Study of Treatment for Newly Diagnosed Multiple Myeloma Patients Older Than 65 Years With Sequential Melphalan/Prednisone/Velcade (MPV) Followed by Revlimid/Low Dose Dexamethasone (Rd) Versus Alternating Velcade/Melphalan/Prednisone (MPV) With Revlimid/Low Dose Dexamethasone

Sponsor

PETHEMA Foundation (Other)

Overall Status

Completed

CT.gov ID

NCT01237249

Collaborator

Janssen-Cilag Ltd. (Industry), Celgene (Industry), TFS Trial Form Support (Industry)

250

Enrollment

Locations

Arms

62.9

Duration (Months)

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a national, multicenter, open-label, randomized, comparative study designed to compare, first, the TTP of the two treatment schemes proposed (MPV followed by Rd or MPV alternating with Rd) in newly diagnosed MM patients older than 65 years. This comparison will be performing in terms of both efficacy and safety. Up to 120 patients will be included in each treatment arm and evaluated at scheduled visits in up to 3 study periods: Pre-treatment, Treatment and Follow-up.

Primary outcome measure:

To evaluate the efficacy in terms of time to progression (TTP) at 18 months of MPV and Rd used as either in a sequential or alternating approach in newly diagnosed MM patients older than 65 years.
To evaluate the toxicity (safety and tolerability) of the sequential versus the alternating use of MPV and Rd.

Secondary outcome measure:

To evaluate the response, duration of response, progression free survival (PFS), time to next therapy (TNT) and overall survival (OS) in the two different groups of patients.
To identify, within the group of patients treated with the alternating scheme, the biological characteristics (including a comprehensive genomic analysis) of those patients resistant to one or the other, and patients refractory to both treatments

Condition or Disease	Intervention/Treatment	Phase
Multiple Myeloma	Drug: Melphalan Drug: Prednisone Drug: Velcade Drug: Revlimid Drug: Dexamethasone	Phase 2

Detailed Description

The Pre-treatment period includes Screening visit. After providing written informed consent form to participate in the study, patients will be evaluated for eligibility during a screening period of 14 days (Days -14 to -1). If patients meet all inclusion and exclusion criteria will be randomized at the moment of entry in the trial in a 1:1 allocation to receive either MPV followed by Rd (Treatment Group A) or MPV alternating with Rd (Treatment Group B).

Patients in the Treatment Group A will receive nine cycles of MPV consisting on one 6-weeks cycle of Velcade (Bortezomib) as an intravenous bolus twice weekly (days 1, 4, 8, 11, 22, 25, 29 and 32) followed by a 10 day rest period (day 33 to 42), in combination with oral Melphalan, once daily on days 1 to 4 and oral Prednisone, once daily on days 1 to 4, followed by eight 4-weeks cycles of Velcade (Bortezomib) as an intravenous bolus on days 1, 8, 15 and 22 followed by a 6 day rest period (days 23 to 28), in combination with Melphalan and Prednisone per os once daily on days 1 to 4, followed by a 24-day rest period (days 5 to 28). After the nine MPV cycles, patients will receive nine cycles of Rd consisting on 4-weeks cycles, including Revlimid (lenalidomide), once daily on days 1-21 followed by a 7 day rest period (days 22 to 28) plus oral dexamethasone, once weekly on days 1,8,15 and 22, followed by a 6 day rest period (days 23 to 28).

Patients in the Treatment Group B will receive the same schedule of therapy, but the MPV cycles will be alternated with Rd cycles. In this treatment Group B, patients will be again randomized to start receiving either MPV or Rd as first cycle of therapy. Overall, patients will receive an identical number of cycles, nine cycles of MPV and nine of Rd. Patients randomized to Treatment Group A relapsing/progressing or with major toxicities under treatment with MPV will be crossover to receive Rd, but only after study coordinator approval.

During the Treatment Period, patients will be evaluated at day 1 of each cycle. After completion of the Treatment Period, all patients will be evaluated every 2 months thereafter.

Safety will be assessed by the monitoring of adverse events, physical examinations, vital signs measurements, and haematology and clinical chemistry test. Response to treatment will be based on EBMT an IMWG criteria. Response to treatment will be evaluated at day 1 of each induction cycle, and every 2 months during thereafter.

