HO95: Study to Compare VMP With HDM Followed by VRD Consolidation and Lenalidomide Maintenance in Patients With Newly Diagnosed Multiple Myeloma

Sponsor

Stichting Hemato-Oncologie voor Volwassenen Nederland (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT01208766

Collaborator

European Myeloma Network (Other), Gruppo Italiano Malattie EMatologiche dell'Adulto (Other), DSMM (Deutsche Studiengruppe Multiples Myelom) (Other), NMSG (Nordic Myeloma Study Group) (Other), Central European Myeloma Study Group (Other)

1,503

Enrollment

208

Locations

Arms

147

Anticipated Duration (Months)

7.2

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Study phase: phase III

Study objective:

Comparison of Bortezomib, Melphalan, Prednisone (VMP) with High Dose Melphalan followed autologous stem cell transplantation (ASCT)
Comparison of Bortezomib, Lenalidomide, Dexamethasone(VRD) as consolidation versus no consolidation
Comparison of single versus tandem high dose Melphalan with ASCT

Patient population: Patients with symptomatic multiple myeloma,previously untreated, ISS stages 1-3, age 18-65 years inclusive

Study design: Prospective, multicenter, intergroup, randomized

Duration of treatment: Expected duration of induction, stem cell collection and intensification is 6 - 9 months. Consolidation with VRD will last 2 months Maintenance therapy with Lenalidomide will be given until relapse. All patients will be followed until 10 years after registration.

Condition or Disease	Intervention/Treatment	Phase
Multiple Myeloma	Drug: Bortezomib, Melphalan, Prednisone (VMP) Drug: 1 or 2 cycle(s) HDM (High Dose Melphalan) Drug: 2 cycles of Bortezomib, Lenalidomide, Dexamethasone (VRD)	Phase 3

Study Design

Study Type:

Interventional

Actual Enrollment :

1503 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Randomized Phase III Study to Compare Bortezomib, Melphalan, Prednisone (VMP) With High Dose Melphalan Followed by Bortezomib, Lenalidomide, Dexamethasone (VRD) Consolidation and Lenalidomide Maintenance in Patients With Newly Diagnosed Multiple Myeloma

Actual Study Start Date :

Jan 1, 2011

Actual Primary Completion Date :

Dec 1, 2020

Anticipated Study Completion Date :

Apr 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: R1: 4 cycles Bortezomib, Melphalan, Prednisone (VMP) All patients randomized to VMP treatment, will be treated with Bortezomib, Melphalan, Prednisone(VMP, 4 cycles) and will start intensification with VMP between 4 and 6 weeks after stem cell collection.	Drug: Bortezomib, Melphalan, Prednisone (VMP) Bortezomib _ 1.3 mg/m2 _ i.v. rapid infusion _ days 1,4,8,11,22,25,29,32 Melphalan _ 9 mg/m² _ p.o. _ days 1-4 Prednisone _ 60 mg/m² _ p.o. _ days 1-4
Experimental: R1: 1 (2) cycle(s) HDM All patients randomized to intensification with High Dose Melphalan will start intensification with HDM (in hospitals with a policy of double intensification, patients will be randomized between VMP, 1 HDM and 2 HDM) between 4 and 6 weeks after stem cell collection.	Drug: 1 or 2 cycle(s) HDM (High Dose Melphalan) - Melphalan _ 100 mg/m² _ i.v. rapid infusion _ -3, -2* *Patients with renal insufficiency 100 mg/m2 only at day -3 If a patient is randomized to receive 2 x HDM a second course of High Dose Melphalan may be administered between 2 and 3 months after the first course when the patient achieved at least PR.
No Intervention: R2: none No consolidation, patients will continue to Lenalidomide maintenance.
Experimental: R2: 2 cycles of VRD In patients randomized to consolidation treatment, 2 cycles of Bortezomib, Lenalidomide,Dexamethasone (VRD) will start at 8 weeks after the end of the last course of VMP or HDM.	Drug: 2 cycles of Bortezomib, Lenalidomide, Dexamethasone (VRD) Bortezomib _ 1.3 mg/m2 _ i.v. rapid infusion _ days 1,4,8,11 Lenalidomide _ 25 mg _ p.o. _ days 1-21 Dexamethasone _ 20 mg _ p.o. _ days 1,2,4,5,8,9,11,12

