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Current options for therapy of Myeloma in the era of novel therapies Jean-Luc Harousseau

Inter. groupe Francophone du Myélome. Current options for therapy of Myeloma in the era of novel therapies Jean-Luc Harousseau. History of MM treatment. Melphalan MP MEDIAN OS 3 years First reports on High-dose Tt 1983 VAD 1984 ASCT>CC 1996

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Current options for therapy of Myeloma in the era of novel therapies Jean-Luc Harousseau

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  1. Inter groupe Francophone du Myélome Current options for therapy of Myeloma in the era of novel therapies Jean-LucHarousseau

  2. History of MM treatment Melphalan MP MEDIAN OS 3 years First reports on High-dose Tt 1983 VAD 1984 ASCT>CC 1996 Thalidomide 1999 Double ASCT > single 2003 Bortezomib 2004 IFM 99 median OS Lenalidomide 2005 not reached at 7 years 1960 1970 1980 1990 2000

  3. Impact of novel agents on outcome in newly diagnosed disease Overall survival from diagnosis 1.0 0.8 0.6 0.4 0.2 0.0 1971-76 1977-82 1983-88 1989-94 1994-00 2001-06 Survival 0 20 40 60 80 100 120 140 Time Kumar et al. Blood 2008;111:2516–2520

  4. Frontline Therapy in Elderly Patients

  5. Improvements in survival according to the age Period estimates of 10-yr survival by major age groups in defined calendar periods 50 45 <50 40 35 30 50–59 25 20 10-year relative survival (%) 60–69 15 70–79 10 80+ 5 0 1984–1986 1987–1989 1990–1992 1993–1995 1996–1998 1999–2001 2002–2004 Calendar period Improvements in survival for elderly patients expected with longer follow up of ongoing trials Brenner et al. Blood 2008;111:2521–26

  6. MP-based combinations

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

  8. MP vs MPT : PFS and OS In 4/5 studies, MPT was superior to MP in terms of PFS In 2/5 studies, MPT was superior to MP in terms of OS.

  9. MP vs MPT Studies : Patient characteristics and MPT regimens

  10. MP/MPT 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 • Prelimiary results of CTD (Morgan ASH 07) are encouraging as well 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.

  11. VISTA : VELCADE as Initial Standard Therapy in multiple myeloma: Assessment with melphalan and prednisone San Miguel et al. NEJM 2008 VMP Cycles 1-4 Bortezomib 1.3 mg/m2 IV: days 1,4,8,11,22,25,29,32 Melphalan 9 mg/m2 and prednisone 60 mg/m2 days 1-4 Cycles 5-9 Bortezomib 1.3 mg/m2 IV: days 1,8,22,29 Melphalan 9 mg/m2 and prednisone 60 mg/m2 days 1-4 Newly diagnosed MM patients; age >65 years Primary endpoint: TTP 9 x 6-week cycles (54 weeks) in both arms MP Cycles 1-9 Melphalan 9 mg/m2 and prednisone 60 mg/m2 days 1-4

  12. Response to treatmentHigh CR rate with VMP †Post-hoc analysis by International Uniform Response Criteria2 *CT or Urine 1. Bladé et al. Br J Haematol 1998;102:1115-23 2. Durie et al. Leukemia 2006;20:1467-73 San Miguel et al. N Engl J Med 2008;359:906–17

  13. VMP MP Time to progression:52% reduced risk of progression with VMP 100 90 80 70 60 50 Patients without event (%) 40 30 20 VMP: 24.0 months (83 events) MP: 16.6 months (146 events) HR=0.483, p<0.000001 10 0 0 3 6 9 12 15 18 21 24 27 Time (months) Number of patients at risk: VMP: 344 295 272 245 185 111 65 31 17 MP: 338 296 241 206 152 86 53 22 5 San Miguel et al. N Engl J Med. 2008; 359:906-17; EHA 2008;110:Abstract 473.

