Stem Cell Transplantation in Individuals With Multiple Myeloma (BMT CTN 0102)

NCT ID: NCT00075829

Last Updated: 2021-11-01

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 710 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2003-12-31
• Study Completion Date: 2013-03-31

Brief Summary

The study is designed as a Phase III, multi-center trial of tandem autologous transplants versus the strategy of autologous followed by Human Leukocyte Antigen (HLA)-matched sibling non-myeloablative allogeneic transplant. Study subjects will be biologically assigned to the appropriate arm depending on the availability of an HLA-matched sibling. There is a nested randomized phase III trial of observation versus maintenance therapy following the second autologous transplant for patients on the tandem autologous transplant arm.

Detailed Description

Multiple myeloma (MM), characterized by malignant plasma cell proliferation, bone destruction, and immunodeficiency, is a disease with a median age at diagnosis of approximately 65 years. It is responsible for about 1 percent of all cancer-related deaths in Western Countries. Conventional treatments with chemotherapy and radiation therapy are non-curative but improve quality of life and duration of survival. Attempts to cure myeloma through high-dose therapy followed by autografting or allografting have largely failed due to a combination of relapsed disease or transplant related mortality (TRM). High-dose therapy with autologous transplantation is safe and has low TRM (less than 5%), but is associated with a continuing and nearly universal risk of disease progression and relapse. Even so, autologous transplantation is superior to continued conventional chemotherapy. Recent data indicate that tandem autologous transplants are superior to a single procedure. Even with this approach, patients remain at risk of relapse and additional approaches are needed.

DESIGN NARRATIVE:

The overall study design is that of biologic assignment, based on the availability of an HLA-matched sibling, to one of two treatment strategies for MM patients. Patients without an HLA-matched sibling will undergo tandem autologous transplants. Patients with an HLA-matched sibling will undergo an autologous transplant followed by a non-myeloablative allogeneic transplant. In addition, the tandem autologous transplant recipients will be randomized to either observation or one year of maintenance therapy to begin following the second autologous transplant. The large number of MM patients without an HLA-matched sibling enables us to evaluate the role of maintenance therapy following tandem autologous transplants.

Conditions

Multiple Myeloma

Keywords

Stage II Multiple Myeloma; Stage III Multiple Myeloma; Refractory Plasma Cell Neoplasm

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Auto transplants plus Therapy

One autologous transplant along with a second autologous transplant will be preformed followed by one year of Dexamethasone and Thalidomide maintenance therapy.

Group Type: ACTIVE_COMPARATOR

One Autologous Transplant

Intervention Type: PROCEDURE

Melphalan will be administered at a dose of 200 mg/m2. Melphalan will be given in one dose infused on Day -2. Melphalan dose is based on ideal body weight (IBW) for patients who weigh 100-120% of their IBW. All patients will receive an autologous graft with a minimum cell dose of 2.0 x 106 CD34+ cells/kg patient weight. Patients will receive \~5 ug/kg/day of Granulocyte-Colony Stimulating Factor (G-CSF) subcutaneously from Day 5 post-transplant until absolute neutrophil count (ANC) \> 500/mm3 for two days.

Second Autologous Transplant

Intervention Type: PROCEDURE

Upon recovery from the first autograft, but at least 60 days (preferably between 60-120 days) after the first autograft, patients without an HLA-matched sibling donor will receive a second autograft, also conditioned with melphalan 200 mg/m2.

Thalidomide

Intervention Type: DRUG

Patients will be initiated on a starting dose of 50 mg/day. The dose will be increased weekly by 50 mg as tolerated to achieve a target dose of 200 mg/day. Patients will be treated for 12 months with thalidomide.

Dexamethasone

Intervention Type: DRUG

Patients will receive dexamethasone at a dose of 40 mg per day during Days 1-4 of each month for 12 months. The first dose of dexamethasone to be given the same day the patient starts thalidomide.

Auto transplants

One autologous transplant along with a second autologous transplant will be preformed followed by one year of observation.

Group Type: ACTIVE_COMPARATOR

One Autologous Transplant

Intervention Type: PROCEDURE

Melphalan will be administered at a dose of 200 mg/m2. Melphalan will be given in one dose infused on Day -2. Melphalan dose is based on ideal body weight (IBW) for patients who weigh 100-120% of their IBW. All patients will receive an autologous graft with a minimum cell dose of 2.0 x 106 CD34+ cells/kg patient weight. Patients will receive \~5 ug/kg/day of Granulocyte-Colony Stimulating Factor (G-CSF) subcutaneously from Day 5 post-transplant until absolute neutrophil count (ANC) \> 500/mm3 for two days.

