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(Drug information on 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(Drug information on cyclophosphamide) with PBSC collection and EDAP (etoposide, dexamethasone(Drug information on dexamethasone), cytarabine(Drug information on cytarabine) and cisplatin(Drug information on 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(Drug information on 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).