Clinical Trial - Tandem Autologous Stem Cell Transplantation with Or Without Maintenance Therapy After the Second Transplantation Compared with Autologous Stem Cell Transplantation Followed by Matched Sibling Allogeneic Stem Cell Transplantation in Patients with Stage II Or Stage III Multiple Myeloma

Title:	Tandem Autologous Stem Cell Transplantation with Or Without Maintenance Therapy After the Second Transplantation Compared with Autologous Stem Cell Transplantation Followed by Matched Sibling Allogeneic Stem Cell Transplantation in Patients with Stage II Or Stage III Multiple Myeloma

Phase:	III

Purpose:	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.

Eligibility:	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 70 and under Karnofsky 70-100% Bilirubin < 2 times upper limit of normal (ULN) ALT and AST < 3 times ULN Creatinine clearance > 40 mL/min LVEF > 40% at rest No uncontrolled hypertension DLCO > 50% of predicted FEV_1 > 50% of predicted* FVC > 50% of predicted* NOTE: *Corrected for hemoglobin 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 No prior autograft or allograft No prior mid-intensity melphalan (> 50 mg IV) 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

Treatment:	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.

Contact:	Arizona Phoenix, AZ Banner Good Samaritan Medical Center PI-Jeffrey Schriber, MD 602-239-4526 California Stanford, CA Stanford Cancer Center at Stanford University Medical Center PI- Keith Stockerl-Goldstein, MD 650-722-0822 La Jolla, CA Scripps Cancer Center at Scripps Clinic PI- James R. Mason, MD 858-554-8597 Florida Gainsville, FL University of Florida Shands Cancer Center PI- John R. Wingard, MD 352-846-1846 Georgia Atlanta, GA Blood and Marrow Transplant Group of Georgia at Northside Hospital Claudet Ryan � Clinical Research Nurse 404-255-1930 Massachusetts Boston, MA Dana Farber/Harvard Cancer Center at Dana Farber Cancer Institute PI- Edwin P. Alyea 617-632-3903 Minnesota Minneapolis, MN University of Minnesota Cancer Center PI- Daniel J. Weisdorf 612-624-3101 New Jersey Hackensack, NJ Cancer Center at Hackensack University Medical Center PI- Scott D. Rowley, MD, FACP 201-996-5900 Oregon Portland, OR Cancer Institute at Oregon Health and Science University PI-Richard Maziarz, MD 503-494-1551 Pennsylvania Philadelphia, PA Abramson Cancer Center of the University of Pennsylvania PI- Edward A. Stadtmauer, MD 215-662-7910 Texas Houston, TX M.D. Anderson Cancer Center at the University of Texas PI- Sergio Giralt, MD 713-794-5745 San Antonio, TX Texas Transplant Institute PI� Paul Shaughnessy, MD 210-575-8500 Virginia Richmond, VA Massey Cancer Center at Virginia Commonwealth University PI- John M. McCarty, MD 804-828-4360 Wisconsin Milwaukee, WI Medical College of Wisconsin Cancer Center PI- J. Douglas Rizzo 414-805-4693

Please note: the trials indicated do not include the full inclusion or exclusion criteria. For full protocols, please contact the Principal Investigator (PI) listed.