Nouveaux Médicaments du Myélome Multiple

Présentation au sujet: "Nouveaux Médicaments du Myélome Multiple"— Transcription de la présentation:

1 Nouveaux Médicaments du Myélome Multiple
Cyrille Hulin CHU NANCY

2 Nouveaux Médicaments du Myélome
Le Thalidomide Le Bortezomib (Velcade) Le Lenalidomide (Revlimid)

3 Thalidomide Drogue développée dans les années 50 par la firme Grunenthal comme sédatif Retirée du marché en 1962 : tératogène (phocomélie) et neuropathie déjà signalée Efficacité dans la lèpre puis anti-inflammatoire et immunomodulateur Modes d’action multiples pas seulement anti-angiogène

4 Thalidomide/Lenalidomide Target MM Cells in the BM Microenvironment
C. Lenalidomide/IMID MM Cells IL-6 TNF IL-1 B.Lenalidomide/IMID A.Lenalidomide/IMID Bone Marrow Stromal Cells ICAM-1 Bone Marrow Vessels VEGF bFGF IL-2 IFN  PBMC D. Lenalidomide/IMID CD8+ T Cells E. Lenalidomide/IMiD NK Cells Hideshima T et al. Blood. 2000;96:2943. Davies FE et al. Blood. 2001;98:210. Gupta D et al. Leukemia. 2001;15:1950. Mitsiades N et al. Blood 2002;99:4525. Lentzsch S et al. Cancer Res. 2002;62:2300.

5 AUTEUR TRAITEMENT N REPONSE ≥ 50 % SURVIE SANS EVENEMENT SINGHAL THAL SEUL 84 25 % 22 % à 1 an BARLOGIE " " 169 30 % 20 % à 2 ans YAKOUB-AGHA " " 83 48 % 50 % à 1 an DIMOPOULOS THAL + DXM 44 55 % 50 % à 10 mois PALUMBO 120 52 % 50 % à 12 mois

6 IFM 01/02 Study design R 1 year 100mg/d Arm B 400mg/d Arm A
Dex 40mg/d - 4d/Mo SD at 3Mo or Progression Pamidronate 90 mg/Mo Multicenter Prospective Randomized Study Testing Non-Inferiority of Thalidomide 100 mg/day as Compared with 400 mg/day in Patients with RRMM. 100mg/d Arm B 1 year 400mg/d Arm A R Robert, no mention is made of bisphosphonate use in this trial in the rationale. It just appears in very small font in the trial design figure. The rationale for dexamethasone use is given and I think the rationale for the use of pamidronate should be explained as well. The need for decreasing the amount of calcium in the blood and for treating bone lesions is obvious in this RRMM patient population but still needs to be explained in detail on the slide.

7 Intent-to-treat analysis
Period of inclusion December 2000 through October 2004 (last patient last visit on Oct 8, 2005) Number of patients, 400 Arm A: 400 mg/d, 195 pts Arm B: 100 mg/d, 205 pts Intent-to-treat analysis

8 Patients characteristics at randomization (1)
400 mg/day (n=195) 100 mg/day (n=205) p Age, median years 67 68 ns Time from diagnosis to Randomization (median) 29 Mo 31 Mo Lines of prior therapy ≥2 (%) 45% 46% Only one line chemotherapy(%) 13% 17% Prior intensive treatment (%) 57% 52%

9 Dexamethasone addition in the 400 patients according to treatment arm
Time (days) 100 mg (n=109) 400 mg (n=90) P=.002 Proportion of pts on Dex

10 Overall Survival in the 400 patients according to treatment arm
400 mg/d 100 mg/d SURVIVAL 1-year OS 400 mg/d 73 ± 3% 100 mg/d 69 ± 3% Upper limit of the 1- sided 95%CI = 11.5 % Time (months)

11 Somnolence 400 mg/day 100 mg/day p All grades 74% 61% .004 Grade - I
42% 48% Grade - II 22% 9% Grade - III 11% 4% <.001 Grade - IV 0% 33% 13%

12 Constipation 400 mg/day 100 mg/day p All grades 89% 74% <.001
Grade - I 48% 46% Grade - II 39% 27% Grade - III 0% 2% .01 Grade - IV 1% 40% 28%

13 Neuropathies Périphériques
400 mg/day (n=184) 100 mg/day (n=195) p All grades 74% 60% .004 Grade - I 42% 41% Grade - II 23% 17% Grade - III 8% 2% .05 Grade - IV 1% 32% 19%

14 Complications Thrombo-Emboliques
400 mg/day (n=193) 100 mg/day (n=202) p Overall thrombosis 9% 7% NS Non – serious thrombosis 3% 1% Serious thrombosis 6%

