Stem Cell Transplant With Lenalidomide Maintenance in Patients With Multiple Myeloma (BMT CTN 0702)

A Trial of Single Autologous Transplant With or Without Consolidation Therapy Versus Tandem Autologous Transplant With Lenalidomide Maintenance for Patients With Multiple Myeloma (BMT CTN 0702)

The study is designed as a Phase III, multicenter trial of tandem autologous transplants plus maintenance therapy versus the strategy of single autologous transplant plus consolidation therapy with lenalidomide, bortezomib and dexamethasone (RVD) followed by maintenance therapy or single autologous transplant plus maintenance therapy as part of upfront treatment of multiple myeloma (MM). Lenalidomide will be used as maintenance therapy for three years in all arms.

Study Overview

• Status: Completed
• Conditions: Multiple Myeloma
• Intervention / Treatment: Drug: Lenalidomide; Drug: Lenalidomide; Drug: lenalidomide, bortezomib and dexamethasone

Detailed Description

The primary objective of the randomized trial is to compare three-year progression-free survival (PFS) between the three treatment arms as a pairwise comparison. Mobilization therapy will not be specified for the study. Randomization to three treatment arms will be done prior to the first transplants. All patients will undergo a first autologous peripheral blood stem cell (PBSC) transplant with high-dose melphalan (200 mg/m^2 IV) given on Day -2. Upon recovery from the first transplant patients will receive either a second autologous PBSC transplant with the same conditioning regimen as the first transplant or consolidation therapy with RVD (lenalidomide 15 mg/day on Days 1-14, dexamethasone 40 mg on Days 1, 8 and 15, and bortezomib 1.3mg/m^2 on Days 1, 4, 8 and 11 of every 21 day cycle, patients will receive four cycles) or maintenance with lenalidomide (15 mg daily). All patients will also receive maintenance lenalidomide which will start after the second transplant, after the first autologous transplant or after consolidation therapy depending on the treatment arm. Maintenance therapy with lenalidomide will start at 10 mg daily for three months and increase to 15 mg daily. The duration of maintenance will be three years in all treatment arms.

