Abstract:

Background The present global, open-label, single-arm, multicenter, phase IIb study was designed to determine the efficacy and tolerability of oral vorinostat combined with standard doses of bortezomib in patients with multiple myeloma considered refractory to novel myeloma agents. Patients and Methods Eligible patients were age ≥ 18 years, had received ≥ 2 previous regimens, had disease refractory to ≥ 1 previous bortezomib-containing regimen, and had received ≥ 1 dose of an immunomodulatory drug (thalidomide or lenalidomide)-based regimen. The patients received 21-day cycles of bortezomib (1.3 mg/m2 intravenously on days 1, 4, 8, and 11) plus oral vorinostat (400 mg/d on days 1-14). Oral dexamethasone, 20 mg, on the day of and the day after each dose of bortezomib could be added for patients with progressive disease after 2 cycles or no change after 4 cycles. The primary endpoint was the objective response rate. Results The objective response rate was 11.3% (95% confidence interval, 6.6%-17.7%), and the median duration of response was 211 days (range, 64-550 days). The median overall survival duration was 11.2 months (95% confidence interval, 8.5-14.4 months), with a 2-year survival rate of 32%. The frequently reported adverse events were thrombocytopenia (69.7%), nausea (57.0%), diarrhea (53.5%), anemia (52.1%), and fatigue (48.6%); the overall safety profile was consistent with that of bortezomib and vorinostat. Conclusion The combination of vorinostat and bortezomib is active in patients with multiple myeloma refractory to novel treatment modalities and offers a new therapeutic option for this difficult-to-treat patient population (ClinicalTrials.gov identifier, NCT00773838). © 2016 Elsevier Inc.

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Cited By :4Export Date: 18 February 2017References: Anderson, K.C., Kyle, R.A., Rajkumar, S.V., Stewart, A.K., Weber, D., Richardson, P., Clinically relevant end points and new drug approvals for myeloma (2008) Leukemia, 22, pp. 231-239;Elkinson, S., McCormack, P.L., Pomalidomide: First global approval (2013) Drugs, 73, pp. 595-604; Richardson, P.G., Siegel, D., Baz, R., Phase 1 study of pomalidomide MTD, safety, and efficacy in patients with refractory multiple myeloma who have received lenalidomide and bortezomib (2013) Blood, 121, pp. 1961-1967; San Miguel, J.F., Richardson, P.G., Gunther, A., Phase Ib study of panobinostat and bortezomib in relapsed or relapsed and refractory multiple myeloma (2013) J Clin Oncol, 31, pp. 3696-3703; Miguel, J.S., Weisel, K., Moreau, P., Pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003): A randomised, open-label, phase 3 trial (2013) Lancet Oncol, 14, pp. 1055-1066; Richardson, P.G., Schlossman, R.L., Alsina, M., PANORAMA 2: Panobinostat in combination with bortezomib and dexamethasone in patients with relapsed and bortezomib-refractory myeloma (2013) Blood, 122, pp. 2331-2337; Thompson, J.L., Carfilzomib: A second-generation proteasome inhibitor for the treatment of relapsed and refractory multiple myeloma (2013) Ann Pharmacother, 47, pp. 56-62; Jagannath, S., Vij, R., Stewart, A.K., An open-label single-arm pilot phase II study (PX-171-003-A0) of low-dose, single-agent carfilzomib in patients with relapsed and refractory multiple myeloma (2012) Clin Lymphoma Myeloma Leuk, 12, pp. 310-318; Xu, W.S., Parmigiani, R.B., Marks, P.A., Histone deacetylase inhibitors: Molecular mechanisms of action (2007) Oncogene, 26, pp. 5541-5552; Jeong, J.W., Bae, M.K., Ahn, M.Y., Regulation and destabilization of HIF-1alpha by ARD1-mediated acetylation (2002) Cell, 111, pp. 709-720; Bali, P., Pranpat, M., Bradner, J., Inhibition of histone deacetylase 6 acetylates and disrupts the chaperone function of heat shock protein 90: A novel basis for antileukemia activity of histone deacetylase inhibitors (2005) J Biol Chem, 280, pp. 26729-26734; Chen, C.S., Weng, S.C., Tseng, P.H., Lin, H.P., Chen, C.S., Histone acetylation-independent effect of histone deacetylase inhibitors on Akt through the reshuffling of protein phosphatase 1 complexes (2005) J Biol Chem, 280, pp. 38879-38887; Haggarty, S.J., Koeller, K.M., Wong, J.C., Grozinger, C.M., Schreiber, S.L., Domain-selective small-molecule inhibitor of histone deacetylase 6 (HDAC6)-mediated tubulin deacetylation (2003) Proc Natl Acad Sci U S A, 100, pp. 4389-4394; Mitsiades, C.S., Mitsiades, N.S., McMullan, C.J., Transcriptional signature of histone deacetylase inhibition in multiple myeloma: Biological and clinical implications (2004) Proc Natl Acad Sci U S A, 101, pp. 540-545; Hideshima, T., Bradner, J.E., Wong, J., Small-molecule inhibition of proteasome and aggresome function induces synergistic antitumor activity in multiple myeloma (2005) Proc Natl Acad Sci U S A, 102, pp. 8567-8572; Santo, L., Hideshima, T., Kung, A.L., Preclinical activity, pharmacodynamic, and pharmacokinetic properties of a selective HDAC6 inhibitor, ACY-1215, in combination with bortezomib in multiple myeloma (2012) Blood, 119, pp. 2579-2589; Prince, H.M., Bishton, M., Harrison, S., The potential of histone deacetylase inhibitors for the treatment of multiple myeloma (2008) Leuk Lymphoma, 49, pp. 385-387; Kumar, S.K., Lee, J.H., Lahuerta, J.J., Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: A multicenter international myeloma working group study (2012) Leukemia, 26, pp. 149-157; Richardson, P.G., Sonneveld, P., Schuster, M.W., Bortezomib or high-dose dexamethasone for relapsed multiple myeloma (2005) N Engl J Med, 352, pp. 2487-2498; Orlowski, R.Z., Nagler, A., Sonneveld, P., Randomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma: Combination therapy improves time to progression (2007) J Clin Oncol, 25, pp. 3892-3901; Dimopoulos, M., Siegel, D.S., Lonial, S., Vorinostat or placebo in combination with bortezomib in patients with multiple myeloma (VANTAGE 088): A multicenter, randomised, double-blind study (2013) Lancet Oncol, 14, pp. 1129-1140

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