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 et de Reherches Thérapeutique IFR 114
Conflict of Interests Lecture fees Research grants Boards Janssen, Celgene, LeoPharma, Amgen, Novartis, Onyx
Period estimates of 10-year survival of patients with MM by major age groups in defined calendar periods from 1984-19861986 to 2002-2004 2004 Brenner et al; Blood 2008; 111:2521-26
Age- and Sex- Incidence Rates per 100 000/year for MM in the South Thames Area (1999-2000) 60.00 Males 50.00 Females Females and Males combined 40.00 te per 100,000 Ra 30.00 20.00 10.00 0.00 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
Current platform Future platform Platform Mel Pred MPV (IV) MPT Other alkylating agents BP CTD Platform Dexamethasone TD Rd C. cyclophosphamide; T. thalidomide; V. bortezomib; P. prednisone; M. melphalan; R. lenalidomide; D. low dose dexamethasone; B. bendamustine
MPT vs MP: Meta-analysis of 1685 individualpatient data from 6 randomized trials PFS OS Survival proportion 0.0 0 0.2 0.4 0.6 0.8 1.0 HR=0.67 in favor of MPT, p<0.0001 Median 14.9 mos (14.0-16.6) Median 20.3 mos (18.8-21.6) MPT MP 0 12 24 36 48 months 1.0 0.6 0.8 0.0 0 0.2 0.4 HR=0.83 in favor of MPT, p=0.005* Median 39.3 3 mos (35.6-44.6) Median 32.7 mos (30.5-36.6) MPT MP 0 12 24 36 48 months Fayers et al. Blood 2011, accepted for publication 30 May 2011
MP vs MPT : PFS and OS PFS (med,mo.) MP MPT P OS (med,mo.) MP MPT P GIMEMA 1,2 IFM 99-06 3 IFM 01-01 4 NMSG 5 HOVON 6 14.5 21.8.0004 47.6 45 NS 18 27.5 <.0001 33 51.55.0006 18.5 24.001 29 44.028 14 15 NS 32 29 NS 9 * 13 <.001 31 40.05 * Event-free survival In 4/5 studies, MPT was superior to MP in terms of PFS. In 3/5 studies, MPT was superior to MP in terms of OS. 1. Palumbo et al, Lancet 2006; 367:825-831 2. Palumbo et al. Blood 2008; 112:3107-14 3. Facon et al. Lancet 2007;370:1209-1218 4. Hulin et al. JCO 2009 ;27:3664-3670 5. Waage et al. Blood Epub May 6, 2010 6. Wijermans et al. JCO Epub June 1, 2010
MP vs MPT Studies : Patient characteristics and MPT regimens GIMEMA 1,2 IFM 99-06 3 IFM 01-01 4 NMSG 5 HOVON 6 No.pts (MPT) 331 (167) 447 (125) 232 (113) 363 (182) 333 (165) Age median 72 69 78.5 74.5 (mean) 72 range 60-85 65-75 75-89 49-92 NA WHO 3/4 (%) 5 8 7 30 4 MPT regimen No. Cycles 6 12 12 Until plateau Until plateau M dosing 4 mg/m 2 0.25 mg/kg 0.2 mg/kg 0.25 mg/kg 0.25 mg/kg d1-7 d1-4 d1-4 d1-4 d1-5 Thal. dosing 100 up to 400 100 up to 400 200 Maintenance + - - + + 1. Palumbo et al, Lancet 2006; 367:825-831 2. Palumbo et al. Blood 2008; 112:3107-14 3. Facon et al. Lancet 2007;370:1209-1218 4. Hulin et al. JCO 2009 ;27:3664-3670 5. Waage et al. Blood Epub May 6, 2010 6. Wijermans et al. JCO Epub June 1, 2010
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 Primary objective MM patients (n = 445) 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 SV, et al. Lancet Oncol. 2010;11:29-37. VU University Medical Center Amsterdam The Netherlands
High dose dexamethasone results in early mortality 1.0 100 Rd 0.8 80 RD Su urvival 0.6 0.4 Patients (%) 60 40 3-Year OS rate 75% 0.2 00 0.0 0 High-dose Low-dose 20 Log-rank p = 0.46 Pepe-Fleming p = 0.01 6 12 18 24 0 0 6 12 18 24 30 36 42 Months Number at risk Time (months) High-dose 223 179 103 37 0 RD 223 208 195 184 173 123 78 7 Low-dose 221 192 103 37 0 Rd 222 217 212 201 192 146 83 9 Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37. VU University Medical Center Amsterdam The Netherlands
ECOG/E4A03 Adverse events Type ( Grade 3) RD (N=223) Rd (N=220) P DVT/PE 26% 12% 0.0003 Infection/Pneumonia 16% 9% 0.04 Cardiac ischaemia 3% 0.5% 0.07 Any non-haem toxicity (Grade 3) Toxicity of any type (Grade 4) 65% 48% 0.0002 21% 14% 0.0002 Early deaths (< 4 mo. All pts) 5% 0.5% 0.003 Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37. VU University Medical Center Amsterdam The Netherlands
MM-015: phase III trial of MPR vs MP for long-term control in newly diagnosed MM Patients with newly diagnosed, untreated MM who are not eligible for a transplant t R A N D O M I Z A T I O N 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 Melphalan 0.18 21 mg/kg, days 1 4 Prednisone 2 mg/kg, days 1 4 Lenalidomide 10 mg/day p.o., days 1 Melphalan 0.18 21 mg/kg, days 1 4 Prednisone 2 mg/kg, days 1 4 Placebo days 1 21 Lenalidomide Placebo 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.
