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

Phase 3

Completed

Conditions: Multiple Myeloma

Interventions: Procedure: One Autologous Transplant
Procedure: Second Autologous Transplant
Procedure: Non-Myeloablative Allogeneic Transplant
Behavioral: Observation
Drug: Thalidomide
Drug: Dexamethasone

Registration Number: NCT00075829

Lead Sponsor: National Heart, Lung, and Blood Institute (NHLBI)

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 710

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Auto transplants plus Therapy	One Autologous Transplant	One autologous transplant along with a second autologous transplant will be preformed followed by one year of Dexamethasone and Thalidomide maintenance therapy.
Auto transplants plus Therapy	Second Autologous Transplant	One autologous transplant along with a second autologous transplant will be preformed followed by one year of Dexamethasone and Thalidomide maintenance therapy.
Auto transplants	One Autologous Transplant	One autologous transplant along with a second autologous transplant will be preformed followed by one year of observation.
Auto transplants	Second Autologous Transplant	One autologous transplant along with a second autologous transplant will be preformed followed by one year of observation.
Auto transplants	Observation	One autologous transplant along with a second autologous transplant will be preformed followed by one year of observation.
Auto and Allo transplants	One Autologous Transplant	One autologous transplant and one non-myeloablative allogeneic transplant will be preformed and followed by one year of observation.
Auto and Allo transplants	Non-Myeloablative Allogeneic Transplant	One autologous transplant and one non-myeloablative allogeneic transplant will be preformed and followed by one year of observation.
Auto and Allo transplants	Observation	One autologous transplant and one non-myeloablative allogeneic transplant will be preformed and followed by one year of observation.
Auto transplants plus Therapy	Thalidomide	One autologous transplant along with a second autologous transplant will be preformed followed by one year of Dexamethasone and Thalidomide maintenance therapy.
Auto transplants plus Therapy	Dexamethasone	One autologous transplant along with a second autologous transplant will be preformed followed by one year of Dexamethasone and Thalidomide maintenance therapy.

Primary Outcome Measures

Name	Time	Method
Progression-Free Survival (PFS)	Year 3	Patients are considered a failure for this endpoint if they die or if they progress or relapse.

Secondary Outcome Measures

Name	Time	Method
Overall Survival (OS) for Standard Risk	Years 1, 2, and 3	The event is death from any cause, patients alive at the time of last observation are considered censored.
Overall Survival (OS) for High Risk	Year 3	The event is death from any cause, patients alive at the time of last observation are considered censored.
Cumulative Incidence of Progression/Relapse	Year 3	Patients are considered experiencing an event when they progress. Deaths without progression are considered as a competing risk. Patients initiating non-protocol anti-myeloma therapy are considered to have progressed on this protocol.
Cumulative Incidence of Treatment Related Mortality (TRM)	Year 3	TRM is defined as death occurring in a patient from causes other than relapse or progression.
Interval From First to Second Transplantation	Year 1	Upon recovery from the first autograft, but at least 60 days (preferably between 60-120 days) after the first autograft, patients will receive a second transplant according to treatment assignments.
Incidences of Graft Versus Host Disease (GVHD)	Day 100	Incidence and severity of GVHD will be scored according to the BMT clinical trials network Manual of Procedures.
Incidences of Chronic GVHD	Years 1 and 2	Incidence and severity of chronic GVHD will be scored according to the BMT clinical trials network Manual of Procedures.

Trial Locations

Locations (36): DFCI/Brigham & Women's
🇺🇸
Boston, Massachusetts, United States
Fred Hutchinson Cancer Research Center
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Seattle, Washington, United States
University of Minnesota
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Minneapolis, Minnesota, United States
Duke University Medical Center
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Durham, North Carolina, United States
Vanderbilt University
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Nashville, Tennessee, United States
Texas Transplant Institute
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San Antonio, Texas, United States
University of Alabama at Birmingham
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Birmingham, Alabama, United States
Scripps Clinic/Green Hospital
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La Jolla, California, United States
City of Hope Samaritan
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Phoenix, Arizona, United States
UCSD Medical Center
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La Jolla, California, United States
Tufts - New England Medical Center
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Boston, Massachusetts, United States
University of Texas/MD Anderson Cancer Research Center
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Houston, Texas, United States
University of Oklahoma Medical Center
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Oklahoma City, Oklahoma, United States
University Hospitals of Cleveland/Case Western
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Cleveland, Ohio, United States
Memorial Sloan-Kettering Cancer Center
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New York, New York, United States
Fox Chase - Temple University - BMT Program
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Philadelphia, Pennsylvania, United States
Virginia Commonwealth University MCV Hospitals
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Richmond, Virginia, United States
Baylor College of Medicine/The Methodist Hospital
🇺🇸
Houston, Texas, United States
Stanford Hospital and Clinics
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Stanford, California, United States
Loyola University
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Maywood, Illinois, United States
University of Florida College of Medicine (Shands)
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Gainesville, Florida, United States
Wichita CCOP
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Wichita, Kansas, United States
University of Pennsylvania Cancer Center
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Philadelphia, Pennsylvania, United States
University of Wisconsin Hospitals & Clinics
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Madison, Wisconsin, United States
Hackensack University Medical Center
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Hackensack, New Jersey, United States
BMT Group of Georgia/Northside Hospital
🇺🇸
Atlanta, Georgia, United States
IBMT (Indiana Blood and Marrow Transplant) at St Francis Franciscan Health
🇺🇸
Indianapolis, Indiana, United States
Emory University
🇺🇸
Atlanta, Georgia, United States
Colorado Blood Cancer Institute
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Denver, Colorado, United States
City of Hope National Medical Center
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Duarte, California, United States
Jewish Hospital BMT Program
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Cincinnati, Ohio, United States
Utah BMT/Univ of Utah Med School
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Salt Lake City, Utah, United States
Oregon Health Sciences University (A)
🇺🇸
Portland, Oregon, United States
University of Michigan Medical Center
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Ann Arbor, Michigan, United States
University of Nebraska Medical Center
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Omaha, Nebraska, United States
Medical College of Wisconsin
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Milwaukee, Wisconsin, United States