15 CONCLUSION THAL 100 mg/d ± Dex is comparable in terms of survival with 400 mg/d ± Dex in pts with RRMM. THAL 100mg/d is better tolerated than 400mg/d specific with less drowsiness, constipation, and peripheral neuropathy

16 Thalidomide + dexamethasone en traitement d’induction
AUTEUR N REPONSE ≥ 50 % RAJKUMAR (12) 50 64 % WEBER (13) 40 72 % RAJKUMAR (14) 99 CAVO (15) 100 76 %

17 Etude française du groupe MAG
204 patients < 66 ans MM de novo Randomisation Thal/DXM vs VAD avants recueil CSP et intensification autogreffe Répartition similaire dans les 2 groupes Thal/DXM 34,7% TBRP ] Avant VAD ,6% TBRP] Greffe TVP : 22,8% Thal/DXM vs 7,5% VAD Neuropathie : 17% Thal/DXM vs 13% VAD

18 Etude Total Therapy 668 patients jeunes MM de novo
Thalidomide vs placebo durant séquence complète très intensive : 4 cycles d’induction + double intensification autogreffe + 4 cycles de consolidation + entretien par interferon /DXM Avantage en réponse 62% RC vs 43% RC Survie sans progression à 5 ans : 56% vs 46 % Survie globale 65% dans les 2 bras Déficit de survie en rechute après Thalidomide

19 Etude IFM 99/02 597 patients < 65 ans MM de novo
Patients avec Del 13 et Beta 2 > 3 exclus 4 VAD puis double autogreffe Melphalan 140 puis Melphalan 200 Randomisation post greffe : Bras A Abstention Bras B Pamidronate mensuel Bras C Pamidronate mensuel + Thalidomide

20 Etude IFM 99/02 Augmentation du taux de RC + TBRP :
67% Bras C vs 55% Bras A / 57% Bras B Avantage en survie sans progression à 3 ans : 52% Bras C vs 36% Bras A / 37% Bras B Avantage en survie globale à 4 ans : 87% Bras C vs 77% Bras A / 74% Bras B Confirmation récente par une étude australienne

21 Eclosion du MP + Thalidomide
Etude Italienne multicentrique randomisée : MM de novo, ans, 01/02-05/05 6 MP mensuels : Melphalan 4mg/m2 + Prednisone 40mg/m2 J1-J7 Versus 6 MP + Thalidomide 100mg/j jusque progression Age médian 72 ans et 20% >75 ans Palumbo, A. et al. Lancet 2006;367:

22 Palumbo, A. et al. Lancet 2006;367:825-831
Profil de l’étude Palumbo, A. et al. Lancet 2006;367:

23 Tableau des réponses thérapeutiques
Palumbo, A. et al. Lancet 2006;367:

24 Courbes de survie sans événement et de survie globale
Palumbo, A. et al. Lancet 2006;367:

25 Eclosion du MP + Thalidomide
Toxicité : MP MPT >1 épisode 25% 48% TVP 02% 12% Neurologique 01% 10% Neuropathie 00% 08% Infections 02% 12% Digestif 01% 06% Durée médiane de TTT : 8 mois Arrêt du thalidomide pour 43 pts, réduction à 50mg 37 pts (4 mois) Palumbo, A. et al. Lancet 2006;367:

26 IFM 99-06 MM des sujets de 65-75 ans
Bras A MP 1 MP 12 Bras C VAD 1 VAD 2 Cyclophosphamide 3g/m2 + G-CSF + collecte de CSP MHD 100 mg/m2 + CSP + G-CSF Bras B + Thalidomide  400 mg/j Clodronate pour tous les pts

27 Bras de Traitement et Analyses intermédiaires
Deux objectifs principaux : 1. comparaison de la survie entre MP et MP+Thal. 2. comparaison de la survie entre MP et MHD 100 Randomisation stratifiée par centre : MP, 2 MP+Thalidomide, 2 MHD 100 Deux analyses intermédiaire planifiées et revues par un comité indépendant de 3 experts internationaux : Pr.M. Boccadoro/Torino ; Dr.R. Schots, Pr.Van Camp/ Brussels ; Pr.S. Chevret Biostatistiques/Paris- StLouis. Suite à la seconde analyse intermédiaire, le comité recommandait une 3ème analyse avec une date de point au 1/05/2005

28 3ème analyse intermédiaire
Date de point : 1/05/2005 Patients analysés = 436 MP = 191 MP-T = 124 MHD100 = 121 Médiane de suivi = 32 mois

29 Traitement MHD100 - Faisabilité
7/121 pts n’ont reçu aucun VAD (6%) 96/114 pts ont reçu le cyclophosphamide (80%) 72/114 pts ont reçu les deux MHD 100 prévues(63%) (10 pts de plus n’ont reçu qu’1 MHD 100) Aucun décès toxique sur 154 cures MHD 100