  14. OS: Confirmed survival benefit with VMP ~36% reduced risk of death on VMP 100 VMP MP 90 80 70 60 50 40 30 20 10 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 Time (months) Subjects w/o event (%) Median follow-up=25.9 months VMP: median OS not reached (75 deaths); 3-year OS rate=72% MP: median OS not reached (111 deaths); 3-year OS rate=59% HR=0.644, p=0.0032 • 43% of MPpatients who received subsequent therapy received bortezomib upon progression • Patients received bortezomib >4 cycles: OSat 1 & 2 years: 98.5% & 89%

  15. Efficacy in patients with poor prognostic characteristics TTP OS Age ≥75 vs <75 years CrCl <60 vs ≥60 mL/min High-risk (t(4;14), t(14;16), del 17p) vs standard-risk cytogenetics by FISH 52

  16. EMN/Celgene study in patients > 65 years Pre-randomization Melphalan 0.18 mg/kg, days 1–4 Prednisone 2 mg/kg, days 1–4 Lenalidomide 10 mg/day p.o., days 1–28 Lenalidomide Eligible candidates with newly diagnosed, untreated MM Melphalan 0.18 mg/kg, days 1–4 Prednisone 2 mg/kg, days 1–4 Lenalidomide 10 mg/day p.o., days 1–28 R A N D O M I Z A T I O N Placebo Melphalan 0.18 mg/kg, days 1–4 Prednisone 2 mg/kg, days 1–4 Placebo days 1–28 until PD Placebo Primary end-point: PFS. Palumbo A, et al. Haematologica. 2006;91:181 [abstract 0491]. Palumbo A, et al. J Clin Oncol. 2006;24: [abstract 7518]. EMN = European Myeloma Network.

  17. MP + novel agents Grade 3/4 Toxicities The 3 novel agents have somewhat different toxicity profiles. All 3 novel agents are needed for optimal treatment

  18. Dex-based combinations

  19. Thal/Dex vs MP in Newly Diagnosed MM (n=274, Median 72y) Thal/dex MP p ≥VGPR (CR) 26% (2%) 13% (2%) ≥PR 68% 50% 0.044 Time to progression Overall Survival Survival: pts > 75 yrs MP; 49,4 m (n=141) MP; 41,3 m (n=34) MP; 29,1 m (n=131) ThalDex; 41,5 m (n=142) ThalDex; 19,8 m (n=35) ThalDex; 21,2 m (n=142) • . Higher mortality during the first year with thal/dex (28 vs 16, p=0.01): PN,DVT • . No significant difference in OS with Thal-IFN or IFN maintenance • . OS at 2y: 61 vs 70%; Short survival after relapse ( 3 & 6,7m) • .. Thal:200mg; Dex:40mg x 2pulses .Mel: 0,25mg/K; Pred: 2mg/k Ludwig, et al. Blood Prepublished online Oct 27, 2008

  20. Len HD Dex vs Len LD DexV.Rajkumar ASH 2007 Days 1 8 15 22 28 Lenalidomide 25 mg PO d1-21 Total Dex dose per Cycle = 480 mg RD Dex Dex Dex d1-4 d9-12 d17-20 Lenalidomide 25 mg PO days 1-21 Total Dex dose per Cycle = 160 mg Rd Dex Dex Dex Dex d1 d8 d15 d22

  21. ECOG/E4A03 Adverse events Rajkumar et al. JCO 2008;26:455s

  22. Overall Survival: Age ≥65

  23. Impact of Novel Agentsin elderly patients • MP is no longer the standard (at last !!) • With novel agents response rates (including CR/VGPR ) and PFS are quite comparable to those achieved in younger patients with HDT • In some but not all randomized studies (IFM ,Vista) OS is improved as well Patients over the age of 75 can be successfully treated (IFM,Vista,Rd)

  24. Impact of Novel Agentsin elderly patients However some questions remains • Which is the best regimen and should we add a third agent to Rd or a fourth agent to MP-based regimens ? • Incidence and severity of AE - toxic deaths - treatment discontinuation • Duration of treatment (fixed, until maximum result or until relapse) • Role of alkylating agents

