Patients with multiple myeloma may have improved tolerance of panobinostat when combined with low-dose thalidomide and subcutaneous bortezomib, according to the results of the phase I/II MUK-six trial.
Patients with multiple myeloma may have improved tolerance of panobinostat when combined with low-dose thalidomide and subcutaneous bortezomib, according to the results of the phase I/II MUK-six trial published in Lancet Oncology.
Panobinostat is currently approved in combination with bortezomib and dexamethasone for patients with myeloma who have received two or more prior lines of therapy. This multicenter trial was designed to improve the tolerability of the US Food and Drug Administration (FDA)-approved regimen and investigate its efficacy by incorporating low-dose thalidomide and reducing the frequency of bortezomib administration.
The trial used a rolling six escalation design to determine the maximum tolerated dose of panobinostat, and assigned patients aged 18 or older with relapsed or refractory myeloma to subcutaneous bortezomib 1.3 mg/m2 or oral thalidomide 100 mg, dexamethasone 20 mg, and panobinostat 10, 15, or 20 mg. All patients had received between one to four prior lines of therapy. The primary objective was to estimate the proportion of patients with an overall response that was equal to a partial response or greater within 16 cycles of treatment.
“The findings from our study showed that panobinostat at 20 mg is effective and can be safely given in combination with bortezomib, thalidomide, and dexamethasone for patients with relapsed multiple myeloma,” wrote researchers led by Rakesh Popat, MD, of the National Institute of Health Research, London. “The proportions of patients with an equal to or better than a partial response were high and did not differ by previous bortezomib exposure, showing effectiveness for patients who were previously treated with bortezomib.”
In the trial, 57 patients received at least one dose of the tested regimen or any drug. Only one dose-limiting toxicity was reported: a grade 3 hyponatremia at the 20 mg dose. The maximum tolerated dose, therefore, was not reached and 20 mg became the recommended dose.
The intention-to-treat population comprised 46 patients treated at 20 mg panobinostat. The median number of previous therapies in this group was one. Patients received a median of 10 cycles of treatment and about one-half came off study after a median of 8 cycles. Of these 46 patients, 42 patients (91%) achieved an overall response equal to a partial response or greater.
According to the researchers, “the depth of response was higher for those treated at first relapse than those at later stages.” In addition, responses were similar whether or not a patient had previous bortezomib exposure, but were slightly lower with previous immunomodulatory drug exposure.
The median progression-free survival was 15.6 months, and more than three-quarters of patients were alive and free from progression at 1 year.
Most adverse events were grade 1/2, but there were a few occurrences of grade 3/4 diarrhea or fatigue. The most common grade 3 or worse adverse events in the safety population of 57 patients were reduced neutrophil count (26%), hypophosphatemia (19%), and decreased platelet count (14%). Of the 46 serious adverse events that occurred, 14 were suspected to be related to the trial medication.
“The MUK-six trial predominantly included patients at first relapse and adds to the evidence that a combination of panobinostat and a proteasome inhibitor can be safely and effectively delivered, particularly earlier in the currently indicated treatment pathway,” the researchers wrote.