RATIONALE: Drugs used in chemotherapy, such as melphalan, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving chemotherapy with a peripheral stem cell transplant, using stem cells from the patient or a brother or sister, may allow more chemotherapy to be given so more cancer cells are killed. Giving maintenance therapy after a stem cell transplant may kill any cancer cells that remain. Sometimes the transplanted cells can be rejected by the body's tissues. Cyclosporine, total-body irradiation, and mycophenolate mofetil may prevent this. It is not yet known whether an autologous stem cell transplant followed by maintenance therapy is more effective than an autologous stem cell transplant followed by an allogeneic stem cell transplant in treating multiple myeloma.

PURPOSE: This randomized phase III trial is studying to compare the effectiveness of tandem (two) autologous stem cell transplantation with or without maintenance therapy with that of autologous stem cell transplantation followed by matched sibling (brother or sister) allogeneic (donor) stem cell transplantation in treating patients who have stage II or stage III multiple myeloma.

Condition	Treatment or Intervention	Phase
stage II multiple myeloma stage III multiple myeloma refractory plasma cell neoplasm	Drug: cyclosporine  Drug: dexamethasone  Drug: filgrastim  Drug: melphalan  Drug: mycophenolate mofetil  Drug: thalidomide  Procedure: anti-cytokine therapy  Procedure: antiangiogenesis therapy  Procedure: biological response modifier therapy  Procedure: bone marrow ablation with stem cell support  Procedure: chemotherapy  Procedure: colony-stimulating factor therapy  Procedure: cytokine therapy  Procedure: endocrine therapy  Procedure: graft versus host disease prophylaxis/therapy  Procedure: graft versus tumor induction  Procedure: growth factor antagonist therapy  Procedure: high-dose chemotherapy  Procedure: hormone therapy  Procedure: non-specific immune-modulator therapy  Procedure: peripheral blood stem cell transplantation  Procedure: radiation therapy  Procedure: steroid therapy  Procedure: supportive care/therapy	Phase III

Further Study Details: 

OBJECTIVES: Primary

• Compare the 3-year progression-free survival of patients with stage II or III multiple myeloma treated with tandem autologous stem cell transplantations (SCTs) with or without maintenance therapy after the second transplantation vs single autologous SCT followed by matched sibling nonmyeloablative allogeneic SCT.

Secondary

• Compare "current" myeloma-stable survival and 3-year overall survival of patients treated with these regimens.
• Compare the incidence of progression in patients treated with these regimens.

Tertiary

• Compare the 2-month and 12-month complete remission (CR) and CR plus partial remission (PR) rates after the second SCT in patients treated with tandem autologous SCTs with or without maintenance therapy.
• Compare the 2-month and 12-month CR and CR plus PR rates after allograft in patients treated with a single autologous SCT followed by allogeneic SCT.
• Compare the time to CR and CR plus PR in patients treated with these regimens.
• Compare the time to off-study therapy in patients treated with these regimens.
• Compare the time to second SCT in patients treated with these regimens.
• Determine the rate of discontinuation of maintenance therapy and the duration of maintenance therapy in patients treated with tandem autologous SCTs.
• Compare the incidence of infections and grade 3 or greater toxic effects in patients treated with tandem autologous SCTs with or without maintenance therapy.
• Determine the quality of life of patients treated with these regimens.
• Determine the incidence of primary and secondary graft failure in patients treated with a single autologous SCT followed by allogeneic SCT.
• Determine the incidence and severity of graft-versus-host disease in patients treated with a single autologous SCT followed by allogeneic SCT.

OUTLINE: This is a multicenter study with a randomized portion. Patients are stratified according to disease risk status (high vs standard) and participating center.

All patients receive an initial autologous stem cell transplantation (SCT).

