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

Front-line treatment in multiple myeloma patients not eligible for stem cell transplantation. Thierry FACON Lille University Hospital , France. Period estimates of 10-year survival of patients with MM by major age groups in defined calendar periods from 1984-1986 to 2002-2004.

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

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  1. Front-line treatment in multiple myelomapatients not eligible for stem cell transplantation Thierry FACON Lille University Hospital , France

  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. Frontline treatment in elderly patients with myeloma Dex-based • THAL-DEX (ECOG10,Celgene 00311,CEMSG12) • REV-DEX (SWOG13,ECOG14, CC-5013-020 /IFM 07-01) Alkylating agent-based • MPT (GIMEMA1,IFM2,3,NMSG4,HOVON5) • MPV (PETHEMA6,VISTA7) • MPR (GIMEMA8,CC-5013-015) • CTD9 (MRC IX) 1.Palumbo et al. Lancet 2006; 367:825-831 8. Palumbo et al. JCO 2007; 25:4459-65 2. Facon et al. Lancet 2007;370:1209-1218 9. Morgan et al. Blood 2007; 110:1051a (abs.3593) 3. Hulin et al. Blood 2007;110:31a (abs 75) 10. Rajkumar et al. JCO 2006; 24:431-36 4. Waage et al. Blood 2007; 110:32a (abs 78) 11. Rajkumar et al. JCO 2008; 26:2171-2177 5. Wijermans et al. Interim analysis, EHA 2008 12. Ludwig et al. Blood 2007; 110:163a (abs 529) 6. Mateos et al. Blood 2006;108:2165-72 13. Zonder et al. Blood 2007; 110:32a (abs.77) 7. San Miguel et al. Blood 2007; 110:31a (abs 76) 14. Rajkumar et al. Blood 2005; 106:4050-53

  4. MP vs MPT in Newly Diagnosed Myeloma Patients, Aged 60-85 Years GIMEMA Trial Design Standard MP 6 courses at 4-week intervals Previously untreated patients with MM Median age, 72 years (N = 255) Primary endpoint : response and EFS MPT Arm MP + Thal at 100 mg/day, continuously Palumbo A et al. Lancet 2006; 367:825-831

  5. Palumbo et al. Blood First Edition Prepublished onlineMay27. 2008 PFS OS

  6. MP vs MPT vs Mel 100 in Newly Diagnosed Myeloma Patients, Aged 65-75 Years IFM 99-06 Trial Design Standard MP12 cycles at 6-week intervals 3 Newly diagnosed MM patients; age 65-75 years (N = 447) MPT Arm MP + Thal at MTD but  400 mg/day, no maintenance Primary endpoint: overall survival 2 2 Mel 100 x 2 Arm VAD x 2; cyclophosphamide 3 g/m2; Mel 100 mg/m2 Facon et al. The Lancet 2007, 370:1209-1218

  7. CR  VGPR  PR MP 2 7 35 MP-T 13 47 76 MEL100 18 43 65 MP vs MPT <.0001 <.0001 0.0008 MP vs MEL100 <.0001 <.0001 <.0001 % of patients Best response to treatment at 12 months in the IFM 99-06 trial P

  8. MP vs MPT vs Mel 100 in Newly Diagnosed Myeloma Patients, Aged 65-75 Years PFS OS 1 1 MP-T vs MP, P<0.0001 MP-T vs MEL100, P<0.0002 MP-T vs MP, P=0.0006 MP-T vs MEL100, P=0.02 0.8 0.8 0.6 0.6 Proportion of surviving patients Proportion of progression-free surviving patients 0.4 0.4 0.2 0.2 0 0 0 12 24 36 48 60 72 84 0 12 24 36 48 60 72 Time from randomization (month) Time from randomization (month) Facon et al. The Lancet 2007, 370:1209-1218

