Clinical trial NCT01237249: 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
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Multiple Myeloma
Keywords: Multiple Myeloma
Velcade
Revlimid
Lead sponsor: PETHEMA Foundation
Sponsor class: OTHER
Collaborators: name: Janssen-Cilag Ltd.
name: Celgene
name: TFS Trial Form Support
First posted: 2010-11-09
Enrollment: 250
Sex: ALL
Minimum age (years): 65
Standard ages: OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
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.
timeFrame: 18 months
measure: 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
timeFrame: 6 months
Secondary outcomes:
measure: To evaluate the response in both groups of patients
timeFrame: 1 year
measure: 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
timeFrame: 2 years
measure: Duration of response in two groups of patients
timeFrame: 2 years
measure: Progression free survival (PFS) in two different groups of patients
timeFrame: 18 months
measure: Time to next therapy (TNT)
timeFrame: 2 years
measure: Overall survival (OS) in the two different groups of patients
timeFrame: 5 years
Other outcomes:
Locations:
city: Palma de Mallorca
country: Spain
facility: H. Son Llatzer
state: Baleares
city: Alcalá de Henares
country: Spain
facility: Hospital Principe de Asturias
state: Madrid
city: Pamplona
country: Spain
facility: Clínica Universitaria de Navarra
state: Navarra
city: Alcorcón
country: Spain
facility: Fundación Hospital Alcorcón
city: Badalona
country: Spain
facility: Hospital de Badalona Germans Trias i Pujol
city: Barcelona
country: Spain
facility: H. Vall d'Hebron, Barcelona
city: Barcelona
country: Spain
facility: Hospital Clinic i Provincial de Barcelona
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu i Sant Pau
city: Barcelona
country: Spain
facility: Hospital del Mar
city: Barcelona
country: Spain
facility: ICO - Duran i Reynals, Hospitalet de Llobregat
city: Bilbao
country: Spain
facility: Hospital de Cruces
city: Castellón
country: Spain
facility: Hospital General de Castellón
city: Ciudad Real
country: Spain
facility: Hospital General
city: Cuenca
country: Spain
facility: Hospital Virgen de la Luz
city: Cáceres
country: Spain
facility: Complejo Hospitalario de Cáceres
city: Cádiz
country: Spain
facility: Hospital Puerta del Mar
city: Donostia
country: Spain
facility: Hospital Donostia
city: Gandía
country: Spain
facility: Hospital Francesc Borja
city: Girona
country: Spain
facility: ICO - Josep Trueta
city: Guadalajara
country: Spain
facility: Hospital General de Guadalajara
city: Jerez de la Frontera
country: Spain
facility: H. de Jerez
city: Leon
country: Spain
facility: Complejo Hospitalario León
city: Madrid
country: Spain
facility: Clínica Puerta de Hierro
city: Madrid
country: Spain
facility: Hospital 12 de Octubre. Madrid
city: Madrid
country: Spain
facility: Hospital Clinico San Carlos
city: Madrid
country: Spain
facility: Hospital de Fuenlabrada
city: Madrid
country: Spain
facility: Hospital de la Princesa
city: Madrid
country: Spain
facility: Hospital de Madrid, S.A.- Norte Hospital General
city: Madrid
country: Spain
facility: Hospital del Tajo
city: Madrid
country: Spain
facility: Hospital Infanta Leonor
city: Madrid
country: Spain
facility: Hospital Infanta Sofia
city: Madrid
country: Spain
facility: Hospital la Paz
city: Madrid
country: Spain
facility: Hospital Ramón y Cajal
city: Madrid
country: Spain
facility: Hospital Severo Ochoa
city: Madrid
country: Spain
facility: Hospital Universitario Gregorio Marañón
city: Madrid
country: Spain
facility: MD Anderson
city: Manresa
