Tanespimycin with bortezomib: activity in relapsed/refractory patients with multiple myeloma.
Tanespimycin (17-allylamino-17-demethoxygeldanamycin, 17-AAG) disrupts heat shock protein 90 (HSP90), a key molecular chaperone for signal transduction proteins critical to myeloma growth, survival and drug resistance. In previous studies, tanespimycin monotherapy was well tolerated and active in heavily pretreated patients with relapsed/refractory multiple myeloma (MM). Preclinical data have shown antitumour synergy between tanespimycin and bortezomib, with more pronounced intracellular accumulation of ubiquitinated proteins than either drug alone, an effect attributed to the synergistic suppression of chymotryptic activity in the 20S proteasome. HSP70 induction has been observed in all Phase 1 tanespimycin studies in which it has been measured, with several separate reports of HSP70 overexpression protecting against peripheral nerve injury. In this Phase 2, open-label multicentre study, we compared 1.3 mg/m2 bortezomib + three doses of tanespimycin: 50, 175 and 340 mg/m2 in heavily pretreated patients with relapsed and refractory MM and measured HSP70 expression and proteasome activity levels in plasma of treated patients. The study was closed prematurely for resource-based reasons, precluding dose comparison. Nonetheless, antitumour activity was observed, with promising response rates and promising severity of peripheral neuropathy.
Richardson
Paul G
PG
Dana-Farber Cancer Institute, Boston, MA 02115, USA. paul_richardson@dfci.harvard.edu
Badros
Ashraf Z
AZ
Jagannath
Sundar
S
Tarantolo
Stefano
S
Wolf
Jeffrey L
JL
Albitar
Maher
M
Berman
David
D
Messina
Marianne
M
Anderson
Kenneth C
KC
D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D016227:Benzoquinones / Q000008:administration & dosage / Q000009:adverse effects; D001897:Boronic Acids / Q000008:administration & dosage / Q000009:adverse effects; D000069286:Bortezomib; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D018840:HSP70 Heat-Shock Proteins / Q000097:blood; D006801:Humans; D047029:Lactams, Macrocyclic / Q000008:administration & dosage / Q000009:adverse effects; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy*; D009504:Neutrophils / Q000473:pathology; D010976:Platelet Count; D011719:Pyrazines / Q000008:administration & dosage / Q000009:adverse effects; D012008:Recurrence; D016896:Treatment Outcome
D016227:Benzoquinones; D001897:Boronic Acids; D018840:HSP70 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D011719:Pyrazines; C112765:tanespimycin; D000069286:Bortezomib