SWOG-9321 Melphalan, TBI, and Transplant vs Combo Chemo in Untreated Myeloma
SWOG-9321 Melphalan, TBI, and Transplant vs Combo Chemo in Untreated Myeloma
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.
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.
DISEASE CHARACTERISTICS:

 -  Newly diagnosed, active multiple myeloma of any stage requiring treatment

 -  Smoldering myeloma (Durie-Salmon stage I) must have a 25% or greater increase in
 M component levels and/or Bence-Jones protein excretion or development of
 symptoms

 -  Quantifiable M component of IgG, IgA, IgD, IgE, and/or urinary kappa or lambda light
 chain (Bence-Jones protein) excretion required

 -  Plasmacytosis of at least 30% allowed for non-secretory disease or secretory
 disease without quantifiable protein

 -  IgM peaks excluded

 -  Evaluation of siblings as potential allogeneic bone marrow transplant donors required
 for patients 55 years of age and younger (As of 8/1/97, permanently closed)

 -  HLA followed by DR and MLC testing required

 -  Renal failure, even on dialysis, eligible provided:

 -  Cause is attributed to myeloma (Bence-Jones protein or hypercalcemia)

 -  Duration does not exceed 2 months

 -  If medically appropriate, the following conditions should be treated prior to
 registration:

 -  Pathologic fractures

 -  Pneumonia at diagnosis

 -  Hyperviscosity with shortness of breath

 PATIENT CHARACTERISTICS:

 Age:

 -  70 and under

 Performance status:

 -  SWOG 0-2 (SWOG 3 or 4 based solely on bone pain allowed)

 Hematopoietic:

 -  Not specified

 Hepatic:

 -  Not specified

 Renal:

 -  See Disease Characteristics

 Cardiovascular:

 -  Normal ejection fraction by ECHO or MUGA

 -  No myocardial infarction within 6 months

 -  No unstable angina

 -  No difficult to control congestive heart failure

 -  No uncontrolled hypertension

 -  No difficult to control arrhythmias

 -  No history of chronic cerebral vascular accident

 Pulmonary:

 -  No history of chronic obstructive or restrictive pulmonary disease

 -  Pulmonary function studies and DLCO at least 50% of predicted except for demonstrated
 myeloma involvement on bronchoscopy and/or open lung biopsy

 Other:

 -  No uncontrolled diabetes

 -  No significant comorbid medical condition

 -  No uncontrolled, life-threatening infection

 -  No prior malignancy within 5 years except adequately treated nonmelanoma skin cancer
 or carcinoma in situ of the cervix

 -  No prior malignancy treated with cytotoxic drugs used on this protocol

 -  Not pregnant or nursing

 -  Fertile patients must use effective contraception

 PRIOR CONCURRENT THERAPY:

 Biologic therapy:

 -  Not specified

 Chemotherapy:

 -  No prior chemotherapy

 Endocrine therapy:

 -  Not specified

 Radiotherapy:

 -  No prior radiotherapy except local radiotherapy provided the following cumulative dose
 limits for prior dose plus potential TBI dose on protocol are not exceeded:

 -  Less than 5,000 cGy to bone

 -  Less than 4,000 cGy to mediastinum, heart, small bowel, brain, and spinal cord

 -  Less than 2,000 cGy to the liver

 -  Less than 1,500 cGy to the kidney and lungs

 Surgery:

 -  Not specified