title: Tanespimycin and bortezomib combination treatment in patients with relapsed or relapsed and refractory multiple myeloma: results of a phase 1/2 study.
abstract: This open-label, dose escalation, multicentre phase 1/2 trial was undertaken to determine the safety and tolerability of the heat shock protein 90 (HSP90) inhibitor tanespimycin (100-340 mg/m(2) )+ bortezomib (0·7-1·3 mg/m(2) ) given on days 1, 4, 8 and 11 in each 21-d cycle. Phase 2 expansion occurred at the highest tested dose of tanespimycin at 340 mg/m(2) and bortezomib at 1·3 mg/m(2) . Seventy-two patients (median age, 60 years) with relapsed or relapsed and refractory multiple myeloma (MM) were enrolled; 63 patients (89%) completed the study. Tanespimycin in combination with bortezomib was well tolerated; few patients experienced significant neutropenia, constipation and anorexia (<10%), and no patients developed severe peripheral neuropathy. Among 67 efficacy-evaluable patients, there were 2 (3%) complete responses and 8 (12%) partial responses, for an objective response rate (ORR) of 27%, including 8 (12%) minimal responses. Response rates were highest among bortezomib-naive patients and proved durable in all patient subgroups, including those with bortezomib-refractory disease. Pharmacodynamic analyses indicated that tanespimycin plus bortezomib effectively inhibited the proteasome, as evidenced by decreased 20S proteasome activity, and inhibited HSP90, as reflected by increased HSP70 expression. The results of this study support additional studies of this combination approach in MM.
authors.affiliation: Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA. paul_richardson@dfci.harvard.edu
authors.forename: Paul G
authors.initials: PG
authors.lastname: Richardson
authors.forename: Asher A
authors.initials: AA
authors.lastname: Chanan-Khan
authors.forename: Sagar
authors.initials: S
authors.lastname: Lonial
authors.forename: Amrita Y
authors.initials: AY
authors.lastname: Krishnan
authors.forename: Michael P
authors.initials: MP
authors.lastname: Carroll
authors.forename: Melissa
authors.initials: M
authors.lastname: Alsina
authors.forename: Maher
authors.initials: M
authors.lastname: Albitar
authors.forename: David
authors.initials: D
authors.lastname: Berman
authors.forename: Marianne
authors.initials: M
authors.lastname: Messina
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D016227:Benzoquinones / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood; D001897:Boronic Acids / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood; D000069286:Bortezomib; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D047029:Lactams, Macrocyclic / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy*; D011719:Pyrazines / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood; D012008:Recurrence; D016896:Treatment Outcome
chemical_list: D016227:Benzoquinones; D001897:Boronic Acids; D047029:Lactams, Macrocyclic; D011719:Pyrazines; C112765:tanespimycin; D000069286:Bortezomib