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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