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Blood, Vol. 93 No. 1 (January 1), 1999:
pp. 55-65
Total Therapy With Tandem Transplants for Newly Diagnosed Multiple
Myeloma
B. Barlogie,
S. Jagannath,
K.R. Desikan,
S. Mattox,
D. Vesole,
D. Siegel,
G. Tricot,
N. Munshi,
A. Fassas,
S. Singhal,
J. Mehta,
E. Anaissie,
D. Dhodapkar,
S. Naucke,
J. Cromer,
J. Sawyer,
J. Epstein,
D. Spoon,
D. Ayers,
B. Cheson, and
J. Crowley
From the Myeloma and Transplantation Research Center (MTRC),
University of Arkansas for Medical Sciences, Arkansas Cancer Research
Center, Little Rock, AR; St Vincent's Comprehensive Cancer Center, New
York, NY; the Medical College of Wisconsin, Milwaukee, WI; the
Greenbaum Cancer Center, Baltimore, MD; CTEP, National Cancer
Institute, Bethesda, MD; and the Fred Hutchinson Cancer Research Center
and Southwest Oncology Group Office, Seattle, WA.
Between August 1990 and August 1995, 231 patients
(median age 51, 53% Durie-Salmon stage III, median serum
 -2-microglobulin 3.1 g/L, median C-reactive protein 4 g/L) with symptomatic multiple myeloma were enrolled in a program 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 cyclophosphamide and granulocyte-macrophage
colony-stimulating factor with peripheral blood stem cell collection,
and etoposide-dexamethasone-cytarabine-cisplatin). The first high-dose
treatment comprised melphalan 200 mg/m2 and was repeated if
complete (CR) or partial (PR) remission was maintained after the first
transplant; in case of less than PR, total body irradiation or
cyclophosphamide was added. Interferon- -2b maintenance
was used after the second autotransplant. Fourteen patients with
HLA-compatible donors underwent an allograft as their second high-dose
therapy cycle. Eighty-eight percent completed induction therapy whereas
first and second transplants were performed 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-to-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 was 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
-2-microglobulin at diagnosis. CR duration was significantly longer
with early onset of CR and favorable karyotypes. Time-dependent
covariate analysis suggested that timely application of a second
transplant extended both EFS and OS significantly, independent of
cytogenetics and -2-microglobulin. Total Therapy represents a
comprehensive treatment approach for newly diagnosed myeloma patients,
using multi-regimen induction and tandem transplantation followed by interferon maintenance. As a result, the proportion of patients attaining CR increased progressively with continuing therapy. This
observation is particularly important because CR is a sine qua non for
long-term disease control and, eventually, cure.
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