  25. MPT vs Revlimid-low dose Dexamethasone in Newly Diagnosed Myeloma Patients, Aged > 65 Years CC5013-MM-020, IFM 2007-01, FIRST study MPT 12 cycles MP at 6-week interval + Thal at 100 or 200 mg/day, no maintenance Newly diagnosed MM >65Y 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

  26. Frontline Therapy in Younger Patients

  27. ASCT vs Conventional CTResults of Randomized Studies EFS 7-yr EFS 16% vs 8% 39 m vs 13m 32m vs 20m 28m vs 15m 25m vs 19m 42 m vs 33m 7-yr PFS 17% vs 16% OS 7-yr OS 43% vs 27% 65m vs 64m 54m vs 42m 58m+ vs 42m 48m vs 47m 61m vs 66m 7-yr OS 37% vs 42% • Age • 65 • 55 • 65 <70 55-65 <65  70 CR rate 38% vs 14% *** 19% vs 5% 44% vs 8% 25% vs 6% 42% vs 20% *** 30%vs 11% 11% vs 11% Author Attal 1996 Fermand 1998** Child 2003 Palumbo 2004 Fermand 2005 Blade 2005* Barlogie 2006 * N of pts 200 185 401 195 190 164 516 • Randomized after induction Chemo ** early vs late ASCT • *** CR + VGPR

  28. Improvements in survival according to the age Period estimates of 10-yr survival by major age groups in defined calendar periods 50 45 <50 40 35 30 50–59 25 20 10-year relative survival (%) 60–69 15 70–79 10 80+ 5 0 1984–1986 1987–1989 1990–1992 1993–1995 1996–1998 1999–2001 2002–2004 Calendar period Improvements in survival for elderly patients expected with longer follow up of ongoing trials Brenner et al. Blood 2008;111:2521–26

  29. Impact of CR + VGPR on outcome IFM 99 double ASCT 1.00 P=0.0007 IFM 90 0.75 p=7.105 100 Survival Distribution Function 0.50 PR: 290 0.25 75 CR + VGPR: 440 0.00 ≥90% (n=51) 0 250 500 750 1,000 1,250 1,500 1,750 2,000 2,250 50 EFS 1.00 ≥50% (n=81) p=7.105 25 0.75 <50% (n=46) Survival Distribution Function 0.50 0 PR: 290 0.25 CR + VGPR: 440 0 22 44 66 88 0.00 0 250 500 750 1,000 1,250 1,500 1,750 2,000 2,250 OS

  30. Single versus double ASCT results of published randomized

  31. The only factor predicting the impact of the 2nd ASCT is the result of the first (n=46) B (n=128) B A (n=81) <VGPR p < 0.001 A (n=84) VGPR or CR p = 0.7

  32. Cytogenetic + b2m model H Avet Loiseau Blood 2007 OS No t(4;14), no del(17p), b2m<4, no del(13) 155 pts No t(4;14), no del(17p), b2m<4, del(13)+ 110 pts No t(4;14), no del(17p), b2m>4, no del(13) 74 pts No t(4;14), no del(17p), b2m>4, del(13)+ 69 pts t(4;14) or del(17p)>60%, b2m<4 63 pts t(4;14) or del(17p)>60%, b2m>4 42 pts

  33. NOVEL AGENTS IN COMBINATION WITH ASCT

  34. INDUCTION TREATMENTPRIOR TO ASCT

  35. Thal-Dex prior to ASCT TD vs D TD vs VAD HISTORICAL CONTROL TD vs VAD Author Rajkumar J Clin Oncol 2006 Cavo Blood 2005 MacroASH 2006 Pts (N) 201 200 204 RR prior to ASCT 69% vs 51%No ≠ce in CR rate 76% vs 52%No ≠ce in CR rate VGPR 35% vs 17% RR after ASCT – – VGPR 44% vs 42% DVT 17% vs 3% 15% vs 2% 23% vs 7.5%

  36. IFM 2005-01VAD vs Vel/DexResponse To Induction VAD (A1+A2) N=219 1 % 7% 16% 65% Vel-Dex (B1+B2) N=223 6 % 15% 39% 82% P value 0.004 0.0004 < 0.0001 < 0.0001 • CR • CR+nCR • VGPR • > PR Response assessed by Independent Review Committee