Phase III study: MPR in elderly patients Patients: n=459, 65 years Response data MPR+R MPR MP Median age 71 71 71 >75 years 24% 24% 25% 18/33/4 21/31/4 ISS stage I/II/III 18/31/51 9 8 MPR+R MPR MP P (MPR+R vs MP) ORR 77% 67% 49% <0.001 CR 18% 13% 5% <0.001 VGPR 32% 33% 11% <0.001 PR 45% 34% 37% Median time to first response 1.9 months 1.9 months 2.8 months <0.001 Palumbo et al. ASH 2009 (Abstract 613)
No. at Risk Patients (%) 100 75 50 25 0 Progression-Free Survival 65-75 Years of Age 2-Year PFS Median PFS MPR-RR 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 0 5 10 15 20 25 30 35 40 Time (months) MPR-R 116 91 75 57 31 15 2 MPR 116 97 77 31 16 7 MP 116 82 62 29 13 1
FIRST: lenalidomide + low-dose Dex vs MPT (IFM 07-01) Inclusion criteria Previously untreated MM Age g 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
How to define? Definitions Comorbidity Frailty Disability Age? Social context? VU University Medical Center Amsterdam The Netherlands
Which scoring system? Clinical impression/feeling not sufficient? Karnofsky Performance Score ECOG Performance Score Quality of Life questionnaire Prognostic Inflammatory and Nutritional Index (PINI index) Comprehensive Geriatric Assessment Do we need an onco-geriatric score or just geriatric score? VU University Medical Center Amsterdam The Netherlands
Comprehensive Geriatric Assessment (CGA) Comorbidity Functional status Physical performance Cognitive status Psychological status Nutritional status Medication review Social support Detects unsuspected conditions that may affect the ability to complete cancer treatment in 50% of patients > 65 years However, laborious process: ~100 minutes VU University Medical Center Amsterdam The Netherlands
Dose recommendations for the elderly Annual IMWG Summit Meeting. London, UK. June 2011. VU University Medical Center Amsterdam The Netherlands
Current platform Future platform Platform Mel Pred MPV (IV) MPT Other alkylating agents BP CTD Platform Dexamethasone TD Rd Platform Melphalan Prednisone MP +Carfilzomib (Carmysap) MP +MLN9708 (oral) MP +pomalidomide (oral) MPV (weekly sub cutaneous) Platform Len-low dose Dexamethasone CRd / CRP (oral) Rd +Carfilzomib (Weekly) Rd +Bortezomib sub cutaneous Rd +HDAC inhibiteur (oral) Rd +MLN9708 (oral) Rd +Elotuzumab (IV) Maintenance to develop C. cyclophosphamide; T. thalidomide; V. bortezomib; P. prednisone; M. melphalan; R. lenalidomide; D. low dose dexamethasone; B. bendamustine
Future risk stratification IV SC VTE PNP oral Cyto genetics CGA Patients older than DM Cardiac History of 75 years of complicated disease SPM age CURRENTLY USED FUTURE USE VU University Medical Center Amsterdam The Netherlands
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