NEW YORK—Calling the synergy with the proteasome inhibitor “profound,” Paul G. Richardson, MD, presented results on the combination of the pan deacetylase inhibitor panobinostat with bortezomib and dexamethasone in relapsed/refractory multiple myeloma (MM).
The phase 3 PANORAMA 1 study confirmed data from the phase 1 and 2 trials, in which the triple combination demonstrated durable responses, even in bortezomib-refractory disease.
Dr Richardson, of the Dana-Farber Cancer Institute in Boston, presented updated data from the PANORAMA 1 trial, which received an award for the most clinically relevant myeloma abstract at the Lymphoma & Myeloma 2014 congress, held October 23–25.
Investigators randomized 768 patients with relapsed or relapsed and refractory MM to receive either panobinostat (n=387) or placebo (n=381) with bortezomib and dexamethasone. Bortezomib-refractory patients were excluded.
The study was conducted in 2 treatment phases, and patients with clinical benefit at the end of the first 24-week phase could proceed to the second treatment phase, consisting of four 42-day cycles.
The primary endpoint was progression-free survival (PFS) according to modified European Society for Blood and Marrow Transplantation criteria.
The key secondary endpoint was overall survival, and additional secondary endpoints included overall response rate, complete response/near complete response, duration of response, time to response, time to progression, quality of life, and safety.
Dr Richardson pointed out that in the first treatment phase, bortezomib was administered twice a week at 1.3 mg/m2 intravenously, and, in the second phase, it was given once a week. The panobinostat dose was 20 mg orally 3 times a week, and oral dexamethasone was given at 20 mg on the same day and the day after bortezomib administration.
Patients were a median age of 63 years, and nearly half (48.4%) had received 2 or more prior therapies, including bortezomib, at 43.7% in the panobinostat arm and 42.3% in the placebo arm. Half the patients had prior exposure to thalidomide, and 1 in 4 patients had received bortezomib and an immunomodulator.
Approximately two-thirds of the patients had relapsed MM, and one-third had relapsed and refractory disease.
Twenty-six percent of patients in either arm completed treatment. Forty-four percent of patients in the panobinostat arm and 50% in the placebo arm entered treatment phase 2.
The dose intensity of panobinostat decreased to 78.2% at cycle 3 and remained stable through the rest of the trial. By cycle 3, the majority of patients were receiving 15 mg of panobinostat.
Results
The 3-drug combination met its primary endpoint, with a clinically relevant increase in median PFS of 3.9 months (P<0.0001).
The benefit with panobinostat was maintained regardless of prior treatment history or baseline characteristics.
“There was benefit across all subgroups,” Dr Richardson said, “but especially in the poor-risk group.”
He noted that the overall survival curve was holding between the 2 arms at about a 3-month difference.
And the complete response/near complete response rate in the panobinostat arm was nearly double that of the control arm, at 27.6% and 15.7%, respectively (P=0.00006).
While not significant, there were clinically meaningful improvements in overall response rate, duration of response, and time to progression. The overall response rate with panobinostat was 34.5%, the clinical benefit rate 52.7%, and the median PFS 5.4 months.
Safety
“Overall, side effects were relatively low,” Dr Richardson said, the major ones consisting of hematologic laboratory abnormalities.
Almost 98% of the patients receiving panobinostat and 83.5% of those in the placebo arm had thrombocytopenia of any grade. And 1.6% of patients on panobinostat discontinued due to thrombocytopenia, compared with 0.5% in the control arm.
Dr Richardson said the thrombocytopenia was reversible and not cumulative. Platelet levels rebounded to baseline by day 1 of each cycle.
Lymphopenia, neutropenia, and anemia were also more frequent in the panobinostat arm.
Nonhematologic adverse events, particularly diarrhea and fatigue, were, for the most part, increased over control, with 4.5% of patients on the panobinostat arm discontinuing due to diarrhea and 2.9% discontinuing due to fatigue.
The incidence of adverse events was lower in the second treatment phase, when bortezomib was administered once a week.
And deaths related to study drug were very low, Dr Richardson said, with 11 in the panobinostat arm and 7 in the control arm.
The triple drug combination is “a very important concept going forward,” Dr Richardson said.
Other combinations and additional histone deacetylase inhibitors are being evaluated for MM.