• Study Type: Interventional
• Enrollment (Actual): 758
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Tucson, Arizona, United States, 85724
      • Arizona Cancer Center
  • California
    • Duarte, California, United States, 91010-3000
      • City of Hope National Medical Center
    • La Jolla, California, United States, 92093
      • UCSD Medical Center
    • San Francisco, California, United States, 94143-0324
      • University of California, San Francisco
    • Stanford, California, United States, 94305
      • Stanford Hospital and Clinics
  • Colorado
    • Denver, Colorado, United States, 80218
      • Colorado Blood Cancer Institute
  • Delaware
    • Newark, Delaware, United States, 19718
      • Christiana Care Health System
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida College of Medicine
    • Orlando, Florida, United States, 32804
      • Florida Hospital Cancer Institute
    • Tampa, Florida, United States, 33624
      • H. Lee Moffitt Cancer Center
  • Georgia
    • Atlanta, Georgia, United States, 30342
      • Blood and Marrow Transplant Program at Northside Hospital
    • Augusta, Georgia, United States, 30912
      • Georgia Health Sciences University
  • Idaho
    • Boise, Idaho, United States, 83712
      • St. Lukes Mountain States Tumor Institute
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
    • Chicago, Illinois, United States, 60612
      • University of Illinois
    • Park Ridge, Illinois, United States, 60068
      • Advocate Lutheran General Hospital
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Hospital
    • Wichita, Kansas, United States, 67214
      • Wichita CCOP
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • University Of Kentucky
  • Louisiana
    • Shreveport, Louisiana, United States, 71130
      • Louisiana State University Health Sciences Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • DFCI, Brigham and Womens Hospital
    • Boston, Massachusetts, United States, 02114
      • DFCI, Massachusetts General Hospital
  • Michigan
    • Ann Arbor, Michigan, United States, 48105-2967
      • University of Michigan Medical Center
    • Detroit, Michigan, United States, 48201
      • Karmanos Cancer Institute/BMT
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University, Barnes Jewish Hospital
  • Nebraska
    • Omaha, Nebraska, United States, 68198-7680
      • University of Nebraska Medical Center
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center
  • New York
    • Buffalo, New York, United States, 14263
      • Roswell Park Cancer Center
    • Lake Success, New York, United States, 11042
      • North Shore University Hospital
    • New York, New York, United States, 10029
      • Mount Sinai Medical Center
    • New York, New York, United States, 10174
      • Memorial Sloan-Kettering Cancer Center
    • Rochester, New York, United States, 14642
      • University of Rochester Medical Center
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599-7305
      • University of North Carolina Hospital at Chapel Hill
    • Durham, North Carolina, United States, 27705
      • Duke University Medical Center
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest University Health Sciences
  • Ohio
    • Cincinnati, Ohio, United States, 45236
      • Jewish Hospital BMT Program
    • Cleveland, Ohio, United States, 44106-5061
      • University Hospitals of Cleveland
    • Columbus, Ohio, United States, 43210
      • Ohio State/Arthur G. James Cancer Hospital
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • University of Oklahoma Medical Center
  • Oregon
    • Portland, Oregon, United States, 97239-3098
      • Oregon Health & Science University
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Penn State College of Medicine, The Milton S. Hershey Medical Center
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania Cancer Center
  • Tennessee
    • Knoxville, Tennessee, United States, 37916
      • Thompson Cancer Survival Center
    • Nashville, Tennessee, United States, 37203
      • Sarah Cannon Blood & Marrow Transplant Program
    • Nashville, Tennessee, United States, 37232-8210
      • Vanderbilt University Medical Center
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern Medical Center
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine/The Methodist Hospital
    • Houston, Texas, United States, 77030
      • University of Texas, MD Anderson CRC
    • San Antonio, Texas, United States, 78229
      • Texas Transplant Institute
  • Washington
    • Seattle, Washington, United States, 98109-1024
      • Fred Hutchinson Cancer Research Center
  • West Virginia
    • Morgantown, West Virginia, United States, 26506
      • West Virginia University Hospital
  • Wisconsin
    • Madison, Wisconsin, United States, 53792-5156
      • University of Wisconsin Hospital & Clinics
    • Milwaukee, Wisconsin, United States, 53211
      • Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 70 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients meeting the criteria for symptomatic multiple myeloma (MM).
• Patients who are 70 years of age, or younger, at time of enrollment.
• Patients who have received at least two cycles of any regimen as initial systemic therapy and are within 2 - 12 months of the first dose of initial therapy.
• Cardiac function: left ventricular ejection fraction at rest greater than 40 percent.
• Hepatic: bilirubin less than 1.5x the upper limit of normal and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than 2.5x the upper limit of normal. (Patients who have been diagnosed with Gilbert's Disease are allowed to exceed the defined bilirubin value of 1.5x the upper limit of normal.)
• Renal: Creatinine clearance of grater than or equal to 40 mL/min, estimated or calculated.
• Pulmonary: Diffusing capacity of the lung for carbon monoxide (DLCO), forced expiratory volume in one second (FEV1), or forced vital capacity (FVC) greater than 50 percent of predicted value (corrected for hemoglobin).
• Patients with an adequate autologous graft defined as a cryopreserved PBSC graft containing greater than or equal to 4 x 10^6 CD34+ cells/kg patient weight. The graft may not be CD34+ selected or otherwise manipulated to remove tumor or other cells. The graft can be collected at the transplanting institution or by a referring center. The autograft must be stored so that there are two products each containing at least 2 x 10^6 CD34+ cells/kg patient weight.
• Signed informed consent form.

