Trial Information

Standard Dose Versus Myeloablative Therapy for Previously Untreated Symptomatic Multiple Myeloma, A Phase III Intergroup Study

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.