Peter M Voorhees1, Cristina Gasparetto2, Dominic T Moore3, Diane Winans3, Robert Z Orlowski4, David D Hurd5. 1. Department of Hematologic Oncology and Blood Disorders, Levine Cancer Institute, Carolinas HealthCare System, Charlotte, NC. Electronic address: peter.voorhees@carolinashealthcare.org. 2. Division of Hematological Malignancies and Cellular Therapy, Duke University Medical Center, Durham, NC. 3. Division of Hematology-Oncology, University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, NC. 4. Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX. 5. Section on Hematology and Oncology, Department of Internal Medicine, Comprehensive Cancer Center of Wake Forest University, Winston-Salem, NC.
Abstract
INTRODUCTION/ BACKGROUND: Deacetylase inhibitors have synergistic activity in combination with proteasome inhibitors and anthracyclines in preclinical models of multiple myeloma (MM). We therefore evaluated the safety and efficacy of the deacetylase inhibitor vorinostat in combination with pegylated liposomal doxorubicin (PLD) and bortezomib in relapsed/refractory MM. PATIENTS AND METHODS: Thirty-two patients were treated with PLD and bortezomib in combination with escalating doses of vorinostat on days 4 to 11 or 1 to 14. RESULTS: The maximum tolerated dose of vorinostat was 400 mg on days 4 to 11. Neutropenia and thrombocytopenia attributable to protocol therapy were seen in 59% and 94% of patients, of which 37% and 47% were of grade 3 or higher severity, respectively. Constitutional and gastrointestinal adverse events of all grades were common, the majority of which were less than grade 3 in severity. The overall response rate (partial response rate or better) was 65% and the clinical benefit rate (minimal response rate or better) 74%. The overall response rate was 83%, 71%, and 45% for patients with bortezomib-naive, -sensitive, and -refractory MM, respectively. The median progression-free survival was 13.9 months and the 3-year overall survival 77%. Whole blood proteasome activity assays demonstrated a potential impact of vorinostat on the chymotryptic-like activity of the proteasome. CONCLUSION: Further evaluation of PLD, bortezomib, and deacetylase inhibitor combinations is warranted, with special attention directed toward strategies to improve tolerability.
INTRODUCTION/ BACKGROUND: Deacetylase inhibitors have synergistic activity in combination with proteasome inhibitors and anthracyclines in preclinical models of multiple myeloma (MM). We therefore evaluated the safety and efficacy of the deacetylase inhibitor vorinostat in combination with pegylated liposomal doxorubicin (PLD) and bortezomib in relapsed/refractory MM. PATIENTS AND METHODS: Thirty-two patients were treated with PLD and bortezomib in combination with escalating doses of vorinostat on days 4 to 11 or 1 to 14. RESULTS: The maximum tolerated dose of vorinostat was 400 mg on days 4 to 11. Neutropenia and thrombocytopenia attributable to protocol therapy were seen in 59% and 94% of patients, of which 37% and 47% were of grade 3 or higher severity, respectively. Constitutional and gastrointestinal adverse events of all grades were common, the majority of which were less than grade 3 in severity. The overall response rate (partial response rate or better) was 65% and the clinical benefit rate (minimal response rate or better) 74%. The overall response rate was 83%, 71%, and 45% for patients with bortezomib-naive, -sensitive, and -refractory MM, respectively. The median progression-free survival was 13.9 months and the 3-year overall survival 77%. Whole blood proteasome activity assays demonstrated a potential impact of vorinostat on the chymotryptic-like activity of the proteasome. CONCLUSION: Further evaluation of PLD, bortezomib, and deacetylase inhibitor combinations is warranted, with special attention directed toward strategies to improve tolerability.
Authors: Johannes M Waldschmidt; Alexander Keller; Gabriele Ihorst; Olga Grishina; Stefan Müller; Dagmar Wider; Anna V Frey; Kristina King; Roman Simon; Annette May; Pierfrancesco Tassone; Justus Duyster; Manfred Jung; Noopur Raje; Ralph Wäsch; Monika Engelhardt Journal: Haematologica Date: 2018-04-19 Impact factor: 9.941