Study Comparing Conventional Dose Combination RVD to High-Dose Treatment With ASCT in the Initial Myeloma up to 65 Years (IFM/DFCI2009)

Randomized Study Comparing Conventional Dose Treatment Using a Combination of Lenalidomide, Bortezomib and Dexamethasone to High-Dose Treatment With ASCT in the Initial Management of Myeloma in Patients up to 65 Years of Age

Objective of this study is to determine if, in the era of novel drugs, high dose therapy (HDT) is still necessary in the initial management of multiple myeloma in younger patients. HDT as compared to conventional dose treatment would be considered superior if it significantly prolongs Progression-free survival (by at least 9 months).

Study Overview

• Status: Completed
• Conditions: Myeloma
• Intervention / Treatment: Drug: Lenalidomide, Bortezomib; Drug: Lenalidomide, Bortezomib

Detailed Description

Study design Phase III, multicenter, randomized, open-label study designed to evaluate the clinical benefit from the drug combination RVD without immediate high-dose therapy (HDT) followed by lenalidomide maintenance (Arm A) versus RVD plus HDT and PBSCT followed by lenalidomide maintenance (Arm B).

• Study Type: Interventional
• Enrollment (Actual): 700
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • AMIENS cedex 1, France, 80054
    • CHRU - Hôpital Sud Amiens
  • ANGERS cedex 01, France, 49033
    • CHU d'Angers
  • Aix-en-provence, France, 13 616
    • CH du Pays d'Aix
  • Argenteuil, France, 95 100
    • Centre hospitalier Argenteuil Victor Dupouy
  • Avignon, France, 84902
    • Centre Hospitalier H.Duffaut
  • Bayonne, France, 64109
    • Centre Hospitalier de la Côte Basque
  • Besançon, France, 25030
    • Hopital Jean Minjoz
  • Blois, France, 41016
    • Centre Hospitalier de Blois
  • Bobigny, France, 93009
    • Hôpital Avicenne
  • Bordeaux, France, 33 300
    • Polyclinique Bordeaux Nord Aquitaine
  • Brest, France, 29609
    • Hôpital A.Morvan
  • Caen, France, 14076
    • Centre Francois Baclesse
  • Caen, France, 14033
    • CHU Caen Côte de Nacre
  • Cergy-Pontoise, France, 95303
    • CH René Dubos
  • Chalon-sur-saone, France, 71 321
    • Centre Hospitalier William Morey
  • Chambéry, France, 73011
    • CH Chambery
  • Clamart cedex, France, 92 141
    • Hôpital Antoine Béclère
  • Clamart cedex, France, 92141
    • Hôpital d'Instruction des Armées PERCY
  • Clermont - Ferrand, France, 63050
    • Pôle Santé République
  • Clermont-Ferrand, France, 63000
    • Chu D'Estaing
  • Colmar, France, 68024
    • CH Louis Pasteur - Colmar
  • Corbeil-Essonnes, France, 91106
    • CH SUd Francilien
  • Créteil, France, 94 010
    • CHU Henri Mondor
  • Dijon, France, 21000
    • CHRU DIjon
  • Dunkerque, France, 59 385
    • Centre Hospitalier Général - Dunkerque
  • Grenoble, France, 38043
    • Hôpital A.Michallon
  • La Roche sur Yon cedex, France, 85025
    • Centre hospitalier départemental - La Roche sur Yon cedex
  • Le Coudray, France, 26630
    • CH de Chartres - Hôpital Louis Pasteur
  • Le Mans, France, 72037
    • Centre Hospitalier Le Mans
  • Le Mans, France, 72000
    • Centre Jean Bernard
  • Lille, France, 59037
    • CHRU - Hôpital Claude Huriez
  • Limoges, France, 87042
    • CHU de Limoges
  • Lorient, France, 56322
    • Centre hospitalier Bodelio
  • Lyon, France
    • Centre LEON BERARD
  • Lyon, France, 69437
    • Chu - Hôpital Edouard Herriot
  • Marseille, France, 13273
    • Institut Paoli Calmettes
  • Meaux, France, 77104
    • CH Meaux
  • Mulhouse, France, 68100
    • Hôpital E Muller
  • NICE cedex 3, France, 06202
    • Hôpital Archet 1
  • Nancy, France, 54511
    • Hôpitaux de Brabois
  • Nantes, France, 44 202
    • Centre Catherine de Sienne
  • Nantes, France, 44093
    • CHRU - Hôtel Dieu
  • Nice cedex 3, France, 06202
    • Hopital de L'Archet
  • Nîmes Cédex 9, France, 30029
    • Groupe hospitalo-universitaire Caremeau
  • PARIS cedex 10, France, 75475
    • Hôpital Saint-Louis
  • Paris, France, 75014
    • Hôpital Cochin
  • Paris, France, 75005
    • Institut Curie
  • Paris cedex 12, France, 75571
    • Hôpital St-Antoine
  • Perpignan, France, 66046
    • CH Saint Jean
  • Pessac, France, 33604
    • CHRU - Hôpital du Haut Lévêque
  • Pierre - Bénite cedex, France, 69495
    • Centre Hospitalier Lyon Sud
  • Poitiers, France, 86021
    • CHRU - Hôpital Jean Bernard
  • Pringy, France, 74374
    • Centre Hospitalier de la Région d'Annecy
  • Reims, France, 51092
    • Hôpital R.Debré
  • Rennes, France, 35056
    • CHRU - Hôpital Sud
  • Rennes, France, 35033
    • CHRU - Hôpital de Pontchaillou
  • Rouen, France, 76038
    • Centre Henri Becquerel
  • SAINT-PIERRE cedex, France, 97448
    • Groupe hospitalier Sud Reunion
  • St Cloud, France, 92210
    • Centre René Huguenin
  • St-Brieuc cedex 1, France, 22 027
    • Centre Hospitalier Yves Le Foll
  • St-denis, France, 97 405
    • Centre Hospitalier Départemental - La réunion St Denis
  • St-priest-en-jarez, France, 42 271
    • Institut de Cancerologie de La Loire
  • Strasbourg, France, 67091
    • Hôpitaux Universitaires de Strasbourg
  • Toulouse, France, 31059 Cedex 9
    • University Hospital of Toulouse, Purpan
  • Tours, France, 37044
    • CHRU - Hôpital Bretonneau
  • Valence, France, 26953
    • Centre Hospitalier de Valence
  • Vannes cedex, France, 56017
    • CH Bretagne Atlantique Vannes et Auray
  • Villejuif cedex, France, 94 805
    • Institut Gustave Roussy