Exclusion Criteria:

• Patients who never fulfill the criteria for symptomatic MM.
• Patients with purely non-secretory MM [absence of a monoclonal protein (M protein) in serum as measured by electrophoresis and immunofixation and the absence of Bence Jones protein in the urine defined by use of conventional electrophoresis and immunofixation techniques]. Patients with light chain MM detected in the serum by free light chain assay are eligible.
• Patients with plasma cell leukemia.
• Karnofsky performance score less than 70 percent.
• Patients with greater than grade 2 sensory neuropathy (CTCAE).
• Patients with uncontrolled bacterial, viral or fungal infections (currently taking medication and progression of clinical symptoms).
• Patients seropositive for the human immunodeficiency virus (HIV).
• Myocardial infarction within 6 months prior to enrollment 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. Prior to study entry, any ECG abnormality at Screening has to be documented by the investigator as not medically relevant.
• Patient has hypersensitivity to bortezomib, boron or mannitol.
• Patient has received other investigational drugs with 14 days before enrollment.
• Patients with prior malignancies except resected basal cell carcinoma or treated cervical carcinoma in situ. Cancer treated with curative intent less than 5 years previously will not be allowed unless approved by the Protocol Officer or one of the Protocol Chairs. Cancer treated with curative intent greater than 5 years previously is allowed.
• Female patients who are pregnant (positive B-HCG) or breastfeeding.
• Females of childbearing potential (FCBP) or men who have sexual contact with FCBP unwilling to use contraceptive techniques during the length of lenalidomide maintenance therapy.
• Prior allograft or prior autograft.
• Patients who have received mid-intensity melphalan (greater than 50 mg IV) as part of prior therapy.
• Patients unable or unwilling to provide informed consent.
• Prior organ transplant requiring immunosuppressive therapy.
• Patients with disease progression prior to enrollment.
• Patients who have received lenalidomide as initial therapy for MM and have experienced toxicities resulting in treatment discontinuation.
• Patients who experienced thromboembolic events while on full anticoagulation during prior therapy with lenalidomide or thalidomide.
• Patients unwilling to take deep vein thrombosis (DVT) prophylaxis.
• Patients who cannot undergo an intervention in any treatment arm due to a priori denial of medical costs coverage by third party payers.
• Patients unable to unwilling to return to the transplant center for their assigned treatments.

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

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Tandem auto transplant; Initial autologous transplant followed by a second autologous transplant and lenalidomide maintenance	Drug: Lenalidomide; All patients will undergo a first autologous peripheral blood stem cell (PBSC) transplant with high-dose melphalan (200 mg/m^2 IV) given on Day -2. Upon recovery from the first transplant patients will receive a second autologous PBSC transplant with the same conditioning regimen as the first transplant. All patients will also receive maintenance lenalidomide which will start after the second transplant. Maintenance therapy with lenalidomide will start at 10 mg daily for 3 months and increase to 15 mg daily. The duration of maintenance will be three years in all treatment arms.; Other Names: Revlimid™; Drug: Lenalidomide; All patients will undergo a first autologous peripheral blood stem cell (PBSC) transplant with high-dose melphalan (200 mg/m^2 IV) given on Day -2. Upon recovery from the first transplant patients will receive maintenance with lenalidomide (15 mg daily). Maintenance lenalidomide will start after the first autologous transplant. Maintenance therapy with lenalidomide will start at 10 mg daily for 3 months and increase to 15 mg daily. The duration of maintenance will be three years in all treatment arms.; Other Names: Revlimid™
Active Comparator: RVD consolidation; Initial autologous transplant followed by lenalidomide, bortezomib and dexamethasone (RVD) consolidation and lenalidomide maintenance	Drug: lenalidomide, bortezomib and dexamethasone; All patients will undergo a first autologous peripheral blood stem cell (PBSC) transplant with high-dose melphalan (200 mg/m^2 IV) given on Day -2. Upon recovery from the first transplant patients will receive consolidation therapy with RVD (lenalidomide 15 mg/day on Days 1-14, dexamethasone 40mg on Days 1, 8 and 15, and bortezomib 1.3mg/m2 on Days 1, 4, 8 and 11 of every 21 day cycle, patients will receive four cycles). All patients will also receive maintenance lenalidomide which will start after consolidation therapy. Maintenance therapy with lenalidomide will start at 10 mg daily for 3 months and increase to 15 mg daily. The duration of maintenance will be three years in all treatment arms.; Other Names: Revlimid™, Velcade®, and Decadron
Active Comparator: Lenalidomide maintenance; Initial autologous transplant followed by lenalidomide maintenance	Drug: Lenalidomide; All patients will undergo a first autologous peripheral blood stem cell (PBSC) transplant with high-dose melphalan (200 mg/m^2 IV) given on Day -2. Upon recovery from the first transplant patients will receive a second autologous PBSC transplant with the same conditioning regimen as the first transplant. All patients will also receive maintenance lenalidomide which will start after the second transplant. Maintenance therapy with lenalidomide will start at 10 mg daily for 3 months and increase to 15 mg daily. The duration of maintenance will be three years in all treatment arms.; Other Names: Revlimid™; Drug: Lenalidomide; All patients will undergo a first autologous peripheral blood stem cell (PBSC) transplant with high-dose melphalan (200 mg/m^2 IV) given on Day -2. Upon recovery from the first transplant patients will receive maintenance with lenalidomide (15 mg daily). Maintenance lenalidomide will start after the first autologous transplant. Maintenance therapy with lenalidomide will start at 10 mg daily for 3 months and increase to 15 mg daily. The duration of maintenance will be three years in all treatment arms.; Other Names: Revlimid™

