Abstract
Proteasome (PIs) and hystone deacetylase inhibitors (HDACis) have previously shown synergistic activity in the treatment of relapesed/refractory multiple myeloma (RRMM) patients. In this phase 1 study, we combined carfilzomib, a second generation PI, with panobinostat, a HDACi, to determine the maximum tolerated dose (MTD) of the combination (CarPan) and assess safety and efficacy among RRMM patients. Thirty-two patients (median of 4 prior lines of therapy) were enrolled. The MTD was carfilzomib 36 mg/m2 (on days 1, 2, 8, 9, 15, and 16) and panobinostat 20 mg (TIW, 3 weeks on/1 week off, every 28 days), administered until progression. At the MTD, the most common grade 3/4, treatment-related adverse events were thrombocytopenia (41%), fatigue (17%), and nausea/vomiting (12%). The objective response rate (ORR) and clinical benefit rate were 63% and 68%, respectively. Median progression-free survival (PFS) and overall survival (OS) for the entire population were 8 and 23 months, respectively. No differences in terms of ORR (55% vs. 57%), median PFS (months 8 vs. 7 months) and OS (24 vs. 22 months) were observed between bortezomib-sensitive and -refractory patients. CarPan proved to be a safe and effective steroid-sparing regimen in a heavily pre-treated population of MM patients. (Trial registered at ClinicalTrial.gov: NCT01549431)
Highlights
Multiple myeloma (MM) is a neoplasm characterized by a clonal proliferation of plasma cells in the bone marrow and the accumulation of monoclonal protein in serum and/or urine, with related organ dysfunction
1 aThe first 2 doses of carfilzomib in cycle 1 were administered at 20 mg/m2 and premedication with dexamethasone 4 mg was mandatory prior to each dose of carfilzomib during cycle 1 and was thereafter administered as clinically indicated bThree times a week the first-generation novel agents– the proteasome inhibitor (PI) bortezomib and the immunomodulatory drugs (IMiDs) thalidomide and lenalidomide– has revolutionized treatment and led to a dramatic improvement in the survival of MM patients[2,3]
Carfilzomib, a second-generation PI, is an epoxyketone that irreversibly binds to the β5 subunit of the proteasome, preventing protein degradation by the proteasome itself and causing an accumulation of intracellular proteins that eventually leads to cell death via apoptosis[5]
Summary
Multiple myeloma (MM) is a neoplasm characterized by a clonal proliferation of plasma cells in the bone marrow and the accumulation of monoclonal protein in serum and/or urine, with related organ dysfunction. Carfilzomib, a second-generation PI, is an epoxyketone that irreversibly binds to the β5 subunit of the proteasome, preventing protein degradation by the proteasome itself and causing an accumulation of intracellular proteins that eventually leads to cell death via apoptosis[5]. It has significant activity among patients relapsed and/or refractory (RR) to bortezomib and IMiDs, and has been approved by American and European regulatory agencies[6,7]. Carfilzomib is approved with the twiceweekly schedule at a dose of 27 mg/m2, over a 2- to 10-
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