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Tanespimycin with bortezomib: activity in relapsed/refractory patients with multiple myeloma
Paul G Richardson1, Ashraf Z Badros, Sundar Jagannath
1Dana-Farber Cancer Institute, Boston, MA 02115, USA. paul_richardson@dfci.harvard.edu
Abstract:
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.
Insights
Tanespimycin combined with bortezomib showed anti-myeloma activity in relapsed/refractory multiple myeloma patients. The combination therapy demonstrated promising response rates and induced peripheral neuropathy, warranting further investigation.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Heat shock protein 90 (HSP90) is crucial for myeloma cell growth, survival, and drug resistance.
- Tanespimycin (17-AAG) inhibits HSP90, showing prior activity and tolerability in relapsed/refractory multiple myeloma (MM).
- Preclinical studies suggest synergistic anti-tumor effects between tanespimycin and bortezomib, involving increased ubiquitinated protein accumulation and proteasome inhibition.
Purpose of the Study:
- To evaluate the antitumour activity and safety of combined tanespimycin and bortezomib in heavily pretreated patients with relapsed and refractory multiple myeloma.
- To measure heat shock protein 70 (HSP70) expression and proteasome activity in plasma following combination therapy.
- To explore potential correlations between HSP70 levels, proteasome activity, and clinical outcomes.
Main Methods:
- Phase 2, open-label, multicenter study.
- Patients received bortezomib (1.3 mg/m2) plus one of three doses of tanespimycin (50, 175, or 340 mg/m2).
- Plasma samples were analyzed for HSP70 expression and proteasome activity.
Main Results:
- The study was closed prematurely, preventing direct dose comparison.
- Antitumour activity was observed, with promising overall response rates.
- Peripheral neuropathy was noted as a significant adverse event, with promising severity.
Conclusions:
- Combination therapy of tanespimycin and bortezomib demonstrated antitumour activity in relapsed/refractory multiple myeloma.
- The observed peripheral neuropathy warrants careful monitoring and management.
- Further studies are needed to optimize dosing and confirm efficacy.
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