Standard of care for patients with newly diagnosed multiple myeloma who are not eligible for a transplant

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1 Standard of care for patients with newly diagnosed multiple myeloma who are not eligible for a transplant Pr Philippe Moreau University Hospital, Nantes, France

2 MP: Standard of care until 2007 J Clin Oncol 1998;16: randomized trials, 6633 pts MP vs combination chemotherapy 1617 pts years 497 pts 75+ Response rate: CCT 60 vs 53% Survival: MP vs CCT identical MP: standard of care until 2007

3 Survival benefit MP +

IFM 99-06: Newly diagnosed MM patients 65 75 years 3 MP arm (n = 196)

patients, age 65 75 years (N = 447) 2 2 MPT arm (n = 125) MP arm +

Primary end-point: OS VAD 2; cyclophosphamide 3 g/m 2 + G-CSF + PBSC

4 IFM 99-06: Newly diagnosed MM patients years 3 MP arm (n = 196) Standard MP; 12 courses at 6-week intervals Newly diagnosed MM patients, age years (N = 447) 2 2 MPT arm (n = 125) MP arm + Thal at MTD but 400 mg/day, stopped at end of MP MEL100 arm (n = 126) Primary end-point: OS VAD 2; cyclophosphamide 3 g/m 2 + G-CSF + PBSC harvest (M 100 mg/m 2 + PBSC + G-CSF) 2 Facon T, et al. Lancet. 2007;370:

5 Progression-free patients (%) IFM 99-06: progression-free survival benefit with MPT Treatment PFS, months p value MP (n = 196) 17.8 ± 1.4 MPT (n = 125) 27.5 ± 2.1 < MEL100 (n = 126) 19.4 ± Median follow-up duration 51.5 (range ) months 20 0 MP MPT MEL Time from randomization (months) Facon T, et al. Lancet. 2007;370:

6 Patients (%) IFM : survival benefit Treatment OS, months p value MP (n = 196) 33.2 ± MPT (n = 125) 51.6 ± MEL100 (n = 126) 38.3 ± Median follow-up duration 51.5 (range ) months MP MPT MEL Time from randomization (months) Facon T, et al. Lancet. 2007;370:

8 IFM 01/01 Study protocol Newly diagnosed MM > 75 years 12 cycles MP every 6 weeks Melphalan 0.2 mg/kg/d Day 1-4 Prednisone 2 mg/kg/d Day 1-4 Double Blind Placebo 2 caps 50 mg/d 72 weeks Thalidomide 2 caps 50 mg/d 72 weeks Hulin C, et al, J Clin Oncol. 2009; 27:

9 Proportion of surviving patients IFM 01-01: Progression-free survival 1,0 0,8 0, vs 18.5 months, p = ,4 0,2 MP MP+Thalidomide 0, Months Hulin C, et al, J Clin Oncol. 2009; 27:

10 Proportion of surviving patients IFM 01-01: Overall survival 1,00 0,80 0,60 44 vs 29.1 months, p = ,40 0,20 MP MP+Thalidomide 0, Months Hulin C, et al, J Clin Oncol. 2009;27:

11 MP vs MPT: progression-free survival and overall survival Median PFS, months MP MPT GIMEMA 1,2 IFM IFM Nordic 5 HOVON p value < TTP < Median OS, months MP MPT p value NS NS NS *Event-free survival. Significant. In 5 of 5 studies, MPT was superior to MP in terms of PFS or TTP (or both) In 2 of 5 studies, MPT was superior to MP in terms of OS * Palumbo A, et al. Lancet. 2006;111: Palumbo A, et al. Blood. 2008;112: Facon T, et al. Lancet. 2007;370: Hulin C, et al. J Clin Oncol. 2009; in press. 5. Waage A, et al. Blood. 2007;110:[abstract 78]. 6. Wijermans P, et al. Blood. 2008;112:[abstract 241]; updated data presented at ASH, 2008.

