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Arkansas Pioneers 'Total Therapy' for Multiple Myeloma

Arkansas Pioneers 'Total Therapy' for Multiple Myeloma

LITTLE ROCK, Ark--Little prog-ress has been made during the last
30 years toward improving the prognosis of patients with myeloma.
Because of the patients' often brittle condition and advanced
age, dose intensity concepts had not been evaluated until the
late Tim McElwain from the Royal Marsden Hospital reported responses
to high-dose melphalan [Alkeran] at 140 mg/m² in patients
with refractory disease or high-risk newly diagnosed patients.

Barlogie and colleagues built on this approach and introduced
autologous bone marrow transplantation (ABMT) in support of myeloablative
therapy with melphalan, 140 mg/m², and total body irradiation
(TBI), achieving complete responses (CRs) in 20% to 25% of refractory
multiple myeloma patients.

The Arkansas Cancer Research Center has now conducted double transplants
at an intended interval of 6 months in 470 myeloma patients (180
newly diagnosed, 290 previously treated). The preparative regimens
consisted of melphalan, 200 mg/m², for the first and again
for the second transplant (PR or better), or melphalan, 140 mg/m²
plus TBI (less thanPR).

Treatment-related mortality during the first year from transplant
was 6%; CR was 34%, and higher with sensitivity to prior standard
therapy and limited prior treatment of 12 months or less. Event-free
and overall survival from transplant were 27 and 40 months, respectively,
and superior with low beta-2-microglobulin of 2.5 mg/L or less
and C-reactive protein of 0.4 mg/dL or less prior to ABMT.

The absence of certain chromosomal abnormalities involving 11q
and deletions of chromosome 13 turned out to be the most favorable
feature for long-term prognosis. At 6 months, analysis identified
both induction of CR and the application of two transplants within
6 months as additional significant variables extending both event-free
and overall survival.

Timely application of two transplants seems to improve patients'
prognosis by raising the incidence of true CR into the 50% range,
a threshold probably needed to achieve durable disease control
and possibly cure.

"Total Therapy" vs Standard SWOG Treatment

At the American Society of Hematology meeting, the Arkansas group
reported on a historical comparison between "Total Therapy"
and standard SWOG* treatment for newly diagnosed myeloma. "Total
Therapy" was given to 155 newly diagnosed patients and consisted
of remission induction with VAD ´ 3, high dose cyclophosphamide
with PBSC collection and EDAP (etoposide, dexamethasone, cytarabine
and cisplatin) followed by 2 autotransplants in support of melphalan
200 mg/m² × 2 (for PR or better after first transplant)
or melphalan 200 mg/m² followed by melphalan 140 mg/m²
+ TBI (850-1120 cGy) (for less than PR post first transplant).
Standard treatment employed VMCP/VBAP, VMCPP/VBAPP (with more
frequent prednisone) or VAD in 884 patients. Three-year event-free
and overall survival after "Total Therapy" were 60%
and 76%, respectively, compared to 30% and 50% among SWOG patients
(both P = .0001). In order to account for differences in disease
and host variables, Cox regression analysis and a highly stratified
log rank test were employed (matching patients for age, creatinine
and B2M). "Total Therapy" was superior to standard treatment,
reducing the relative risk of relapse to 0.47 (P = .0001) and
of death to 0.52 (P = .001). These data strongly suggest that
myeloablative therapy as practiced with "Total Therapy"
was superior to standard regimens (ASH abstract 816).

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