Multicenter Phase II Trial of the Histone Deacetylase Inhibitor Depsipeptide (FK228) for the Treatment of Relapsed or Refractory Multiple Myeloma (MM). (2005)

Abstract Background: Depsipeptide is a cyclic compound with histone deacetylase inhibitory activity as well as antiproliferative and apoptotic effects. Dysregulation of the cell cycle and apoptosis control have been implicated as critical events behind the genesis of MM. Previously, we demonstrated that depsipeptide induces apoptosis in vitro in MM cell lines; those containing t (11q13-cyclin D1) were most sensitive. In vivo studies of primary MM cells treated with depsipeptide show evidence of cell cycle modulation. Here, we report the preliminary results of a Phase II trial which evaluates the safety and efficacy of depsipeptide in MM patients (pts) with documented progressive disease. Methods: To date, 12 pts with relapsed or refractory MM Stage IIIa with progressive disease documented after 4 (mean 3) lines of therapy (Rx) were treated. Mean age 63 years (range 54–74). Baseline mean levels: WBC 4.6 K/uL (range 3.2–5.9); platelets 193 K/uL (63–272); hemoglobin 11g/dL (8–14); albumin 3.8 g/dL (range 2.7–4.6); creatinine 1.0 mg/dL (range 0.6–1.5); LDH 197 u/L (range 156–245); calcium 9.1 mg/dL (range 8.2–10.2). Pretreatment FISH in 9 pts identified 2 with del 13q14 including one with t(11;14), one patient with tetrasomy 11, one with trisomy 11 and 6 normals. Conventional cytogenetics identified one with inversion 9. Depsipeptide was administered IV at 13 mg/m2 as a 4-hr infusion on days 1, 8 and 15 of a 28 day cycle. Cardiac monitoring included pre and post Rx EKG as well as serum troponin-I levels. Results: 11 of 12 pts had stable disease (SD) measured by SPEP or free light chain measurement after receiving one to 6 cycles of depsipeptide; 2 of these pts continue with SD with ongoing Rx (including one patient in cycle 7), 5 discontinued the trial with SD, and 4 progressed after completion of 1 to 2 cycles. Preliminary results indicate that the drug has been well tolerated apart from thrombocytopenia (grade 3) reported in 2 pts necessitating dose reductions; one patient had ST-segment depression (grade 1) noted by EKG. Toxicities commonly associated with depsipeptide administration including fatigue and nausea (grade 2) were reported in 4 and 5 pts, respectively. Conclusions: Depsipeptide treatment was generally well tolerated at the dose and regimen used. Results suggest that the drug is active in pts with advanced MM producing stabilization of disease in those who had progressive relapsed and refractory disease after numerous cycles of prior chemotherapy. Clinical beneffit was noted with improvement of hypercalcemia and pain in 2 pts. Correlative IHC (CD138/Ki-67, BCL-2, MCL-1, CD56, cleaved caspase 3, nuclear cyclin D1 and D3, nuclear p18, p21, p27) and gene array studies are being conducted in these pts and will be reported. Future studies will evaluate depsipeptide at other dosing schedules and combinations with other agents such as bortezomib. Patient accrual continues by the NY Phase II Trial Consortium. Supported by The LLS SCOR grant, RFP S03-058 SAIC-Frederick, NCI K24 CA100287-02 and NCI K23 CA109260-01