Study Design

Study Type:

Interventional

Actual Enrollment :

250 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A National, Open-label, Multicenter, Randomized, Comparative Phase IIb Study of Treatment for Newly Diagnosed Multiple Myeloma Patients Older Than 65 Years With Sequential Melphalan/Prednisone/Velcade (MPV) Followed by Revlimid/Low Dose Dexamethasone (Rd) Versus Alternating Velcade/Melphalan/Prednisone (MPV) With Revlimid/Low Dose Dexamethasone (Rd).

Study Start Date :

Feb 1, 2011

Actual Primary Completion Date :

Aug 1, 2014

Actual Study Completion Date :

May 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: MPV followed by Revlimid/Low Dose Dexamethasone (Rd) Melphalan/Prednisone/Velcade (MPV) followed by Revlimid/Low Dose Dexamethasone (Rd)	Drug: Melphalan Drug: Prednisone Drug: Velcade
Experimental: Alternating MPV with Revlimid/Low Dose Dexamethasone Alternating Velcade/Melphalan/Prednisone (MPV) with Revlimid/Low Dose Dexamethasone (Rd)	Drug: Revlimid Drug: Dexamethasone

Arm

Intervention/Treatment

Active Comparator: MPV followed by Revlimid/Low Dose Dexamethasone (Rd)

Melphalan/Prednisone/Velcade (MPV) followed by Revlimid/Low Dose Dexamethasone (Rd)

Drug: Melphalan

Drug: Prednisone

Drug: Velcade

Experimental: Alternating MPV with Revlimid/Low Dose Dexamethasone

Alternating Velcade/Melphalan/Prednisone (MPV) with Revlimid/Low Dose Dexamethasone (Rd)

Drug: Revlimid

Drug: Dexamethasone

Outcome Measures

Primary Outcome Measures

To evaluate the efficacy in terms of time to progression (TTP) at 18 months of MPV and Rd used as either in a sequential or alternating approach in newly diagnosed MM patients older than 65 years. [18 months]
To evaluate the toxicity (safety and tolerability) of the sequential versus the alternating use of MPV and Rd,in terms of adverse events presented in both groups of patients [6 months]

Secondary Outcome Measures

To evaluate the response in both groups of patients [1 year]
To identify, within the group of patients treated with the alternating scheme, the biological characteristics (including a comprehensive genomic analysis) of those patients resistant to one or the other, and patients refractory to both treatments [2 years]
Duration of response in two groups of patients [2 years]
Progression free survival (PFS) in two different groups of patients [18 months]
Time to next therapy (TNT) [2 years]
Overall survival (OS) in the two different groups of patients [5 years]

Eligibility Criteria

Criteria

Ages Eligible for Study:

65 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Written informed consent obtained before starting any study-specific procedure.
Symptomatic elderly MM newly diagnosed by EBMT criteria older than 65 years.
Performance status (ECOG) ≤ 2.
Have pre-treatment clinical laboratory values meeting the following criteria within 14 days of randomization:

platelet count ≥ 75x109/L
haemoglobin ≥ 8g/dL
absolute neutrophil count (ANC) ≥ 1.0x109/L
Serum bilirubin ≤ 1.5 mg/dL and alkaline phosphatise ≤ 2.5 x ULN AST, ALT ≤ 2.5 x ULN
Serum creatinine ≤2,5 mg/dl

Exclusion Criteria:

Patient previously received treatment with Velcade or Revlimid.
Patient previously received treatment for Multiple Myeloma.
Patient has ≥ Grade 2 peripheral neuropathy within 14 days before enrolment.
Patient has hypersensitivity to bortezomib, boron, mannitol or lenalidomide.
Patient has received other investigational drugs with 28 days before enrolment.
Patient had a myocardial infarction within 6 months of enrolment or has New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities.
Patient currently is enrolled in another clinical research study and/or is receiving an investigational agent for any reason.
Radiation therapy within 30 days before randomization, at least patient has had antialgic radiation. Radiation therapy will be afterwards permitted during the treatment period if it is indicated due to the presence of plasmacytomas