Outcome Measures

Primary Outcome Measures

For all registered patients: progression free survival (PFS) as defined by time from registration to progression or death from any cause (whichever occurs first). [end of trial (last patient last visit)]
For all patients included in R1; PFS as defined by time from randomization R1 to progression or death from any cause whichever comes first [end of trial (last patient last visit)]
For all patients included in R2; PFS as defined by time from randomization R2 to progression or death from any cause whichever comes first [end of trial (last patient last visit)]

Secondary Outcome Measures

Overall survival measured from the time of registration /randomization R1/ randomization R2. Patients still alive or lost to follow up are censored at the date they were last known to be alive. [end of trial (last patient last visit)]
Toxicity [End of trial (last patient last visit)]
Response (PR, VGPR, CR and stringent CR), and improvement of response during the various stages of the treatment. [end of trial (last patient last visit)]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patients with a confirmed diagnosis of symptomatic multiple myeloma stage I to III according to the International Staging System ISS (see appendix A), i.e. at least one of the CRAB criteria should be present;
Measurable disease as defined by the presence of M-protein in serum or urine (serum M-protein> 10 g/l or urine M-protein > 200 mg/24 hours), or abnormal free light chain ratio;
Age 18-65 years inclusive;
WHO performance status 0-3 (WHO=3 is allowed only when caused by MM and not by comorbid conditions);
Negative pregnancy test at inclusion if applicable;
Written informed consent.

Inclusion for randomisation 1:

WHO performance 0-2;
Bilirubin and transaminases < 2.5 times the upper limit of normal values;
A suitable stem cell graft containing at least 4 x 106 CD34+ cells/kg (or according to national guidelines).

Inclusion for randomisation 2:

Bilirubin and transaminases < 2.5 times the upper limit of normal values;
ANC >= 0.5 x 109/l and platelets > 20 x 10^9/l;
Patient is able to adhere to the requirements of the Lenalidomide Pregnancy Prevention Risk Management Plan.

Exclusion Criteria:

Known intolerance of Boron;
Systemic AL amyloidosis;
Primary Plasmacell Leukemia;
Non-secretory MM;
Previous chemotherapy or radiotherapy except local radiotherapy in case of local myeloma progression or corticosteroids maximum 5 days for symptom control;
Severe cardiac dysfunction (NYHA classification II-IV);
Significant hepatic dysfunction, unless related to myeloma;
Patients with GFR <15 ml/min,
Patients known to be HIV-positive;
Patients with active, uncontrolled infections;
Patients with neuropathy, CTC grade 2 or higher;
Patients with a history of active malignancy during the past 5 years with the exception of basal carcinoma of the skin or stage 0 cervical carcinoma;
Patients who are not willing or capable to use adequate contraception during the therapy (all men, all pre-menopausal women);
Lactating women.

Exclusion for randomisation 1:

Severe pulmonary, neurologic, or psychiatric disease;
CTCAE grade 3-4 polyneuropathy during Bortezomib treatment;
Allogeneic Stem Cell Transplantation (Allo SCT) planned;
Progressive disease.'

Exclusion for randomisation 2:

Progressive disease;
Neuropathy, except CTCAE grade 1;
CTCAE grade 3-4 polyneuropathy during Bortezomib treatment.