• Conditioning for autologous SCT: Patients receive high-dose melphalan IV over 15-20 minutes on day -2.
• Autologous SCT: Patients receive autologous SCT on day 0. Patients also receive filgrastim (G-CSF) subcutaneously or IV daily beginning on day 5 and continuing until blood counts recover. Upon recovery from the initial autologous SCT (between 60-120 days), patients with an HLA-matched sibling donor receive an allogeneic SCT with nonmyeloablative conditioning. Patients without an HLA-matched sibling donor receive a second autologous SCT with conditioning as above.
• Nonmyeloablative conditioning for allogeneic SCT: Patients undergo total body irradiation (TBI) on day 0.
• Allogeneic transplantation: Patients receive allogeneic SCT on day 0 after the completion of TBI.
• Immunosuppression: Patients receive oral or IV cyclosporine twice daily beginning on day -3 followed by a taper beginning on day 84 and continuing until day 114 if disease is not in complete remission (CR) or partial remission (PR) on day 84 OR until day 180 if disease is in CR or PR on day 84. Patients also receive oral mycophenolate mofetil twice daily OR IV 3 times daily on days 0-27. Patients receiving a second autologous SCT are randomized to 1 of 2 treatment arms for maintenance therapy or observation beginning at least 60 days after the second transplantation.
• Arm I: Patients receive oral thalidomide daily beginning on day 1 and oral dexamethasone on days 1-4. Courses repeat monthly for 12 months in the absence of disease progression or unacceptable toxicity.
• Arm II: Patients undergo observation. Quality of life is assessed at baseline, before the second transplantation, at 6 months, 1 year, and then annually for 2 years post-transplantation.

Patients receiving an allogeneic SCT are followed weekly for approximately 14 weeks, at 6 months, and then every 6 months for 2.5 years post-transplantation.

Patients receiving tandem autologous SCTs are followed weekly for approximately 14 weeks, monthly for 6 months, and then every 6 months for 2.5 years post-transplantation.

PROJECTED ACCRUAL: A total of 450-750 patients, including 150 standard-risk patients assigned to the autologous/allogeneic arm, will be accrued for this study within 3 years.

Ages Eligible for Study:  up to  70 Years,  Genders Eligible for Study:  Both

Criteria

DISEASE CHARACTERISTICS:

• Diagnosis of multiple myeloma meeting the Durie and Salmon criteria
• Stage II or III disease
• Symptomatic disease requiring treatment
• Previously treated with at least 3 months of systemic therapy with no more than 2-9 months since the initiation of that therapy, excluding the time for mobilization chemotherapy
• Adequate autologous graft defined as a cryopreserved peripheral blood stem cell graft containing ≥ 4.0 x 10
• CD34+ cells/kg*
• No graft CD34+ selected or otherwise manipulated to remove tumor or other cells
• Patients without an HLA-matched sibling donor must have 2 products, each containing ≥ 2 x 10^6 CD34+ cells/kg NOTE: *Patients with an identified HLA-matched sibling must have ≥ 2.0 x 106 CD34+ cells/kg
• No non-secretory multiple myeloma (i.e., absence of Bence Jones protein in the urine by conventional electrophoresis and immunofixation techniques)
• No plasma cell leukemia
• 6/6 HLA genotypically identical sibling donor (for patients receiving allogeneic stem cell transplantation [SCT])
• No identical twin

PATIENT CHARACTERISTICS: Age

• 70 and under

Performance status

• Karnofsky 70-100%

Life expectancy

• Not specified

Hematopoietic

• Not specified

Hepatic

• Bilirubin < 2 times upper limit of normal (ULN)
• ALT and AST < 3 times ULN

Renal

• Creatinine clearance > 40 mL/min

Cardiovascular

• LVEF > 40% at rest
• No uncontrolled hypertension

Pulmonary

• DLCO > 50% of predicted*
• FEV_1 > 50% of predicted*
• FVC > 50% of predicted* NOTE: *Corrected for hemoglobin

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 12 months after study participation
• HIV negative
• No uncontrolled bacterial, viral, or fungal infection (i.e., currently treating with medication with progression of clinical symptoms)
• No other malignancy within the past 5 years except resected basal cell carcinoma or treated carcinoma in situ of the cervix

PRIOR CONCURRENT THERAPY: Biologic therapy

• No prior autograft or allograft

Chemotherapy

• See Disease Characteristics
• No prior mid-intensity melphalan (> 50 mg IV)

Endocrine therapy

• Not specified

Radiotherapy

• No concurrent radiotherapy during melphalan administration
• Concurrent radiotherapy allowed for the following reasons provided patient is recovered from autologous SCT:
• Palliation of pain from bone lesions
• Prevention of pathologic fractures
• Relief of spinal cord compression or nerve root compression