30 Décès /Toxicité (% pts)
MP 3 8 2 11 32 5 MP-T 1 17 41 12 MHD100 9 4 39 100 6.5 Décès < 1 mois Décès < 3 mois Décès infectieux Infection sévère Neutropénie sévère Thrombose/EP Neuropathie chez 30 % des pts MP-T

31 Réponse au traitement dans l’essai IFM 99-06
Type de réponse Réponse complète  90%  50% MP 2 7 40 MP-T 15 49 81 MHD100 17 41 72 % patients (à 12 mois)

32 SURVIE SANS PROGRESSION
Proportion O/N Survie mediane ± se (mois) MP 141/ ± 1.5 MP+Thal 57/ ± 3.6 Int. 82/ ± 1.3 Temps depuis inclusion (mois)

33 SURVIE SANS PROGRESSION
Comparaison HR P MP / MP-T < MP / MHD MHD100 / MP-T

34 SURVIE GLOBALE Proportion O/N Survie Temps depuis inclusion (mois)
mediane±se (mois) MP 86/ ± 5.8 MP+Thal 34/124 not reached at 56. Int. 54/ ± 3.0 Temps depuis inclusion (mois)

35 SURVIE GLOBALE Comparaison HR P MP / MP-T MP / MHD MHD100 / MP-T

36 Conclusions Les résultats de l’essai IFM montrent la supériorité de MP-T dans le traitement des patients MM au diagnostic âgés de 65 à 75 ans et le recrutement a été interrompu après cette analyse La supériorité de MP-T sur MP et MHD 100 est démontrée pour la réponse, la survie sans progression et la survie globale Même s’il reste des questions concernant la posologie optimale, la durée de traitement et la toxicité du thalidomide, le traitement MP-T pourrait être considéré à ce jour comme le traitement de référence du MM du sujet âgé.

37 Bortezomib ou Velcade Premier médicament de la classe des inhibiteurs du protéasome Réduction de la prolifération des cellules malignes par blocage de leur progression dans le cycle cellulaire et régulation négative des inhibiteurs d’apoptose Diminution des capacités de réparation de l’ADN Effet synergique avec glucocorticoïdes et potentialisateur des agents alkylants

38

39 Study Design Open-label, multi-centre phase II study in 202 patients
Primary endpoint: overall response rate (CR+PR+MR) Response evaluated using Bladé criteria Confirmed by an independent review committee Secondary endpoints: safety, quality of life, clinical benefit Relapsed and refractory multiple myeloma At least 2 prior lines of treatment Progressing on last therapy Platelet count 30 x 109/L Creatinine clearance 30 ml/min SUMMIT trial represents one of the largest for multiple myeloma thus far. Bladé criteria, the most stringent criteria to date, was used to assess response. Eligibility criteria allowed heavily pre-treated patients and patients with reduced renal function and low platelet counts. *CR=Complete Response, PR=Partial Response, MR=Minimal Response

40 Treatment Plan VELCADE™ 1.3 mg/m2 IV push over 3-5 seconds
21-day cycle Administered on days 1, 4, 8, and 11 Maximum of 8 cycles For CR patients, 2 cycles beyond confirmed CR Addition of dexamethasone permitted after at least 2 cycles (PD patients*) or after first 4 cycles (SD patients) Extension protocol available for patients experiencing benefit Patients in the SUMMIT study received 1.3 mg/m2 of bortezomib by IV push on days 1, 4, 8, & 11 of a 21 day cycle. No pre-medication was specified. Dosing was twice weekly for 2 weeks with 1 week off. Patients received a maximum of 8 cycles of bortezomib therapy. Patients demonstrating a complete response (CR) received bortezomib for 2 cycles beyond their documented CR. Patients demonstrating no response after 2 cycles of bortezomib were eligible for the addition of dexamethasone to regimen. Patients with stable disease (SD) after the first 4 cycles of bortezomib were also eligible for the addition of dexamethasone to the regimen. At the completion of 8 cycles of therapy, responding patients were eligible to enter an extension study. * SD – stable disease PD – progressive disease

41 Prior Therapy Median number of lines of prior therapy = 6 (range 2-15)
99.5% Median number of lines of prior therapy = 6 (range 2-15) 92% of patients received at least 3 of the drug therapies listed here (excluding stem cell transplant) 91% of patients were refractory to the last prior therapy 92% 83% 81% 64% This slide shows the percentage of a specific drug therapy received by patients Patients in this study typically were heavily pre-treated with a median of six prior lines of therapy. 92% received at least 3 of the listed drug therapies (98% received at least 2, 66% received all 4). Supplemental review of source documentation by the sponsor confirmed that 91% of patients were refractory to their last prior treatment at time of study entry. 78% progressed while on the last prior therapy. 13% progressed within 60 days of the last dose of prior therapy. 6% progressed greater than 60 days after last therapy. 3% had stable disease on last therapy. Steroids Alkylating Thalidomide Anthracyclines HSCT Agents