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria for registration :

(with labs performed within 21 days of initiation of protocol therapy):

• Patients diagnosed with multiple myeloma based on International Myeloma Foundation 2003 Diagnostic Criteria.
• Patients must have symptomatic myeloma with myeloma-related organ damage.
• Patients must have myeloma that is measurable by either serum or urine evaluation of the monoclonal component or by assay of serum free light chains.
• Age between 18 and 65 years at the time of signing the informed consent document.
• ECOG performance status <2 (Karnofsky ≥ 60%)
• Negative HIV blood test

Exclusion Criteria for registration (section 4.2):

• Participants must not have been treated with any prior systemic therapy for multiple myeloma. Treatment by localized radiotherapy is not an exclusion criterion if an interval of at least two weeks between the end of radiotherapy and initiation of protocol therapy entry in the study is observed. Similarly, the dose of corticosteroids received by the participant should not exceed the equivalent of 160 mg of dexamethasone over a two-week period before initiation of protocol therapy.
• Primary amyloidosis (AL) or myeloma complicated by amylosis.
• Participants may not be receiving any other study investigational agents.
• Participants with known brain metastases
• Poor tolerability or known allergy to any of the study drugs or compounds of similar chemical or biologic composition to study agents
• Platelet count < 50,000/mm3 per µLwithin 21 days of initiation of protocol therapy. Transfusion within 7 days of screening is not allowed to meet platelet eligibility criteria.
• ANC < 1,000 cells/mm3 within 21 days of initiation of protocol therapy. Growth factor within 7 days of screening is not allowed to meet ANC eligibility criteria.
• Hemoglobin < 8.0 g/dL within 21 days of initiation of protocol therapy. Transfusion may be used to meet hemoglobin eligibility criteria.
• Hepatic impairment, defined a bilirubin > 1.5 x institutional upper limit of normal (ULN) > 2 mg/dL (Patients with benign hyperbilirubinemia (e.g., Gilbert's syndrome) are eligible) and or AST (SGOT), or ALT (SGPT), or alkaline phosphatase > 2 x ULN
• Renal insufficiency, defined as serum creatinine > 2.5 mg/dl and/or creatinine clearance < <40 60 ml/min (actual or calculated). The Cockgroft-Gault formula should be used for calculating creatinine clearance values, and may be located in Section 4.2
• Respiratory compromise, defined as ventilation tests and with DLCO < 50%
• Participant must not demonstrate with clinical signs of heart or coronary failure, or evidence of LVEF < 40%. Participant must not have with myocardial infarction within 6 months prior to enrollment or have New York Heart Association (NYHA Appendix VII) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any ECG abnormality at screening has to be documented by the investigator as not medically relevant.
• Intercurrent illness including, but not limited to ongoing or active severe infection, known (active or not) infection with hepatitis B or C virus, poorly controlled diabetes, severe uncontrolled psychiatric disorder or psychiatric illness/social situations that would limit compliance with study requirements.
• Participant with previous history of another malignant condition, except for basal cell carcinoma and stage I cervical cancer
• Female participant who is pregnant or breast-feeding
• Inability to comply with an anti-thrombotic treatment regimen
• Peripheral neuropathy ≥ Grade 2 peripheral neuropathy on clinical examination within 21 days of initiation of protocol therapy
• Mental illness likely to interfere with participation in the study and Adults under juridical protection

