WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• There has been one previous population pharmacokinetic analysis of total melphalan given as a short infusion in 84 adults (mixed diagnoses) and creatinine clearance and body size were found to be important determinants of total melphalan clearance. Dose and exposure to total melphalan were found to correlate with the development of mucositis. WHAT THIS STUDY ADDS• This is the largest population pharmacokinetic study on melphalan conducted to date. It is the first conducted in a uniform patient population (patients with multiple myeloma) and the first in which both total and unbound melphalan pharmacokinetics are examined. Factors found to be important determinants of total and unbound plasma clearance of melphalan were creatinine clearance, fat free mass and haematocrit. Haematocrit has not previously been identified as an influential covariate in any previous study. The importance of total and unbound melphalan exposure on transplant outcome was demonstrated by preliminary pharmacodynamic results showing significant associations with melphalan-related toxicity. A preliminary analysis of the association with disease response showed promising trends, but will be examined in more detail with longer follow-up of the whole cohort. AIMSTo i) investigate the pharmacokinetics of total and unbound plasma melphalan using a population approach, ii) identify clinical factors that affect melphalan disposition and iii) evaluate the role of melphalan exposure in melphalan-related toxicity and disease response. METHODSPopulation pharmacokinetic modelling (using NONMEM) was performed with total and unbound concentration-time data from 100 patients (36-73 years) who had received a median 192 mg m -2 melphalan dose. Model derived estimates of total and unbound melphalan exposure (AUC) in patients with serious melphalan toxicity and those who had a good disease response (Ն90% decrease in paraprotein concentrations) were compared using the Mann-Whitney test. RESULTSA two compartment model generated population mean estimates for total and unbound melphalan clearance (CL) of 27.8 and 128 l h -1 , respectively. Estimated creatinine clearance, fat free mass and haematocrit were important determinants of total and unbound CL, reducing the inter-individual variability in total CL from 34% to 27% and in unbound CL from 42% to 30%. Total AUC (range 4.9-24.4 mg l -1 h) and unbound AUC (range 1.0-6.5 mg l -1 h) were significantly higher in patients who had oral mucositis (Նgrade 3) and long hospital admissions (P < 0.01). Patients who responded well had significantly higher unbound AUC (median 3.2 vs. 2.8 mg l -1 h, P < 0.05) when assessed from diagnosis to post-melphalan and higher total AUC (median 21.3 vs. 13.4 mg l -1 h, P = 0.06), when assessed from pre-to post-melphalan. CONCLUSIONSCreatinine clearance, fat free mass and haematocrit influence total and unbound melphalan plasma clearance. Melphalan exposure is related to melphalan toxicity while the association with efficacy shows promising tren...

AIMHigh dose melphalan (HDM) and autologous stem cell transplantation (ASCT) retains a central role in the treatment of myeloma. The aim of this study was to determine whether HDM exposure (area under the concentration vs. time curve, AUC), is significantly associated with transplant outcomes. METHODSMelphalan concentrations were measured in six to 11 plasma samples collected after HDM (median 192 mg m -2 ) to determine melphalan AUC for a total of 114 patients. Binary logistic regression was used to assess whether melphalan AUC was associated with severe (≥ grade 3) oral mucositis. Multivariate Cox regression was used to assess whether melphalan AUC was significantly associated with time to progression, progression-free survival and overall survival (OS). RESULTSMelphalan AUC ranged from 4.9 to 24.6 mg l -1 h, median 12.84 mg l -1 h. Melphalan AUC above the median was a risk factor for severe mucositis (HR 1.21, 95% CI 1.06, 1.38, P = 0.004) but was also associated with significantly improved overall survival (OS) (HR 0.40, 95% CI 0.20, 0.81, P = 0.001), with an estimated median survival of 8.50 years vs. 5.38 years for high vs. low AUC groups. Multivariate analysis did not identify melphalan AUC as being significantly associated with time to progression or progression-free survival. CONCLUSIONSThis large scale pharmacodynamic analysis of HDM demonstrates that high melphalan exposure is associated with improved survival, with an acceptable increase in transplant toxicity. These results suggest studies targeting a higher AUC are warranted in patients undergoing HDM and ASCT for myeloma.

Autologous stem cell transplantation (ASCT) has a well-established role in the treatment of haematological malignancies. Stem cells are commonly collected following salvage chemotherapy although there may be advantages in collecting earlier in the disease course. A 'rainy day' harvest (RDH) refers to the collection of autologous haemopoietic stem cells for long-term storage. Although there are few data to support RDH, there is increasing evidence that such harvests are being carried out, creating storage pressures in stem cell laboratories across New South Wales. The Bone Marrow Transplant Network New South Wales conducted a three-staged exercise to develop consensus-based RDH guidelines. Using available evidence, guidelines were developed supporting RDH for specific patients with acute and chronic myeloid leukaemias, follicular and other lymphomas, and multiple myeloma. Physician agreement with these disease-specific guidelines ranged between 58 and 100%. These consensus guidelines will improve equity of access to appropriate RDH and assist the planning of future storage requirements in New South Wales.

A total of 23 patients with advanced gastric adenocarcinoma were treated with a combination of moderate-dose methotrexate (MDMTX), 250 mg/m2 i.v., with folinic acid rescue and 5-fluorouracil (5-FU) 600 mg/m2 i.v. Therapy was given every 7 days for 4 courses and then at 14-day intervals. All patients were evaluable for response. No complete responses occurred, but five patients (22%) had partial remissions (95% confidence limit, 5%-39%). The median duration of remission was 6 months, with a median survival of 11 months amongst responding patients. In all, six patients (26%) had stable disease for a median period of 5 months. The overall median survival was 6 months. Therapy was generally well tolerated, with principal toxicities consisting of neutropenia, nausea and vomiting, mucositis and diarrhoea. In terms of activity or survival in advanced gastric carcinoma, the combination of moderate-dose MTX and 5-FU does not appear to offer an advantage over single-agent therapy.