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

Authors

Christa E. Nath, Children's Hospital, Westmead
Judith Trotman, University of Sydney
Campbell Tiley, University of Newcastle
Peter J. Presgrave, University of WollongongFollow
Douglas Joshua, University of Sydney
Ian Kerridge, University of Sydney
Yiulam Kwan, Concord Hospital
Howard Gurney, University of Sydney
Andrew J. McLachlan, University of Sydney
John W. Earl, University of Sydney
Ian Nivison-Smith, Australasian Bone Marrow Transplant Recipient Registry
Lihua Zeng, Children's Hospital, Westmead
Peter J. Shaw, Children's Hospital, Westmead

RIS ID

107222

Publication Details

Nath, C. E., Trotman, J., Tiley, C., Presgrave, P. J., Joshua, D., Kerridge, I., Kwan, Y., Gurney, H., McLachlan, A. J., Earl, J. W., Nivison-Smith, I., Zeng, L. & Shaw, P. J. (2016). High melphalan exposure is associated with improved overall survival in myeloma patients receiving high dose melphalan and autologous transplantation. British Journal of Clinical Pharmacology, 82 (1), 149-159.

Abstract

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.