Second Autologous Transplant

Intervention Type: PROCEDURE

Upon recovery from the first autograft, but at least 60 days (preferably between 60-120 days) after the first autograft, patients without an HLA-matched sibling donor will receive a second autograft, also conditioned with melphalan 200 mg/m2.

Observation

Intervention Type: BEHAVIORAL

One year of observation post-transplants.

Auto and Allo transplants

One autologous transplant and one non-myeloablative allogeneic transplant will be preformed and followed by one year of observation.

Group Type: ACTIVE_COMPARATOR

One Autologous Transplant

Intervention Type: PROCEDURE

Melphalan will be administered at a dose of 200 mg/m2. Melphalan will be given in one dose infused on Day -2. Melphalan dose is based on ideal body weight (IBW) for patients who weigh 100-120% of their IBW. All patients will receive an autologous graft with a minimum cell dose of 2.0 x 106 CD34+ cells/kg patient weight. Patients will receive \~5 ug/kg/day of Granulocyte-Colony Stimulating Factor (G-CSF) subcutaneously from Day 5 post-transplant until absolute neutrophil count (ANC) \> 500/mm3 for two days.

Non-Myeloablative Allogeneic Transplant

Intervention Type: PROCEDURE

Upon recovery and at least Day 60 post-autograft, patients with an available 6/6 HLA matched sibling will receive an allograft after non-myeloablative conditioning. Day 0 patients will receive Total Body Irradiation (TBI) 2.0 Gy from a linear accelerator ≤ 20 cGy/min, followed by allogeneic peripheral blood stem cell (PBSC) infusion. Commence cyclosporine (CSA) on Day -3 at 5 mg/kg bid PO for a daily dose of 10 mg/kg/day through Day +84 based on actual body weight. Starting on Day 84, patients in partial or complete response with the absence of graph versus host disease (GVHD) will have CSA tapered so the patient will be off CSA by Day 180. Oral administration of Mycophenolate Mofetil will be at a daily dose of 30 mg/kg/day from the evening of Day 0 until Day 27 post-transplant.

Observation

Intervention Type: BEHAVIORAL

One year of observation post-transplants.

Interventions

One Autologous Transplant

Melphalan will be administered at a dose of 200 mg/m2. Melphalan will be given in one dose infused on Day -2. Melphalan dose is based on ideal body weight (IBW) for patients who weigh 100-120% of their IBW. All patients will receive an autologous graft with a minimum cell dose of 2.0 x 106 CD34+ cells/kg patient weight. Patients will receive \~5 ug/kg/day of Granulocyte-Colony Stimulating Factor (G-CSF) subcutaneously from Day 5 post-transplant until absolute neutrophil count (ANC) \> 500/mm3 for two days.

Intervention Type: PROCEDURE

Non-Myeloablative Allogeneic Transplant

Upon recovery and at least Day 60 post-autograft, patients with an available 6/6 HLA matched sibling will receive an allograft after non-myeloablative conditioning. Day 0 patients will receive Total Body Irradiation (TBI) 2.0 Gy from a linear accelerator ≤ 20 cGy/min, followed by allogeneic peripheral blood stem cell (PBSC) infusion. Commence cyclosporine (CSA) on Day -3 at 5 mg/kg bid PO for a daily dose of 10 mg/kg/day through Day +84 based on actual body weight. Starting on Day 84, patients in partial or complete response with the absence of graph versus host disease (GVHD) will have CSA tapered so the patient will be off CSA by Day 180. Oral administration of Mycophenolate Mofetil will be at a daily dose of 30 mg/kg/day from the evening of Day 0 until Day 27 post-transplant.

Intervention Type: PROCEDURE

Second Autologous Transplant

Upon recovery from the first autograft, but at least 60 days (preferably between 60-120 days) after the first autograft, patients without an HLA-matched sibling donor will receive a second autograft, also conditioned with melphalan 200 mg/m2.

Intervention Type: PROCEDURE

Thalidomide

Patients will be initiated on a starting dose of 50 mg/day. The dose will be increased weekly by 50 mg as tolerated to achieve a target dose of 200 mg/day. Patients will be treated for 12 months with thalidomide.

