SWOG-9321 Melphalan, TBI, and Transplant vs Combo Chemo in Untreated Myeloma
Condition: Multiple Myeloma
MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell
Study type: Interventional
Phase: Phase 3

Summary: 
      RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing
      so they stop growing or die. Radiation therapy uses high-energy x-rays to damage cancer
      cells. Combining chemotherapy and radiation therapy with peripheral stem cell transplantation
      may allow the doctor to give higher doses of chemotherapy and radiation therapy and kill more
      cancer cells. It is not yet known which treatment regimen is more effective for multiple
      myeloma.

      PURPOSE: Randomized phase III trial to compare the effectiveness of melphalan, total-body
      irradiation, and peripheral stem cell transplantation with that of combination chemotherapy
      in treating patients who have previously untreated multiple myeloma.
    

Detailed description: 
      OBJECTIVES:

        -  Compare tumor cytoreduction achieved with VBMCP
           (vincristine/carmustine/melphalan/cyclophosphamide/prednisone) vs myeloablative
           melphalan (L-PAM) and total-body irradiation (TBI) with peripheral blood stem cell
           (PBSC) rescue in symptomatic myeloma patients with stable or responding disease after
           induction therapy with VAD (vincristine/doxorubicin/dexamethasone) followed by high dose
           cyclophosphamide plus filgrastim (G-CSF).

        -  Compare the efficacy of interferon alfa vs no maintenance therapy in those patients
           achieving at least 75% cytoreduction to either VBMCP or myeloablative therapy with PBSC
           rescue.

        -  Assess allogeneic bone marrow transplantation following the same myeloablative regimen
           of L-PAM/TBI in patients up to age 55 with an HLA-compatible, MLC-nonreactive donor. (As
           of 8/1/97, permanent partial closure)

        -  Determine whether myeloablative therapy with PBSC rescue can extend the duration of
           survival by 33% compared to results from standard dose VBMCP.

        -  Evaluate the toxic effects and possible long term side effects, including development of
           myelodysplastic disease and/or acute myeloblastic leukemia, associated with these
           treatments.

      OUTLINE: This is a randomized study. Patients are registered at 5 different points, with
      stratification occurring at some of these registrations.

        -  Registration I: Induction I

        -  Registration II: Induction II. Patients are stratified according to stage of disease
           (I/II vs IIIA vs IIIB), beta-2 microglobulin at diagnosis (less than 6 micrograms/mL vs
           at least 6 micrograms/mL), and response to Induction I (75-100% regression vs 50-74%
           regression vs less than 50% regression vs not applicable).

        -  Registration III: Patients are randomized to allogeneic bone marrow transplant (BMT)
           (this arm closed as of 8/1/97) or autologous BMT. Patients are stratified according to
           treatment received (high dose cyclophosphamide (CTX) and peripheral blood stem cells
           (PBSC) prior to autologous BMT vs prior to chemotherapy) and beta-2 microglobulin at
           this registration (less than 2 micrograms/mL vs no greater than 3 micrograms/mL vs
           unknown).

        -  Registration IV: Patients are randomized to maintenance therapy or no further therapy.
           Those patients who are randomized to maintenance therapy are stratified according to
           treatment (autologous BMT vs chemotherapy vs chemotherapy followed by autologous BMT)
           and response to treatment (75-99% regression vs complete response).

        -  Registration V: Patients receive autologous BMT as in registration III. Patients are
           stratified according to prior best response (50% or better vs less than 50% vs not
           applicable), duration of chemotherapy (at least 6 months vs less than 6 months), and
           progression after therapy (chemotherapy vs interferon alfa vs observation).

        -  Induction I: Patients receive vincristine IV and doxorubicin IV by continuous infusion
           on days 1-4 and dexamethasone IV or orally on days 1-4, 9-12, and 17-20. Treatment
           repeats every 5 weeks for up to 4 courses. Patients with progressive disease after 2
           courses proceed to PBSC stimulation/harvest.

      Allogeneic BMT arm is permanently closed as of 8/1/97.

        -  Autologous BMT: Therapy begins 4-8 weeks following high dose cyclophosphamide. Patients
           receive melphalan IV over 1 hour on day -5 and total body irradiation twice a day on
           days -4 to -1. PBSC are reinfused on day 0. G-CSF SQ is administered beginning on day 1
           until blood counts recover.

        -  Chemotherapy: Patients receive vincristine IV, carmustine IV, and cyclophosphamide IV on
           day 1, oral melphalan on days 1-4, and oral prednisone on days 1-7. Treatment repeats
           every 5 weeks for at least 12 months.

      Patients who have at least a 75% response to autologous BMT or chemotherapy are randomized to
      maintenance vs no further therapy. Patients who progress on chemotherapy proceed to
      autologous BMT (registration V).

        -  Maintenance therapy: Therapy begins between 5 and 12 weeks after PBSC rescue. Patients
           receive interferon alfa SQ three times a week. Treatment continues for 4 years in the
           absence of disease progression or unacceptable toxicity.

      Patients who progress on chemotherapy undergo an autologous BMT within 8 weeks after the last
      course of chemotherapy.

      Patients who are randomized to receive no further therapy are observed for 1 year.

      PROJECTED ACCRUAL: A total of 500 patients will be randomized over about 4 years to
      autologous transplantation vs chemotherapy as follows: about 250 patients/year will be
      accrued for induction of whom 200 will achieve at least stable disease, 125 will be
      randomized, and 15 will have a suitable donor for allogeneic transplant (as of 8/1/97,
      allogeneic arm of study is closed). Approximately 300 patients are expected to be randomized
      to maintenance vs no further therapy.
    

Intervention name(s): recombinant interferon alfa; carmustine; cyclophosphamide; dexamethasone; doxorubicin hydrochloride; melphalan; prednisone; vincristine sulfate; allogeneic bone marrow transplantation; autologous bone marrow transplantation; peripheral blood stem cell transplantation; radiation therapy
Intervention type(s): Biological; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Procedure; Procedure; Procedure; Radiation
Intervention description(s): 3 million units/m2 SQ Monday-Wednesday
-Friday (3 times a week); 20 mg/m2 I.V. day 1 q 35 days; 1.5 g/m2 in 100 ml of D5W, IV intravenously over 1 hour every 3 hour x 3 (total dose 4.5 g/m2); 40 mg/day PO or IVPB days 1-4, 9-12, 17-20 q 5 weeks; 10 mg/m2/day continuous 1 - 4 q 5 weeks; 140 mg/m2 is given IV within 30 minutes of constitution on Day -5; 40 mg/m2 PO days 1-7 q 35 days; 0.5 mg/day continuous 1 - 4 q 5 weeks; day 0; day 0; day 0; administered in fractionated doses of 150 cGy, 6 - 10 hours apart bid, on Days -4, -3, -2, and -1 (Total 1,200 cGy)
Other intervention name(s): IFN, alpha interferon; BCNU; cytoxan; steroid, decadron; Adriamycin
Intervention MeSH terms: Interferons; Interferon-alpha; Dexamethasone; Prednisone; Cyclophosphamide; Melphalan; Carmustine; Doxorubicin; Liposomal doxorubicin; Vincristine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: stage I multiple myeloma; stage II multiple myeloma; stage III multiple myeloma