Adding Bortezomib Ups Dual Transplant Results in Myeloma

ASCO — The addition of bortezomib (Velcade) to tandem transplantation as upfront therapy for multiple myeloma is safe and associated with high rates of complete and near complete response, according to a study reported at the 2006 Annual Meeting of the American Society of Clinical Oncology (abstract 7519). The trial, Total Therapy 3 (TT3), is the third in a series attempting to integrate all active modalities in multiple myeloma, said lead author Bart Barlogie, MD, PhD, of the University of Arkansas for Medical Science. It built on Total Therapy 2 (TT2) by adding bortezomib, reducing the number of cycles of induction therapy from four to two, and using thalidomide (Thalomid) and dexamethasone to bridge drug-free intervals.

TT3 patients were treated with two induction cycles of VDT PACE (bortezomib, dexamethasone, thalidomide, cisplatin, Adriamycin, cyclophosphamide, etoposide); melphalan with tandem transplants 2 to 3 months apart; and two consolidation cycles with VDT PACE, with thalidomide/dexamethasone given during intervening periods. Maintenance therapy was bortezomib, thalidomide, and dexamethasone in year 2; thalidomide/dexamethasone in years 3 and 4.

Analyses compared the first 249 patients enrolled in TT3 with the 323 patients enrolled on the thalidomide arm of TT2 (TT2-Thal). Patients in both trials had symptomatic or progressive myeloma and were aged 75 years or younger. Median follow-up was 15 months in TT3 and 51 months in TT2-Thal.

Compared with patients in TT2-Thal, patients in TT3 had a higher CD34 yield and completed transplantation more rapidly (12-month estimated rate of completion of the second transplant, 84% vs 61%). TT3 patients had significantly higher 18-month cumulative rates of partial response (92% vs 83%) and near complete response (80% vs 69%), and a nonsignificantly higher cumulative rate of complete response (53% vs 45%).

The estimated 18-month treatment-related mortality was identical in the TT3 and TT2-Thal populations at 6%, even though patients in the new study were older, on average. The groups had nearly the same estimated 18-month event-free survival (83% vs 82%) and equivalent estimated overall survival (88%).

In a multivariate analysis of TT3 patients, significant determinants of event-free survival were LDH level ≥ 190 U/L (HR 4.1) and light-chain-only disease (0.3); for overall survival, LDH ≥ 190

U/L (7.2), creatinine 2 mg/dL or greater (2.9), and light-chain-only disease (0.2).

Compared with TT2-Thal, patients in TT3 (who received less thalidomide during induction) had a significantly lower incidence of grade 2 or higher thromboembolic events (27% vs 37%), syncope (2% vs 12%), constipation or bowel obstruction (7% vs 14%), tremor (3% vs 13%), and neuropathy (10% vs 16%). All received low-molecular-weight heparin and antibiotic prophylaxis.