Originally published as JCO Early Release 10.1200/JCO.2007.12.3323 on September 4 2007

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Phase II Pethema Trial of Alternating Bortezomib and Dexamethasone As Induction Regimen Before Autologous Stem-Cell Transplantation in Younger Patients With Multiple Myeloma: Efficacy and Clinical Implications of Tumor Response Kinetics

Laura Rosiñol, Albert Oriol, Maria Victoria Mateos, Anna Sureda, Pedro García-Sánchez, Norma Gutiérrez, Adrián Alegre, Juan José Lahuerta, Javier de la Rubia, Carlos Herrero, Xiangyang Liu, Helgi Van de Velde, Jesús San Miguel, Joan Bladé

From the Hospital Clinic Barcelona; Hospital Sant Pau, Barcelona; Hospital Germans Trias i Pujol, Badalona; Hospital Clínico Salamanca, Salamanca; Hospital Clínico Madrid; Hospital La Princesa; Hospital 12 de Octubre; Janssen Cilag Spain, Madrid; Hospital La Fe, Valencia; Johnson & Johnson Pharmaceutical R&D, Beerse, Belgium; and Johnson & Johnson Pharmaceutical R&D, Raritan, NJ

Address reprint requests to Joan Bladé, MD, Department of Hematology, Hospital Clínic, Villarroel, 170, Barcelona 08036 Spain; e-mail: jblade{at}clinic.ub.es

Purpose This is the first study in which bortezomib and dexamethasone were administered on an alternating basis as up-front therapy in multiple myeloma (MM). We investigated the efficacy and kinetics of response to each drug and safety.

Patients and Methods Patients with newly diagnosed MM who were less than 66 years old were treated with bortezomib at 1.3 mg/m² on days 1, 4, 8, and 11 (cycles 1, 3, and 5) and dexamethasone 40 mg orally on days 1 through 4, 9 to 12, and 17 to 20 (cycles 2, 4, and 6), followed by autologous stem-cell transplantation (ASCT). Responses were evaluated by modified European Bone Marrow Transplantation criteria. Random effects models were used to analyze the tumor response kinetics.

Results Forty patients were enrolled. Partial response (PR) or greater was 65% (12.5% complete response [CR], 10% very good PR [VGPR], and 42.5% PR) plus 17.5% minor response. Time to response was rapid, with 82% serum M-protein reduction achieved within the first two cycles. The M-protein decrease was similar with dexamethasone and with bortezomib (P = .48). Chromosome 13 deletion, t(4;14), and t(14;16) did not have a negative impact on response. Toxicity was low, with no grade 3 to 4 peripheral neuropathy and no grade 2 to 4 thrombocytopenia. The response rate after ASCT was 88%, with 33% CR (negative immunofixation) plus 22% VGPR.

Conclusion Bortezomib alternating with dexamethasone is a highly effective induction regimen with low toxicity. The kinetic study has shown a high degree of heterogeneity in response and rapid effect from both agents, supporting the use of a short induction regimen before ASCT in MM.

published online ahead of print at www.jco.org on September 4, 2007.

Supported in part by Grants No. V-2005-F55240-0 and RD 06/0020/005 from Fondo de Investigaciones Sanitarias de la Seguridad Social and by a grant from Johnson and Johnson Pharmaceuticals R&D.

Presented as an oral communication at the 43rd Annual Meeting of the American Society of Clinical Oncology, June 1-5, 2007, Chicago, IL.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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