Contacts and Locations

Locations

	Site	City	Country
1	AU-Brisbane-PAH	Brisbane	Australia
2	AU-Canberra-CANBERRAHOSPITAL	Canberra	Australia
3	AU-Melbourne-ALFRED	Melbourne	Australia
4	AU-Sydney-CONCORD	Sydney	Australia
5	AU-Sydney-NEPEAN	Sydney	Australia
6	Prince of Wales Hospital	Sydney	Australia
7	St George Hospital	Sydney	Australia
8	Krankenhaus d.Elisabethinen	Linz	Austria
9	Landeskrankenhaus Salzburg	Salzburg	Austria
10	AT-Vienna-HANUSCH	Vienna	Austria
11	BE-Antwerpen Edegem-UZA	Antwerpen	Belgium
12	BE-Antwerpen-ZNASTUIVENBERG	Antwerpen	Belgium
13	BE-Haine-Saint-Paul-JOLIMONT	Haine-Saint-Paul	Belgium
14	CHU Tivoli	La Louvière	Belgium
15	BE-Liege-CHRCITADELLE	Liège	Belgium
16	BE-Mons-AMBROISE	Mons	Belgium
17	CHR Saint Joseph	Mons	Belgium
18	BE-Roeselare-AZDELTA	Roeselare	Belgium
19	RHMS	Saint-Ghislain	Belgium
20	CH Wapi	Tournai	Belgium
21	AZ Turnhout	Turnhout	Belgium
22	CZ-Brno-UHBRNO	Brno	Czechia
23	Kralove-University Hospital Hradec Kralove	Hradec	Czechia
24	CZ-Olomouc-FNOL	Olomouc	Czechia
25	CZ-Ostrava-Poruba-FNO	Ostrava	Czechia
26	University Hospital Plzen	Plzen	Czechia
27	University Hospital Kralovske Vinohrady	Prague	Czechia
28	DK-Aalborg-AALBORGUH	Aalborg	Denmark
29	DK-Aarhus N-AUH	Aarhus	Denmark
30	DK-Copenhagen-RIGSHOSPITALET	Copenhagen	Denmark
31	DK-Herlev-HERLEV	Herlev	Denmark
32	DK-Odense-OUH	Odense	Denmark
33	DK-Roskilde-ROSKILDE	Roskilde	Denmark
34	FI-Turku-TYKS	Turku	Finland
35	GR-Athens-ALEXANDRA	Athens	Greece
36	St. Istvan and St. Laszlo Korhaz Hospital	Budapest	Hungary
37	Szeged University Hospital	Szeged	Hungary
38	SS Antonio e Biogio	Alessandria	Italy
39	AOU Umberto I-Clinica di Ematologica	Ancona	Italy
40	Ospedale C. e G. Mazzoni-Ematologia	Ascoli Piceno	Italy
41	A.O.R.N. San G. Moscati	Avellino	Italy
42	Policlinico di Bari	Bari	Italy
43	Oaspedali Riuniti_Div di Ematologia	Bergamo	Italy
44	Instituto di Ematologia e Oncologia Medica	Bologna	Italy
45	Ospedale Generale Regionale_Div di Ema e Centro	Bolzano	Italy
46	Spedali Civili_U.O.Ematologia	Brescia	Italy
47	Pres Osp Di Summa	Brindisi	Italy
48	Presidio Osp R. Binaghi	Cagliari	Italy
49	Inst per la Ricerca e la Cura del Cancro Di	Candiolo	Italy
50	Ospedale Ferrarotto-Ema	Catania	Italy
51	Presidio ospedaliero dell'annunziata	Cosenza	Italy
52	OspedaleCivico S Croce e carle	Cuneo	Italy
53	Ospedali Riuniti di Foggia	Foggia	Italy
54	Azienda Ospedaliera San Antonio Abate	Gallarate	Italy
55	Azienda Ospedaliera Universitaria S. Martino_Clinica Ematologica	Genova	Italy
56	Azienda Ospedaliera Universitaria S. Martino_Ematologia 1	Genova	Italy
57	Azienda Ospedaliera Universitaria S. Martino_Ematologia 2	Genova	Italy
58	Università La Sapienza Polo Pontino	Latina	Italy
59	Ospedale A. Manzoni	Lecco	Italy
60	ASUR Regione Marche	Marche	Italy
61	IRST	Meldola	Italy
62	Azienda Ospedaliera Papardo	Messina	Italy
63	Policlinico Gaetano Martino	Messina	Italy
64	Osp Dell Angelo	Mestre	Italy
65	Istituto Nazionale dei Tumori-Ema	Milano	Italy
66	Ospedale Niguarda Cà Grande	Milano	Italy
67	Policlinico- servizio di Ematologia	Modena	Italy
68	Ospedale Cardarelli-ematologia e Trapianto di Midollo Osseo	Napoli	Italy
