Opinion 22 January 2014

Transcription

1 The legally bidig text is the origial Frech versio TRANSPARENCY COMMITTEE Opiio 22 Jauary 214 VELCADE 1 mg, powder for solutio for ijectio B/1 vial (CIP: ) VELCADE 3.5 mg, powder for solutio for ijectio B/1 vial (CIP: ) Applicat: JANSSEN-CILAG INN ATC code (212) Reaso for the review List cocered bortezomib L1XX32 (atieoplastic aget, proteasome ihibitor) Extesio of idicatio Hospital use (Frech Public Health Code L ) Idicatio cocered VELCADE i combiatio with dexamethasoe, or with dexamethasoe ad thalidomide, is idicated for the iductio treatmet of adult patiets with previously utreated multiple myeloma who are eligible for high-dose chemotherapy with haematopoietic stem cell trasplatatio. HAS - Medical, Ecoomic ad Public Health Assessmet Divisio 1/3

2 Actual Beefit The actual beefit of VELCADE is substatial i the iductio treatmet of patiets with ewly diagosed multiple myeloma who are eligible for haematopoietic stem cell trasplatatio (HSCT). Improvemet i Actual Beefit I combiatio with dexamethasoe or with dexamethasoe ad thalidomide, VELCADE provides a moderate improvemet i actual beefit (level III) i terms of efficacy i the iductio treatmet of adult patiets with previously utreated multiple myeloma who are eligible for high-dose chemotherapy with HSCT. Therapeutic use VELCADE is a first-lie, stadard therapy i the iductio treatmet of adult patiets aged 65 years with previously utreated multiple myeloma who are eligible for high-dose chemotherapy with HSCT. HAS - Medical, Ecoomic ad Public Health Assessmet Divisio 2/3

3 1 ADMINISTRATIVE AND REGULATORY INFORMATION Marketig Authorisatio (cetralised procedure) Prescribig ad dispesig coditios/special status Iitial date: 26 April 24 Date of extesio of idicatio: 31 July 213 List I Medicie for hospital prescriptio oly Prescriptio restricted to ocology or haematology specialists or doctors with cacer traiig. Medicie requirig special moitorig durig treatmet. ATC Classificatio 212 L L1 L1X L1XX L1XX32 Atieoplastic ad immuomodulatig agets Atieoplastic agets Other atieoplastic agets Other atieoplastic agets bortezomib 2 BACKGROUND The Committee is examiig the applicatio for iclusio of VELCADE o the list of medicies approved for hospital use i the extesio of idicatio VELCADE i combiatio with dexamethasoe, or with dexamethasoe ad thalidomide, is idicated for the iductio treatmet of adult patiets with previously utreated multiple myeloma who are eligible for high-dose chemotherapy with haematopoietic stem cell trasplatatio. 3 THERAPEUTIC INDICATIONS VELCADE as mootherapy is idicated for the treatmet of adult patiets with progressive multiple myeloma who have received at least 1 prior therapy ad who have already udergoe or are usuitable for haematopoietic stem cell trasplatatio. VELCADE i combiatio with melphala ad predisoe is idicated for the treatmet of adult patiets with previously utreated multiple myeloma who are ot eligible for high-dose chemotherapy with haematopoietic stem cell trasplatatio. VELCADE i combiatio with dexamethasoe, or with dexamethasoe ad thalidomide, is idicated for the iductio treatmet of adult patiets with previously utreated multiple myeloma who are eligible for high-dose chemotherapy with haematopoietic stem cell trasplatatio. HAS - Medical, Ecoomic ad Public Health Assessmet Divisio 3/3

4 4 DOSAGE Posology for previously utreated multiple myeloma patiets eligible for haematopoietic stem cell trasplatatio (iductio therapy) Combiatio therapy with dexamethasoe VELCADE 1 mg powder for solutio for ijectio is admiistered via itraveous ijectio at the recommeded dose of 1.3 mg/m² body surface area twice weekly for two weeks o days 1, 4, 8, ad 11 i a 21-day treatmet cycle. This 3-week period is cosidered a treatmet cycle. At least 72 hours should elapse betwee cosecutive doses of VELCADE. Dexamethasoe is admiistered orally at 4 mg o days 1, 2, 3, 4, 8, 9, 1 ad 11 of the VELCADE treatmet cycle. Four treatmet cycles of this combiatio therapy are admiistered. Combiatio therapy with dexamethasoe ad thalidomide VELCADE 1 mg powder for solutio for ijectio is admiistered via itraveous ijectio at the recommeded dose of 1.3 mg/m² body surface area twice weekly for two weeks o days 1, 4, 8, ad 11 i a 28-day treatmet cycle. This 4-week period is cosidered a treatmet cycle. At least 72 hours should elapse betwee cosecutive doses of VELCADE. Dexamethasoe is admiistered orally at 4 mg o days 1, 2, 3, 4, 8, 9, 1 ad 11 of the VELCADE treatmet cycle. Thalidomide is admiistered orally at 5 mg daily o days 1-14 ad if well tolerated the dose is icreased to 1 mg o days 15-28, ad thereafter may be further icreased to 2 mg (see Table 4). Four treatmet cycles of this combiatio are admiistered. It is recommeded that patiets with at least partial respose receive 2 additioal cycles. Table 4: Posology for VELCADE combiatio therapy for patiets with previously utreated multiple myeloma eligible for haematopoietic stem cell trasplatatio Vc+Dx Cycles 1 to 4 Week Vc (1.3 mg/m 2 ) Day 1, 4 Day 8, 11 Rest Period Dx 4 mg Day 1, 2, 3, 4 Day 8, 9, 1, 11 - Vc+Dx+T Cycle 1 Week Vc (1.3 mg/m 2 ) Day 1, 4 Day 8, 11 Rest Period Rest Period T 5 mg Daily Daily - - T 1 mg a - - Daily Daily Dx 4 mg Day 1, 2, 3, 4 Day 8, 9, 1, Cycles 2 to 4 b Vc (1.3 mg/m 2 ) Day 1, 4 Day 8, 11 Rest Period Rest Period T 2 mg a Daily Daily Daily Daily Dx 4 mg Day 1, 2, 3, 4 Day 8, 9, 1, Vc=VELCADE; Dx=dexamethasoe; T=thalidomide a Thalidomide dose is icreased to 1 mg from week 3 of Cycle 1 oly if 5 mg is tolerated ad to 2 mg from Cycle 2 owards if 1 mg is tolerated. HAS - Medical, Ecoomic ad Public Health Assessmet Divisio 4/3

5 b Up to six cycles may be give to patiets who achieve at least a partial respose after four cycles. HAS - Medical, Ecoomic ad Public Health Assessmet Divisio 5/3

