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

Christa E. Nath, Judith Trotman, Campbell Tiley, Peter Presgrave, Douglas Joshua, Ian Kerridge, Yiu Lam Kwan, Howard Gurney, Andrew J. McLachlan, John W. Earl, Ian Nivison-Smith, Lihua Zeng, Peter J. Shaw

Research output: Contribution to journalArticleResearchpeer-review

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.

LanguageEnglish
Pages149-159
Number of pages11
JournalBritish Journal of Clinical Pharmacology
Volume82
Issue number1
DOIs
Publication statusPublished - Jul 2016
Externally publishedYes

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Melphalan
Autologous Transplantation
Area Under Curve
Survival
Stem Cell Transplantation
Disease-Free Survival
Transplants
Stomatitis
Mucositis
Multivariate Analysis

Keywords

  • melphalan
  • pharmacokinetics
  • treatment outcome

Cite this

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. / High melphalan exposure is associated with improved overall survival in myeloma patients receiving high dose melphalan and autologous transplantation. In: British Journal of Clinical Pharmacology. 2016 ; Vol. 82, No. 1. pp. 149-159.
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title = "High melphalan exposure is associated with improved overall survival in myeloma patients receiving high dose melphalan and autologous transplantation",
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.",
keywords = "melphalan, pharmacokinetics, treatment outcome",
author = "Nath, {Christa E.} and Judith Trotman and Campbell Tiley and Peter Presgrave and Douglas Joshua and Ian Kerridge and Kwan, {Yiu Lam} and Howard Gurney and McLachlan, {Andrew J.} and Earl, {John W.} and Ian Nivison-Smith and Lihua Zeng and Shaw, {Peter J.}",
year = "2016",
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Nath, CE, Trotman, J, Tiley, C, Presgrave, P, Joshua, D, Kerridge, I, Kwan, YL, Gurney, H, McLachlan, AJ, Earl, JW, Nivison-Smith, I, Zeng, L & Shaw, PJ 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, vol. 82, no. 1, pp. 149-159. https://doi.org/10.1111/bcp.12906

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

In: British Journal of Clinical Pharmacology, Vol. 82, No. 1, 07.2016, p. 149-159.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - High melphalan exposure is associated with improved overall survival in myeloma patients receiving high dose melphalan and autologous transplantation

AU - Nath, Christa E.

AU - Trotman, Judith

AU - Tiley, Campbell

AU - Presgrave, Peter

AU - Joshua, Douglas

AU - Kerridge, Ian

AU - Kwan, Yiu Lam

AU - Gurney, Howard

AU - McLachlan, Andrew J.

AU - Earl, John W.

AU - Nivison-Smith, Ian

AU - Zeng, Lihua

AU - Shaw, Peter J.

PY - 2016/7

Y1 - 2016/7

N2 - 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.

AB - 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.

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KW - pharmacokinetics

KW - treatment outcome

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