69	Ospedale Cardarelli-Sezione di Ematologia TERE	Napoli	Italy
70	Universita Federico II-Ema	Napoli	Italy
71	Università Amedeo Avogrado-Ospedale Maggiore	Novara	Italy
72	Ospedale San Francesco	Nuoro	Italy
73	Osp San Luigi Gonzaga-Pat med	Orbassano	Italy
74	Ospedaliera di Pavona_Ematologia e	Padova	Italy
75	Giaccone di Palermo	Palermo	Italy
76	Fondazione Maugeri	Pavia	Italy
77	Policlinico San Matteo	Pavia	Italy
78	Azienda Ospedaliera S. Maria della Misericordia	Perugia	Italy
79	AO Ospedali Riunti Marche Nord	Pesaro	Italy
80	Presidio Osp dello Spirito Santo	Pescara	Italy
81	Osp S Maria delle Croci_Ema	Ravenna	Italy
82	A.O. Bianchi Melacrino Morelli_Ops Riunti	Reggio Calabria	Italy
83	Azienda Ospedaliera S. Maria Nuova	Reggio Emilia	Italy
84	Ospedale Infermi	Rimini	Italy
85	Ospedale Oncologica Regionale	Rionero In Vulture	Italy
86	Azienda Osp S. Andrea	Roma	Italy
87	Inst Regina elena-SC Ema IFO	Roma	Italy
88	Osp. san Camillo Forlanini	Roma	Italy
89	Ospedale S Eugenio_Ema	Roma	Italy
90	Ospedale San Giovanni Addolorata	Roma	Italy
91	UC Biomedico_Divisione di Ematologia	Roma	Italy
92	Universita La Sapienza_Ospedale Umberto I	Roma	Italy
93	Istituto Clinico Humanitas	Rozzano	Italy
94	AOU Senese Policlinico S. Maria alle Scotte	Siena	Italy
95	PO SS Ann e S.G. Moscati-Ema	Taranto	Italy
96	St. Maria_Oncoematologia	Terni	Italy
97	San Giovanni Battista Le Molinette-Ema 1	Torino	Italy
98	San Giovanni Battista Le Molinette-Ema 2	Torino	Italy
99	AO Cardinale G. Panico	Tricase	Italy
100	AOU Ospedali Riuniti	Trieste	Italy
101	AOU S.Maria della Misericordia	Udine	Italy
102	LU-Luxembourg-CHL	Luxembourg	Luxembourg
103	NL-Alkmaar-NWZ	Alkmaar	Netherlands
104	NL-Almere-FLEVOZIEKENHUIS	Almere	Netherlands
105	NL-Amersfoort-MEANDERMC	Amersfoort	Netherlands
106	NL-Amstelveen-AMSTELLAND	Amstelveen	Netherlands
107	NL-Amsterdam-AMC	Amsterdam	Netherlands
108	NL-Amsterdam-AVL	Amsterdam	Netherlands
109	NL-Amsterdam-OLVG	Amsterdam	Netherlands
110	NL-Amsterdam-VUMC	Amsterdam	Netherlands
111	NL-Apeldoorn-GELREAPELDOORN	Apeldoorn	Netherlands
112	NL-Arnhem-RIJNSTATE	Arnhem	Netherlands
113	NL-Assen-WZA	Assen	Netherlands
114	NL-Beverwijk-RKZ	Beverwijk	Netherlands
115	NL-Breda-AMPHIA	Breda	Netherlands
116	NL-Capelle a/d IJssel-YSL	Capelle Aan Den IJssel	Netherlands
117	NL-Delft-RDGG	Delft	Netherlands
118	NL-Den Bosch-JBZ	Den Bosch	Netherlands
119	NL-Den Haag-HAGA	Den Haag	Netherlands
120	NL-Deventer-DZ	Deventer	Netherlands
121	NL-Dirksland-VANWEELBETHESDA	Dirksland	Netherlands
122	NL-Doetinchem-SLINGELAND	Doetinchem	Netherlands
123	NL-Dordrecht-ASZ	Dordrecht	Netherlands
124	Nij Smellinghe	Drachten	Netherlands
125	NL-Ede-ZGV	Ede	Netherlands
126	NL-Eindhoven-CATHARINA	Eindhoven	Netherlands
127	NL-Eindhoven-MAXIMAMC	Eindhoven	Netherlands
128	NL-Emmen-SCHEPER	Emmen	Netherlands
129	NL-Enschede-MST	Enschede	Netherlands
130	NL-Geldrop-STANNA	Geldrop	Netherlands
131	NL-Goes-ADRZ	Goes	Netherlands
132	NL-Gorinchem-BEATRIX	Gorinchem	Netherlands
133	NL-Gouda-GROENEHART	Gouda	Netherlands
134	NL-Groningen-UMCG	Groningen	Netherlands
135	NL-Heerlen-ATRIUMMC	Heerlen	Netherlands
136	NL-Helmond-ELKERLIEK	Helmond	Netherlands