country: Spain
facility: Althaia
city: Murcia
country: Spain
facility: Hospital General Univeristario Morales Messeguer
city: Murcia
country: Spain
facility: Hospital Virgen de la Arrixaca
city: Málaga
country: Spain
facility: Complejo Hospital Costa del Sol
city: Málaga
country: Spain
facility: Hospital Nuestra Señora de Valme
city: Navarra
country: Spain
facility: Hospital de la Diputación de Navarra
city: Palma de Gran Canaria
country: Spain
facility: Hospital de Gran Canaria Doctor Negrín
city: Palma de Mallorca
country: Spain
facility: Complejo Asistencial Son Dureta
city: Pamplona
country: Spain
facility: Hospital Virgen del Camino
city: Sabadell
country: Spain
facility: Corporació Sanitaria Parc Taulí
city: Salamanca
country: Spain
facility: Hospital Clínico de Salamanca
city: Santander
country: Spain
facility: Hoaspital Marqués de Valdecilla
city: Santiago de Compostela
country: Spain
facility: Complejo Hospitalario Universitario de Santiago
city: Segovia
country: Spain
facility: Hospital General de Segovia
city: Sevilla
country: Spain
facility: Complejo Hospitalario Regional Virgen del Rocío
city: Tarragona
country: Spain
facility: Hospital Joan XXIII
city: Tenerife
country: Spain
facility: Hospital Universitario de Canarias
city: Toledo
country: Spain
facility: Hospital Nuestra Señora del Prado
city: Toledo
country: Spain
facility: Hospital Virgen de la Salud
city: Valencia
country: Spain
facility: Hospital Arnau de Vilanova
city: Valencia
country: Spain
facility: Hospital Clínico de Valencia.
city: Valencia
country: Spain
facility: Hospital La Fe
city: Valencia
country: Spain
facility: Hospital Universitario Dr. Peset
city: Vitoria
country: Spain
facility: Hospital Txagorritxu
city: Zamora
country: Spain
facility: Hospital Virgen de la Concha
city: Zaragoza
country: Spain
facility: Hospital Clinico Lozano Blesa
city: Zaragoza
country: Spain
facility: Miguel Servet
Study officials:
References:
citation: Quwaider D, Corchete LA, Misiewicz-Krzeminska I, Sarasquete ME, Perez JJ, Krzeminski P, Puig N, Mateos MV, Garcia-Sanz R, Herrero AB, Gutierrez NC. DEPTOR maintains plasma cell differentiation and favorably affects prognosis in multiple myeloma. J Hematol Oncol. 2017 Apr 18;10(1):92. doi: 10.1186/s13045-017-0461-8.
citation: Paiva B, Cedena MT, Puig N, Arana P, Vidriales MB, Cordon L, Flores-Montero J, Gutierrez NC, Martin-Ramos ML, Martinez-Lopez J, Ocio EM, Hernandez MT, Teruel AI, Rosinol L, Echeveste MA, Martinez R, Gironella M, Oriol A, Cabrera C, Martin J, Bargay J, Encinas C, Gonzalez Y, Van Dongen JJ, Orfao A, Blade J, Mateos MV, Lahuerta JJ, San Miguel JF; Grupo Espanol de Mieloma/Programa para el Estudio de la Terapeutica en Hemopatias Malignas (GEM/PETHEMA) Cooperative Study Groups. Minimal residual disease monitoring and immune profiling in multiple myeloma in elderly patients. Blood. 2016 Jun 23;127(25):3165-74. doi: 10.1182/blood-2016-03-705319. Epub 2016 Apr 26.
citation: Paiva B, Corchete LA, Vidriales MB, Puig N, Maiso P, Rodriguez I, Alignani D, Burgos L, Sanchez ML, Barcena P, Echeveste MA, Hernandez MT, Garcia-Sanz R, Ocio EM, Oriol A, Gironella M, Palomera L, De Arriba F, Gonzalez Y, Johnson SK, Epstein J, Barlogie B, Lahuerta JJ, Blade J, Orfao A, Mateos MV, San Miguel JF; Spanish Myeloma Group / Program for the Study of Malignant Blood Diseases Therapeutics (GEM / PETHEMA) Cooperative Study Groups. Phenotypic and genomic analysis of multiple myeloma minimal residual disease tumor cells: a new model to understand chemoresistance. Blood. 2016 Apr 14;127(15):1896-906. doi: 10.1182/blood-2015-08-665679. Epub 2016 Jan 11.