term control in newly diagnosed MM Randomized, placebo-controlled, double-blind trial in 51 centres in Europe, Australia, and Israel (N = 450) Up to 9 courses in the absence of disease progression or unacceptable adverse events; treatment in 28-day cycles Melphalan 0.18 mg/kg, days 1–4 Prednisone 2 mg/kg, days 1–4 Lenalidomide 10 mg/day p.o., days 1–21 Lenalidomide Patients with newly diagnosed, untreated MM who are not eligible for a transplant Melphalan 0.18 mg/kg, days 1–4 Prednisone 2 mg/kg, days 1–4 Lenalidomide 10 mg/day p.o., days 1–21 R A N D O M I Z T Placebo Melphalan 0.18 mg/kg, days 1–4 Prednisone 2 mg/kg, days 1–4 Placebo days 1–21 Placebo Primary end-point: PFS Secondary end-points: OS, TTP, ORR, TTR, duration of response, and quality of life All patients receive VTE prophylaxis with aspirin (75–100 mg/day) Trial NCT00405756. Available from: www.clinicaltrials.gov. 11 11 11

Progression-Free Survival All Patients 5 10 15 20 25 30 35 40 50 75 100 Time (months) Patients (%) 2-Year PFS Median PFS MPR-R 55% Not reached MPR 24% 14.1 months MP 16% 13.0 months HR 0.423 Log rank P < .001 HR 0.850 Log rank P = .307 No. at Risk MPR-R 152 115 89 66 35 17 2 – MPR 153 120 90 36 7 MP 154 112 85 43 19

Progression-Free Survival 65 - 75 Years of Age 5 10 15 20 25 30 35 40 50 75 100 Time (months) Patients (%) 2-Year PFS Median PFS MPR-R 61% Not reached MPR 27% 14.7 months MP 10% 12.4 months HR 0.315 Log rank P < .001 HR 0.675 Log rank P = .031 No. at Risk MPR-R 116 91 75 57 31 15 2 – MPR 97 77 16 7 MP 82 62 29 13 1

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

x 4 cycles (cycle length : 28 d) Len + high-dose Dex vs Len + low-dose Dex in newly diagnosed patients with myeloma ECOG E4A03 Trial Design Len. + high-dose Dex x 4 cycles (cycle length : 28 d) Rev. 25 mg/d, days 1-21 Dex. 40 mg/d, days 1-4, 9-12, 17-20 Newly diagnosed MM patients (n = 445) Primary objective: response rate and toxicity Len. + low-dose Dex x 4 cycles Rev. 25 mg/d, days 1-21 Dex. 40 mg/d, days 1, 8, 15, 22 Rajkumar et al. Lancet Oncology 2010;11:29-37 15 15

ECOG/E4A03 Adverse events Type (≥ Grade3) RD (N=223) Rd (N=220) P DVT/PE 26 % 12 % 0.0003 Infection/Pneumonia 16 % 9 % 0.04 Cardiac ischemia 3 % 0.5 % 0.07 Any non Hem toxicity (Grade ≥ 3) 65 % 48 % 0.0002 Toxicity of any type (Grade ≥ 4) 21 % 14 % Early deaths (< 4 mo. All pts) 5 % 0.003 Rajkumar et al. Lancet Oncology 2010;11:29-37

FIRST: Lenalidomide + LD-dex vs. MPT (IFM 07-01) Pts: Previously untreated MM pts >65 yrs old or not a candidate for ASCT Primary Endpoint: Progression-free survival (PFS) LD (28-day cycle) Oral dexamethasone on day 1, 8, 15, 22 Oral lenalidomide once daily on days 1-21 M Treatment until progressive disease (PD) LD (28-day cycle; up to 18 cycles) Oral dexamethasone on day 1, 8, 15, 22 Oral lenalidomide once daily on days 1-21 R MPT (6-wk cycle; up to 12 cycles) Oral melphalan and prednisone on days 1-4 Oral thalidomide once daily on days 1-42 17 17

Treatment selection: elderly patients Treatment should be selected based on: Biological age, comorbidities, overall clinical impression Dose adjustments: Standard schedules for fit patients requiring quick relief from symptoms Less intense treatment approach for frail patients and those with comorbidities (heart, lung, kidney, liver, diabetes) or aged >75 years Need to do what is best for an average elderly MM patient

Newly diagnosed frail elderly patients with MM Symptomatic treatments remain essential Highest doses of drugs are not optimal  Dexamethasone  MP+ studies Avoid excessive toxicity  careful treatment monitoring  dose reduction guidelines  particularly in early stages of treatment Need to consider Quality of life as factor 19

New options for patients eligible for transplantation Induction regimens in the era of novel agents 20 20

