A phase I/II trial combining high-dose melphalan and autologous transplant with bortezomib for multiple myeloma: a dose- and schedule-finding study.
OBJECTIVE
We did a randomized phase I/II trial designed to evaluate the safety and efficacy of combining the proteasome inhibitor bortezomib with high-dose melphalan as the conditioning for high-dose therapy and autologous transplant for myeloma.


METHODS
Enrolled patients were limited to those who did not achieve a very good partial remission (VGPR) following one or more induction regimens, and were randomized to receive a single escalating dose of bortezomib (1.0, 1.3, or 1.6 mg/m(2)) either 24 hours before or 24 hours after high-dose melphalan. Dose escalation was based on the escalation with overdose control (EWOC), a Bayesian statistical model. Bone marrow aspirates were collected before initiation of therapy and at the time of transplant to evaluate which sequence resulted in maximal plasma cell apoptosis, and response to transplant was assessed by the International Myeloma Working Group criteria.


RESULTS
Among 39 randomized patients, 20 received bortezomib after melphalan and 19 received bortezomib before melphalan. Toxicities and posttransplant hematopoietic recovery rates were similar between arms. The overall response rate for all patients was 87%, with 51% achieving a VGPR or better. Pharmacodynamic studies showed greater plasma cell apoptosis among patients who received bortezomib following melphalan.


CONCLUSIONS
The use of bortezomib in conjunction with high-dose melphalan is safe, with data suggesting improved efficacy. A single dose of bortezomib administered after high-dose melphalan is the recommended dose and schedule for future clinical investigation.
Lonial
Sagar
S
Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322, USA. sloni01@emory.edu
Kaufman
Jonathan
J
Tighiouart
Mourad
M
Nooka
Ajay
A
Langston
Amelia A
AA
Heffner
Leonard T
LT
Torre
Claire
C
McMillan
Stephanie
S
Renfroe
Heather
H
Harvey
R Donald
RD
Lechowicz
Mary J
MJ
Khoury
H Jean
HJ
Flowers
Christopher R
CR
Waller
Edmund K
EK
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001897:Boronic Acids / Q000008:administration & dosage / Q000009:adverse effects; D000069286:Bortezomib; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods*; D006801:Humans; D008297:Male; D008558:Melphalan / Q000008:administration & dosage / Q000009:adverse effects; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy / Q000601:surgery / Q000628:therapy*; D011719:Pyrazines / Q000008:administration & dosage / Q000009:adverse effects; D019172:Transplantation Conditioning / Q000009:adverse effects / Q000379:methods
D001897:Boronic Acids; D011719:Pyrazines; D000069286:Bortezomib; D008558:Melphalan