6 5 THERAPEUTIC NEED 1,2,3 Symptomatic multiple myeloma should be treated as early as possible, whereas asymptomatic multiple myeloma oly requires close cliical moitorig. It is recogised that the level of respose obtaied, ad particularly a complete respose, is associated with a improvemet i log-term results, i particular o progressio-free survival ad overall survival. The therapeutic strategy for symptomatic multiple myeloma depeds primarily o the age of the patiet, ad to a lesser extet o the presece of comorbidities: i patiets aged uder 65 years with o comorbidities, especially cardiac, pulmoary or hepatic comorbidities, ad/or o sigificat deterioratio i geeral health, the iitial treatmet cosists of a iductio phase followed by a coditioig phase, ad the a autologous haematopoietic stem cell trasplat followed by a maiteace phase; i patiets aged uder 65 years with comorbidities, especially cardiac, pulmoary or hepatic comorbidities, ad/or a sigificat deterioratio i geeral health, the iitial treatmet cosists of less itesive iductio ad coditioig phases, the a autologous haematopoietic stem cell trasplat followed by a maiteace phase; i patiets aged over 65 years, the iitial treatmet cosists of covetioal chemotherapy. I the past, the stadard iductio treatmet was the VAD protocol (vicristie + doxorubici + dexamethasoe), which has a post-iductio complete respose rate of 5% to 1%. 4 However, iductio protocols have chaged radically over the past decade or so. Bortezomib-based combiatios are thus recommeded (pre-datig the gratig of Marketig Authorisatio) as iductio therapy i Europea ad America guidelies. Despite these advaces, the complete respose rates to iductio therapies remai relatively low. 1 Palumbo A, et al. Multiple myeloma. N Egl J Med. 211; 364(11): Raab MS et al. Multiple myeloma. Lacet. 29; 374(9686): Smith D et al. Multiple myeloma. BMJ. 213; 346: f VELCADE EPAR 213. HAS - Medical, Ecoomic ad Public Health Assessmet Divisio 6/3

7 6 CLINICALLY RELEVANT COMPARATORS The cliically relevat comparators for the bortezomib + dexamethasoe (VcD or VD) protocol or the bortezomib + thalidomide + dexamethasoe (VcTD or VTD) protocol are the other protocols recommeded 5,6,7,8 for the iductio treatmet of adult patiets with previously utreated multiple myeloma who are eligible for high-dose chemotherapy with haematopoietic stem cell trasplatatio which are available i Frace: thalidomide + dexamethasoe (TD) lealidomide + dexamethasoe (RD) vicristie + doxorubici + dexamethasoe (VAD). It should be oted that other iductio protocols icludig bortezomib were recommeded before the molecule was grated Marketig Authorisatio, amely: bortezomib + lealidomide + dexamethasoe (VcRD or VRD) bortezomib + cyclophosphamide + dexamethasoe (VcCD or VCD) bortezomib + doxorubici + dexamethasoe (VcAD or PAD). Coclusio The thalidomide + dexamethasoe (TD) protocol is the most cliically relevat comparator for the bortezomib + thalidomide + dexamethasoe (VcTD or VTD) iductio protocol. 9 5 NCCN (Natioal Comprehesive Cacer Network). Multiple Myeloma. NCCN Guidelies. Versio September ESMO (Europea Society for Medical Ocology). Moreau P, et al. Multiple myeloma: ESMO Cliical Practice Guidelies for diagosis, treatmet ad follow-up. A Ocol. 213; 24 Suppl. 6: vi133-vi SFH [Frech Society of Haematology]. Référetiel HAS [Frech Natioal Authority for Health]. Tumeur malige, affectio malige du tissu lymphatique ou hématopoïétique - Myélome multiple. Guide - Affectio de logue durée. [Maligat tumours, maligat disease of lymphatic or haematopoietic tissue - Multiple myeloma. Chroic Coditios Guide.] December It should be oted that the 29 SFH guidelies refer to both of these protocols. HAS - Medical, Ecoomic ad Public Health Assessmet Divisio 7/3

8 7 INTERNATIONAL INFORMATION ON THE MEDICINAL PRODUCT The extesio of idicatio for VELCADE is reimbursed i the major Europea coutries: Coutry Reimbursed Scope (idicatios) ad special coditio(s) Switzerlad Demark Italy Swede Greece Germay Austria Spai Filad Luxembourg Netherlads Portugal Uited Kigdom Belgium Yes Yes Yes Yes Yes Reimbursed i all idicatios, icludig iductio treatmet of adult patiets with previously utreated multiple myeloma who are eligible for high-dose chemotherapy with HSCT. Reimbursed i the treatmet of matle cell lymphoma (broader Marketig Authorisatio wordig tha i the EU-15). Reimbursed i all idicatios, icludig iductio treatmet of adult patiets with previously utreated multiple myeloma who are eligible for high-dose chemotherapy with HSCT. Reimbursed i all idicatios. Reimbursed i o-hodgki s lymphoma o a case-by-case basis. Reimbursed i all idicatios. Irelad No Not applicable. Reimbursemet limited to a maximum of eight cycles over 8 moths i the idicatio for the treatmet of adult patiets with progressive multiple myeloma who have received at least oe prior therapy. HAS - Medical, Ecoomic ad Public Health Assessmet Divisio 8/3

9 8 SUMMARY OF PREVIOUS ASSESSMENTS Date of Opiio Idicatio AB IAB Date of Opiio Idicatio AB IAB Date of Opiio Idicatio IAB Date of Opiio Idicatio AB IAB Date of Opiio Idicatio AB IAB 13 October 24: iclusio (VELCADE 3.5 mg) VELCADE is idicated i the treatmet of patiets with multiple myeloma who have received at least two prior therapies ad whose disease progressed durig the last treatmet. Substatial I patiets i whom at least two previous treatmets have failed, ad i compariso with usual maagemet, the Committee is allocatig VELCADE a substatial improvemet i actual beefit (level II) i terms of efficacy. However, this IAB is coditioal o a follow-up cohort study beig coducted. 12 April 26: extesio of idicatio (VELCADE 3.5 mg) VELCADE as mootherapy is idicated for the treatmet of progressive multiple myeloma i patiets who have received at least 1 prior therapy ad who have already udergoe or are usuitable for boe marrow trasplatatio. Substatial Takig ito accout the questioable coditios of use of the comparator i the APEX study ad the existece of alterative secod-lie therapies with comparable efficacy, VELCADE does ot provide ay improvemet i actual beefit (level V) i the therapeutic strategy. 28 March 27: re-assessmet of IAB (VELCADE 3.5 mg) VELCADE as mootherapy is idicated for the treatmet of progressive multiple myeloma i patiets who have received at least 1 prior therapy ad who have already udergoe or are usuitable for boe marrow trasplatatio. VELCADE provides a mior improvemet i actual beefit (level IV) compared with dexamethasoe i the secod-lie treatmet of multiple myeloma. 16 July 28: additio to rage (VELCADE 1 mg) VELCADE as mootherapy is idicated for the treatmet of progressive multiple myeloma i patiets who have received at least 1 prior therapy ad who have already udergoe or are usuitable for boe marrow trasplatatio. Substatial This proprietary medicial product is a additio to the rage which does ot provide ay improvemet i actual beefit (level V). 1 Jue 29: extesio of idicatio (VELCADE 1 mg ad 3.5 mg) VELCADE is idicated i combiatio with melphala ad predisoe for the treatmet of patiets with previously utreated multiple myeloma, who are ot eligible for high-dose chemotherapy with boe marrow trasplatatio. Substatial VELCADE, whe added to the combiatio of melphala ad predisoe, provides a moderate (level III) improvemet i actual beefit with respect to efficacy whe compared with the combiatio of melphala ad predisoe aloe i the first-lie treatmet of patiets with multiple myeloma who are ot eligible for high-dose chemotherapy with boe marrow trasplatatio. HAS - Medical, Ecoomic ad Public Health Assessmet Divisio 9/3