Intervention Type: DRUG

Dexamethasone

Patients will receive dexamethasone at a dose of 40 mg per day during Days 1-4 of each month for 12 months. The first dose of dexamethasone to be given the same day the patient starts thalidomide.

Intervention Type: DRUG

Observation

One year of observation post-transplants.

Intervention Type: BEHAVIORAL

Other Intervention Names

Thalomid™; Decadron, DexPak

Eligibility Criteria

Inclusion Criteria

• Meeting the Durie and Salmon criteria for initial diagnosis of MM
• Stage II or III MM at diagnosis or anytime thereafter
• Symptomatic MM requiring treatment at diagnosis or anytime thereafter
• Received at least three cycles of initial systemic therapy and are within 2-10 months of initiation of the initial therapy (this time frame excludes the time for mobilization therapy)
• If receiving chemotherapy-based mobilization regimens, must be able to receive high-dose melphalan between 2 and 8 weeks after the initiation of mobilization therapy whether delivered at the transplant center or at a referring center
• Adequate organ function as measured by:

1. Cardiac: Left ventricular ejection fraction at rest greater than 40%

2. Hepatic: Bilirubin less than 2 times the upper limit of normal and alanine transaminase (ALT) and aspartate transaminase (AST) less than 3 times the upper limit of normal

3. Renal: Creatinine clearance greater than 40 ml/min (measured or calculated/estimated)

4. Pulmonary: Carbon monoxide diffusion (DLCO), Volume forcibly exhaled in one second (FEV1), and Forced Vital Capacity (FVC) greater than 50% of predicted value (corrected for hemoglobin), or O2 saturation greater than 92% of room air

• An adequate autologous graft defined as a cryopreserved PBSC graft containing at least 4.0 x 106 CD34+ cells/kg patient weight; if prior to enrollment it is known that a patient will be on the auto-allo arm (i.e., a consenting, eligible HLA-matched sibling donor is available), the required autograft must contain at least 2.0 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; for patients without an HLA-matched sibling donor, the autograft must be stored so that there are two products each containing at least 2 x 10^6 CD34+ cells/kg patient weight

Exclusion Criteria

• Never advanced beyond Stage I MM since diagnosis
• 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)
• Plasma cell leukemia
• Karnofsky performance score less than 70%, unless approved by the Medical Monitor or one of the Protocol Chairs
• Uncontrolled hypertension
• Uncontrolled bacterial, viral, or fungal infections (currently taking medication and progression of clinical symptoms)
• 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 Medical Monitor or one of the Protocol Chairs; cancer treated with curative intent more than 5 years previously will be allowed
• Pregnant or breastfeeding
• Seropositive for the human immunodeficiency virus (HIV)
• Unwilling to use contraceptive techniques during and for 12 months following treatment
• Prior allograft or prior autograft
• Received mid-intensity melphalan (more than 50 mg IV) as part of prior therapy
• Prior organ transplant requiring immunosuppressive therapy

• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Blood and Marrow Transplant Clinical Trials Network

NETWORK

Sponsor Role: collaborator

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

National Marrow Donor Program

OTHER

Sponsor Role: collaborator

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Mary Horowitz, MD

Role: STUDY_DIRECTOR

Center for International Blood and Marrow Transplant Research

Locations

University of Alabama at Birmingham

Birmingham, Alabama, United States

City of Hope Samaritan

Phoenix, Arizona, United States

City of Hope National Medical Center

Duarte, California, United States

Scripps Clinic/Green Hospital

La Jolla, California, United States

UCSD Medical Center

La Jolla, California, United States

Stanford Hospital and Clinics

Stanford, California, United States

Colorado Blood Cancer Institute

Denver, Colorado, United States

University of Florida College of Medicine (Shands)

