S0204: Melphalan (MEL)-Based Tandem Autotransplants (TAT) for Multiple Myeloma (MM) with Thalidomide/Dexamethasone (TD) Induction and Thalidomide/Prednisone (TP) Maintenance: A Phase II Trial of the Southwest Oncology Group.

Background: TAT has recently been shown to double the 7-yr event-free (EFS) & overall survival (OS) rates achieved with a single AT (20% & 40%; IFM94). Completion of TAT in most randomized & phase II trials seldom exceeds 70%, due to toxicities encountered with prolonged induction chemotherapy & posed by the 1^st AT. TD is effective salvage therapy &, when used up-front, effects high response rates including ~10% CR.

Patients and Methods: To reduce induction toxicities & thus deliver TAT in a timely fashion to the majority of pts, SWOG embarked on a trial of TD induction, modest-dose cyclophosphamide (CTX) for PBSC mobilization, melphalan (MEL)-based TAT & subsequent TP maintenance.

Results: Between July 2002 and December 2005, 147 newly diagnosed patients with MM were enrolled from 28 institutions. Among 138 eligible, analyzable patients, the median age was 56.5yr (range, 23.2–66.0), 83% were white, 62% male. Baseline prognostic features included serum levels of albumin <3.5g/dL in 21%, beta-2-microglobulin (B2M) >5.5mg/L in 21%, creatinine >=2mg/dL in 7%; ISS stage distribution I-48%, II-30%, III-22%. With a median follow-up of 14mo, 64 patients have come off protocol: 15 patients were removed from study due to adverse events, 10 refused further participation, 14 suffered progression or relapse, 1 died, 9 came off for other reasons, and 15 are presently under review. Therapy was well tolerated except for an increased incidence of hyper-coagulable events at the start of the protocol 27% (8/30); following an amendment to decrease the start dose of thalidomide to 50mg, the incidence of hyper-coagulable events decreased to 7% (7/101). Through the induction and PBSC mobilization phases, 4.4% achieved CR & 64.3% achieved Response (SWOG: >=75% M-protein reduction) or partial response (PR, >=50% M-protein reduction) pre-transplant for an overall response rate of 68.7%. 102 eligible patients proceeded to 1^st transplant (74%) and 66 (47%) to 2^nd transplant, with a median time to 2^nd AT of 8mo and 96% of patients receiving 2^nd AT within 4mo from 1^st AT. Confirmed and unconfirmed CR after the transplant phase was 22%. Two-year OS from 1^st transplant registration among 98 patients was 84% and 2-yr OS from TP maintenance among 62 patients was 87%.

Conclusion: Our data show that hyper-coagulable events with the TD regimen could be reduced by decreasing the starting dose of thalidomide from 100mg to 50mg/d. In a multi-institution setting, MEL200-based TAT could be performed safely. Timeliness of the 2^nd AT was achieved where 96% of the patients were able to received the procedure within 4 months of the 1^st AT. Response rates and quality are promising. Longer follow up should clarify the impact of the improved timeliness of 2^nd AT, quality and response rate on PFS and OS.