42 Response Rates VELCADE™ Alone
35% + - 27% CR+PR 35% overall response (CR+PR+MR) 24% stable disease 59% of patients SD or better This slide breaks down the frequency of response by type for bortezomib alone. 91% of patients enrolled in the SUMMIT trial were refractory to their prior therapy upon entry. Of 202 Patients, 193 were evaluable for response and duration of response by an Independent Review Committee. All response data based on stringent Bladé criteria: CR as defined by Bladé required disappearance of M protein by immunofixation; bone marrow <5% plasma cells; no new bone disease; no plasmacytomas; and confirmation 6 weeks apart.

43 Votre protéasome est peut-être un peu trop inhibé

44 Most Common Adverse Events
This slide shows the most common adverse events Replace with updated slide

45

46 Response to VELCADE™ Alone
19% 12% 35% - 4% 50% 1.3 mg/m2 (n=26) 23% 8% 26% 41% All Patients (n=53) SD MR PR 7% CRIF+ CRIF- 33%b ORRa (CR+PR+MR) 1.0 mg/m2 (n=27) The response to bortezomib alone for both dosing groups, and overall, is shown here. An overall response rate of 41% was demonstrated with bortezomib alone. Patients receiving the 1.0 mg/m2 dose had a 33% response rate. Patients receiving the 1.3 mg/m2 dose had a 50% response rate. A small percentage of patients achieved a CRIF- (4%). This increased to 8% if patients achieving a CRIF+ status were included. The percentage of patients achieving PR was 26% (19% in the 1.0 mg/m3 group, and 35% in the 1.3 mg/m3 group) The percentage of patients achieving MR was 8% (4% mg/m3 group, and 12% in the 1.3 mg/m3 group) This was not designed or powered to be a comparative trial, and therefore no statistical conclusions can be drawn. a1 pt with nonsecretory myeloma inevaluable for response. b3(11%) and 3(12%) were not IRC evaluable in 1.0 mg/m2 and 1.3 mg/m2 dose groups, respectively; numbers rounded to the nearest integer.

47 MM en rechute ou réfractaire
1-3 lignes de traitement(s) antérieur(s) (N=669) dexamethasone : 40 mg PO (N=330) Induction 4 cycles : j 1-4, 9-12, / cycle de 5 semaines Maintenance 5 cycles: j 1-4 / cycle de 4 semaines VELCADE™ 1.3 mg/m2 IV (N=327) Induction 8 cycles :J 1, 4, 8, et 11 / cycle de 3 semaines Maintenance 3 cycles :J 1, 8, 15, 22 / cycle de 5 semaines Objectif primaire : Temps sans progression Objectifs secondaires : Survie globale Temps sans anomalies squelettiques Incidence d’infection G3 ou + Taux et durée de réponse Exploratoire Qualité de vie Pharmacodynamique APEX

48 Time to Progression (N = 669)
78% improvement in median TTP with bortezomib Median TTP: Bortezomib 6.2 mos Dexamethasone 3.5 mos

49 Updated Results of APEX Trial
SURVIVAL Overall and 1-Year Survival P=.0272 Bortezomib continues to demonstrate superior survival despite > 62% of HD dex pts crossing over to bortezomib Median OS: 29.8 months (95% CI: 23.2, not estimable) vs 23.7 months (95% CI: 18.7, 29.1); hazard ratio = 0.77; P = 1-year survival rate: 80% vs 67%; P = SLIDE 49 Richardson P, et al. ASH 2005, abstract #2547

50 Response Rates (CR, PR) Median TTR - 43 d in both arms DOR
- Bortezomib 8.0 mos vs dex 5.6 mos - Median follow-up ~8.3 mos 100 90 80 P < 70 60 Response, % 50 38% 40 30 25% PR 18% 20 < 1% nCR 10 7% nCR 16% PR < 1% CR 6% CR Bortezomib Dexamethasone

51 Updated Results of APEX Trial
RESPONSE Overall response (CR + PR) improved from 38% to 43% 76/135 responders (56%) - improved response after week 6 (cycle 2) 20 pts MR or PR to CR 56 pts MR to PR 100 90 80 70 Median TTP, months 6.2 Median TTR*, months 1.4 CR 0.8 PR nCR Median DOR*, months 7.8 9.9 7.6 11.5 60 43% Response, % 50 38% 40 34% PR 30 32% PR 20 (7% nCR) (7% nCR) 10 9% CR 6% CR Update Initial analysis *CR + PR Richardson P, et al. ASH 2005, abstract #2547 SLIDE 51

