Author(s):  J. F. San-Miguel, O. Sezer, D. S. Siegel, A. Guenther, J. Blade, I. W. Prosser, B. Bengoudifa, M. Klebsattel, P. M. Bourquelot, K. C. Anderson

ABSTRACT:

Background: Panobinostat (PAN; LBH589) is a potent pan-deacetylase inhibitor (pan-DACi) that disrupts aggresome and HSP90 function via inhibition of HDAC6, promoting cytotoxic misfolded protein aggregates and MM cell death. Combination of PAN with the proteasome inhibitor bortezomib (BTZ) demonstrated synergistic cytotoxicity in preclinical studies.

Methods: Pts with Rel or Rel and Ref MM receive PAN (po thrice weekly) and BTZ (iv days 1, 4, 8, 11) on a 21-day cycle to establish the MTD of the combination.

Results: Per October 9, 2009, cutoff, 38 pts were treated in 5 cohorts (Co) (Table): median age 62 (range 46-78), median 2 prior therapies (range 1-7), including stem cell transplant (n=30) and BTZ (n=22; 13 pts BTZ-refractory). No dose-limiting toxicities (DLTs) occurred in Co 1 or 3, 1 DLT in Co 2 (neutropenia [NP]), 4 DLTs in Co 4 (2 thrombocytopenia [TCP], 1 pneumonia/TCP/NP, 1 fatigue), and 1 DLT in Co 5 (TCP/asthenia/dizziness). Hematologic adverse events (AEs) included Gr 3/4 TCP (n=30), NP (n=23), and anemia (n=6). Other AEs included diarrhea (n=23), nausea (n=18), pyrexia (n=17), fatigue (n=16), and asthenia (n=13). There has been no Gr 3/4 peripheral neuropathy and no treatment-related death. Responses were observed in 26/38 pts (68%) across all Co (Table). Notably, responses were also seen in 8/13 (62%) BTZ-refractory pts. Management of AEs, including TCP, permitted by dose reduction or interruption, allowed for longer time on study in Co 3, which also had the most favorable efficacy profile (7/8 pts responded). These results support the use of Co 3 dose levels in subsequent trials.

Conclusions: The combination of oral PAN and BTZ has a predictable and manageable safety profile with promising activity in pts with Rel or Rel and Ref MM, including MM refractory to prior BTZ. Enrollment at 20 mg PAN + 1.3 mg/m2 BTZ is ongoing to determine MTD. A modified dose schedule is now introduced in phase II and III trials with this combination in order to maximize therapy duration.