  9. MPn=193 MP-Tn=124 MEL100n=122 P NS .05 .04 NS* <.001* NS* Death < 1 mo. Death < 3 mo. Toxic death Anemia Neutropenia Thrombocytopenia 3 7 2 14 26 10 1 2 0 14 48 14 2 9 5 100 100 100 IFM 99-06 - Grade  3 toxicity (% of pts) (1) *MP vs MP-T

  10. MP n=193 MP-T n=124 MEL100n=122 P .03 <.001 <.001 <.001 <.001 <.001 Thrombosis / PE Peripheral neuropathy Infections Cardiac Constipation Any non hematological 4 0 9 0.5 0 16 12 6 13 2 10 42 8 0 49 10 0 58 IFM 99-06 - Grade  3 toxicity (% of pts) (2)

  11. MP- Placebo vs MPT in Newly Diagnosed Myeloma Patients, Aged >75 Years IFM 01-01 Trial Design MP + placebo M=0.2mg/kg/d, days 1-412 courses at 6-week intervals Newly diagnosed MM patients; age >75 years (N = 232) Primary endpoint: overall survival MPT Arm MP + Thal at 100 mg/day, stopped at end of MP Hulin et al. Blood 2007;110:31a(abs.75)

  12. Best response to treatment at 12 months in the IFM 01-01 trial

  13. MPT Median = 24.1 months MPT Median = 45.3 months PFS MP Median = 19 months 1.00 1.00 0.75 0.75 MP Median = 27.7 months Survival Distribution Function 0.50 0.50 0.25 0.25 0.00 0.00 0 10 20 30 40 50 60 0 10 20 30 40 50 60 Time from randomization (months) MPT vs MP in Elderly Patients with Multiple Myeloma:Progression-Free Survival (PFS) and Overall Survival (OS) 232 Pts,Median follow-up time = 24 months OS Survival Distribution Function Time from randomization (months) Log-Rank test p=0.001 Log-Rank test p=0.033

  14. IFM 01-01 - Grade 2 or 3 - 4 toxicity (% of pts)

  15. MP vs MPT Studies : Patient characteristics and MPT regimens 1. Palumbo et al, Lancet 2006; 367:825-831 and Blood prepublished online May 27,2008 2. Facon et al. Lancet 2007;370:1209-1218 4. Waage et al. Blood 2007; 110:32a (abs78) 3. Hulin et al. Blood 2007;110:31a (abs 75) 5. Wijermans et al. Interim analysis, EHA 2008

  16. MP vs MPT: Response rates In all 5 studies, MPT was better than MP in terms of response, including CR+VGPR

  17. MP vs MPT : PFS and OS In 5/5 studies, MPT was superior to MP in terms of PFS and/or TTP. In 2/5 studies, MPT was superior to MP in terms of OS. 1. Palumbo et al, Lancet 2006; 367:825-831 and Blood prepublished online May 27,2008 2. Facon et al. Lancet 2007;370:1209-1218 4. Waage et al. Blood 2007; 110:32a (abs78) 3. Hulin et al. Blood 2007;110:31a (abs 75) 5. Wijermans et al. Interim analysis, EHA 2008

  18. Thal,>75 years

  19. MRC Myeloma IX non intensive pathwayOlder less fit patients (approximately > 65 y) Response rate Randomize Clodronate Zoledronic acid  VS MP CTDa VS Randomize  Thalidomide  no Thalidomide VS P <.001 CTDa:Cyclophosphamide 500 mg orally QW , Thal.200 mg/d, Dex.20 mg d1-4, 15-18 of a 28 day cycle Morgan et al. Blood 2007; 110:1051a(abs 3593)

  20. MPT/CTDa Studies : 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 approximately 18 months • Preliminary analysis of the results of MRC IX are consistent with MP vs MPT findings MPT is a new standard of care for newly diagnosed elderly patients with myeloma. CTDa might become another standard treatment for older less fit patients. EMEA approved front-line MPT in elderly MM patients in April 2008.