Gainesville, Florida, United States

Emory University

Atlanta, Georgia, United States

BMT Group of Georgia/Northside Hospital

Atlanta, Georgia, United States

Loyola University

Maywood, Illinois, United States

IBMT (Indiana Blood and Marrow Transplant) at St Francis Franciscan Health

Indianapolis, Indiana, United States

Wichita CCOP

Wichita, Kansas, United States

Tufts - New England Medical Center

Boston, Massachusetts, United States

DFCI/Brigham & Women's

Boston, Massachusetts, United States

University of Michigan Medical Center

Ann Arbor, Michigan, United States

University of Minnesota

Minneapolis, Minnesota, United States

University of Nebraska Medical Center

Omaha, Nebraska, United States

Hackensack University Medical Center

Hackensack, New Jersey, United States

Memorial Sloan-Kettering Cancer Center

New York, New York, United States

Duke University Medical Center

Durham, North Carolina, United States

Jewish Hospital BMT Program

Cincinnati, Ohio, United States

University Hospitals of Cleveland/Case Western

Cleveland, Ohio, United States

University of Oklahoma Medical Center

Oklahoma City, Oklahoma, United States

Oregon Health Sciences University (A)

Portland, Oregon, United States

University of Pennsylvania Cancer Center

Philadelphia, Pennsylvania, United States

Fox Chase - Temple University - BMT Program

Philadelphia, Pennsylvania, United States

Vanderbilt University

Nashville, Tennessee, United States

Baylor College of Medicine/The Methodist Hospital

Houston, Texas, United States

University of Texas/MD Anderson Cancer Research Center

Houston, Texas, United States

Texas Transplant Institute

San Antonio, Texas, United States

Utah BMT/Univ of Utah Med School

Salt Lake City, Utah, United States

Virginia Commonwealth University MCV Hospitals

Richmond, Virginia, United States

Fred Hutchinson Cancer Research Center

Seattle, Washington, United States

University of Wisconsin Hospitals & Clinics

Madison, Wisconsin, United States

Medical College of Wisconsin

Milwaukee, Wisconsin, United States

Countries

United States

References

Krishnan A, Pasquini MC, Logan B, Stadtmauer EA, Vesole DH, Alyea E 3rd, Antin JH, Comenzo R, Goodman S, Hari P, Laport G, Qazilbash MH, Rowley S, Sahebi F, Somlo G, Vogl DT, Weisdorf D, Ewell M, Wu J, Geller NL, Horowitz MM, Giralt S, Maloney DG; Blood Marrow Transplant Clinical Trials Network (BMT CTN). Autologous haemopoietic stem-cell transplantation followed by allogeneic or autologous haemopoietic stem-cell transplantation in patients with multiple myeloma (BMT CTN 0102): a phase 3 biological assignment trial. Lancet Oncol. 2011 Dec;12(13):1195-203. doi: 10.1016/S1470-2045(11)70243-1. Epub 2011 Sep 29.

Reference Type: RESULT

PMID: 21962393 (View on PubMed)

Logan B, Leifer E, Bredeson C, Horowitz M, Ewell M, Carter S, Geller N. Use of biological assignment in hematopoietic stem cell transplantation clinical trials. Clin Trials. 2008;5(6):607-16. doi: 10.1177/1740774508098326.

Reference Type: RESULT

PMID: 19029209 (View on PubMed)

Giralt S, Costa LJ, Maloney D, Krishnan A, Fei M, Antin JH, Brunstein C, Geller N, Goodman S, Hari P, Logan B, Lowsky R, Qazilbash MH, Sahebi F, Somlo G, Rowley S, Vogl DT, Vesole DH, Pasquini M, Stadtmauer E. Tandem Autologous-Autologous versus Autologous-Allogeneic Hematopoietic Stem Cell Transplant for Patients with Multiple Myeloma: Long-Term Follow-Up Results from the Blood and Marrow Transplant Clinical Trials Network 0102 Trial. Biol Blood Marrow Transplant. 2020 Apr;26(4):798-804. doi: 10.1016/j.bbmt.2019.11.018. Epub 2019 Nov 19.

Reference Type: DERIVED

PMID: 31756536 (View on PubMed)

Provided Documents

Document Type: Study Protocol, Statistical Analysis Plan, and Informed Consent Form

View Document

Study Documents

Document Type: Individual Participant Data Set

View Document

Document Type: Study Protocol

View Document

Document Type: Study Forms

View Document

Other Identifiers

BMT CTN 0102

Identifier Type: OTHER

Identifier Source: secondary_id

SUMC-79730

Identifier Type: OTHER

Identifier Source: secondary_id

417

Identifier Type: OTHER

Identifier Source: secondary_id

BMTCTN0102

Identifier Type: -

Identifier Source: org_study_id

NCT00321607

Identifier Type: -

Identifier Source: nct_alias

NCT00386568

Identifier Type: -

Identifier Source: nct_alias