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Combination regimen extended PFS in multiple myeloma

CHICAGO — The addition of panobinostat to bortezomib and dexamethasone significantly extended PFS in patients with relapsed or relapsed/refractory multiple myeloma, according to results of a randomized, double blind, placebo-controlled phase 3 trial presented at the ASCO Annual Meeting.

The combination also had a manageable toxicity profile.

The PANORAMA 1 trial included 768 patients (median age, 63 years) with relapsed or relapsed/refractory disease who had undergone one to three prior treatments. About half of patients (48%) had received two or three prior regimens, and 57% had undergone prior autologous stem cell transplant.

Patients refractory to bortezomib (Velcade, Millennium) and those with primary-refractory disease were excluded.

Initial treatment was administered in eight 3-week cycles.

All patients received 1.3 mg/m² IV bortezomib on days 1, 4, 8 and 11, as well as 20 mg oral dexamethasone on days 1, 2, 4, 5, 8, 9, 11 and 12.

Researchers randomly assigned patients to receive 20 mg oral panobinostat (LBH589, Novartis) or placebo on days 1, 3, 5, 8, 10 and 12.

Patients who demonstrated clinical benefit after eight cycles of treatment proceeded to a second phase during which bortezomib and dexamethasone treatments were reduced. Bortezomib was administered on days 1 and 8, and dexamethasone was administered on days 1, 2, 8 and 9.

PFS served as the primary endpoint. Secondary endpoints included OS, overall response rate, the combined rate of near complete and complete responses, duration of response and safety.

Researchers reported significantly longer median PFS among patients assigned to panobinostat (12 months vs. 8.1 months; HR=0.63; 95% CI, 0.52-0.76). Patients assigned to panobinostat also demonstrated a higher rate of overall response (61% vs. 55%), a higher combined rate of near complete response and complete response (28% vs. 15%), and a longer median duration of response (13.1 months vs. 10.9 months).

 

Paul G. Richardson

“This study clearly demonstrates the superiority of the three-drug combination over the control group, proven with the 4-month improvement observed in PFS,” Paul G. Richardson, MD, clinical program leader and director of clinical research at the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute, a professor of medicine at Harvard Medical School and HemOnc Today’s myeloma section editor, said during a presentation. “What is particularly striking is that the PFS benefit was maintained across all subgroups, and there was an almost twofold increase in high-quality response rate.”

Grade 3 and grade 4 adverse events occurred more frequently in the panobinostat arm. They included thrombocytopenia (67% vs. 31%), neutropenia (35% vs. 11%) and diarrhea (26% vs. 8%). Researchers reported 4.5% of patients assigned to panobinostat discontinued treatment due to adverse events.

“We believe this represents a significant advance in this field and in patients with relapsed/refractory disease,” Richardson said. “Importantly, other combinations including panobinostat are under evaluation for multiple myeloma, and we have seen very promising results with panobinostat in other cancers during [ASCO].”

For more information:

Richardson PG. Abstract #8510. Presented at: ASCO Annual Meeting; May 30-June 3, 2014; Chicago.

Disclosure:  The researchers report consultant/advisory roles with Amgen, Bristol-Myers Squibb, Celgene, Janssen-Cilag, Johnson & Johnson, Merck Sharp & Dohme, Millennium, Novartis, Onyx and Sanofi; employment or leadership positions with Novartis; honoraria from Amgen, Celgene, Janssen-Cilag Novartis and Onyx; and expert testimony and other remuneration from Novartis.