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Progression-free Survival (PFS)	Progression-free survival is defined as survival without disease progression or initiation of non-protocol anti-myeloma therapy. To account for loss to follow-up of a few participants, the Kaplan-Meier estimator was used to estimate progression-free survival at 38 months post-randomization.	38 months post-randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Disease Progression	Disease Progression is defined as progression of multiple myeloma, including one or more of the following: A reappearance of serum monoclonal paraprotein, with a level of at least 0.5 g/dL; 24-hour urine protein electrophoresis with at least 200 mg paraprotein/24 hours; Abnormal free light chain levels of >10 mg/dl, only in patients without measurable paraprotein in the serum and urine; At least 10% plasma cells in a bone marrow aspirate or on trephine biopsy; Definite increase in the size of existing bone lesions or soft tissue plasmacytomas; Development of new bone lesions or soft tissue plasmacytomas; Development of hypercalcemia (corrected serum Ca >11.5 mg/dL or >2.8 mmol/L) not attributable to any other cause To account for loss to follow-up of a few participants, the cumulative incidence of TRM at 38 months post-randomization was estimated using the Aalen-Johansen estimator, treating death prior to disease progression as a competing risk.	38 months post-randomization
Percentage of Participants With Overall Survival (OS)	Overall survival is defined as survival of death from any cause. To account for loss to follow-up of a few participants, the Kaplan-Meier estimator was used to estimate overall survival at 38 months post-randomization.	38 months post-randomization
Percentage of Participants With Treatment-related Mortality (TRM)	TRM is defined as death prior to progression of multiple myeloma. To account for loss to follow-up of a few participants, the cumulative incidence of TRM at 38 months post-randomization was estimated using the Aalen-Johansen estimator, treating disease progression as a competing risk.	Up to 38 months post-randomization
Number of Participants With Treatment Response	The number of participants with very good partial response (VGPR) or better [complete response (CR), near CR (nCR), and stringent CR (sCR)] according to the International Uniform Response Criteria will be calculated. The "Worse than VGPR" group includes PR, stable disease, and progressive disease. sCR requires, in addition to CR: Normal free light chain ratio (FLC), Absence of clonal cells in bone marrow CR requires, in addition to nCR: Absence of the original monoclonal paraprotein (PPN), Disappearance of soft tissue plasmacytomas nCR is defined as: < 5% plasma cells in a bone marrow aspirate, No increase in lytic bone lesions VGPR requires: Serum or urine PPN not detectable on electrophoresis OR >=90% reduction in serum PPN plus urine PPN <100 mg/24hrs, >= 50% reduction in the level of serum monoclonal PPN or reduction in 24 hour urinary monoclonal PPN either >= 90% or to <200 mg/24 hours in light chain disease, >= 50% reduction in the size of soft tissue plasmacytomas	1 and 2 years post-randomization
FACT-G Total Score	The Functional Assessment of Cancer Therapy-General (FACT-G) is a quality of life instrument that assesses the effects of cancer therapy on a patient's physical, social/family, emotional, and functional well-being. The assessment has 27 questions, each scored on a Likert scale from 0-4. The overall score is computed by adding scores of the questions and falls in the range 0-108, with higher scores indicating higher levels of overall well-being.	Up to 3 years post-randomization
FACT-BMT Score	The Functional Assessment of Cancer Therapy-Bone Marrow Transplant scale (FACT-BMT) is a quality of life instrument that assesses the effects of bone marrow transplantation (BMT) on a patient's physical, social/family, emotional, and functional well-being while taking into consideration BMT-specific concerns. The assessment has 37 questions, each scored on a Likert scale from 0-4. The overall score is computed by adding scores of the questions and falls in the range 0-148, with higher scores indicating higher levels of overall well-being.	Up to 3 years post-randomization
FACT-BMT Trial Outcome Index	The Functional Assessment of Cancer Therapy (FACT) Trial Outcome Index is a quality of life instrument that assesses the impact of bone marrow transplantation (BMT) on a patient's physical and functional well-being while taking into consideration BMT-specific concerns. The assessment has 24 questions, each scored on a Likert scale from 0-4. The overall score is computed by adding scores of the questions and falls in the range 0-96, with higher scores indicating higher levels of overall well-being.	Up to 3 years post-randomization
MOS SF-36 Physical Component Summary	The Medical Outcome Study (MOS) SF-36 Physical Component Summary is a subscale of the SF-36 intended to measure physical well-being. It is scored on a scale of 0-100, with higher scores indicating higher levels of well-being.	Up to 3 years post-randomization
MOS SF-36 Mental Component Summary	The Medical Outcome Study (MOS) SF-36 Mental Component Summary is a subscale of the SF-36 intended to measure mental well-being. It is scored on a scale of 0-100, with higher scores indicating higher levels of well-being.	Up to 3 years post-randomization