52 Updated Results of APEX Trial
Time to Response - Bortezomib Updated summary of pts achieving 1st response by cycle 73/135 (54%) responding pts achieved first response after cycle 2 39 (29%) pts on or after cycle 4 10 (7%) pts on or after cycle 6 Time to max serum M-protein reduction in responding bortezomib pts ~20% responding pts achieved max M-protein reduction in cycle 8 or later SLIDE 52 Richardson P, et al. ASH 2005, abstract #2547

53 Updated Results of APEX Trial
Conclusions Bortezomib provides 6 mo improvement in median survival vs. HD dex (29.8 vs 23.7 mo, P=0.0272), despite substantial crossover from HD dex to bortezomib 1-yr survival rate significantly higher with bortezomib Data are mature - median follow-up 22 months With this update: Median TTP, TTR, and DOR remain unchanged RR are higher (overall, CR, PR) SLIDE 53 Richardson P, et al. ASH 2005, abstract #2547

54 Frequency, Characteristics, and Reversibility of PN in the APEX trial
Peripheral Neuropathy Incidence of treatment-emergent PN: 37% (124/331) New or worsened PN N (%) Grade 1 33 (10%) Grade 2 61 (18%) Grade 3 28 (8%) Grade 4 2 (<1%) Grade > 2 91 (27%) Majority of PN was sensory, 2% motor SLIDE 54 San Miguel J, et al. ASH 2005, abstract #366

55 Frequency, Characteristics, and Reversibility of PN in the APEX trial
Time to Onset of PN Onset generally occurs by cycle 5 5 cycles 8 cycles SLIDE 55 San Miguel J, et al. ASH 2005, abstract #366

56 Frequency, Characteristics, and Reversibility of PN in the APEX trial
PN Reversibility PN is reversible in the majority of pts: 64% (58/91) of pts with ≥ Grade 2 PN experienced improvement or resolution 55% (50/91) had complete resolution (return to baseline) 9% (8/91) experienced improvement by at least one CTC grade Median time to improvement or resolution was 110 days from initial diagnosis SLIDE 56 San Miguel J, et al. ASH 2005, abstract #366

57 Hematological Profiles With Bortezomib Or HD Dex: Phase III APEX Trial
Characterization of Thrombocytopenia Mean Platelet Count With Bortezomib Platelet count followed a cyclical pattern, with recovery toward baseline during the rest period of each cycle Nadir ~ 40% of baseline SLIDE 57 Lonial S, et al. ASH 2005, abstract # 3474

58 Bortezomib + doxorubicine pegylée
Etude internationale randomisée :646 MM en rechute après au moins 1 ligne de traitement Bortezomib (1,3mg J1,4,8,11) vs Bortezomib + doxorubicine pegylée (30mg J4)pour 8 cycles Avantage en réponse partielle Avantage confirmé en survie sans progression 6 mois versus 9 mois

59 Bortezomib + Thalidomide + DXM
Etude pilote en rechute post intensification 58 patients association Bortezomib + Thalidomide + Dexaméthasone Réponse globale 70% dont 22% RC Absence de surcroit de toxicité notamment neurologique au cours de cette association

60 Bortezomib + Melphalan + Prednisone + Thalidomide (V-MPT)
Relapsed or Refractory Bortezomib + Melphalan + Prednisone + Thalidomide (V-MPT) Trial Design: Phase II multicenter trial of V-MPT as salvage treatment to evaluate safety and tolerability, response rate, overall and progression-free survival Patients: 30 pts treated Treatment: Six 5-week cycles Bortezomib days 1, 4,15, 22 followed by 13 days rest First cohort 1.0mg/m² , Second cohort 1.3mg/m², Third cohort 1.6mg/m² Melphalan 6 mg/m² PO and Prednisone 60 mg/m² PO days 1-5 Thalidomide 100 mg QD Response 2O (67%) RP>50%, 13 (43%) TBRP >90% Median of 3 cycles PFS at 1 year : 61%, OS at 1 year : 84% Hematologic toxicity , neuropathy (grade3) 2 cases SLIDE 60 Palumbo A, et al. ASH 2005, abstract # 2553

61 Bortezomib + DXM en induction
Etude pilote IFM :52 MM de novo <65 ans 4 cycles Bortezomib + DXM avec recueil de CSP après 3 cycles puis intensification autogreffe Melphalan 2OO mg Taux de réponse globale = 66% dont 31% TBRP et 21% RC Bonne faisabilité recueil et greffe 14% neuropathie périphérique

62 MM au diagnostic, patients d'âge  65 ans
Protocole IFM 2005/01 MM au diagnostic, patients d'âge  65 ans R A1 VAD x 4 A2 DCEP x 2 B1 Vel/Dex x 4 B2 1 ou 2 autogreffe(s) de CSP