10 9 ANALYSIS OF AVAILABLE DATA The extesio of the idicatio for VELCADE to the iductio treatmet of adult patiets with previously utreated multiple myeloma who are eligible for high-dose chemotherapy with haematopoietic stem cell trasplatatio, i combiatio with dexamethasoe or with dexamethasoe ad thalidomide, is based o three ope-label, radomised phase III cliical trials: Oe study comparig the bortezomib + dexamethasoe (VcD or VD) iductio protocol with the vicristie + doxorubici + dexamethasoe (VAD) iductio protocol: o the IFM 25-1 trial, 1 coducted i Frace, Belgium ad Switzerlad; two studies comparig the bortezomib + thalidomide + dexamethasoe (VcTD or VTD) iductio protocol with the thalidomide + dexamethasoe (TD) iductio protocol: o o the MMY-31 trial 11 (or PETHEMA study), coducted i Spai; the MMY-36 trial 12 (or GIMEMA study), coducted i Italy. 9.1 Efficacy IFM 25-1 trial1 A ope-label, radomised study evaluatig the efficacy ad safety of iductio chemotherapy with the VcD protocol (bortezomib ad dexamethasoe), followed (group B2) or ot followed (group B1) by itesificatio chemotherapy with the DCEP protocol (dexamethasoe, cyclophosphamide, etoposide ad cisplati), i compariso with iductio chemotherapy with the VAD protocol (vicristie, doxorubici ad dexamethasoe), followed (group A2) or ot followed (group A1) by the same itesificatio chemotherapy, i adult patiets aged 65 with ewly diagosed, utreated multiple myeloma who are eligible for high-dose chemotherapy with autologous HSCT (see Figure 1). The primary efficacy edpoit was the complete (CR) ad early complete (CR) respose rate 13 post-iductio (the best respose to treatmet with or without immuofixatio), defied as the proportio of patiets with a complete (CR) or early complete (CR) respose. The secodary edpoits icluded: - the overall respose rate (CR+CR+VGPR+PR) post-iductio ad post-trasplatatio, - the complete ad early complete respose rate (CR+CR) post-trasplatatio, - progressio-free survival, - time to disease progressio, - overall survival. 1 Harousseau JL, et al. Bortezomib plus dexamethasoe is superior to vicristie plus doxorubici plus dexamethasoe as iductio treatmet prior to autologous stem-cell trasplatatio i ewly diagosed multiple myeloma: results of the IFM 25-1 phase III trial. J Cli Ocol. 21; 28(3): [IFM 25-1 trial]. 11 Rosiñol L, et al. Superiority of bortezomib, thalidomide, ad dexamethasoe (VTD) as iductio pretrasplatatio therapy i multiple myeloma: a radomized phase 3 PETHEMA/GEM study. Blood. 212; 12(8): [MMY-31 trial.] 12 Cavo M, et al. Bortezomib with thalidomide plus dexamethasoe compared with thalidomide plus dexamethasoe as iductio therapy before, ad cosolidatio therapy after, double autologous stem-cell trasplatatio i ewly diagosed multiple myeloma: a radomised phase 3 study. Lacet. 21; 376(9758): [MMY-36 trial]. 13 Accordig to EBMT criteria ad determied by a idepedet cetral committee. HAS - Medical, Ecoomic ad Public Health Assessmet Divisio 1/3

11 Figure 1: IFM 25-1 trial desig Radomisatio VAD iductio therapy (four cycles) VAD iductio therapy (four cycles) + DCEP itesificatio therapy (two cycles) VcD iductio therapy (four cycles) VcD iductio therapy (four cycles) + DCEP itesificatio therapy (two cycles) HSC mobilisatio ad collectio (G-CSF) High-dose chemotherapy (HDM) + HSCT Off-protocol treatmet Follow-up Patiets were radomised ito four treatmet groups: four cycles of the VAD protocol, combiig vicristie, doxorubici ad dexamethasoe, without itesificatio (group A1), four cycles of the VAD protocol, followed by two itesificatio cycles with the DCEP protocol combiig dexamethasoe, cyclophosphamide, etoposide ad cisplati (group A2), four cycles of the VcD protocol, combiig bortezomib ad dexamethasoe, without itesificatio (group B1), four cycles of the VcD protocol, followed by two itesificatio cycles with the DCEP protocol (group B2). These protocols are detailed i the table below: Table 1: Descriptio of protocols used i the IFM 25-1 trial Protocol VAD VcD DCEP Treatmets Four 28-day cycles: - IV vicristie.4 mg/day o days 1 to 4 - IV doxorubici 9 mg/m² o days 1 to 4 - oral dexamethasoe 4 mg/day o days 1 to 4, 9 to 12 ad 17 to 2 i cycles 1 ad 2, ad o days 1 to 4 i cycles 3 ad 4 Four 21-day cycles: - IV bortezomib 1.3 mg/m² o days 1, 4, 8 ad 11 - oral dexamethasoe 4 mg/day o days 1 to 4, 9 to 12 ad 17 to 2 i cycles 1 ad 2, ad o days 1 to 4 i cycles 3 ad 4 Two 28-day cycles: - oral dexamethasoe 4 mg/day o days 1 to 4 - IV cyclophosphamide 4 mg/m²/day o days 1 to 4 - IV etoposide 4 mg/m²/day o days 1 to 4 - IV cisplati 15 mg/m²/day o days 1 to 4 HAS - Medical, Ecoomic ad Public Health Assessmet Divisio 11/3

12 Mai iclusio criteria: - age 65 years, - ewly diagosed multiple myeloma accordig to the South West Ocology Group (SWOG) criteria, - Stage II or III disease or stage I disease with a symptomatic boe lesio (Durie-Salmo classificatio), - ot previously treated, apart from local radiotherapy i the case of a icapacitatig or life-threateig lesio or a 4-day course of dexamethasoe (4 mg) i a emergecy case, - secretio of a measurable moocloal secretory spike (> 1 g/l i the serum or.2 g/24h i the urie), - absece of active ifectio (i the case of ifectio, appropriate atibiotic therapy must be admiistered ad patiets must be apyretic for at least 48 hours before the start of treatmet). Mai o-iclusio criteria: - idolet stage I accordig to the Durie-Salmo classificatio, - ECOG performace status > 2, - history of maligat tumour (other tha basal cell carcioma or carcioma of the cervix i situ), - life expectacy < 2 moths, - cofirmed amyloidosis, - positive HIV serology, - serious psychiatric history, - real failure requirig dialysis, - ucotrolled diabetes, cotraidicatig the use of corticosteroids, - peripheral europathy (grade 2), - cliical sigs of heart failure or coroary disease, - bilirubi 3 times ormal, - trasamiases or γgt 4 times ormal, - platelets < 5 x 1 9 /l durig the 15 days prior to iclusio, - eutrophils <.75 x 1 9 /l durig the 15 days prior to iclusio, - use of a experimetal therapy durig the 3 days prior to iclusio, - kow hypersesitivity to bortezomib, boro or maitol. Results The ITT populatio cosisted of 482 patiets with a media age of 57 years, radomised as follows: 242 i the VAD group, cosistig of 121 without itesificatio (group A1) ad 121 with DCEP itesificatio (group A2), 24 i the VcD group, cosistig of 121 without itesificatio (group B1) ad 119 with DCEP itesificatio (group B2). The evaluable populatio cosisted of 474 patiets: 238 i the VAD group, icludig 99 without itesificatio (group A1) ad 98 with DCEP itesificatio (group A2), 236 i the VcD group, cosistig of 118 without itesificatio (group B1) ad 118 with DCEP itesificatio (group B2). Demographic characteristics at the start of treatmet were similar betwee the VAD ad VcD treatmet groups ad whether patiets were to receive itesificatio treatmet or ot. The patiets had a media age of 57 years ad a media body surface area of 1.8 m². The majority of patiets (55%) were male. HAS - Medical, Ecoomic ad Public Health Assessmet Divisio 12/3

