Total therapy with tandem transplants for newly diagnosed multiple myeloma

Between August 1990 and August 1995, 231 patients (median age 51, 53% Durie -Salmon stage III, median serum beta-2-microglobulin 3.1 g/L, median C-reac tive protein 4 g/L) with symptomatic multiple myeloma were enrolled in a pr ogram that used a series of induction regimens and two cycles of high-dose therapy ("Total Therapy"). Remission induction utilized non-cross-resistant regimens (vincristine-doxorubicin-dexamethasone [VAD], high-dose cyclophos phamide and granulocyte-macrophage colony-stimulating factor with periphera l blood stem cell collection, and etoposide-dexamethasone-cytarabine-cispla tin). The first high-dose treatment comprised melphalan 200 mg/m(2) and was repeated if complete (CR) or partial (PR) remission was maintained after t he first transplant; in case of less than PR, total body irradiation or cyc lophosphamide was added. Interferon-alpha-2b maintenance was used after the second autotransplant. Fourteen patients with HLA-compatible donors underw ent an allograft as their second high-dose therapy cycle. Eighty-eight perc ent completed induction therapy whereas first and second transplants were p erformed in 84% and 71% (the majority within 8 and 15 months, respectively) . Eight patients (3%) died of toxicity during induction, and 2 (1%) and 6 ( 4%) during the two transplants. True CR and at least a PR (PR plus CR) were obtained in 5% (34%) after VAD, 15% (65%) at the end of induction, and 26% (75%) after the first and 41% (83%) after the second transplants (intent-t o-treat). Median overall (OS) and event-free (EFS) survival durations were 68 and 43 months, respectively. Actuarial 5-year OS and EFS rates were 58% and 42%, respectively. The median time to disease progression or relapse wa s 52 months. Among the 94 patients achieving CR, the median CR duration was 50 months. On multivariate analysis, superior EFS and OS were observed in the absence of unfavorable karyotypes (11q breakpoint abnormalities, -13 or 13-q) and with low beta-2-microglobulin at diagnosis. CR duration was sign ificantly longer with early onset of CR and favorable karyotypes. Time-depe ndent covariate analysis suggested that timely application of a second tran splant extended both EFS and OS significantly, independent of cytogenetics and beta-2-microglobulin. Total Therapy represents a comprehensive treatmen t approach for newly diagnosed myeloma patients, using multi-regimen induct ion and tandem transplantation followed by interferon maintenance. As a res ult, the proportion of patients attaining CR increased progressively with c ontinuing therapy. This observation is particularly important because CR is a sine qua non for long-term disease control and, eventually, cure. (C) 19 99 by The American Society of Hematology.