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

Abstract

e18574 Background: We and others have shown that PAN, a potent histone deacetylase inhibitor (HDACi), significantly inhibits the growth of MM cells in vitro and enhances the cytotoxicity triggered by chemotherapeutic agents. Using our SCID-hu models of MM, we have also shown an increased inhibition of MM cell growth in vivo when PAN was combined with low doses of melphalan compared to treatment with either drug alone. Thus, these preclinical studies provided the rationale for evaluating the combination of oral melphalan with oral PAN for the treatment of MM patients with relapsed or refractory disease. Methods: Thus, we initiated a Phase I/II, open-label, dose-escalation study to treat R/R MM patients using oral PAN every Monday, Wednesday and Friday in combination with oral MEL (0.05 mg/kg) on days 1-5 of a 28 day cycle. After amendments to dose & schedule because of toxicity including cytopenias and fatigue, PAN 15 mg is now being administered with oral MEL 0.05 mg/kg on days 1, 3 & 5 of a 28-day cycle in the current cohort as part of the Phase I portion of the trial. Results: To date, 25 (of 40 planned) patients have been enrolled with a median of 4 (4-17) prior regimens. Sixteen were previously treated with MEL. To date, 4 patients (16%) have shown objective responses to this combination with 2 complete (8%) and 2 partial (8%) responses. An additional 11 (44%) patients have had stable disease while 10 (40%) have progressed while on study. Fourteen patients experienced grade 3 or 4 adverse events, including: reversible neutropenia (n=7), reversible thrombocytopenia (n=9), reversible worsening anemia (n=1), and one case each of a forearm rash, fatigue/weakness, hypokalemia, and hyponatremia. Conclusions: The combination of PAN and low-dose oral MEL has shown an encouraging response rate (16%) in heavily pretreated patients with relapsed/refractory MM. An expanded Phase II part of the trial will be conducted using this oral combination treatment once the MTD has been determined from the current Phase I portion of the trial.