  37. Response to First ASCTIntent-to-treat Analysis Vel-Dex (B1+B2) N=223 17% 37% 57% 84% VAD (A1+A2) N=219 9% 19% 38% 79% P value 0.0041 0.0063 < 0.0001 NS • CR • CR + nCR • VGPR • > PR

  38. Best response (including 2nd ASCT) Vel-Dex N = 223 34% 39% 68% VAD p value N = 218 32% < 0.0001 47% < 0.0001 % 2nd ASCT 47% At least n-CR At least VGPR

  39. PFS (2 yr median f-up) Vel-Dex VAD Median 28 m 2- yr PFS 60 % Median NR 2 - yr PFS 69% Months

  40. IFM 2005-01 Impact of t(4;14) and del(17p) on PFS in patients treated with Vel/dex

  41. Len-Dex prior to ASCT - No randomized study comparing Len-Dex to other regimens - In available studies, patients who were candidates for ASCT and received 4 cycles of Len-Dex were mixed with patients who received long-term treatment - The only large randomized study with Len-Dex as induction therapy (4 cycles) actually compared two doses of Dexamethasone - In the ECOG randomized trial the CR rate was underestimated Len-Dex Len-dex PR rate 80% 67% VGPR rate: 44% 26%

  42. Three-drug combinations

  43. ONE NOVEL AGENTRESULTS OF RANDOMIZED STUDIESCR + VGPR rates TCD vs CVAD Morgan ASH 2007 251 38% vs 26% 67% vs 43% PAD vs VAD Sonneveld ASH 2008 839 42 % vs 15 % 80 % vs 50 % TAD vs VAD Lokhorst Haematologica 2008 402 33% vs 15% 49% vs 32% No of patients Post Induction Post-ASCT

  44. TWO NOVEL AGENTSVTS vs TD (Cavo ASH 2008) VTD N = 199 61 % 75 % TD N = 200 30 % 53 % Post Induction CR+VGPR Post ASCT CR+VGPR

  45. MAINTENANCE

  46. † ‡ Single ASCT + thalidomide vs double ASCT Thal/PDN vs PDN ** Thal/Pam vs Pam vs no tt Randomized Studies on Post-ASCT With Thalidomide

  47. Thalidomide maintenance treatment (MRC trial) Although thalidomide maintenance may improve PFS, there is nodemonstrable benefit onOS • Intensive pathway: • Significant improvement in PFS in patients with less than a VGPR post induction (p=0.007) • PFS difference did not translate into survival benefit because survival after progression in PR patients receiving maintenance thalidomide was poor (p=0.002) • Non-intensive pathway:similar but less pronounced effect of thalidomide maintenance on PFS Morgan et al. ASH 2008 (abstract 656)

  48. IFM 99-02 : EFS According to Response at Random Response at Random ≥ 90% Response at Random < 90% Thal + Thal + Thal - (n = 391) Thal - NS P < 0.0003 Thal -

  49. CONCLUSION • - Post-ASCT maintenance with thalidomide improves • - CR/VGPR • - PFS • - OS ? • - Peripheral neuropathy is a concern: • what is the optimal duration of maintenance ? • (from 6 months until unlimited duration) • - Factors predicting efficacy : <VGPR (IFM,MRC) • Maintenance or consolidation ? • - Ongoing studies with bortezomib and lenalidomide

  50. VTD consolidation • Aim • Assess impact of VTD consolidation on residual MM cells in patients achieving ≥VGPR after ASCT by qualitative and quantitative PCR • Treatment • VTD started within 6 months from ASCT (for 4 cycles) • Bortezomib 1.6 mg/m2 once weekly (days 1, 8, 15, 22) • Thalidomide 50 mg/day (increments of 50 mg every 7 days up to 200 mg) • Dex 20 mg/day, days 1-4, 8-11, 15-18 • Results (n=40) • Six patients converted to MR • No clinical relapse observed in MR patients at median follow-up of 26 months Ladetto et al. ASH 2008 (abstract 3683)

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