title: High melphalan exposure is associated with improved overall survival in myeloma patients receiving high dose melphalan and autologous transplantation.
abstract: High 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.
  
  
  
  Melphalan 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).
  
  
  
  Melphalan 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.
  
  
  
  This 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.
authors.affiliation: The Children's Hospital at Westmead, Hawkesbury Rd, Westmead, 2145.
authors.forename: Christa E
authors.initials: CE
authors.lastname: Nath
authors.affiliation: Concord Hospital, Hospital Road, Concord, NSW, 2139.|University of Sydney, Sydney, NSW, 2006.
authors.forename: Judith
authors.initials: J
authors.lastname: Trotman
authors.affiliation: Gosford Hospital, Holden St, Gosford, NSW, 2250.|University of Newcastle, University Dr, Callaghan, NSW, 2308.
authors.forename: Campbell
authors.initials: C
authors.lastname: Tiley
authors.affiliation: Wollongong Hospital, Loftus St, Wollongong, NSW, 2500.|University of Wollongong, Northfields Ave, Wollongong, NSW, 2522.
authors.forename: Peter
authors.initials: P
authors.lastname: Presgrave
authors.affiliation: University of Sydney, Sydney, NSW, 2006.|Royal Prince Alfred Hospital, Missenden Rd, Camperdown, NSW, 2050.
authors.forename: Douglas
authors.initials: D
authors.lastname: Joshua
authors.affiliation: University of Sydney, Sydney, NSW, 2006.|Westmead Hospital, Hawkesbury Rd, Westmead, NSW, 2145.
authors.forename: Ian
authors.initials: I
authors.lastname: Kerridge
authors.affiliation: Concord Hospital, Hospital Road, Concord, NSW, 2139.
authors.forename: Yiu Lam
authors.initials: YL
authors.lastname: Kwan
authors.affiliation: University of Sydney, Sydney, NSW, 2006.|Westmead Hospital, Hawkesbury Rd, Westmead, NSW, 2145.
authors.forename: Howard
authors.initials: H
authors.lastname: Gurney
authors.affiliation: Concord Hospital, Hospital Road, Concord, NSW, 2139.|University of Sydney, Sydney, NSW, 2006.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: McLachlan
authors.affiliation: The Children's Hospital at Westmead, Hawkesbury Rd, Westmead, 2145.|University of Sydney, Sydney, NSW, 2006.
authors.forename: John W
authors.initials: JW
authors.lastname: Earl
authors.affiliation: Australasian Bone Marrow Transplant Recipient Registry, 370 Victoria Street, Darlinghurst, NSW, 2010, Australia.
authors.forename: Ian
authors.initials: I
authors.lastname: Nivison-Smith
authors.affiliation: The Children's Hospital at Westmead, Hawkesbury Rd, Westmead, 2145.
authors.forename: Lihua
authors.initials: L
authors.lastname: Zeng
authors.affiliation: The Children's Hospital at Westmead, Hawkesbury Rd, Westmead, 2145.|University of Sydney, Sydney, NSW, 2006.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Shaw
mesh_terms: D000328:Adult; D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D019540:Area Under Curve; D003131:Combined Modality Therapy; D018572:Disease-Free Survival; D005260:Female; D006207:Half-Life; D006801:Humans; D016015:Logistic Models; D008297:Male; D008558:Melphalan / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D008875:Middle Aged; D009101:Multiple Myeloma / Q000473:pathology / Q000628:therapy*; D015999:Multivariate Analysis; D011446:Prospective Studies; D012307:Risk Factors; D033581:Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods*; D015996:Survival Rate; D014182:Transplantation, Autologous; D016896:Treatment Outcome
chemical_list: D018906:Antineoplastic Agents, Alkylating; D008558:Melphalan
keywords: melphalan; pharmacokinetics; treatment outcome