13 Table 2: Descriptio of patiets baselie demographic characteristics ad extet of disease (where missig = umber of patiets out of N for whom o data is available) VAD group VcD group A1 (N=121) A2 (N=121) Total (N=242) B1 (N=121) B2 (N=119) Total (N=24) Type of myeloma, (%) missig IgG IgA IgD IgE IgM Bicloal Light chais Iteratioal Stagig System (ISS) disease stage, (%) missig I II III (63) 24 (23) 2 (2) 1 (1) 1 (1) 11 (1) 2 51 (43) 42 (35) 26 (22) (6) 21 (21) 1 (1) 1 (1) 3 (3) 15 (15) 2 49 (41) 41 (34) 29 (24) (62) 45 (22) 3 (1) 1 (<1) 1 (<1) 4 (2) 26 (13) 4 1 (42) 83 (35) 55 (23) 8 67 (59) 21 (19) 2 (2) 3 (3) 2 (18) 55 (45) 37 (31) 29 (24) (6) 26 (25) 2 (2) 13 (13) 47 (39) 41 (34) 31 (26) (6) 47 (22) 4 (2) 3 (1) 33 (15) 12 (43) 78 (33) 6 (25) Serum M-protei cocetratio (g/dl) missig mea (SD) media mi-max (2.14) (2.19) (2.15) (2.19) (1.89) (2.4) Urie M-protei excretio (mg/24 h) missig mea stadard deviatio media mi-max Presece of osteolytic lesios, (%) missig Yes No , (78) 25 (22) , (79) 24 (21) , (79) 49 (21) , (82) 2 (18) , (71) 33 (29) , (77) 53 (23) Presece of osteopeia, (%) missig No Yes 5 57 (49) 59 (51) 9 57 (51) 55 (49) (5) 114 (5) 7 64 (56) 5 (44) 7 52 (46) 6 (54) (51) 11 (49) Nb. of boe plasmacytomas, (%) HAS - Medical, Ecoomic ad Public Health Assessmet Divisio 13/3

14 missig (92) 7 (6) 2 (2) 4 16 (91) 7 (6) 3 (3) 1 (1) (91) 14 (6) 5 (2) 1 (<1) 5 19 (94) 5 (4) 2 (2) 5 16 (93) 6 (5) 2 (2) (93) 11 (5) 2 (1) 2 (1) Plasma cells i boe marrow (%) missig mea (SD) media mi-max (24.4) (24.9) (24.6) (24.8) (24.3) (24.6) Approximately 99% of patiets i the evaluable populatio received the iductio treatmet ad approximately 12% of those i each group left the study durig this phase (32/238 i the VAD group ad 26/236 i the VcD group). The most commo reaso was adverse evet i both groups (11/32 versus 12/26). A total of 27 patiets received itesificatio therapy (43% i each group). HSCT was performed i 46 patiets: 82% of patiets (198/242) i the VAD group ad 87% of patiets (28/24) i the VcD group. Durig this phase, 52 patiets left the study: 18% (35/198) versus 8% (17/28). The most commo reaso was ivestigator s decisio i both groups (11/35 versus 5/17). Results for post-iductio respose rates (icludig the primary edpoit) As regards the study s primary edpoit, patiets i the VcD group had a higher post-iductio complete ad early complete respose rate tha patiets i the VAD group (14.6% versus 6.2%, OR=2.58, 95% CI [1.37; 4.85], p=.3). After the iductio treatmet phase, patiets i the VcD group also had higher respose rates tha patiets i the VAD group for the followig parameters: complete respose (5.4% versus 1.2%, OR=4.71, 95% CI [1.31; 16.93], p=.1), complete, early complete ad very good partial respose (37.1% versus 14.9%, OR=3.36, 95% CI [2.16; 5.21], p<.1), overall respose (77.1% versus 6.7%, OR=2.18, 95% CI [1.46; 3.24], p<.1). There was o differece i the post-iductio complete ad early complete respose rate betwee patiets who did ot receive DCEP itesificatio therapy ad those who did (13.2% versus 15.8% respectively, OR=1.23, 95% CI [.74; 2.6], p=.42). Results for other secodary efficacy edpoits o post-trasplatatio respose rate After trasplatatio, patiets i the VcD group had higher respose rates tha patiets i the VAD group for the followig parameters: complete respose (18.3% versus 1.3%, OR=1.95, 95% CI [1.15; 3.29], p=.11), complete ad early complete respose (37.5% versus 23.1%, OR=1.98, 95% CI [1.33; 2.95], p=.1), complete, early complete ad very good partial respose (62.5% versus 45.%, OR=2.4, 95% CI [1.42; 2.94], p<.1). The post-trasplatatio overall respose rate did ot differ betwee the two groups (VcD versus VAD): 79.6% versus 74.4% (OR=1.34, 95% CI [.87; 2.5], p=.179). HAS - Medical, Ecoomic ad Public Health Assessmet Divisio 14/3