  21. Melphalan, Prednisone, and Lenalidomide (MPR) treatment for newly diagnosed MM Palumbo et al. JCO 2007; 25:4459-4465 on behalf of the GIMEMA • 54 Patients, median age 71 • Treatment Induction: M 0.18–0.25 mg/kg, P 2 mg/kg, Len 5-10 mg/d , 9 cycles Maintenance : Len 10 mg/d • Results MTD: M 0.18 mg/kg + Len 10 mg/d (n=21) Response Toxicity (at MTD, grade 3) MPR therapy is a promising first-line treatment for elderly MM patients This study formed the basis for the MM-015 trial (MP vs MPR vs MPR + R)

  22. MP vs MPR in Newly Diagnosed Myeloma Patients, Aged > 65 Years Phase III international study / MM-015 study MM-015 Trial Design MP + Placebo 9 cycles MP at 4-week intervals Newly diagnosed MM patients; age >65 years (N = 450) Primary endpoint: PFS MPR 9 cycles MPR at 4-week intervals MPR 9 cycles MPR at 4-week intervals + R maintenance

  23. Lenalidomide plus high-dose Dexamethasone versus Lenalidomide plus low-dose Dexamethasone in newly diagnosed patients with myeloma Rajkumar et al. Blood 2007;110:31a(abs74) and JCO 2008;26:455s (abs 8504) 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

  24. ECOG/E4A03 Adverse events Rajkumar et al. JCO 2008;26:455s (abs8504)

  25. Lenalidomide plus high-dose Dexamethasone versus Lenalidomide plus low-dose Dexamethasone in newly diagnosed patients with myeloma Survival Rate pts ≥ 65 yr Primary Rd beyond 4 cycles P=.009 Rajkumar et al. Blood 2007;110:31a(abs74) Rajkumar et al. JCO 2008;26:455s (abs 8504)

  26. MP + novel agents ; most divergent grade 3/4 Toxicities (% of pts) The 3 novel agents have somewhat different toxicity profiles. All 3 novel agents are needed for optimal treatment • Facon et al. Lancet 2007;370:1209-1218 3. Palumbo et al. JCO 2007;25:4459-65 • Palumbo et al, Lancet 2006;367:825-831 4. San Miguel et al. Blood 2007;110:31a (abs 76) • and Blood prepublished online May 27, 2008

  27. CC-5013 MM-020 / IFM 07-01 • Frontline Investigation of Revlimid vs. Standard Thalidomide

  28. MPT vs Revlimid-low dose Dexamethasone in Newly Diagnosed Myeloma Patients, Aged > 65 Years CC5013-MM-020, IFM 2007-01, FIRST study FIRST study / Trial Design MPT 12 cycles MP at 6-week interval + Thal at 100 or 200 mg/day, no maintenance Newly diagnosed MM patients; age >65 years (N = 1590) Rd Rev 25mg/day, days 1-21 ; Dex 20 or 40 mg/day, days 1,8,15, 22 18 cycles at 4-week interval Primary objective: PFS Rd same schedule as above given until disease progression

  29. Newly diagnosed elderly patients with MM • Symptomatic treatments remain essential • Highest doses of drugs are not always optimal  Dexamethasone  MPR dose escalating study • Avoid excessive toxicity  careful treatment monitoring  dose reduction guidelines  particurlarly in patients with bad performance status and in early stages of treatment • Outpatient administration of drugs should also befavored andpatient quality of life is important

  30. Open questions… • How to reduce toxicity ? Dose reduction guidelines DVT prophylaxis • How to tailor treatment ? Cytogenetic abnormalities Comorbidities Renal function • How to delay relapse ? Role of maintenance treatment

  31. Conclusions • MPT and MPV currently appear to be the treatments of choice for a large proportion of elderly MM patients ineligible for ASCT. • CTD, MPR, and Rd are other promising therapeutic options which are currently being evaluated. • MP remains appropriate for a minority of patients with poor performance status and/or significant comorbidities. • These new and emerging therapies offer multiple effective treatment options for MM patients and greatly enhanced treatment strategies for clinicians.

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