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

Multiple Myeloma Clinical Trial

Official title:

A Trial of Tandem Autologous Stem Cell Transplants +/- Post Second Autologous Transplant Maintenance Therapy vs Single Autologous Stem Cell Transplant Followed by Matched Sibling Non-myeloablative Allogeneic Stem Cell Transplant for Patients With Multiple Myeloma (BMT CTN #0102)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00075829
• Other study ID #: BMTCTN0102
• Secondary ID: BMT CTN 0102SUMC
• Status: Completed
• Phase: Phase 3
• Start date: December 2003
• Est. completion date: March 2013

Study information

• Verified date: August 2017
• Source: National Heart, Lung, and Blood Institute (NHLBI)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Other known NCT identifiers

• NCT00321607
• NCT00386568

Recruitment information / eligibility

• Status: Completed
• Enrollment: 710
• Est. completion date: March 2013
• Est. primary completion date: June 2012
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 70 Years

Eligibility

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

Related Conditions & MeSH terms

• Multiple Myeloma
• Neoplasms, Plasma Cell

Intervention

Procedure:
• 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.
• 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.
• 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.

Drug:
• 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.
• 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.

Behavioral:
• Observation
One year of observation post-transplants.

Locations

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

Sponsors (4)

Lead Sponsor	Collaborator
National Heart, Lung, and Blood Institute (NHLBI)	Blood and Marrow Transplant Clinical Trials Network, National Cancer Institute (NCI), National Marrow Donor Program

Country where clinical trial is conducted

United States, 

References & Publications (2)

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 M — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression-Free Survival (PFS)	Patients are considered a failure for this endpoint if they die or if they progress or relapse.	Year 3
Secondary	Overall Survival (OS) for Standard Risk	The event is death from any cause, patients alive at the time of last observation are considered censored.	Years 1, 2, and 3
Secondary	Overall Survival (OS) for High Risk	The event is death from any cause, patients alive at the time of last observation are considered censored.	Year 3
Secondary	Cumulative Incidence of Progression/Relapse	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.	Year 3
Secondary	Cumulative Incidence of Treatment Related Mortality (TRM)	TRM is defined as death occurring in a patient from causes other than relapse or progression.	Year 3
Secondary	Interval From First to Second Transplantation	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.	Year 1
Secondary	Incidences of Graft Versus Host Disease (GVHD)	Incidence and severity of GVHD will be scored according to the BMT clinical trials network Manual of Procedures.	Day 100
Secondary	Incidences of Chronic GVHD	Incidence and severity of chronic GVHD will be scored according to the BMT clinical trials network Manual of Procedures.	Years 1 and 2

External Links

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