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: lenalidomide, bortezomib with ASCT; RVD q 21 days (2 cycles) Collection of peripheral blood stem cells (PBSCs) using cyclophosphamide and GCSF (type Granocyte® or equivalent) Autologous stem cell transplant: Melphalan: infused over two days (day -2 and day -1) or as a single infusion (day-2) according to institutional practice Re-infusion of PBSCs RVD q 21 days (2 cycles) Maintenance Lenalidomide q28 days (12 months)	Drug: Lenalidomide, Bortezomib; Lenalidomide/Bortézomib/Dexamethasone cycles: Number of cycles: 8 cycles for arm A Cycle length Dosage: Lenalidomide: 25 mg/day on days 1-14 of each cycle; Bortézomib: 1.3 mg/m2 on days 1, 4, 8, and 11 for 1 cycle of each cycle Maintenance phase (12 months): Cycle length: 28 days Dosage: Lenalidomide: 10 mg/day continuously for 28 days during 3 months and if the participant tolerates 10 mg/day without complication, a dose increase to 15 mg/day will be allowed; Other Names: Lenalidomide (REVLIMID®); Bortezomib (VELCADE®); Drug: Lenalidomide, Bortezomib; Lenalidomide Bortezomib Dexamethasone cycles: Number of cycles: 5 cycles for arm B Cycle length Dosage: Lenalidomide: 25 mg/day on days 1-14 of each cycle; Bortézomib: 1.3 mg/m2 on days 1, 4, 8, and 11 for 1 cycle of each cycle Maintenance phase (12 months): Cycle length: 28 days Dosage: Lenalidomide: 10 mg/day continuously for 28 days during 3 months and if the participant tolerates 10 mg/day without complication, a dose increase to 15 mg/day will be allowed; Other Names: Lenalidomide (REVLIMID®); Bortézomib (VELCADE®)
Experimental: lenalidomide, bortezomib without ASCT; RVD q 21 days (2 cycles) Collection of peripheral blood stem cells (PBSCs) using cyclophosphamide and GCSF (type Granocyte® or equivalent) RVD q 21 days (5 cycles) Maintenance Lenalidomide q28 days (12 months)	Drug: Lenalidomide, Bortezomib; Lenalidomide/Bortézomib/Dexamethasone cycles: Number of cycles: 8 cycles for arm A Cycle length Dosage: Lenalidomide: 25 mg/day on days 1-14 of each cycle; Bortézomib: 1.3 mg/m2 on days 1, 4, 8, and 11 for 1 cycle of each cycle Maintenance phase (12 months): Cycle length: 28 days Dosage: Lenalidomide: 10 mg/day continuously for 28 days during 3 months and if the participant tolerates 10 mg/day without complication, a dose increase to 15 mg/day will be allowed; Other Names: Lenalidomide (REVLIMID®); Bortezomib (VELCADE®); Drug: Lenalidomide, Bortezomib; Lenalidomide Bortezomib Dexamethasone cycles: Number of cycles: 5 cycles for arm B Cycle length Dosage: Lenalidomide: 25 mg/day on days 1-14 of each cycle; Bortézomib: 1.3 mg/m2 on days 1, 4, 8, and 11 for 1 cycle of each cycle Maintenance phase (12 months): Cycle length: 28 days Dosage: Lenalidomide: 10 mg/day continuously for 28 days during 3 months and if the participant tolerates 10 mg/day without complication, a dose increase to 15 mg/day will be allowed; Other Names: Lenalidomide (REVLIMID®); Bortézomib (VELCADE®)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival	To compare progression-free survival (PFS) between the Arm A and Arm B up to 4 years or until progression	up to 4 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response Rates	-Response rates (RR) between the two arms up to 4 years or until progression	up to 4 years
Time To Progression	Time to progression (TTP) between the two arms up to 4 years or until progression	up to 4 years
Toxicity comparison	Toxicity comparison between the two arms randomization up to 4 years or until progression	up to 4 years
Genetic prognostic groups definition	Genetic prognostic groups definition (evaluated by gene expression profiling-GEP) from randomization up to 4 years or until progression	up to 4 years
Best treatment examination in each GEP-defined prognostic group.	Best treatment examination in each GEP-defined prognostic group. from randomization up to 4 years or until progression	up to 4 years