12 MPT : Conclusions Five studies (GIMEMA, IFM 99-06, IFM 01-01, NMSG, HOVON) have shown that the use of thalidomide in combination with MP (MPT) improves response rates and TTP and/or PFS compared with MP The 2 IFM studies have shown that MPT improves OS compared with MP, extending OS by months MPT is a new standard of care for newly diagnosed elderly patients with myeloma. EMEA approved front-line MPT in elderly MM patients in April 2008.

13 The VMP schedule was based on the standard bortezomib monotherapy dosing schedule Mateos, M.-V. et al. Blood 2006;108:

14 Phase III study of VMP versus MP in previously untreated multiple myeloma 682 untreated MM patients ineligible for HDT-SCT from 151 centres in 22 countries R A N D O M I S A T I O N VMP (N = 344) Bortezomib 1.3 mg/m 2 on days: cycles 1 4: 1, 4, 8, 11, 22, 25, 29, and 32; cycles 5 9: 1, 8, 22, and 29 + melphalan 9 mg/m 2 and prednisone 60 mg/m 2 on days 1 4 MP (N = 338) Melphalan 9 mg/m 2 and prednisone 60 mg/m 2 on days week cycles 54 weeks treatment Stratification for baseline beta-2-microglobulin and albumin levels and region Primary end point TTP Secondary end points: CR rate, ORR, time to response, DOR, time to next therapy (TNT), OS, QoL (PRO)

Event-free patients (%) Patients (%) VISTA: time to progression and overall survival Time to progression Overall survival 100 VMP 100 80 MP 80 60 60 40 20 0 VMP: 24 months (83 events) MP: 16.

15 Event-free patients (%) Patients (%) VISTA: time to progression and overall survival Time to progression Overall survival 100 VMP MP VMP: 24 months (83 events) MP: 16.6 months (146 events) HR 0.48, p < Median follow-up: 16.3 months VMP: not reached (45 deaths) MP: not reached (76 deaths) HR 0.61, p = Time (months) Time (months) OS at 3 years:72% in VMP group vs 69.5% in MP group San Miguel JF, et al. N Engl J Med. 2008;359: Mateos MV, J Clin Oncol 2010, April 5.

16 Matéos MV, J Clin Oncol 2010

17 Grade 3/4 adverse events (%) VMP (n=340) MP (n=337) Grade 3/4 Grade 3/4 Neutropenia 40% 38% Thrombocytopenia 37% 30% GI 20% 6% Peripheral neuropathy 14% 0% Fatigue 8% 2% Asthenia 8% 2% Pneumonia 7% 5% Herpes Zoster 3% 2%

18 VISTA MPV significantly prolongs survival and is superior for all pre-specified efficacy endpoints in the largest MP-based phase III study Rapid and durable responses with high CR rate (35%) Prolonged TTP, time to next therapy/treatment-free interval, and OS MPV data are consistently superior across all prognostic subgroups MPV was well tolerated, with patients on therapy for 46 weeks These results establish MPV as a new standard of care for MM patients not eligible for ASCT. EMEA and FDA approved frontline bortezomib for previously untreated MM patients in 2008.

19 Cheson BD & Rummel MJ. J Clin Oncol 2009

20 Pönisch et al, J Cancer Res Clin Oncol 2006;132: BP vs MP Prospective comparison Bendamustine-prednisolone vs melphalan prednisolone 131 pts CR rate, time to maximum response, time to treatment failure in favor of BP

21 Phase III: VMP vs VTP in newly diagnosed elderly patients with MM (PETHEMA/GEM study) 260 patients, multicenter Randomization step 1 Induction VMP vs VTP Randomization step 2 Maintenance VT vs VP VT vs VP Mateos et al. ASH 2009 (abstract 3); oral presentation