Collaborators and Investigators

• Sponsor: National Heart, Lung, and Blood Institute (NHLBI)
• Collaborators: National Cancer Institute (NCI); Blood and Marrow Transplant Clinical Trials Network

Publications and helpful links

General Publications

• Stadtmauer EA, Pasquini MC, Blackwell B, Hari P, Bashey A, Devine S, Efebera Y, Ganguly S, Gasparetto C, Geller N, Horowitz MM, Koreth J, Knust K, Landau H, Brunstein C, McCarthy P, Nelson C, Qazilbash MH, Shah N, Vesole DH, Vij R, Vogl DT, Giralt S, Somlo G, Krishnan A. Autologous Transplantation, Consolidation, and Maintenance Therapy in Multiple Myeloma: Results of the BMT CTN 0702 Trial. J Clin Oncol. 2019 Mar 1;37(7):589-597. doi: 10.1200/JCO.18.00685. Epub 2019 Jan 17.

Helpful Links

• Blood and Marrow Transplant Clinical Trials Network Website
• National Marrow Donor Program

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2010
• Primary Completion (Actual): January 15, 2017
• Study Completion (Actual): March 3, 2018

Study Registration Dates

• First Submitted: April 21, 2010
• First Submitted That Met QC Criteria: April 21, 2010
• First Posted (Estimate): April 22, 2010

Study Record Updates

• Last Update Posted (Actual): December 9, 2021
• Last Update Submitted That Met QC Criteria: December 8, 2021
• Last Verified: December 1, 2021

More Information

Terms related to this study

• Keywords: Progression; Lenalidomide; Maintenance Therapy; Autologous Transplant; Symptomatic Multiple Myeloma; Anti-Myeloma Agents; Hematologic Disorders; RVD Consolidation
• 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; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Dexamethasone; Lenalidomide; Bortezomib
• Other Study ID Numbers: BMTCTN0702; 690 (National Heart, Lung, and Blood Institute); BMT CTN 0702 (Other Identifier: Blood and Marrow Transplant Clinicial Trials Network); U01HL069294-05 (NIH)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Results will be published in a manuscript and supporting information submitted to NIH BioLINCC (including data dictionaries, case report forms, data submission documentation, documentation for outcomes dataset, etc where indicated).
• IPD Sharing Time Frame: Within 6 months of official study closure at participating sites.
• IPD Sharing Access Criteria: Available to the public
• IPD Sharing Supporting Information Type: Study Protocol; Informed Consent Form (ICF)