15 Patiets who did ot receive DCEP itesificatio therapy had a comparable post-trasplatatio complete ad early complete respose rate to those who did (3.6% versus 3.% respectively, OR=.97, 95% CI [.66; 1.43], p=.888). Media progressio-free survival did ot differ betwee the two groups (VcD versus VAD): 36.1 versus 29.7 moths (HR=.78, 95% CI [.6; 1.1]). Progressio-free survival was comparable i patiets who did ot receive DCEP itesificatio therapy ad i those who did (HR=.96, 95% CI [.74; 1.24], p=.748). O the date of aalysis (5 Jue 29), correspodig to a media follow-up period of 33 moths per patiet, 95 patiets had died: 4 (16.7%) i the VcD group ad 45 (18.6%) i the VAD group. The media overall survival was ot reached i either of the groups. Overall survival was comparable i patiets who did ot receive DCEP itesificatio therapy ad i those who did (HR=.93, 95% CI [.61; 1.42], p=.737). Coclusio: This study showed that i adult patiets aged 65 years with ewly diagosed ad previously utreated multiple myeloma, iductio chemotherapy with the VcD protocol combiig bortezomib ad dexamethasoe, ca improve the quality of the respose i compariso with iductio chemotherapy with the VAD protocol combiig vicristie, doxorubici ad dexamethasoe. This was demostrated by a icrease i the post-iductio complete ad early complete respose rate (14.6% versus 6.2%, OR=2.58, 95% CI [1.37; 4.85], p=.3) ad a icrease i the post-trasplatatio complete ad early complete respose rate (37.5% versus 23.1%, OR=1.98, 95% CI [1.33; 2.95], p=.1). However, o differece i progressio-free survival or overall survival was observed betwee the two groups. The media overall survival was ot reached i either of the two groups o the date of aalysis MMY-31 trial (PETHEMA) A ope-label, radomised phase III study coducted i Spai i adult patiets with ewly diagosed, utreated symptomatic multiple myeloma who were eligible for high-dose chemotherapy with HSCT, which evaluated the efficacy ad safety of: - three iductio protocols: four cycles alteratig the VBMCP protocol (vicristie, carmustie, melphala, cyclophosphamide ad predisoe) with the VBAD protocol (vicristie, carmustie, doxorubici ad dexamethasoe), followed by two cycles of bortezomib, six cycles of the TD protocol, combiig thalidomide ad dexamethasoe, six cycles of the VcTD protocol, combiig bortezomib, thalidomide ad dexamethasoe; - three maiteace protocols usig: iterfero α-2b, thalidomide, thalidomide ad bortezomib. As iductio treatmet that alterates the VBMCP ad VBAD protocols is o loger used i Europe, the results from this treatmet group are ot preseted here, ad oly results cocerig the VcTD ad TD groups will be discussed. HAS - Medical, Ecoomic ad Public Health Assessmet Divisio 15/3

16 Objectives The objectives of this study were to: - evaluate the efficacy of three iductio protocols, as measured by respose rate, ad their safety, - evaluate the efficacy of three maiteace protocols, as measured by respose rate, ad their safety, - aalyse the impact of these treatmets o patiets quality of life, - evaluate the capacity of these three iductio protocols to mobilise peripheral haematopoietic stem cells (HSCs) i the blood. The primary efficacy edpoits were: - the overall respose rate 14 (CR+CR+PR) post-iductio ad post-trasplatatio, - the complete ad early complete respose rate (CR+CR) post-iductio ad post-trasplatatio. The secodary edpoits icluded: - progressio-free survival, - overall survival. Radomisatio O iclusio, patiets were radomised ito each iductio treatmet group usig a 1:1:1 ratio. The, three moths after trasplatatio, patiets whose disease had ot progressed ad i whom a trasplat had bee performed without uacceptable toxicity were 1:1:1 radomised agai ito oe of the three maiteace treatmet groups. Mai iclusio criteria: Patiets must: - be aged 65 years or uder ad eligible for a autologous trasplat, - have symptomatic multiple myeloma that has ot bee treated (with the exceptio of bisphosphoates or corticosteroid treatmet i emergecy), - have measurable disease (quatifiable serum moocloal protei value or urie light chai excretio of 2 mg/24 h), - have a ECOG performace status of, 1 or 2, - have a life expectacy of at least 3 moths, - have the followig laboratory values: 15 platelets 5, mm 3, haemoglobi 8 g/dl, eutrophils 1/mm 3, corrected calcium 14 mg/dl, ASAT 2.5 times the upper limit of ormal, ALAT 2.5 times the upper limit of ormal, total bilirubi 1.5 times the upper limit of ormal, serum creatiie 2 mg/dl. Mai o-iclusio criteria: o-secretory multiple myeloma, 14 Accordig to EBMT criteria ad determied by a idepedet cetral committee. 15 Haematological values were allowed to be lower if this was related to boe marrow ifiltratio. HAS - Medical, Ecoomic ad Public Health Assessmet Divisio 16/3

17 previous treatmet, with the exceptio of bisphosphoates, corticosteroid treatmet i a emergecy or radiotherapy, peripheral europathy (grade 2) i the 14 days prior to iclusio, elective surgery i the 4 weeks followig iclusio, cardiac history: myocardial ifarctio i the 6 moths prior to iclusio, severe heart failure (NYHA class III or IV), cardiac risk factors (ustable agia, ucotrolled vetricular arrhythmia, acute ischaemia, etc.). Results: Table 3: Descriptio of study treatmets by group i the MMY-31 trial (PETHEMA) Iductio treatmet TD Group VcTD Group VBMCP-VBAD/Vc Group Six 28-day TD cycles: - oral thalidomide 5 mg/day util day 15 of cycle 1, the 1 mg/day util the ed of cycle 1, the 2 mg/day i subsequet cycles - oral dexamethasoe 4 mg/day o days 1 to 4 ad 9 to 12 Six 28-day VcTD cycles: - oral thalidomide 5 mg/day util day 15 of cycle 1, the 1 mg/day util the ed of cycle 1, the 2 mg/day i subsequet cycles - oral dexamethasoe 4 mg/day o days 1 to 4 ad 9 to 12 - bortezomib 1.3 mg/m² o days 1, 4, 8 ad 11 Four alteratig VBMCP ad VBAD cycles, followed by two cycles of bortezomib 21-day VBMCP cycle: - IV vicristie.3 mg/kg o day 1 (max. 2 mg) - IV carmustie.5 mg/kg o day 1 - IV cyclophosphamide 1 mg/kg o day 1 - oral melphala.25 mg/kg o days 1 to 4 - oral predisoe 1 mg/kg o days 1 to 4, the.5 mg/kg o days 5 to 8, the.25 mg/kg o days 9 to day VBAD cycle: - IV vicristie 1 mg o day 1 - IV carmustie 3 mg/m² o day 1 - IV doxorubici 4 mg/m² o day 1 - oral dexamethasoe 4 mg/day o days 1 to 4, 9 to 12 ad 17 to 2 Maiteace treatmet 21-day cycle with bortezomib 1.3 mg/m² o days 1, 4, 8 ad 11 T Group VcT Group INF Group oral thalidomide 1 mg/day (reduced to 5 mg i cases of toxicity) - oral thalidomide 1 mg/day (reduced to 5 mg i cases of toxicity) - bortezomib 1.3 mg/m² o days 1, 4, 8 ad 11 every 3 moths Subcutaeous iterfero α-2b at a dose of 1.5 MU 3 times/week. After 4 weeks of treatmet, the dose could be icreased to 3 MU HAS - Medical, Ecoomic ad Public Health Assessmet Divisio 17/3

