Cancer Therapy: Clinical A Phase I/II Trial Combining High-Dose Melphalan and Autologous Transplant with Bortezomib for Multiple Myeloma: A Dose- and Schedule-Finding Study Sagar Lonial 1,3 , Jonathan Kaufman 1,3 , Mourad Tighiouart 2,3 , Ajay Nooka 1,3 , Amelia A. Langston 1,3 , Leonard T. Heffner 1,3 , Claire Torre 1 , Stephanie McMillan 3 , Heather Renfroe 3 , R. Donald Harvey 1,3 , Mary J. Lechowicz 1,3 , H. Jean Khoury 1,3 , Christopher R. Flowers 1,2,3 , and Edmund K. Waller 1,3 Abstract Purpose: We did a randomized phase I/II trial designed to evaluate the safety and efficacy of combin- ing the proteasome inhibitor bortezomib with high-dose melphalan as the conditioning for high-dose therapy and autologous transplant for myeloma. Experimental Design: 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 sta- tistical model. Bone marrow aspirates were collected before initiation of therapy and at the time of trans- plant 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 bortezo- mib following melphalan. Conclusions: The use of bortezomib in conjunction with high-dose melphalan is safe, with data sug- gesting improved efficacy. A single dose of bortezomib administered after high-dose melphalan is the recommended dose and schedule for future clinical investigation. Clin Cancer Res; 16(20); 5079–86. ©2010 AACR. Multiple myeloma (MM) is a clonal plasma cell disor- der characterized by lytic bone disease, renal dysfunction, abnormal hematopoietic function, and the presence of a monoclonal paraprotein in the blood and/or urine. His- torical induction regimens rarely achieved major responses [very good partial remission (VGPR) or complete remis- sion (CR)], and before the use of high-dose therapy (HDT) and autologous transplant, few therapeutic options showed significant improvements in overall survival (OS) for newly diagnosed myeloma patients (1, 2). Led first by the Intergroupe Francophone du Myelome (IFM), several groups have now shown improvements in overall re- sponse rate, progression-free survival (PFS), and OS for patients randomized to receive HDT when compared with conventional dose chemotherapy (3), rendering HDT a standard treatment approach for younger patients with newly diagnosed MM. In addition, the IFM has shown that achievement of a VGPR is a surrogate for improvement in PFS and OS (4), adding it as a new category in the revised International Myeloma Working Group response criteria (5). Despite these improvements, patients are rarely, if ever, cured of MM through the use of HDT. To improve the efficacy of the HDT maneuver itself, groups have ex- plored the use of multiple cycles of HDT (tandem trans- plant; refs. 6–8), the use of combination chemotherapy conditioning regimens using agents in addition to or re- placing melphalan in HDT conditioning (9–12), and the addition of radiation therapy using targeted antibodies (13, 14) or external beam radiation (15). Unfortunately, none of these approaches has been shown to be superior to the use of 200 mg/m 2 of melphalan. Thus, if we are to improve on the efficacy of HDT, alternative combination approaches are needed. Bortezomib is a boronated peptide inhibitor of the chy- motryptic site of the proteasome and has shown efficacy in newly diagnosed, relapsed, and refractory MM (16–18). Authors' Affiliations: Departments of 1 Hematology and Medical Oncology and 2 Biostatistics and Bioinformatics and 3 Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia Corresponding Author: Sagar Lonial, Department of Hematology and Medical Oncology, Emory University, 1365 Clifton Road, Building C, Room 4004, Atlanta, GA 30322. Phone: 404-727-5572; Fax: 404-727- 3520; E-mail: sloni01@emory.edu. doi: 10.1158/1078-0432.CCR-10-1662 ©2010 American Association for Cancer Research. Clinical Cancer Research www.aacrjournals.org 5079 Research. on January 23, 2016. © 2010 American Association for Cancer clincancerres.aacrjournals.org Downloaded from Published OnlineFirst August 25, 2010; DOI: 10.1158/1078-0432.CCR-10-1662