title: Single-agent bortezomib in previously untreated multiple myeloma: efficacy, characterization of peripheral neuropathy, and molecular correlations with response and neuropathy.
abstract: 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/m(2) 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.
authors.affiliation: Dana-Farber Cancer Institute, 44 Binney St, Dana 1B02, Boston, MA 02115, USA. paul_richardson@dfci.harvard.edu
authors.forename: Paul G
authors.initials: PG
authors.lastname: Richardson
authors.forename: Wanling
authors.initials: W
authors.lastname: Xie
authors.forename: Constantine
authors.initials: C
authors.lastname: Mitsiades
authors.forename: Asher A
authors.initials: AA
authors.lastname: Chanan-Khan
authors.forename: Sagar
authors.initials: S
authors.lastname: Lonial
authors.forename: Hani
authors.initials: H
authors.lastname: Hassoun
authors.forename: David E
authors.initials: DE
authors.lastname: Avigan
authors.forename: Anne Louise
authors.initials: AL
authors.lastname: Oaklander
authors.forename: David J
authors.initials: DJ
authors.lastname: Kuter
authors.forename: Patrick Y
authors.initials: PY
authors.lastname: Wen
authors.forename: Santosh
authors.initials: S
authors.lastname: Kesari
authors.forename: Hannah R
authors.initials: HR
authors.lastname: Briemberg
authors.forename: Robert L
authors.initials: RL
authors.lastname: Schlossman
authors.forename: Nikhil C
authors.initials: NC
authors.lastname: Munshi
authors.forename: L Thompson
authors.initials: LT
authors.lastname: Heffner
authors.forename: Deborah
authors.initials: D
authors.lastname: Doss
authors.forename: Dixie-Lee
authors.initials: DL
authors.lastname: Esseltine
authors.forename: Edie
authors.initials: E
authors.lastname: Weller
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
authors.forename: Anthony A
authors.initials: AA
authors.lastname: Amato
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001897:Boronic Acids / Q000009:adverse effects / Q000627:therapeutic use*; D000069286:Bortezomib; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy*; D009364:Neoplasm Recurrence, Local / Q000150:complications* / Q000188:drug therapy; D010523:Peripheral Nervous System Diseases / Q000209:etiology / Q000628:therapy*; D011115:Polyneuropathies / Q000209:etiology; D011480:Protease Inhibitors; D011719:Pyrazines / Q000009:adverse effects / Q000627:therapeutic use*; D033581:Stem Cell Transplantation; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D011480:Protease Inhibitors; D011719:Pyrazines; D000069286:Bortezomib