63 Bortezomib + MP (Etude VISTA en attente)
Etude espagnole ouverte de recherche de posologie optimale de cycle de MP + Velcade 60 MM de novo âge médian 75 ans Mel 9mg/m2 + pred 60mg/m2 J1-4 Velcade 1 ou 1.3mg/m2 8 cycles 60 pts, âge médian 74 (65-85) Rép ap 3 cycles 89%,RC 32%(IF-),RP 45% Toxicité grade ¾ : Digestif 27%, neutropénie 39% Thrombopénie 46%, infection 14% Neuropathie 15% Mateos MV., Session orale, ASH 2005

64 Bortezomib cas particuliers
Efficacité rapportée particulièrement séduisante dans les formes tumorales plasmocytaires lors d’une étude espagnole Plusieurs études confirment la tolérance inchangée au cours de l’insuffisance rénale sévère, utilisable en dialyse sans adaptation de posologie SLIDE 64

65 Lenalidomide Thalidomide Lenalidomide O O O O H H N N N N O O O N H 2
Richardson et al. In: DeVita PPO updates. Feb 2001.

66 Thalidomide/Lenalidomide Target MM Cells in the BM Microenvironment
C. Lenalidomide/IMID MM Cells IL-6 TNF IL-1 B.Lenalidomide/IMID A.Lenalidomide/IMID Bone Marrow Stromal Cells ICAM-1 Bone Marrow Vessels VEGF bFGF IL-2 IFN  PBMC D. Lenalidomide/IMID CD8+ T Cells E. Lenalidomide/IMiD NK Cells Hideshima T et al. Blood. 2000;96:2943. Davies FE et al. Blood. 2001;98:210. Gupta D et al. Leukemia. 2001;15:1950. Mitsiades N et al. Blood 2002;99:4525. Lentzsch S et al. Cancer Res. 2002;62:2300.

67 Lenalidomide More “potent” immunomodulator than thalidomide
Up to 50,000 times more potent inhibitor of TNF 200- to 1000-fold in cytokine modulation Increased stimulation of T-cell proliferation Augmented stimulation of IL-2 and IFN production Fewer side effects: no significant constipation, neuropathy, or sedation Not teratogenic O 2 N H Slide 97. Lenalidomide (CC-5013; Revlimid™) Lenalidomide is a functional derivative of thalidomide that is more potent than thalidomide in cytokine modulation, T-cell proliferation, host immunoregulatory augmentation, and anti-angiogenic properties Marriott JB et al. ? 2003;3(3):181 Schey SA et al. J Clin Oncol. 2004;22:16 ? Richardson P, Anderson K. J Clin Oncol. 2004;22:16 ? Marriott JB et al. Curr Drug Targets Immune Endocr Metabol Disord. 2003;3:181. Richardson P, Anderson K. J Clin Oncol. 2004;22:3212.

68 Lenalidomide Phase 1 Trial in Myeloma Relapsed Following High-Dose Chemotherapy
4-wk, single-center, open-label, escalating-dose (5, 10, 25, 50 mg) trial in 15 patients, median age 62 y Responses identified only at 25- and 50-mg doses Discontinuations 2 at 25 mg: 1 syncope, 1 disease progression 3 at 50 mg: 2 with dose-limiting toxicity and 1 with disease progression Overall, 20% of patients had >50% paraprotein decrease plus bone marrow response 6 patients continued on extension study, 1 at 25 mg/day and 5 at 50 mg/day Slide 103. Lenalidomide (Revlimid™) Phase I Trial in MM Relapse Following High-Dose Chemotherapy In a 4-week, single-center, open-label, escalating-dose, phase I study (presented as an abstract), Zangari et al investigated the use of lenalidomide for the treatment of MM in patients who relapsed after high-dose chemotherapy Enrolled patients consisted of 6 men and 9 women (median age, 62 yr; range, 43–73). All patients had undergone ≥1 high-dose chemotherapy (range, 1–3). Daily dose levels were 5, 10, 25, or 50 mg No responses were seen at the 5- and 10-mg levels. At the 25-mg level, 1 patient had stable M protein and bone marrow plasmacytosis for 5 months; 1 discontinued due to syncope; and 1 discontinued due to disease progression Of 6 patients who started at 50 mg/day, 3 went into an extension study (1 with stable disease and 2 with decreases in both M protein level and bone marrow plasmacytosis). The other 3 patients discontinued the study (2 due to disease-limiting toxicity [thromboembolism and profound thrombocytopenia] and 1 due to disease progression) 6 patients continued on the extension study, 1 at 25 mg/day and 5 at 50 mg/day. 5 of these patients experienced a >50% drop in platelet count The researchers concluded that 20% of the patients in this study showed a >50% M protein reduction plus a bone marrow response. Neurologic toxicity was minimal. Lenalidomide appears to cause significant myelosuppression. There is potential for the drug to cause thromboembolism and syncope Zangari M et al. Blood. 2001;98:775a. Abstract 3226. Zangari M et al. Blood. 2001;98:775a [abstract 3226]

