REVERSAL OF MULTIDRUG-RESISTANCE BY SDZ PSC-833, COMBINED WITH VAD (VINCRISTINE, DOXORUBICIN, DEXAMETHASONE) IN REFRACTORY MULTIPLE-MYELOMA- A PHASE-I STUDY

SDZ PSC 833, a non-immunosuppressive cyclosporin analogue reverses mul tidrug resistance (MDR) in vitro by inhibiting P-glycoprotein (P-gp) m ediated drug efflux. We performed a dose escalation study of SDZ PSC 8 33 combined with VAD chemotherapy in refractory multiple myeloma (MM). Twenty-two MM patients who were refractory to doxorubicin/vincristine /dexamethasone (VADr, n=11) or had failed multiple regimens (n=6) or w ere melphalan-refractory (MELr, n=5), were treated with one to three c ycles of VAD combined with oral SDZ PSC 833, which was administered at escalating dosages starting at 5 mg/kg/day to 15 mg/kg/day for 7 days . The median trough and peak blood levels of SDZ PSC 833 ranged from 4 61/1134 ng/ml at 5 mg/kg/day to 821/2663 ng/ml at 15 mg/kg, respective ly, With addition of SDZ PSC 833 (5 mg/kg) the mean plasma AUC 0-->96 h of doxorubicin as compared with control patients treated with VAD in creased from 779 to 1510 ng/ml/h (P=0.0071), while the doxorubicin cle arance was reduced from 47.6 to 27.8 l/h/m(2) (P=0.0002). The clearanc e of doxorubicinol was reduced accordingly. Because of the increased p lasma AUG, the dose of doxorubicin and vincristine had to be reduced i n 13 patients to 50% (n=1) or 75% (n=12). A further dose-escalation of SDZ PSC 833 did not lead to a proportional increase of doxorubicin AU C. Toxicity WHO CTC grade 2 or 3 included hypoplasia (18/22), constipa tion (10/22), hyponatremia (3/22) and infections (6/22). A partial res ponse or stable disease was achieved in eight and six patients, respec tively. In 17 evaluable patients the mean percentage of pretreatment b one marrow plasma cells which expressed P-glycoprotein was 40%, The pr etreatment in vitro rhodamin retention in CD38(++) myeloma cells was r eversible by 2 mu M SDZ PSC 833 with 15-98% in 7/9 tested patients, In 4/5 responding patients analyzed before and after treatment with VAD + SDZ PSC 833, a reduction of P-gp + plasma cells was observed. It is concluded, that the blood concentrations of SDZ PSC 833 atttained in M M patients increase with dose after oral administration. it can be saf ely combined with VAD chemotherapy. SDZ PSC 833 diminishes the clearan ce of doxorubicin, leading to an increase of the plasma AUC of doxorub icin. In addition, it is an effective inhibitor of P-gp mediated efflu x of doxorubicin in myeloma tumor cells in vitro. Therefore, a proport ional dose-reduction of doxorubicin and vincristine is warranted. Phas e II/III studies in refractory MM are in progress to evaluate the ther apeutic efficacy of SDZ PSC 833 with VAD.