Contacts and Locations

Locations

	Site	City	State	Country
1	H. Son Llatzer	Palma de Mallorca	Baleares	Spain
2	Hospital Principe de Asturias	Alcalá de Henares	Madrid	Spain
3	Clínica Universitaria de Navarra	Pamplona	Navarra	Spain
4	Fundación Hospital Alcorcón	Alcorcón		Spain
5	Hospital de Badalona Germans Trias i Pujol	Badalona		Spain
6	H. Vall d'Hebron, Barcelona	Barcelona		Spain
7	Hospital Clinic i Provincial de Barcelona	Barcelona		Spain
8	Hospital de la Santa Creu i Sant Pau	Barcelona		Spain
9	Hospital del Mar	Barcelona		Spain
10	ICO - Duran i Reynals, Hospitalet de Llobregat	Barcelona		Spain
11	Hospital de Cruces	Bilbao		Spain
12	Hospital General de Castellón	Castellón		Spain
13	Hospital General	Ciudad Real		Spain
14	Hospital Virgen de la Luz	Cuenca		Spain
15	Complejo Hospitalario de Cáceres	Cáceres		Spain
16	Hospital Puerta del Mar	Cádiz		Spain
17	Hospital Donostia	Donostia		Spain
18	Hospital Francesc Borja	Gandía		Spain
19	ICO - Josep Trueta	Girona		Spain
20	Hospital General de Guadalajara	Guadalajara		Spain
21	H. de Jerez	Jerez de la Frontera		Spain
22	Complejo Hospitalario León	Leon		Spain
23	Clínica Puerta de Hierro	Madrid		Spain
24	Hospital 12 de Octubre. Madrid	Madrid		Spain
25	Hospital Clinico San Carlos	Madrid		Spain
26	Hospital de Fuenlabrada	Madrid		Spain
27	Hospital de la Princesa	Madrid		Spain
28	Hospital de Madrid, S.A.- Norte Hospital General	Madrid		Spain
29	Hospital del Tajo	Madrid		Spain
30	Hospital Infanta Leonor	Madrid		Spain
31	Hospital Infanta Sofia	Madrid		Spain
32	Hospital la Paz	Madrid		Spain
33	Hospital Ramón y Cajal	Madrid		Spain
34	Hospital Severo Ochoa	Madrid		Spain
35	Hospital Universitario Gregorio Marañón	Madrid		Spain
36	MD Anderson	Madrid		Spain
37	Althaia	Manresa		Spain
38	Hospital General Univeristario Morales Messeguer	Murcia		Spain
39	Hospital Virgen de la Arrixaca	Murcia		Spain
40	Complejo Hospital Costa del Sol	Málaga		Spain
41	Hospital Nuestra Señora de Valme	Málaga		Spain
42	Hospital de la Diputación de Navarra	Navarra		Spain
43	Hospital de Gran Canaria Doctor Negrín	Palma de Gran Canaria		Spain
44	Complejo Asistencial Son Dureta	Palma de Mallorca		Spain
45	Hospital Virgen del Camino	Pamplona		Spain
46	Corporació Sanitaria Parc Taulí	Sabadell		Spain
47	Hospital Clínico de Salamanca	Salamanca		Spain
48	Hoaspital Marqués de Valdecilla	Santander		Spain
49	Complejo Hospitalario Universitario de Santiago	Santiago de Compostela		Spain
50	Hospital General de Segovia	Segovia		Spain
51	Complejo Hospitalario Regional Virgen del Rocío	Sevilla		Spain
52	Hospital Joan XXIII	Tarragona		Spain
53	Hospital Universitario de Canarias	Tenerife		Spain
54	Hospital Nuestra Señora del Prado	Toledo		Spain
55	Hospital Virgen de la Salud	Toledo		Spain
56	Hospital Arnau de Vilanova	Valencia		Spain
57	Hospital Clínico de Valencia.	Valencia		Spain
58	Hospital La Fe	Valencia		Spain
59	Hospital Universitario Dr. Peset	Valencia		Spain
60	Hospital Txagorritxu	Vitoria		Spain
61	Hospital Virgen de la Concha	Zamora		Spain
62	Hospital Clinico Lozano Blesa	Zaragoza		Spain
63	Miguel Servet	Zaragoza		Spain