137	NL-Hilversum-TERGOOI	Hilversum	Netherlands
138	NL-Hoofddorp-SPAARNEGASTHUIS	Hoofddorp	Netherlands
139	NL-Hoorn-DIJKLANDERHOORN	Hoorn	Netherlands
140	NL-Leeuwarden-MCL	Leeuwarden	Netherlands
141	NL-Leiden-LUMC	Leiden	Netherlands
142	NL-Maastricht-MUMC	Maastricht	Netherlands
143	NL-Nieuwegein-ANTONIUS	Nieuwegein	Netherlands
144	NL-Nijmegen-CWZ	Nijmegen	Netherlands
145	NL-Nijmegen-RADBOUDUMC	Nijmegen	Netherlands
146	NL-Roermond-LZR	Roermond	Netherlands
147	NL-Roosendaal-BRAVIS	Roosendaal	Netherlands
148	NL-Rotterdam-EMCDANIEL	Rotterdam	Netherlands
149	NL-Rotterdam-ERASMUSMC	Rotterdam	Netherlands
150	NL-Rotterdam-IKAZIA	Rotterdam	Netherlands
151	NL-Rotterdam-MAASSTADZIEKENHUIS	Rotterdam	Netherlands
152	NL-Rotterdam-SFG	Rotterdam	Netherlands
153	NL-Sittard-Geleen-ZUYDERLAND	Sittard	Netherlands
154	NL-Spijkenisse-SPIJKENISSEMC	Spijkenisse	Netherlands
155	NL-Terneuzen-ZORGSAAM	Terneuzen	Netherlands
156	NL-Tilburg-ETZ	Tilburg	Netherlands
157	NL-Utrecht-DIAKONESSENUTRECHT	Utrecht	Netherlands
158	NL-Utrecht-UMCUTRECHT	Utrecht	Netherlands
159	NL-Venlo-VIECURI	Venlo	Netherlands
160	NL-Winterswijk-SKBWINTERSWIJK	Winterswijk	Netherlands
161	NL-Zwolle-ISALA	Zwolle	Netherlands
162	Haukeland University Hospital	Bergen	Norway
163	Forde Central Hosiptal	Førde	Norway
164	Harstad University Hospital	Harstad	Norway
165	Sørlandet Hospital	Kristiansand	Norway
166	Levanger Hospital	Levanger	Norway
167	NO-Lørenskog-AKERSHUS	Lørenskog	Norway
168	NO-Oslo-OSLOUH	Oslo	Norway
169	Baerum hospital	Sandvika	Norway
170	NO-Stavanger-HELSESTAVANGER	Stavanger	Norway
171	NO-Tromsø-NORTHNOORWEGEN	Tromsø	Norway
172	NO-Trondheim-STOLAV	Trondheim	Norway
173	Helse Sunnmore	Ålesund	Norway
174	Francisco Gentil	Lisboa	Portugal
175	SE-Boras-SASBORAS	Borås	Sweden
176	Eskilstuna Malar Hospital	Eskilstuna	Sweden
177	Falun Hospital	Falun	Sweden
178	Sahlgrenska University Hospital	Göteborg	Sweden
179	Hallands Hospital Halmstad	Halmstad	Sweden
180	Helsingborg General Hospital	Helsingborg	Sweden
181	Ryhov Hospital	Jönköping	Sweden
182	Lidkoping Hospital	Lidkoping	Sweden
183	SE-Linköping-REGIONOSTERGOTLAND	Linköping	Sweden
184	SE-Luleå-SUNDERBY	Luleå	Sweden
185	SE-Lund-SUH	Lund	Sweden
186	SE-Stockholm-KAROLINSKAHUDDINGE	Stockholm	Sweden
187	Sundsvall Hospital	Sundsvall	Sweden
188	Uddevall Hospital	Uddevalla	Sweden
189	Umea University Hospital	Umeå	Sweden
190	SE-Uppsala-UPPSALAUH	Uppsala	Sweden
191	Centrallasareltet Vaxjo	Växjö	Sweden
192	Orebro University Hospital	Örebro	Sweden
193	CH-Aarau-KSA	Aarau	Switzerland
194	CH-Basel-USB	Basel	Switzerland
195	CH-Bellinzona-IOSI	Bellinzona	Switzerland
196	CH-Bern-INSEL	Bern	Switzerland
197	KS Graubunden	Chur	Switzerland
198	CH-Geneve (14)-HCUGE	Geneve	Switzerland
199	Kantonsspital Baselland	Liestal	Switzerland
200	CH-Luzern-LUKS	Luzern	Switzerland
201	CH-St. Gallen-KSSG	Saint Gallen	Switzerland
202	CH-Zürich-USZ	Zürich	Switzerland
203	Baskent University Hospital	Adana	Turkey
204	Gazi University Hospital	Ankara	Turkey
205	University Hospital Ankara	Ankara	Turkey
206	Istanbul University Hospital	Istanbul	Turkey
207	Ege University Hospital	İzmir	Turkey
208	Erciyes University Hospital	Kayseri	Turkey