High melphalan exposure is associated with improved overall survival in myeloma patients receiving high dose melphalan and autologous transplantation

• Published in: British journal of clinical pharmacology Vol. 82; no. 1; pp. 149 - 159
• Main Authors: Nath, Christa E., Trotman, Judith, Tiley, Campbell, Presgrave, Peter, Joshua, Douglas, Kerridge, Ian, Kwan, Yiu Lam, Gurney, Howard, McLachlan, Andrew J., Earl, John W., Nivison‐Smith, Ian, Zeng, Lihua, Shaw, Peter J.
• Format: Journal Article
• Language: English
• Published: England John Wiley and Sons Inc 01.07.2016
• Subjects: Adult; Aged; Antineoplastic Agents, Alkylating - administration & dosage; Antineoplastic Agents, Alkylating - adverse effects; Antineoplastic Agents, Alkylating - pharmacokinetics; Area Under Curve; Combined Modality Therapy; Disease-Free Survival; Female; Half-Life; Humans; Logistic Models; Male; melphalan; Melphalan - administration & dosage; Melphalan - adverse effects; Melphalan - pharmacokinetics; Middle Aged; Multiple Myeloma - pathology; Multiple Myeloma - therapy; Multivariate Analysis; Pharmacokinetic Dynamic Relationships; pharmacokinetics; Prospective Studies; Risk Factors; Stem Cell Transplantation - adverse effects; Stem Cell Transplantation - methods; Survival Rate; Transplantation, Autologous; Treatment Outcome; pharmacokinetics; melphalan; treatment outcome
• ISSN: 0306-5251; 1365-2125
• DOI: 10.1111/bcp.12906

Aim 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. Methods 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). Results 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. Conclusions 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.