A phase I/II trial of melphalan (MEL) combined with panobinostat (PAN) for patients with relapsed or refractory (R/R) multiple myeloma (MM).

Abstract

e18558 Background: PAN, a potent histone deacetylase inhibitor, significantly inhibits the growth of MM cells in vitro and enhances the cytotoxicity of standard chemotherapy. Studies with our SCID-hu MM models show an increased inhibition of MM cell growth when PAN was combined with MEL compared to treatment with either drug alone. These preclinical studies provided the rationale for evaluating the combination of oral MEL with oral PAN for the treatment of MM patients with R/R disease. Methods: This was a Phase 1/2, open-label, dose‑escalation study to treat R/R MM patients initially using oral PAN every Monday, Wednesday and Fridayin combination with oral MEL (0.05 mg/kg) on days 1-5 of a 28‑day cycle. Results: Thirty-seven patients were enrolled into the Phase 1 portion of this study. The median number of prior regimens received were 4 (range, 1-17) with 22 patients previously treated with MEL. Following amendments to dose and schedule because of toxicity including cytopenias and fatigue, PAN and MEL were both administered only on days 1, 3 and 5 of a 28-day cycle. The maximum tolerated dose for this combination was defined as PAN at 20 mg and MEL at 0.05 mg/kg both administered on only days 1, 3 and 5. Overall, 4 patients (11%) showed objective responses to this combination with 1 complete (3%) and 3 partial (8%) responses and only occurred among patients receiving PAN throughout the cycle. An additional 18 (49%) patients had stable disease while 15 (41%) progressed while on study. Eighteen patients experienced grade 3 or 4 adverse events (AEs) with 6 of these meeting the definition of a dose-limiting toxicity. These AEs included reversible thrombocytopenia (n=11), reversible neutropenia (n=10), reversible worsening anemia (n=3), and one case each of a forearm rash, fatigue/weakness, pneumonia, hypokalemia and hyponatremia. Three more patients who are not yet evaluable have been enrolled into the Phase 2 portion to complete the planned 40 patients on the trial. Conclusions: The combination of intermittent PAN & low-dose oral MEL shows modest activity in heavily pretreated patients with R/R MM. Continuous doses of PAN with MEL yielded better efficacy but this treatment schedule was not tolerable.