22 Phase III: VMP vs VTP in newly diagnosed elderly patients with MM VMP VTP One 6-week cycle Bortezomib twice weekly Melphalan Prednisone Bortezomib twice weekly Thalidomide Prednisone Five 5-week cycles Bortezomib once weekly Melphalan Prednisone Bortezomib once weekly Thalidomide Prednisone Mateos et al. ASH 2009 (abstract 3); oral presentation

23 Phase III: VMPT + VT vs VMP in elderly patients with newly diagnosed MM GIMEMA study Patients (n=511): >65 years old; median age 71 years Treatment VMPT VMP 9 x 5-week cycles Bortezomib Melphalan Prednisone 9 x 5-week cycles Bortezomib Melphalan Prednisone Thalidomide Maintenance: Bortezomib + Thalidomide No maintenance Palumbo et al. ASH 2009 (abstract 128); oral presentation

24 Phase I/II Melphalan, prednisone, and lenalidomide (MPR) treatment schedule Up to 9 cycles Median age, 71 (57-77) 54 patients Palumbo A, et al. J Clin Oncol. 2007;25:

25 Melphalan, prednisone, and lenalidomide (MPR) for newly diagnosed MM Response Patients, % CR 24 VGPR 24 PR 33 SD 19 Adverse events at MTD, grade 3 Patients, % Neutropenia 52 Thrombocytopenia 24 DVT 5 G-CSF support 43 Palumbo A, et al. J Clin Oncol. 2007;25:

26 Event-free patients (%) Patients (%) MPR MPR: median follow-up 14.6 ( ) months (N = 53) Event-free survival Overall survival Time (months) Time (months) Palumbo A, et al. J Clin Oncol. 2007;25:

MM-015: MPR vs MP for long-term control in newly diagnosed MM 51 centres in Europe, Australia, and Israel (N = 459) Patients with newly diagnosed,

A N D O M I Z A T I O N Melphalan 0.18 mg/kg, days 1 4 Prednisone 2 mg/kg, days 1 4 Lenalidomide 10 mg/day p.o. days 1 21 Melphalan 0.

18 mg/kg, days 1 4 Prednisone 2 mg/kg, days 1 4 Placebo days 1 21 Lenalidomide Placebo Placebo Primary end-point: progression-free survival Secondary

27 MM-015: MPR vs MP for long-term control in newly diagnosed MM 51 centres in Europe, Australia, and Israel (N = 459) Patients with newly diagnosed, untreated MM who are not eligible for a transplant Double-blind treatment phase Up to 9 courses in the absence of PD or unacceptable adverse events R A N D O M I Z A T I O N Melphalan 0.18 mg/kg, days 1 4 Prednisone 2 mg/kg, days 1 4 Lenalidomide 10 mg/day p.o. days 1 21 Melphalan 0.18 mg/kg, days 1 4 Prednisone 2 mg/kg, days 1 4 Lenalidomide 10 mg/day p.o. days 1 21 Melphalan 0.18 mg/kg, days 1 4 Prednisone 2 mg/kg, days 1 4 Placebo days 1 21 Lenalidomide Placebo Placebo Primary end-point: progression-free survival Secondary end-points: OS, TTP, ORR, TTR, duration of response, and quality of life All patients will receive aspirin prophylaxis ( mg/day) TTR = time to response. Trial NCT Available from:

28 Patients without Event (%) Progression-Free Survival First Interim Analysis 50% Reduced Risk in PFS 100 Median PFS 75 MPR-R MP Not reached 13.0 months Median follow up: 9.4 mos HR % CI [0.330, 0.755] Logrank P< PFS Time (months) Palumbo et al, ASH

29 Patients without Event (%) Overall Survival % 1-year Overall Survival MPR-R MP 25 0 Total number of deaths: Palumbo et al, ASH OS time (months) 29

5 49 CTD : cyclophosphamide 500 mg orally, once weekly; thalidomide 200 mg/day; dexamethasone 20 mg, days 1 4 and 15

30 MRC Myeloma IX: non-intensive pathway Older, less fit patients (age > 65 years) Clodronate Randomization vs Zoledronic acid Respon se Patients, % CTD MP MP vs CTDa CR Randomization VGPR Thalidomide vs No thalidomide PR CTD : cyclophosphamide 500 mg orally, once weekly; thalidomide 200 mg/day; dexamethasone 20 mg, days 1 4 and of a 28-day cycle Morgan GJ, et al. Blood. 2007;110:[abstract 3593]. Morgan GJ, et al. Blood. 2008;112:[abstract 245].