18 A total of patiets costitutig the ITT populatio were radomised: 127 patiets i the TD group, with 126 (99%) receivig the iductio chemotherapy, 78 (61%) the HSCT ad 69 (54%) the maiteace treatmet (23 i the INF group, 22 i the T group ad 24 i the VcT group), 13 patiets i the VcTD group, with 1% receivig the iductio chemotherapy, 15 (81%) the HSCT ad 94 (72%) the maiteace treatmet (31 i the INF group, 32 i the T group ad 31 i the VcT group). Durig the iductio phase, a higher proportio of patiets i the TD group (38%) left the study tha those i the VcTD group (19%), with the most commo reaso beig disease progressio (22% versus 1% respectively). O the other had, durig the trasplat phase, these proportios were comparable i both groups (12% versus 11% respectively). Durig the maiteace phase, a higher proportio of patiets i the INF ad T groups (58% versus 57% respectively) left the study tha those i the VcT group (37%), mostly due to a adverse evet (22%, 35% ad 22% respectively) or disease progressio (33%, 19% ad 16% respectively). The evaluable populatio cosisted of 384 patiets. Demographic characteristics at the start of treatmet were similar betwee the treatmet groups. The media age of patiets was 57 years. Table 4: Descriptio of the baselie cliical characteristics of patiets i the MMY-31 trial (PETHEMA) (where missig = umber of patiets out of N for whom o data is available) Type of myeloma, (%) missig IgA IgD IgG Light chai ISS disease stage, (%) I II III Serum M-protei cocetratio (g/dl) missig mea (SD) media (mi-max) Urie M-protei excretio (mg/24 h) missig mea (SD) media (mi-max) Presece of boe lesios, (%) Major Mior Noe TD (N=127) 31 (24) 3 (2) 74 (58) 19 (15) 48 (38) 47 (37) 32 (25) (3.8) 3.91 ( 34.7) (4619.2) 17. ( 3,) 42 (33) 54 (43) 31 (24) VcTD (N=13) 26 (2) 3 (2) 86 (66) 15 (12) 44 (34) 57 (44) 29 (22) (3.2) 4.46 (.4 24.) (396.) 39. ( 17,78) 36 (28) 6 (46) 34 (26) Presece of osteopeia, (%) No 85 (67) 83 (64) patiets were radomised ito the VBMCP-VBAD/Vc group ad are ot discussed here. HAS - Medical, Ecoomic ad Public Health Assessmet Divisio 18/3

19 Yes 42 (33) 47 (36) Number of extramedullary plasmacytomas, (%) Plasma cells i boe marrow (%) missig mea (SD) media (mi-max) 17 (84) 13 (1) 3 (2) 4 (3) (27.1) 33. (1 99) 16 (82) 18 (14) 5 (4) 1 (1) (25.7) 36.5 ( 99) Results for the primary edpoits o post-iductio respose rate Followig the iductio treatmet, overall respose ad complete ad early complete respose were higher i the VcTD group tha i the TD group (overall respose: 84.6% versus 61.4%, OR=3.46, 95% CI [1.9; 6.27], p<.1 ad complete ad early complete respose: 49.2% versus 17.3%, OR=4.63, 95% CI [2.61; 8.22], p<.1). o post-trasplatatio respose rate Followig trasplatatio, patiets i the VcTD group had a higher overall respose rate tha those i the TD group (77.7% versus 56.7%, OR=2.66, 95% CI [1.55; 4.57], p<.1) ad a higher complete ad early complete respose rate (55.4% versus 34.6%, OR=2.34, 95% CI [1.42; 3.87], p=.1). The improvemets observed i the post-iductio period were maitaied followig trasplatatio. Ideed, the post-trasplatatio complete respose rate was higher i the VcTD group (46.9%) tha i the TD group (23.6%). Results for other secodary efficacy edpoits o progressio-free survival The media progressio-free survival was 55.5 moths i the VcTD group versus 27.9 moths i the TD group (HR=.65, 95% CI [.45;.92], p=.15). o overall survival The media follow-up period was 35.9 moths (36.4 moths i the TD group ad 35.4 moths i the VcTD group). A total of 58 patiets had died by the cut-off date: 32 (25.2%) i the TD group ad 26 (2.%) i the VcTD group. The media overall survival was ot reached i either of the groups. Coclusio: The MMY-31 trial (PETHEMA) showed that i adult patiets aged 65 years with previously utreated multiple myeloma, i compariso with the TD protocol combiig thalidomide ad dexamethasoe, iductio chemotherapy with the VcTD protocol combiig bortezomib, thalidomide ad dexamethasoe ca improve: - the overall respose rate (84.6% versus 61.4%, OR=3.46, 95% CI [1.9; 6.27], p<.1) ad the post-iductio complete ad early complete respose rate (49.2% versus 17.3%, OR=4.63, 95% CI [2.61; 8.22], p<.1), - the post-trasplatatio complete ad early complete respose rate (55.4% versus 34.6%, OR=2.34, 95% CI [1.42; 3.87], p<.1), HAS - Medical, Ecoomic ad Public Health Assessmet Divisio 19/3

20 - media progressio-free survival (55.5 moths versus 27.9 moths, HR=.65, 95% CI [.45;.92], p=.15), with a gai of 27.6 moths. However, o improvemet i overall survival was demostrated. The media overall survival was ot reached i either of the two groups o the date of aalysis MMY-36 trial (or GIMEMA study) A ope-label, radomised phase III study coducted i Italy i adult patiets with ewly diagosed, utreated symptomatic multiple myeloma who were eligible for high-dose chemotherapy with double hematopoietic stem cell trasplatatio (HSCT), which evaluated the efficacy ad safety of: - two iductio protocols: three cycles of the VcTD protocol, three cycles of the TD protocol, - two cosolidatio protocols based o: TD, VTD. Objectives The objectives of this study were to evaluate the efficacy ad safety of addig bortezomib to a thalidomide-dexamethasoe iductio protocol as preparatio for a double autologous trasplat i patiets with ewly diagosed multiple myeloma. The primary efficacy edpoit was the post-iductio complete ad early complete respose rate (CR+CR). The secodary edpoits icluded: - the complete ad early complete respose rate (CR+CR) followig the double trasplat ad cosolidatio treatmet, - time to disease progressio, - progressio-free survival, - overall survival. Methodology Study desig ad treatmets Patiets were radomised ito oe of two groups for the iductio treatmets evaluated. HSCs were the mobilised usig cyclophosphamide (4 g/m²) ad G-CSF (1 µg/kg) i order to collect at least CD34+/kg, required for the double autologous trasplat. Eligible patiets uderwet the first autologous trasplat after high-dose chemotherapy with 2 mg/m² melphala followed by G-CSF ijectios at a dose of 5 µg/kg/day. Three to six moths later, a secod autologous trasplat was the performed usig the same protocol. Betwee the two trasplats ad after resumptio of haematopoiesis, patiets received thalidomide 1 mg/day ad dexamethasoe 4 mg/day o days 1 to 4 every 28 days. Three moths after the secod autologous trasplat, patiets were give the appropriate cosolidatio treatmet for each treatmet group, the received maiteace treatmet with dexamethasoe 4 mg/day o days 1 to 4 every 28 days which was cotiued util disease progressio or relapse. The treatmets are detailed i Table 5 ad the study desig is preseted i Figure 2. HAS - Medical, Ecoomic ad Public Health Assessmet Divisio 2/3