Summary of post-transplant results in Phase III bortezomib trials IFM 2005/01 GIMEMA HOVON-GMMG PETHEMA/GEM Harousseau VD vs VAD (n=197 vs 184) (ASH 2008, joint ASH/ASCO symposium) Cavo VTD vs TD (n=226 vs 234) (IMW 2009; Abstract 451) Sonneveld PAD vs VAD (n=150 vs 150) (IMW 2009; Abstract 152) Rosinol VTD vs VBCMP/VBAD+V vs TD (n=61 vs 58 vs 61) (IMW 2009; Abstract 160) Results post-ASCT CR 18% vs 10%* 41% vs 20%* 15% vs 4%* 48% vs 43% vs 23% CR + nCR 40% vs 22%* 54% vs 29%* n/a ≥VGPR 61% vs 44%* 75% vs 53%* 59% vs 47% CR + PR 91% vs 91% 92% vs 77%* 77% vs 70% vs 62% *significantly different Bortezomib induction regimen results in high CR/nCR and VGPR rates post-transplant n/a: not available

Phase III VD vs vTD as induction prior to ASCT IFM 2007/02 Z E Bortezomib 1.3 mg/m2 d1, 4, 8, 11 Dex 40 mg d1–4 and 8–11 (c3+4 only) Bortezomib 1.0 mg/m2 d1,4,8,11 Thal 100 mg daily Dex 40 mg d 1–4 and 8–11 (c3+4 only) VD vTD 4 x 21-day cycles Patients with <PR after cycle 2 could have bortezomib increased to 1.3 mg/m2 and thal increased to 200 mg in the absence of PN Stratified by β2M and del(13) by FISH Primary Objective: Induction CR rate Secondary Objectives: ≥VGPR, ≥PR, toxicity (including PN) FISH, fluorescent in situ hybridization Harousseau et al. ASH 2009 (Abstract 354)

IFM 2007/02: VD vs vTD as induction treatment prior to ASCT Harousseau et al. ASH 2009, abs 354 205 patients from Mar. 2008 to Jan. 2009 (191 pts evaluable) Response (%) VD vTD CR 12 14  VGPR* 36 50  PR 81 91 *P=0.047 Toxicity (%) VD vTD Treatment reduction 17 7 PN gr  2* 28 14 PN gr  3 6 2 *P=0.02 vTD should be considered as a new standard for induction treatment prior to ASCT 23

Phase I/II: bortezomib, lenalidomide, dex (VRD) in newly diagnosed MM Treatment Up to 8 3-week cycles: Bortezomib 1.0/1.3 mg/m2, Len 15–25 mg, Dex 40/20 mg Results CR/nCR (%) ≥VGPR (%) ≥PR (%) All patients (n=66) Response at cycle 4 6 11 74 Response at cycle 8 23 53 95 Best response 39 67 100 Most common AEs: Sensory PN (80%), fatigue (64%), constipation (61%), edema limb (45%), muscle pain (44%) Grade 3 PN: 7%, no grade 4 Overall rate of DVT/PE: 6% No treatment-related mortality Median follow-up: 21 months Median PFS not reached Estimated 18-month PFS rate: 75% No difference in PFS for pts undergoing ASCT or not Median OS not reached Estimated 18-month OS rate: 97% Richardson et al. Blood 2010;116;679-686

Post-Transplant Maintenance 25 25

Thalidomide maintenance studies / Summary Transplant setting 5/5 studies showed significant improvement in PFS 2/5 studies showed significant improvement in OS Non-transplant setting 2/2 studies showed significant improvement in PFS No significant improvement in OS Considerations - Short survival following relapse in some studies Worse outcome in patients with poor cytogenetics

IFM 2005-02: Lenalidomide as maintenance therapy After ASCT for MM Ongoing phase III randomized, placebo-controlled trial Patients < 65 years, with non-progressive disease,  6 months after ASCT in first line Randomize Consolidation Lenalidomide 25 mg/day p.o., days 1-21 of every 28 days for 2 months However, 68% of patients enrolled in the IFM 99 trial experienced neuropathy Thus revlimid , an analog of thal without neurological toxicity was an attractive candidate And is evaluated in the current IFM protocol After HDT, patients are to receive a consolidation with rev Then they are randomized to receive rev or placebo as maintenance More than 350 patients have been randomized and I hope to be able to present the results of this trial during the next few years. Lenalidomide 10 -15 mg/day p.o., continuous dosing until relapse Placebo until relapse Primary end-point : PFS Secondary end-points: CR rate, OS, feasibility of long-term lenalidomide. 27

IFM 2005-02 : PFS from randomization Lenalidomide p<10-7 Placebo This result is illustrated on this slide The PFS from randomization of patients treated with revlimid arm or in the placebo arm P < 10-7

HOVON 65 MM / GMMG-HD4 Allogeneic Tx MM Stage II or III, Age 18–65 Accrual goal: 800 patients MM Stage II or III, Age 18–65 Randomization 3 x VAD 3 x PAD 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/m2/2 weeks for 2 years maintenance 29

IFM 2009/ DFCI Trial VRD x 3 SC collection VRD x 5 Rev maintenance (HDM + ASCT at relapse) Mel 200 + ASCT VRD x 2 Major question: Can early SCT prolong EFS of at least 9 months? (1000 pts)

Jean-Paul Fermand Philippe Moreau Thierry Facon 31 31