Surgery

• Not specified

Arizona
      Banner Good Samaritan Medical Center, Phoenix,  Arizona,  85006,  United States; Recruiting
California
      City of Hope Comprehensive Cancer Center, Duarte,  California,  91010-3000,  United States; Recruiting
      Rebecca and John Moores UCSD Cancer Center, La Jolla,  California,  92037-0960,  United States; Recruiting
      Scripps Cancer Center at Scripps Clinic, La Jolla,  California,  92037-1027,  United States; Recruiting
      Stanford Cancer Center at Stanford University Medical Center, Stanford,  California,  94305-5623,  United States; Recruiting
Florida
      University of Florida Shands Cancer Center, Gainesville,  Florida,  32610-100277,  United States; Recruiting
Georgia
      Blood and Marrow Transplant Group of Georgia, Atlanta,  Georgia,  30342-4777,  United States; Recruiting
      Winship Cancer Institute of Emory University, Atlanta,  Georgia,  30322,  United States; Recruiting
Indiana
      Indiana Blood and Marrow Transplantation, Beech Grove,  Indiana,  46107,  United States; Recruiting
Massachusetts
      Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute, Boston,  Massachusetts,  02115,  United States; Recruiting
Michigan
      University of Michigan Comprehensive Cancer Center, Ann Arbor,  Michigan,  48109-0942,  United States; Recruiting
Minnesota
      University of Minnesota Cancer Center, Minneapolis,  Minnesota,  55455,  United States; Recruiting
Missouri
      Kansas City Cancer Centers - Central, Kansas City,  Missouri,  64111,  United States; Recruiting
      Siteman Cancer Center at Barnes-Jewish Hospital, Saint Louis,  Missouri,  63110,  United States; Recruiting
Nebraska
      UNMC Eppley Cancer Center at the University of Nebraska Medical Center, Omaha,  Nebraska,  68198-7680,  United States; Recruiting
New Jersey
      Cancer Center at Hackensack University Medical Center, Hackensack,  New Jersey,  07601,  United States; Recruiting
New York
      Memorial Sloan-Kettering Cancer Center, New York,  New York,  10021,  United States; Recruiting
North Carolina
      Duke Comprehensive Cancer Center, Durham,  North Carolina,  27710,  United States; Recruiting
Ohio
      Cleveland Clinic Taussig Cancer Center, Cleveland,  Ohio,  44195,  United States; Recruiting
      Ireland Cancer Center at University Hospitals of Cleveland and Case Western Reserve University, Cleveland,  Ohio,  44106-5065,  United States; Recruiting
Oregon
      Cancer Institute at Oregon Health and Science University, Portland,  Oregon,  97239-3098,  United States; Recruiting
Pennsylvania
      Abramson Cancer Center at the University of Pennsylvania, Philadelphia,  Pennsylvania,  19104-4283,  United States; Recruiting
      Fox Chase/Temple University BMT Program, Philadelphia,  Pennsylvania,  19111-2442,  United States; Recruiting
Tennessee
      Veterans Affairs Medical Center - Tennessee Valley Healthcare System - Nashville Campus, Nashville,  Tennessee,  37212,  United States; Recruiting
Texas
      MD Anderson Cancer Center at University of Texas, Houston,  Texas,  77030-4009,  United States; Recruiting
      Simmons Cancer Center at University of Texas Southwestern Medical Center - Dallas, Dallas,  Texas,  75235-8590,  United States; Recruiting
      Texas Transplant Institute, San Antonio,  Texas,  78229,  United States; Recruiting
Utah
      Huntsman Cancer Institute at University of Utah, Salt Lake City,  Utah,  84112,  United States; Recruiting
Virginia
      Massey Cancer Center at Virginia Commonwealth University, Richmond,  Virginia,  23298-0037,  United States; Recruiting
Washington
      Fred Hutchinson Cancer Research Center, Seattle,  Washington,  98109-1024,  United States; Recruiting
Wisconsin
      Medical College of Wisconsin Cancer Center, Milwaukee,  Wisconsin,  53226,  United States; Recruiting
      University of Wisconsin Comprehensive Cancer Center, Madison,  Wisconsin,  53792,  United States; Recruiting

Study chairs or principal investigators

David G. Maloney, MD, PhD,  Study Chair,  Fred Hutchinson Cancer Research Center   
Firoozeh Sahebi, MD,  Beckman Research Institute   
David G. Maloney, MD, PhD,  Study Chair,  Fred Hutchinson Cancer Research Center   

Study ID Numbers:  CDR0000349416; BMTCTN-0102; SUMC-79730; SWOG-BMTCTN-0102; NCT00075829
Record last reviewed:  November 2004
Last Updated:  April 4, 2005
Record first received:  January 9, 2004
ClinicalTrials.gov Identifier:  NCT00075829
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08