Bortezomib salvage followed by a Phase I/II study of bortezomib plus high-dose melphalan and tandem autologous transplantation for patients with primary resistant myeloma

We conducted a Phase 1/2 study of bortezomib administered in combination with high-dose melphalan followed by tandem autologous transplants in patients with primary resistant multiple myeloma. Thirty patients received two cycles of salvage bortezomib followed by stem cell mobilization with granulocyte colony-stimulating factor and harvest. Melphalan 100 mg/m2 per day on two consecutive days was administered, immediately followed by one dose of bortezomib (dose escalation) and stem cell infusion. The median beta 2-microglobulin was 4.35 mg/l (range: 1.8-11.4); albumin was 37 g/l (range: 3.1-4.9); high-risk karyotypes were noted in 45% of patients. The maximum planned dose of bortezomib at 1.3 mg/m2 was well tolerated and a formal maximum tolerated dose was not determined. The peak of best overall response (>= partial response) and complete response rates after tandem transplants were 84% and 36%, respectively. With a median follow-up of 48 months, the median progression-free survival was 15 [95% confidence interval (CI): 11-21] months and the median overall survival was 35 (95% CI: 22-43) months. Correlative studies demonstrated decreased expression of BRCA2 (P = 0.0072) and FANCF (P = 0.0458) mRNA following bortezomib treatment. Bortezomib combined with high-dose melphalan is a well-tolerated conditioning with some activity in patients with resistant myeloma.