69 Phase 2 Trial of Lenalidomide With or Without Dexamethasone in Relapsed/Refractory Myeloma
Treatment Scheme RANDOM I ZAT I ON 30 mg/q.d. (3 wk on, 1 wk off q 28 days  6 cycles) PD or SD after cycle 2, 4 Cohort 1 40 mg days 1–4 q 14 days OR 15 mg/b.i.d. (3 wk on, 1 wk off q 28 days  6 cycles) Slide 104. Phase II Trial of Lenalidomide (Revlimid™) With or Without Dexamethasone in Relapsed/Refractory MM Richardson et al are carrying out a randomized phase II study in patients with refractory or relapsed MM of lenalidomide 15 vs 30 mg/day for 3 weeks, followed by a 1-week rest. Dexamethasone (40 mg/day orally for 4 days every 2 wk) is added for progressive disease at ≥4 weeks and for stable disease at ≥8 weeks A history of thalidomide treatment is acceptable. The exclusion criteria are serum creatinine >2 mg/dL, prior treatment with CC-5013, platelets <50,000, and absolute neutrophil count <1000 Overall, 70 patients have been enrolled, with 46 evaluable for response Cohort 2 30 mg/q.d. (3 wk on, 1 wk off q 28 days  6 cycles) Cohort 2 added to confirm response rate/toxicity seen in cohort 1 with q.d. regimen: Dex added if PD or SD after cycle 2, 4 N=70 Richardson PG et al. Blood. 2003;102:235a. Abstract 825. PD, progressive disease; SD, stable disease Richardson PG et al. Blood. 2003;102:235a [abstract 825]

70 Phase 2 Trial of Lenalidomide With or Without Dexamethasone in Relapsed/Refractory Myeloma
Median Number of Prior Regimens: 4 (Range, 1–9) [N=102] 100 96% 75% 80 62% 60 Percentage of Patients 50% 40 16% 20 11% SCT Steroids Alkylators Thalidomide Bortezomib Anthracycline Richardson PG et al. Blood. 2003;102:235a. Abstract 825.

71 Interim Analysis: Phase 2 Trial of Lenalidomide in Relapsed/ Refractory Multiple Myeloma
Total n (%) CR PR MR SD PD Lenalidomide 91 9 (10) 11 (12) 14 (15) 39 (43) 18 (20) Len + Dex* 49 0 (0) 15 (31) 5 (10) 20 (41) 9 (18) Lenalidomide alone: Response Rate (MR + PR + CR); 37% (EBMT Criteria) Len + Dex in 49/91 pts (54%) with PD or SD on Lenalidomide: Response Rate (MR+ PR); 41% Median Time to Best Response (Lenalidomide alone): 57 d *Patients received dexamethasone if they failed to achieve an MR after 8 wk of lenalidomide monotherapy PG Richardson et al. Blood. 2003; 102:235A[abstract 825].

72 Interim Analysis: Phase 2 Trial of Lenalidomide in Relapsed/ Refractory Myeloma
Most common grade 3/4 adverse events 54% Neutropenia 22% Thrombocytopenia 4% DVT 2% Neuropathy No grade 3/4 non-hematologic toxicity Richardson PG et al. Blood. 2003;102:235a. Abstract 825.

73 Protocol Lenalidomide: MM-009/010 (Target n=302/trial)
Lenalidomide 25 mg, d 1–21 TTP Placebo, d 22–28 Dex 40 mg, d 1–4, 9–12, 17–20 OS RR Safety 1st SRE PS  4 COURSES Same except Dex, d 1–4 Continue until PD Placebo, d 1–28 Dex 40 mg, d 1–4, 9–12, 17–20 PI: International (MM010): Dimopoulos (351 pts) North America (MM009) (354 pts)

74 MM-009/010: Patient Characteristics
Len/Dex Dex No. patients 170 171 176 175 Sex (%Male) 60 59 Age, median (y) 63 62 ECOG PS 1 (%) 89 95 85 82 ECOG PS, Eastern Cooperative Oncology Group performance status; Len, lenalidomide *13 pts unavailable at time of analysis Weber DM et al. Haematologica. 2005;90(suppl 1):155. Abstract PO.738.

75 MM-009/010: Prior Therapies 70 60 50 40 % of Patients 30 20 10 009 010 009 010 009 010 009 010 Bortezomib Thalidomide Dexamethasone SCT Weber DM et al. Haematologica. 2005;90(suppl 1):155. Abstract PO.738.