21 Patiets i the VcTD group could also receive prophylactic treatmet with aciclovir i order to prevet shigles. Table 5: Descriptio of study treatmets by group i the MMY-36 trial (GIMEMA) Iductio treatmet Cosolidatio treatmet TD Group Three 21-day TD cycles: - oral thalidomide 1 mg/day util day 14 of the cycle, the 2 mg/day util the ed of the cycle - oral dexamethasoe 4 mg/day o days 1 to 4 ad 9 to 12 Two 35-day TD cycles: - oral thalidomide 1 mg/day - oral dexamethasoe 4 mg/day o days 1 to 4 ad 2 to 23 VcTD Group Three 21-day VcTD cycles: - bortezomib 1.3 mg/m² o days 1, 4, 8 ad 11 - oral thalidomide 1 mg/day util day 14 of the cycle, the 2 mg/day util the ed of the cycle - oral dexamethasoe 4 mg/day o days 1, 2, 4, 5, 8, 9, 11 ad 12 Two 35-day VcTD cycles: - bortezomib 1.3 mg/m² o days 1, 8, 15 ad 22 - oral thalidomide 1 mg/day - oral dexamethasoe 4 mg/day o days 1, 2, 8, 9, 15, 16, 22 ad 23 HAS - Medical, Ecoomic ad Public Health Assessmet Divisio 21/3

22 Figure 2: MMY-36 (GIMEMA) study desig Radomisatio Iductio treatmet (three 21-day cycles) with VcTD Bortezomib 1.3 mg/m² o days 1, 4, 8 ad 11 Thalidomide 1 mg/day util day 14 the thalidomide 2 mg/day Dexamethasoe 4 mg o days 1, 2, 4, 5, 8, 9, 11 ad 12 Iductio treatmet (three 21-day cycles) with TD Thalidomide 1 mg/day util day 14 the thalidomide 2 mg/day Dexamethasoe 4 mg o days 1 to 4 ad 9 to 12 Mobilisatio of autologous peripheral stem cells Cyclophosphamide 4 g/m² G-CSF 1 µg/kg/day startig o day 2 after admiistratio of cyclophosphamide First autologous stem cell trasplat Melphala 2 mg/m² G-CSF 5 µg/kg/day startig o day 5 after admiistratio of melphala Thalidomide 1 mg/day ad dexamethasoe 4 mg o days 1 to 4 every 28 days Secod autologous stem cell trasplat Melphala 2 mg/m² G-CSF 5 µg/kg/day startig o day 5 after admiistratio of melphala Cosolidatio treatmet (two 35-day cycles) with VcTD Bortezomib 1.3 mg/m² o days 1, 8, 15 ad 22 Thalidomide 1 mg/day Dexamethasoe 4 mg o days 1, 2, 8, 9, 15, 16, 22 ad 23 Cosolidatio treatmet (two 35-day cycles) with TD Thalidomide 1 mg/day Dexamethasoe 4 mg o days 1 to 4 ad 2 to 23 Maiteace treatmet Dexamethasoe 4 mg o days 1 to 4 every 28 days HAS - Medical, Ecoomic ad Public Health Assessmet Divisio 22/3

23 Mai iclusio criteria Patiets must: - be aged 18 to 65 years, - have symptomatic ad utreated multiple myeloma, - have measurable disease, - have a Karofsky performace status of at least 6%, - have the followig uchagig haematological values: platelets /l eutrophils /l - have adequate real fuctio (serum creatiie 176 µmol/l), - have o cardiac history (o ucotrolled or severe disease such as myocardial ifarctio i the 6 moths prior to iclusio, NYHA class II to IV, ustable agia, etc.), - have uimpaired liver fuctio: ASAT 2.5 times the upper limit of ormal, ALAT 2.5 times the upper limit of ormal, total bilirubi 1.5 times the upper limit of ormal. Mai o-iclusio criteria: - peripheral europathy (grade 2), - history of veous thromboembolism or thrombophilia. Statistical aalyses Estimatio of the umber of subjects required It was estimated that 45 patiets eeded to be icluded, based o the followig hypotheses: - a 12% differece i complete ad early complete respose rate betwee the groups (15% i the TD group ad 27% i the VcTD group), - a power of 8% ad a sigificace threshold of.5. Radomisatio O iclusio, patiets were radomised ito each iductio treatmet group usig a 1:1 ratio ad stratified accordig to disease stage (ISS iteratioal classificatio). Results A total of 58 patiets were selected ad 48 were radomised, makig up the ITT populatio: 238 patiets i the TD group ad 236 i the VcTD group. Patiet characteristics The baselie demographic ad cliical characteristics of the patiets were similar i both treatmet groups. Patiets had a media age of 57 ad 58 years i the TD ad VcTD groups respectively, ad the majority were male (57%-58%). Most had IgG (62%-65%) or IgA (17%-23%) subtype multiple myeloma. Patiets distributio by ISS disease stage was also similar: 45% had stage I, 39% stage II ad 16% stage III. HAS - Medical, Ecoomic ad Public Health Assessmet Divisio 23/3

24 Primary edpoit results The post-iductio complete ad early complete respose rate was higher i the VcTD group tha i the TD group: 31% versus 11%, p<.1. Similarly, the post-iductio complete respose rate was higher i the VcTD group tha i the TD group (19% versus 5%, p<.1). Table 7: Descriptio of the post-iductio respose rates by type of respose (MMY-36 trial: GIMEMA) complete respose complete ad early complete respose very good partial respose or better partial respose or better miimal respose or stable disease disease progressio TD (N=238) VcTD (N=236) p 11 5 [2.; 7.3] [7.3; 15.4] [22.; 33.4] [73.4; 83.8] [11.7; 21.1] 12 5 [2.3; 7.8] [13.7; 23.6] < [25.; 36.8] < [55.7; 68.1] < [9.; 96.4] < [3.6; 1].11.5 Secodary edpoit results - Other respose rates The improvemets observed i the post-iductio period were maitaied followig trasplatatio ad followig cosolidatio treatmet. The percetage of patiets with at least a partial respose was greater i the VcTD group tha i the TD group for both these treatmet periods. HAS - Medical, Ecoomic ad Public Health Assessmet Divisio 24/3

25 Table 8: Descriptio of post-trasplatatio respose rates by type of respose (MMY-36 trial: GIMEMA) Post-trasplatatio complete respose complete ad early complete respose very good partial respose or better partial respose or better miimal respose or stable disease disease progressio Post-cosolidatio complete respose complete ad early complete respose very good partial respose or better partial respose or better miimal respose or stable disease disease progressio Best respose durig treatmet complete respose complete ad early complete respose very good partial respose or better partial respose or better miimal respose or stable disease or disease progressio TD (N=238) VcTD (N=236) p 72 3 [24.4; 36.1] [34.9; 47.4] [57.8; 7.] [78.9; 88.3] 19 8 [4.5; 11.4] 2 8 [4.9; 11.9] [28.4; 4.5] [39.1; 51.7] [62.1; 74.] [79.9; 89.1] 16 7 [3.5; 9.9] 21 9 [5.2; 12.4] [34.5; 47.] [47.4; 6.1] [67.9; 79.1] [85.1; 93.] [7.; 14.9] [35.2; 47.8] [48.7; 61.4] [76.9; 86.7] < [9.; 96.4] [2.9; 8.9] [.; 2.] [42.8; 55.5] [56.1; 68.5] [8.6; 89.7] < [89.; 95.8] [2.3; 7.9] [.5; 4.6] [51.3; 63.9] [65.4; 77.] < [85.; 93.] < [93.7; 98.6] [1.4; 6.3].31 HAS - Medical, Ecoomic ad Public Health Assessmet Divisio 25/3

