Originally published as JCO Early Release 10.1200/JCO.2008.18.3087 on June 15 2009

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Single-Agent Bortezomib in Previously Untreated Multiple Myeloma: Efficacy, Characterization of Peripheral Neuropathy, and Molecular Correlations With Response and Neuropathy

Paul G. Richardson, Wanling Xie, Constantine Mitsiades, Asher A. Chanan-Khan, Sagar Lonial, Hani Hassoun, David E. Avigan, Anne Louise Oaklander, David J. Kuter, Patrick Y. Wen, Santosh Kesari, Hannah R. Briemberg, Robert L. Schlossman, Nikhil C. Munshi, L. Thompson Heffner, Deborah Doss, Dixie-Lee Esseltine, Edie Weller, Kenneth C. Anderson, Anthony A. Amato

From the Dana-Farber Cancer Institute; Beth Israel Deaconess Medical Center; Massachusetts General Hospital; Millennium Pharmaceuticals; Brigham and Women's Hospital, Boston, MA; Roswell Park Cancer Institute, Buffalo; Memorial Sloan-Kettering Cancer Center, New York, NY; Winship Cancer Institute, Emory University, Atlanta, GA; and University of British Columbia, Vancouver, British Columbia, Canada.

Corresponding author: Paul G. Richardson, MD, Dana-Farber Cancer Institute, 44 Binney St, Dana 1B02, Boston, MA 02115; e-mail: paul_richardson{at}dfci.harvard.edu.

Purpose To assess efficacy and safety of single-agent bortezomib in previously untreated patients with multiple myeloma, investigate prevalence of baseline and treatment-emergent polyneuropathy, and identify molecular markers associated with response and neuropathy.

Patients and Methods Patients received bortezomib 1.3 mg/m² on days 1, 4, 8, and 11, for up to eight 21-day cycles. A subset of patients underwent neurophysiologic evaluation pre- and post-treatment. Bone marrow aspirates were performed at baseline for exploratory whole-genome analyses.

Results Among 64 patients, 41% had partial response or better, including 9% complete/near-complete responses; median duration of response was 8.4 months. Response rates did not differ in the presence or absence of adverse cytogenetics. After median follow-up of 29 months, median time to progression was 17.3 months. Median overall survival had not been reached; estimated 1-year survival was 92%. Thirty-two patients successfully underwent optional stem-cell transplantation. Bortezomib treatment was generally well tolerated. At baseline, 20% of patients had sensory polyneuropathy. Sensory polyneuropathy developed during treatment in 64% of patients (grade 3 in 3%), but proved manageable and resolved in 85% within a median of 98 days. Neurologic examination, neurophysiologic testing, and measurements of epidermal nerve fiber densities in 35 patients confirmed pretreatment sensory neuropathy in 20% and new or worsening neuropathy in 63%. Pharmacogenomic analyses identified molecular markers of response and treatment-emergent neuropathy, which will require future study.

Conclusion Single-agent bortezomib is effective in previously untreated myeloma. Baseline myeloma-associated neuropathy seems more common than previously reported, and bortezomib-associated neuropathy, although a common toxicity, is reversible in most patients.

P.G.R., C.M., and W.X. are co-first authors.

Supported in part by the Public Health Service (Grant No. NINDS R01NS42866, P30 EY 12196) and by Millennium Pharmaceuticals and Johnson & Johnson Pharmaceuticals Research & Development, LLC.

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

Clinical Trials repository link available on JCO.org.

Clinical trial information can be found for the following: NCT00153920.

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