Combining carfilzomib and panobinostat to treat relapsed/refractory multiple myeloma: results of a Multiple Myeloma Research Consortium Phase I Study

Jonathan L Kaufman, Roberto Mina, Andrzej J Jakubowiak, Todd L Zimmerman, Jeffrey J Wolf, Colleen Lewis, Charise Gleason, Cathy Sharp, Thomas Martin, Leonard T Heffner, Ajay K Nooka, R Donald Harvey, Sagar Lonial, Jonathan L Kaufman, Roberto Mina, Andrzej J Jakubowiak, Todd L Zimmerman, Jeffrey J Wolf, Colleen Lewis, Charise Gleason, Cathy Sharp, Thomas Martin, Leonard T Heffner, Ajay K Nooka, R Donald Harvey, Sagar Lonial

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).

Conflict of interest statement

J.L.K. has consulted for Roche, AbbVie, Janssen, BMS, Takeda, and Karyopharm; A.J.J.: Consultant and Advisory Boards with honoraria for AbbVie, Amgen, BMS, Celgene, Karyopharm, SkylineDx, Takeda; L.T.H.: Pharmacyclics Institutional research funding and honorarium, Genentech institutional research funding; T.M. has received research support from Amgen and Sanofi-Aventis; J.W. has consulted for Takeda, Celgene, Amgen, and Novartis; R.D.H. research funding from Amgen and Novartis; A.K.N.: Advisory board: GSK, Spectrum, Celgene, Amgen, Novartis pharmaceuticals, Adaptive biotechnologies; Honorarium: BMS, Janssen pharmaceuticals; S.L. has consulted for Takeda, Celgene, Novartis, Janssen, GSK, BMS, and Merck. T.L.Z.: currently an employee of AbbVie.

Figures

Fig. 1. Time-to-event analysis.
Fig. 1. Time-to-event analysis.
Kaplan–Meier progression-free survival (a) and overall survival (b) curves

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