26 - Other edpoits The probability of progressio or relapse at 3 years was lower i the VcTD group tha i the TD group (29% versus 39%, HR=.61, 95% CI [.43;.87], p=.73). Progressio-free survival was loger i the VcTD group tha i the TD group (HR=.63, 95% CI [.45;.88], p=.61). After a media follow-up period of 36 moths, o differece i overall survival was observed betwee the two groups. Coclusio: This trial showed that i adult patiets aged 65 years with ewly diagosed ad previously utreated multiple myeloma, iductio chemotherapy with the VcTD protocol combiig bortezomib, thalidomide ad dexamethasoe ca improve the post-iductio complete ad early complete respose rate i compariso with the TD protocol combiig thalidomide ad dexamethasoe (31% versus 11%, p<.1). The estimated 3-year progressio-free survival rate was 68% i the VcTD group ad 56% i the TD group (p=.57). No differece i overall survival was demostrated betwee the two groups (3-year survival rate: 86% i the VcTD group ad 84% i the TD group, p=.3). The media overall survival was ot reached i either of the two groups o the date of aalysis. HAS - Medical, Ecoomic ad Public Health Assessmet Divisio 26/3

27 9.2 Safety/Adverse effects IFM 25-1 trial As iductio treatmet with a view to HSCT i previously utreated multiple myeloma, both protocols evaluated (VcD combiig bortezomib ad dexamethasoe versus VAD combiig vicristie, doxorubici ad dexamethasoe) resulted i broadly similar proportios of patiets reportig a adverse evet (AE) (97% i the VcD group versus 92% i the VAD group), a treatmet-related AE (81% versus 79%), a serious AE (28% versus 34%) or a AE resultig i treatmet beig discotiued (8% versus 5%). Oly peripheral europathy was more frequetly reported i the VcD group tha i the VAD group (ay grade: 12% versus 2%; grade 3: 5% versus < 1% respectively). MMY-31 trial (PETHEMA) As iductio treatmet with a view to HSCT i previously utreated multiple myeloma, both protocols evaluated (VcTD combiig VELCADE, thalidomide ad dexamethasoe versus TD combiig thalidomide ad dexamethasoe) had a fairly similar safety profile i terms of the percetages of patiets who reported at least oe AE, a grade 3 or 4 AE or a serious AE. As expected, oly peripheral europathy was more frequetly observed i the VcTD group for ay grade (45% versus 12% respectively) ad for grades 3 (5% versus %). MMY-36 trial (GIMEMA study) The two protocols evaluated i this study were VcTD (combiig VELCADE, thalidomide ad dexamethasoe) ad TD (combiig thalidomide ad dexamethasoe). The percetage of patiets reportig a serious AE was o higher after bortezomib was added to a thalidomide ad dexamethasoe-based iductio protocol as part of HSCT for utreated multiple myeloma. The percetage of patiets reportig a grade 3 or 4 adverse evet was higher, primarily due to ski rashes (1% i the VcTD group versus 2% i the TD group) ad peripheral europathy (1% i the VcTD group versus 2% i the TD group). 9.3 Summary & discussio Three radomised studies (IFM 25-1, MMY-31 ad MMY-36) evaluated the beefit of addig bortezomib (VELCADE) to chemotherapy protocols used as iductio treatmet (the VAD protocol combiig vicristie, doxorubici ad dexamethasoe or the TD protocol combiig thalidomide ad dexamethasoe). The results of these studies are cosistet ad show that the chemotherapy protocols icludig VELCADE (bortezomib) were better i terms of complete ad early complete respose rate, both post-iductio (with a absolute gai of 8% to 31% depedig o the study) ad post-trasplatatio (with a absolute gai of 14% to 2% depedig o the study). The media overall survival was ot reached i ay of the groups i the three studies, ad the estimated overall survival times calculated did ot demostrate ay differeces betwee the protocols, with or without bortezomib, for this edpoit. The mai form of toxicity observed after addig bortezomib (VELCADE) to the differet chemotherapy protocols was eurotoxicity. I the three studies discussed, the icidece of grade > 2 eurotoxicity was variable, at 1% (VCD), 21% (VCAD) ad 31% (VcTD). HAS - Medical, Ecoomic ad Public Health Assessmet Divisio 27/3

28 9.4 Plaed studies Risk maagemet pla (RMP) Various pharmacovigilace follow-up actios are beig take as part of the RMP for VELCADE. These iclude aalysis of the results of the VEL-PMS-JPN-1 study, coducted i Japa, which evaluated the safety of VELCADE with a particular focus o acute pulmoary effects ad iterstitial peumoia, but also o cardiac fuctio disorders, peripheral europathy, haemotoxicity, fever, ski disorders, hypotesio, gastroitestial disorders ad tumour lysis sydrome (last patiet icluded: 31 March 211; study report to be submitted: Jauary 217). The VEL2U study is also beig coducted, evaluatig the safety of VELCADE i actual practice (first patiet icluded: 1 November 211; study report to be submitted: Jauary 217) Ogoig developmet I September 212, the compay submitted a EMA applicatio for extesio of the idicatio to combied treatmet with pegylated liposomal doxorubici or dexamethasoe i patiets with progressive multiple myeloma who have received at least oe prior therapy ad who have already udergoe or are usuitable for haematopoietic stem cell trasplatatio. 1 THERAPEUTIC USE 5,5,5,5 Several iductio protocols are recommeded i adult patiets with previously utreated multiple myeloma who are eligible for high-dose chemotherapy with haematopoietic stem cell trasplatatio. The preferred iductio protocols are: Accordig to America guidelies (NCCN ): bortezomib + thalidomide + dexamethasoe (VcTD or VTD); bortezomib + cyclophosphamide + dexamethasoe (VcCD or VCD); bortezomib + doxorubici + dexamethasoe (VcAD or PAD); bortezomib + lealidomide + dexamethasoe (VcRD or VRD); bortezomib + dexamethasoe (VcD); lealidomide + dexamethasoe (RD). Accordig to Europea guidelies (ESMO ): bortezomib + thalidomide + dexamethasoe (VcTD or VTD); bortezomib + cyclophosphamide + dexamethasoe (VcCD or VCD); bortezomib + doxorubici + dexamethasoe (VcAD or PAD); bortezomib + lealidomide + dexamethasoe (VcRD or VRD). Accordig to Frech guidelies (SFH 29 5 ad HAS 21 5 ): bortezomib + thalidomide + dexamethasoe (VcTD or VTD); bortezomib + dexamethasoe (VcD). Role of VELCADE i the therapeutic strategy: VELCADE is a first-lie, stadard therapy i the iductio treatmet of adult patiets aged 65 years with previously utreated multiple myeloma who are eligible for high-dose chemotherapy with HSCT. I Frace, VELCADE has already bee used i this idicatio i actual cliical practice for several years. HAS - Medical, Ecoomic ad Public Health Assessmet Divisio 28/3