Panobinostat Combination Delays Disease Progression in Myeloma

Jason M. Broderick @jasoncology
Published Online: June 10, 2014
Dr. Paul G. Richardson

Paul G. Richardson, MD

Combining the pan-deacetylase inhibitor panobinostat (LBH589) with bortezomib (Velcade) and dexamethasone delayed disease progression by 3.9 months over bortezomib and dexamethasone alone in patients with relapsed or relapsed and refractory multiple myeloma, according to results from the phase III PANORAMA 1 trial presented at the 2014 ASCO Annual Meeting.1 Novartis, which manufactures panobinostat, reported that based on the PANORAMA 1 data, the FDA has granted a priority review to the drug.

“These are the first phase III results to show meaningful clinical benefit and provide scientific support for adding LBH589 to bortezomib-based treatment for patients with relapsed or relapsed and refractory multiple myeloma and provide a strong rationale for the use of histone deacetylase inhibitors as part of the therapeutic armamentarium in this setting,” lead author Paul Richardson, MD, clinical program leader and director of Clinical Research at the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute, said in a press release.

The oral agent panobinostat is a pan-inhibitor of class I, II, and IV histone and non-histone deacetylase enzymes (HDACs/DACs). Panobinostat increases acetylation of proteins involved in multiple oncogenic pathways, inducing cancer cell death. In preclinical research in multiple myeloma, panobinostat was synergistic with bortezomib and dexamethasone.

PANORAMA 1  involved 768 patients (median age, 63 years) with relapsed or relapsed and refractory multiple myeloma. Approximately two-thirds of patients had relapsed multiple myeloma, with one-third having relapsed and refractory disease. Patients with bortezomib- and primary-refractory disease were excluded from the trial.

Study participants had been treated with one to three prior therapies, with 48% receiving at least two regimens. Previous treatments included bortezomib (43%), thalidomide (51%), and lenalidomide (20%). Twenty-five percent of patients had received both bortezomib and immunomodulatory agents. Approximately 57% of patients had autologous stem cell transplantation.

PANORAMA 1 had two treatment phases. In phase 1, patients were randomized to 20 mg of panobinostat (n = 387) or placebo (n = 381) three times per week plus IV bortezomib (1.3 mg/m2 on days 1, 4, 8, and 11) during weeks 1 and 2 of eight 3-week cycles. Patients received 20 mg of oral dexamethasone on the same day and the day after bortezomib treatment.

Patients in each arm benefiting from the treatment could proceed to the second stage of the study. In treatment phase II, which consisted of four 42-day cycles, the panobinostat regimen remained constant, while the frequency of bortezomib and dexamethasone dosing was reduced. 

Progression-free survival, assessed by modified EBMT criteria, was the primary endpoint of the study. Secondary endpoints included overall survival (OS), overall response rate (ORR), near complete/complete response (nCR/CR) rate, duration of response (DOR), and safety. An independent review committee confirmed PFS and ORR.

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