ECOG-E4A03: Len + standard- or low-dose Dex in newly

diagnosed MM (N = 445) Four courses, every 28 days R

p.o., days 1 21 Standard-dose dexamethasone 40

, days 1 4, 9 12, 17 20 Dexamethasone 480 mg per

Lower-dose dexamethasone 40 , days 1, 8, 15, 22

Less than PR Thal + Dex 4 cycles Patients eligible

31 ECOG-E4A03: Len + standard- or low-dose Dex in newly diagnosed MM Phase III, randomized study in newly diagnosed MM (N = 445) Four courses, every 28 days R A N D O M I Z A T I O N Arm 1 Lenalidomide 25 mg/day p.o., days 1 21 Standard-dose dexamethasone 40 mg/day p.o., days 1 4, 9 12, Dexamethasone 480 mg per cycle (n = 223) Arm 2 Lenalidomide 25 mg/day p.o., days 1 21 Lower-dose dexamethasone 40 mg/day p.o., days 1, 8, 15, 22 Dexamethasone 160 mg per cycle (n = 222) CR or PR Less than PR Thal + Dex 4 cycles Patients eligible for SCT can proceed to SCT CR or PR or SD Rajkumar SV, et al. Lancet Oncol 2010;11:29-37.

32 ECOG-E4A03: adverse events Grade 3 or 4 adverse event Len + high-dose Dex, % (n = 223) Len + low-dose Dex, % (n = 220) p value Infection or pneumonia DVT or PE < Neuropathy Cardiac ischaemia Any non-hematological AEs (Grade 3) <0.001 AEs (Grade 4) Early deaths (< 4 mnth)

33 Rajkumar SV, et al. Lancet Oncol 2010;11:29-37.

34 ECOG-E4A03: efficacy of Len plus low-dose Dex in newly diagnosed MM Primary Rd beyond 4 cycles Patients, % (n = 142) CR + PR 89 CR (IF ) 22 CR + VGPR 56 2-Year survival 93

35 ECOG-E4A03: Len + high-dose Dex vs Len plus low-dose Dex in newly diagnosed MM Survival rate in patients 65 years old Patients, n 2-Year survival probability (95% CI) RD ( ) Rd ( ) p = 0.009

36 Novel combinations as primary therapy Best choice? MPT MPV approved BP, soon MPV once weekly MPR CTD Rev-low dose dex

37 Novel agents as primary treatment Study n Median age, years CR, % CR + VGPR, % CR + PR, % EFS or TTP MPT IFM MPT MPT vs MP MPV VISTA MPR MPR Rd ECOG-E4A Median 28 months Median 22 months Median 24 months 87% at 16 months Median 23 months CTD MRC Myeloma IX NR

Continue therapy until progression or adverse

38 ECOG-E1A06: MPT vs MPR in transplantineligible patients with newly diagnosed MM R A N D O M I Z A T I O N MPT MPR CR, PR, or stable Progression any time Continue therapy until progression or adverse event Off therapy Trial NCT Available at:

HOVON-87: MPT vs MPR in transplantineligible patients with newly diagnosed MM Inclusion criteria Previously untreated MM Age 65 years or not a candidate for transplantation WHO-PS: 0 3 in

0 mg/kg/day, days 1 4, every 28 days Lenalidomide 10 mg/day, days 1 21, every 28 days Melphalan 0.18 mg/kg/day, days 1 4, every 28 days Prednisone 2.

