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

• ClinicalTrials.gov Identifier: NCT01191060
• Recruitment Status: Completed
• First Posted: August 30, 2010
• Last Update Posted: April 18, 2019
• Sponsor: University Hospital, Toulouse
• Collaborators: Dana-Farber Cancer Institute; Celgene Corporation; Janssen-Cilag Ltd.
• Information provided by (Responsible Party): University Hospital, Toulouse

Tracking Information

• First Submitted Date: April 16, 2010
• First Posted Date: August 30, 2010
• Last Update Posted Date: April 18, 2019
• Actual Study Start Date: October 2010
• Actual Primary Completion Date: November 30, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 18, 2015)

Progression Free Survival [ Time Frame: up to 4 years ]

To compare progression-free survival (PFS) between the Arm A and Arm B up to 4 years or until progression

Original Primary Outcome Measures (submitted: August 27, 2010)

Progression Free Survival [ Time Frame: up to 4 years or until progression ]

To compare progression-free survival (PFS) between the Arm A and Arm B.

Current Secondary Outcome Measures (submitted: August 18, 2015)

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

Original Secondary Outcome Measures (submitted: August 27, 2010)

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

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study Comparing Conventional Dose Combination RVD to High-Dose Treatment With ASCT in the Initial Myeloma up to 65 Years
• Official Title: 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
• Brief Summary: 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).
• 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
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Myeloma

Intervention

• 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®)

Study Arms

• 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)

  Intervention: Drug: Lenalidomide, Bortezomib
• 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)
  Intervention: Drug: Lenalidomide, Bortezomib

Publications *

• 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.
• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: August 27, 2010): 700
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: November 30, 2018
• Actual Primary Completion Date: November 30, 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 65 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: France

Administrative Information

• NCT Number: NCT01191060
• Other Study ID Numbers: 09 110 01
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: University Hospital, Toulouse
• Original Responsible Party: LENDRIEUX Arnaud / CRA's Sponsor Project Manager, University Hospital of Toulouse
• Current Study Sponsor: University Hospital, Toulouse
• Original Study Sponsor: Same as current

Collaborators

• Dana-Farber Cancer Institute
• Celgene Corporation
• Janssen-Cilag Ltd.

Investigators

• Principal Investigator: MICHEL ATTAL, MD PhD; University Hospital of Toulouse

• PRS Account: University Hospital, Toulouse
• Verification Date: April 2019