76 MM-009/010: Response1 80 PR + CR PR (>50%) 61.2%* 22.8%* CR (IF-) 60 57.9% 21.7% *P<0.001 Response Rate (%) 40 34.7% 26.5% 18.7% 4.1% 20 44.3% 13.6% 17.7% 4.0% Len/dex Len/dex Dex Dex 1Blade criteria 009 010 009 010 IF, immunofixation

77 MM- 009/010 Time to Progression
Time to Tumor Progression (in Months) Proportion of Patients 2.5 5 7.5 10 12.5 15 17.5 20 22.5 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 009 P < 010 009 Len/Dex 009 Dex alone 010 Len/Dex 010 Dex alone

78 MM- 009/010 Grade 3/4 Hematologic Toxicity
Len/Dex N = 170 Dex N =171 N = 176 N =175 Neutropenia, % 30.0 3.5 17.6 1.1 Febrile Neutropenia 2.9 Thrombocytopenia 10.6 6.4 9.7 5.7 Anemia 4.5 4.0

79 MM- 009/010 Grade 3/4 Other Adverse Events
Len/Dex N = 170 Dex N =171 N = 176 N =175 DVT/PE, % 15.3 3.5 8.5 4.5 Atrial Fibrillation 4.7 0.6 1.7 CHF 2.4 Constipation 1.8 Diarrhea 1.2 Fatigue 5.9 6.8 3.4 Neuropathy 2.9 1.1

80 MM-009/010: Summary Myelosuppression was more frequent in patients treated with len/dex Grade 3/4 infection frequency was similar between the treatment groups Manageable with dose reduction DVT/PE and role of anticoagulation needs to be further clarified Low incidence of Neuropathy, Constipation and Fatigue High Response, CR and Prolonged TTP (in both trials) justify Lenalidomide’s role in relapsed or refractory MM and investigation in untreated MM

81 Phase I Trial of Bortezomib + Lenalidomide
Relapsed or Refractory Phase I Trial of Bortezomib + Lenalidomide Trial Design: Phase I trial to determine the MTD and DLT of bortezomib in combination with lenalidomide, and to evaluate safety, response and PK Patients: N=24 (21 evaluable for response) pts with relapsed or relapsed / refractory MM, > 50% were refractory Median number prior therapies 4 (1-8) 16 pts had prior SCT 12 pts had prior bortezomib, 2 pts prior lenalidomide, and 20 pts prior thalidomide Dose and Schedule Bortezomib 1.0 and 1.3 mg/m2 d 1,4,8,11 and Lenalidomide 5, 10, 15 or 20 mg/d d 1-14 of a 21-day cycle Eight cohorts 3-6 pts planned Dex 20 mg (given on the day of and day after bortezomib dose) could be added in the event of PD SLIDE 81 Richardson P, et al. ASH 2005, abstract #365

82 Bortezomib + lenalidomide
Taux de réponse globale : 58% Schéma optimal retenu en fonction de la toxicité : Lenalidomide15 mg/j J1-J14 Bortezomib 1mg/m2 J1,4,8,11 SLIDE 82

83 Lenalidomide en première ligne
Etude du groupe ECOG 34 patients MM de novo Lenalidomide 25 mg/j + DXM Haute dose Taux de réponse global = 90% TBRP (>90%) = 56% Survie sans progression à 2 ans = 74% 55% toxicité >grade3 hématologique SLIDE 83

84 Lenalidomide en première ligne
Comparaison en cours par le groupe ECOG : Lenalidomide + DXM haute ou faible dose Résultats préliminaires prometteurs de l’association Lenalidomide + MP Indication en entretien post greffe en cours d’évaluation SLIDE 84

85 CONCLUSION Thalidomide
Efficacité reconnue en rechute, particulièrement en association avec la dexaméthasone Efficacité consacrée en association avec MP chez sujet âgé: nouveau standard Efficacité potentielle en consolidation post greffe Pb toxicité neurologique Pas d’indication officielle : ATU cohorte en rechute SLIDE 85

86 CONCLUSION Bortezomib
Efficacité prouvée, AMM en première rechute Potentiel avenir en première ligne en induction pregreffe voire avec conditionnement Efficacité en association au MP en cours de validation Intérêt majeur en association PB administration IV, préparation hospitalière, durée de réponse ? SLIDE 86

87 CONCLUSION Lenalidomide
Analogue du Thalidomide potentiellement supérieur avec une toxicité différente (hématologique) ATU nominative actuelle, AMM très prochaine en première rechute EN pleine expansion première ligne, entretien… Pb toxicité hématologique pour association aux alkylants SLIDE 87

88 CONCLUSION Prise en charge du Myélome Multiple totalement modifiée par l’arrivée de ces nouvelles drogues Multiples associations possibles pour aller vers des taux de réponses majeurs permettant d’espérer dans un premier temps à un passage à une maladie chronique avant quelques cas de guérison Applicables à tous les patients pas de barrière d’âge SLIDE 88