Collaborators and Investigators

• Sponsor: University Hospital, Toulouse
• Collaborators: Dana-Farber Cancer Institute; Celgene Corporation; Janssen-Cilag Ltd.
• Investigators: Principal Investigator: MICHEL ATTAL, MD PhD, University Hospital of Toulouse

Publications and helpful links

General Publications

• Dunavin NC, Wei L, Elder P, Phillips GS, Benson DM Jr, Hofmeister CC, Penza S, Greenfield C, Rose KS, Rieser G, Merritt L, Ketcham J, Heerema N, Byrd JC, Devine SM, Efebera YA. Early versus delayed autologous stem cell transplant in patients receiving novel therapies for multiple myeloma. Leuk Lymphoma. 2013 Aug;54(8):1658-64. doi: 10.3109/10428194.2012.751528. Epub 2012 Dec 31.
• Langerhorst P, Noori S, Zajec M, De Rijke YB, Gloerich J, van Gool AJ, Caillon H, Joosten I, Luider TM, Corre J, VanDuijn MM, Dejoie T, Jacobs JFM. Multiple Myeloma Minimal Residual Disease Detection: Targeted Mass Spectrometry in Blood vs Next-Generation Sequencing in Bone Marrow. Clin Chem. 2021 Nov 26;67(12):1689-1698. doi: 10.1093/clinchem/hvab187.
• Samur MK, Aktas Samur A, Fulciniti M, Szalat R, Han T, Shammas M, Richardson P, Magrangeas F, Minvielle S, Corre J, Moreau P, Thakurta A, Anderson KC, Parmigiani G, Avet-Loiseau H, Munshi NC. Genome-Wide Somatic Alterations in Multiple Myeloma Reveal a Superior Outcome Group. J Clin Oncol. 2020 Sep 20;38(27):3107-3118. doi: 10.1200/JCO.20.00461. Epub 2020 Jul 20.
• Roussel M, Hebraud B, Hulin C, Perrot A, Caillot D, Stoppa AM, Macro M, Escoffre M, Arnulf B, Belhadj K, Karlin L, Garderet L, Facon T, Guo S, Weng J, Dhanasiri S, Leleu X, Moreau P, Attal M. Health-related quality of life results from the IFM 2009 trial: treatment with lenalidomide, bortezomib, and dexamethasone in transplant-eligible patients with newly diagnosed multiple myeloma. Leuk Lymphoma. 2020 Jun;61(6):1323-1333. doi: 10.1080/10428194.2020.1719091. Epub 2020 Feb 22.
• Attal M, Lauwers-Cances V, Hulin C, Leleu X, Caillot D, Escoffre M, Arnulf B, Macro M, Belhadj K, Garderet L, Roussel M, Payen C, Mathiot C, Fermand JP, Meuleman N, Rollet S, Maglio ME, Zeytoonjian AA, Weller EA, Munshi N, Anderson KC, Richardson PG, Facon T, Avet-Loiseau H, Harousseau JL, Moreau P; IFM 2009 Study. Lenalidomide, Bortezomib, and Dexamethasone with Transplantation for Myeloma. N Engl J Med. 2017 Apr 6;376(14):1311-1320. doi: 10.1056/NEJMoa1611750.

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2010
• Primary Completion (Actual): November 30, 2018
• Study Completion (Actual): November 30, 2018

Study Registration Dates

• First Submitted: April 16, 2010
• First Submitted That Met QC Criteria: August 27, 2010
• First Posted (Estimate): August 30, 2010

Study Record Updates

• Last Update Posted (Actual): April 18, 2019
• Last Update Submitted That Met QC Criteria: April 16, 2019
• Last Verified: April 1, 2019

More Information

Terms related to this study

• Keywords: Disease Progression; Overall survival; Progression free survival prolongation
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Multiple Myeloma; Neoplasms, Plasma Cell; Physiological Effects of Drugs; Antineoplastic Agents; Immunologic Factors; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Lenalidomide; Bortezomib
• Other Study ID Numbers: 09 110 01