39 HOVON-87: MPT vs MPR in transplantineligible patients with newly diagnosed MM Inclusion criteria Previously untreated MM Age 65 years or not a candidate for transplantation WHO-PS: 0 3 in patients aged < 75 years and 0 2 in patients aged 75 years Melphalan 0.18 mg/kg/day, days 1 4, every 28 days Prednisone 2.0 mg/kg/day, days 1 4, every 28 days Lenalidomide 10 mg/day, days 1 21, every 28 days Melphalan 0.18 mg/kg/day, days 1 4, every 28 days Prednisone 2.0 mg/kg/day, days 1 4, every 28 days Thalidomide 200 mg/day, daily through 28-day cycle Nine 4-week cycles followed by lenalidomide 10 mg/day maintenance until disease progression Nine 4-week cycles followed by thalidomide 100 mg/day maintenance until disease progression Primary end-point: progression-free survival

FIRST: lenalidomide + low-dose Dex vs MPT (IFM 07-01) Inclusion criteria Previously untreated MM Age 65 years or not a candidate for

mg/day, days 1 21; every 28 days Dexamethasone* 40 mg/day, days 1, 8, 15, 22; every 28 days Lenalidomide 25 mg/day, days 1 21; every 28

0 mg/kg/day, days 1 4, every 42 days Thalidomide* 200 mg/day, daily through 42-day cycle * In patients older than 75 years: dexamethasone

40 FIRST: lenalidomide + low-dose Dex vs MPT (IFM 07-01) Inclusion criteria Previously untreated MM Age 65 years or not a candidate for transplantation No neuropathy of grade > 2 CL Cr > 30 ml/min N = 1,590 Centres in EU, Switzerland, USA, and Canada Lenalidomide 25 mg/day, days 1 21; every 28 days Dexamethasone* 40 mg/day, days 1, 8, 15, 22; every 28 days Lenalidomide 25 mg/day, days 1 21; every 28 days Dexamethasone* 40 mg/day, days 1, 8, 15, 22; every 28 days Melphalan* 0.25 mg/kg/day, days 1 4, every 42 days Prednisone 2.0 mg/kg/day, days 1 4, every 42 days Thalidomide* 200 mg/day, daily through 42-day cycle * In patients older than 75 years: dexamethasone 20 mg/day, melphalan 0.20 mg/kg/day, thalidomide 100 mg/day. Primary end-point: progression-free survival Until PD Eighteen 4-week cycles Twelve 6-week cycles

41 PAD - MEL100 LP L in elderly patients (65 75 years) PAD PBSC Mobilisation (Cyclophosphamide + G-CSF) MEL 100 ASCT LP L 4 cycles 2 cycles 2 cycles 4 cycles PAD = bortezomib + pegylated-doxorubicin + dexamethasone MEL 100 = melphalan 100 mg/m² LP = lenalidomide + prednisone L= lenalidomide Palumbo A, et al.j Clin Oncol 2010;28:

43 Conclusions Adding novel agents to MP improves the response rate and quality of response adding oral thalidomide to MP prolonged PFS in 5 and survival in 2 of 5 phase III trials combination approved adding injectable bortezomib to MP prolonged PFS and survival in one phase III trial combination approved BP in patients with neuropathy MPR shows promising results CTD is a well-tolerated oral regimen that has shown a high response rate in a large MRC phase III trial Lenalidomide plus low-dose dexamethasone Is currently being compared with MPT Role of maintenance therapy?? Role of ASCT with novel agents??

Management of Multiple

Management of Multiple Myeloma in the Elderly Xavier Leleu Service des Maladies du Sang Hôpital Huriez, CHRU, Lille, France INSERM U837, équipe 3 IRCL, CHRU, Lille, France IMPRT Institut de Médecine Prédictive