SAFETY OF AUTOTRANSPLANTS WITH HIGH-DOSE MELPHALAN IN RENAL-FAILURE -A PHARMACOKINETIC AND TOXICITY STUDY

Melphalan (MEL) is probably the most effective chemotherapeutic agent in multiple myeloma (MM) with a clear dose-response effect, It can he escalated without excessive toxicity to 200 mg/m(2), a myeloablative d ose requiring hematopoietic stem cell support, Patients with marked re nal insufficiency, not an infrequent finding in MM, have either receiv ed reduced doses or have been excluded from therapy with high-dose MEL , A prospective study was performed to evaluate the relationship betwe en MEL pharmacokinetics and renal function in 20 patients with MM, Six patients had severe renal insufficiency (creatinine clearance, < 40 m l/min), including five on chronic hemodialysis. Three patients with se vere renal impairment first received a low test dose of MEL (16 mg/m(2 )) for pharmacokinetic studies, All patients received 200 mg/m(2) MEL divided into two equal doses of 100 mg/m(2) i.v. on 2 consecutive days , followed by the administration of peripheral blood stem cells. MEL p harmacokinetics, performed after the first dose of 100 mg/m(2), was no t adversely affected by impaired renal function, The median half-life (t(1/2)), area under the concentration curve, and clearance of MEL wer e 1.1 h, 5.5 mg h/liter, and 27.5 liter/h, respectively, in patients w ith a creatinine clearance of < 40 ml/min compared to 1.9, 7.9, and 23 .6 for the others, Renal insufficiency also had no apparent negative i mpact on the quality of peripheral blood stem cell collections and did not adversely affect posttransplant engraftment, transfusion requirem ents, incidence of severe mucositis, or overall survival, However, it was associated with longer durations of fever (P = 0.0005) and hospita lization (P = 0.004), No transplant-related deaths were observed, Plas ma t(1/2) and area under the concentration curve differed by a factor of 10 and MEL clearance by a factor of 5 between patients with the low est and highest values, These large variations in MEL elimination coul d not be explained by patient or disease characteristics. We conclude that renal failure does not require dose reduction of MEL in autologou s transplant, Due to marked interindividual variation in MEL eliminati on, pharmacokinetically guided dosing as well as cellular pharmacology studies may be helpful in achieving a more uniform antitumor effect.