title: A Phase I/II Study of Escalating Doses of Bortezomib in Conjunction with High-Dose Melphalan as a Conditioning Regimen for Salvage Autologous Peripheral Blood Stem Cell Transplantation in Patients with Multiple Myeloma.
abstract: Escalating doses of bortezomib with high-dose melphalan was evaluated as as a conditioning regimen for autologous stem cell transplantation (ASCT) in patients with relapsed or refractory multiple myeloma (MM). MM patients with less than a partial remission (PR) (or 50% reduction) compared to their pretransplantation paraprotein parameters after a prior ASCT with melphalan conditioning, or who were in relapse after a prior autologous transplantation, were eligible for study. Bortezomib was dose escalated in steps of 1, 1.3, and 1.6 mg/m2(3 × 3 design) on days -4 and -1 before transplantation with melphalan 200 mg/m2given on day -2. Thirty-two patients were enrolled: 12 in the phase I dose escalation phase and an additional 20 in phase II to gain additional experience with the regimen. Twenty-four (75%) patients were Durie Salmon stage III, and 12 (37.5%) had >2 prior lines of therapy. The overall response rate (≥PR) was 44% with 22% complete remission. Two-year overall survival and progression-free survival were 76% and 39%, respectively, with a median follow-up of 31.7 months. The most common grade 3 and 4 nonhematologic adverse events were neutropenic fever (25%), nausea (18.8%), and mucositis (9.4%). Serious adverse events included intensive care unit admission (9.4%), seizure (3.1%), prolonged diarrhea (3.1%), and Guillain-Barre syndrome (3.1%). Two patients (6%) died of sepsis. There was no emergent peripheral neuropathy nor increase in any pre-existing peripheral neuropathy. The addition of bortezomib to melphalan as conditioning for salvage ASCT was well tolerated. More importantly, it can provide durable remission for patients who have a suboptimal response to prior single-agent melphalan conditioning for ASCT, without requiring a reduction in the dose of melphalan. Larger randomized prospective studies to determine the effect of combination conditioning are being conducted.
authors: John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, New Jersey.
authors: Noa
authors: N
authors: Biran
authors: John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, New Jersey. Electronic address: srowley@hackensackumc.org.
authors: Scott D
authors: SD
authors: Rowley
authors: John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, New Jersey.
authors: David H
authors: DH
authors: Vesole
authors: Department of Medicine, Rutgers New Jersey Medical School, Newark, New Jersey.
authors: Shijia
authors: S
authors: Zhang
authors: John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, New Jersey.
authors: Michele L
authors: ML
authors: Donato
authors: John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, New Jersey.
authors: Joshua
authors: J
authors: Richter
authors: John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, New Jersey.
authors: Alan P
authors: AP
authors: Skarbnik
authors: John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, New Jersey.
authors: Andrew
authors: A
authors: Pecora
authors: John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, New Jersey.
authors: David S
authors: DS
authors: Siegel
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D000069286:Bortezomib / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D008297:Male; D008558:Melphalan / Q000008:administration & dosage*; D008875:Middle Aged; D009101:Multiple Myeloma / Q000628:therapy*; D019055:No-Observed-Adverse-Effect Level; D036102:Peripheral Blood Stem Cell Transplantation; D016879:Salvage Therapy / Q000379:methods*; D016019:Survival Analysis; D019172:Transplantation Conditioning / Q000379:methods*; D014182:Transplantation, Autologous
chemical_list: D000069286:Bortezomib; D008558:Melphalan
keywords: Bortezomib; Melphalan; Multiple myeloma; Peripheral blood autologous stem cell transplantation