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

Phase 2

Completed

• Conditions: Multiple Myeloma
• Interventions: Drug: Revlimid; Drug: Melphalan; Drug: Dexamethasone; Drug: Prednisone; Drug: Velcade

• Registration Number: NCT01237249
• Lead Sponsor: PETHEMA Foundation

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

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 Timeline

• Study First Submitted: 2010-11-04
• Study First Submitted QC: 2010-11-07
• Study First Posted: 2010-11-09
• Study Start: 2011-02
• Primary Completion: 2014-08
• Study Completion: 2016-05
• Status Verified: 2017-01
• Last Update Submitted: 2017-01-16
• Last Update Posted: 2017-01-18

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 250

Inclusion Criteria

1. Written informed consent obtained before starting any study-specific procedure.

2. Symptomatic elderly MM newly diagnosed by EBMT criteria older than 65 years.

3. Performance status (ECOG) ≤ 2.

4. 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

1. Patient previously received treatment with Velcade or Revlimid.
2. Patient previously received treatment for Multiple Myeloma.
3. Patient has ≥ Grade 2 peripheral neuropathy within 14 days before enrolment.
4. Patient has hypersensitivity to bortezomib, boron, mannitol or lenalidomide.
5. Patient has received other investigational drugs with 28 days before enrolment.
6. 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.
7. Patient currently is enrolled in another clinical research study and/or is receiving an investigational agent for any reason.
8. 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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Alternating MPV with Revlimid/Low Dose Dexamethasone	Revlimid	Alternating Velcade/Melphalan/Prednisone (MPV) with Revlimid/Low Dose Dexamethasone (Rd)
MPV followed by Revlimid/Low Dose Dexamethasone (Rd)	Velcade	Melphalan/Prednisone/Velcade (MPV) followed by Revlimid/Low Dose Dexamethasone (Rd)
Alternating MPV with Revlimid/Low Dose Dexamethasone	Dexamethasone	Alternating Velcade/Melphalan/Prednisone (MPV) with Revlimid/Low Dose Dexamethasone (Rd)
MPV followed by Revlimid/Low Dose Dexamethasone (Rd)	Melphalan	Melphalan/Prednisone/Velcade (MPV) followed by Revlimid/Low Dose Dexamethasone (Rd)
MPV followed by Revlimid/Low Dose Dexamethasone (Rd)	Prednisone	Melphalan/Prednisone/Velcade (MPV) followed by Revlimid/Low Dose Dexamethasone (Rd)

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
Time to next therapy (TNT)	2 years
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
To evaluate the response in both groups of patients	1 year
Overall survival (OS) in the two different groups of patients	5 years

Trial Locations

Locations (63)

H. Son Llatzer; 🇪🇸 Palma de Mallorca, Baleares, Spain

Hospital Principe de Asturias; 🇪🇸 Alcalá de Henares, Madrid, Spain

Clínica Universitaria de Navarra; 🇪🇸 Pamplona, Navarra, Spain

Fundación Hospital Alcorcón; 🇪🇸 Alcorcón, Spain

Hospital de Badalona Germans Trias i Pujol; 🇪🇸 Badalona, Spain

H. Vall d'Hebron, Barcelona; 🇪🇸 Barcelona, Spain

Hospital Clinic i Provincial de Barcelona; 🇪🇸 Barcelona, Spain

Hospital de la Santa Creu i Sant Pau; 🇪🇸 Barcelona, Spain

Hospital del Mar; 🇪🇸 Barcelona, Spain

ICO - Duran i Reynals, Hospitalet de Llobregat; 🇪🇸 Barcelona, Spain

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