Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Correspondence
  • Published:

Melphalan exposure and outcome in obese and non-obese adults with myeloma. A study of pharmacokinetics and pharmacodynamics

Bone Marrow Transplantation volume 55, pages 1862–1864 (2020)Cite this article

Subjects

Despite extensive literature on dosing of cytotoxic chemotherapy [1, 2], dose selection for individual patients remains uncertain, particularly if they are obese. This is critically important when using high-dose chemotherapy for haematological malignancies, where patients are pushed to the limits of treatment-related toxicity. In a recent CIBMTR publication, 78% (of 1696) obese myeloma patients had their melphalan dose reduced by 20% or more [3]. High-dose melphalan (HDM) is conventionally administered as a body surface area (BSA)–based dose of 200 mg/m2. During the course of our prospective, observational, multicenter, study on the pharmacokinetics and pharmacodynamics of HDM in myeloma (ACTRN0126000231549) [4, 5], we observed a variety of dosing practices for obese patients. These included capping the dose at a BSA of 2 m2; or calculating BSA with an alternative estimate of the patient’s weight such as lean body mass (LBM) [6], ideal body weight (IBW) [7] or adjusted ideal body weight (AIBW) [8]. With the increasing prevalence of obesity, exacerbated by the use of corticosteroids in myeloma treatment, the aim of this study was to evaluate whether melphalan dose modification in the obese results in adequate drug exposure or under-treatment.

This analysis utilized data from a subset of 98 (of 114) patients recruited into ACTRN0126000231549 [4, 5]. Sixteen patients with Cockcroft and Gault creatinine clearance (CrCL) [9] ≤60 ml/min were excluded from this analysis because melphalan is eliminated by renal excretion and dose reduction is recommended in renal impairment [10]. HREC approval was obtained for the six participating hospitals and participants provided written informed consent. Clinical details about the patient population may be obtained from our previous publication [5]. All decisions regarding patient treatment and HDM dose selection was at the discretion of the treating doctor. Thirty-eight patients were obese (BMI ≥30 kg/m2), including two morbidly-obese (≥40 kg/m2). Sixty patients were non-obese; 19 were normal-weight (18.5-25 kg/m2), 41 were overweight (25–30 kg/m2). Modifications to the standard pegylated–free 200 mg/m2 dose were applied in 60 patients; dose reductions were 2.5–10% for 45 patients and >10% for 15 patients. Melphalan infusion over 15–30 min within 60 min of reconstitution was recommended in the protocol to minimise the impact of infusion degradation on dose delivery.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: AUC (observed) vs. AUC (extrapolated for the 200 mg/m2 dose using ABW in the BSA equation) in individual obese patients.

Data availability

The datasets generated and/or analysed during the current study are available from the corresponding author upon reasonable request and human research ethics approval.

References

  1. Griggs JJ, Mangu PB, Anderson H, Balaban EP, Dignam JJ, Hyrniuk WM, et al. Appropriate chemotherapy dosing for obese adult patients with cancer: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2012;30:1553–61.

    Article  Google Scholar 

  2. Bubalo J, Carpenter PA, Majhail N, Perales MA, Marks D, Shaughnessy P, et al. Conditioning chemotherapy dose adjustment in obese patients: a review and position statement by the American Society for Blood and Marrow Transplantation practice guideline committee. Biol Blood Marrow Transpl. 2014;20:600–16.

    Article  CAS  Google Scholar 

  3. Brunstein CG, Pasquini MC, Kim S, Fei M, Adekola K, Ahmed I, et al. Effect of conditioning regimen dose reduction in obese patients undergoing autologous hematopoietic cell transplantation. Biol Blood Marrow Transpl. 2019;25:480–7.

    Article  Google Scholar 

  4. Nath CE, Shaw PJ, Trotman J, Zeng L, Duffull SB, Hegarty G, et al. Population pharmacokinetics of melphalan in patients with multiple myeloma undergoing high dose therapy. Br J Clin Pharm. 2010;69:484–97.

    Article  CAS  Google Scholar 

  5. Nath CE, Trotman J, Tiley C, Presgrave P, Joshua D, Kerridge I, et al. High melphalan exposure is associated with improved overall survival in myeloma patients receiving high dose melphalan and autologous transplantation. Br J Clin Pharmacol. 2016;82:149–59.

    Article  CAS  Google Scholar 

  6. Janmahasatian S, Duffull S, Ash S, Ward LC, Byrne NM, Green B. Quantification of lean body weight. Clin Pharmacokinet. 2005;44:1051–65.

    Article  Google Scholar 

  7. Devine D. Case study number 25 gentamicin therapy. Drug Intell Clin Pharm. 1974;8:650–5.

    Article  Google Scholar 

  8. Bauer LA, Edwards WA, Dellinger EP, Simonowtiz DA. Influence of weight on aminoglycoside pharmacokinetics in normal weight and morbidly obese patients. Eur J Clin Pharm. 1983;24:643–7.

    Article  CAS  Google Scholar 

  9. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16:31–41.

    Article  CAS  Google Scholar 

  10. Dimopoulos MA, Terpos E, Chanan-Khan A, Leung N, Ludwig H, Jagannath S, et al. Renal impairment in patients with multiple myeloma: a consensus statement on behalf of the international Myeloma Working Group. J Clin Oncol. 2010;33:4976–84.

    Article  Google Scholar 

  11. Dubois D, Dubois EF. A formula to estimate the approximate surface area if height and weight be known. Arch Intern Med. 1916;17:863–71.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Dr Yiu Lam Kwan, retired haematologist from St George and Concord Hospitals, NSW, contributed to recruitment of patients for this study. The late A/Prof John Earl was involved in the drug concentration measurements and the pharmacokinetic analysis. We would like to thank the nurses and data managers at each participating institution for their assistance in recruiting patients and collecting blood samples and clinical information for this study. Financial support for this study was from Project Grant 396702, the National Health and Medical Research Council, Australia, and from the Leukaemia Research and Support Fund, The Children’s Hospital at Westmead, Australia.

Author information

Authors and Affiliations

  1. The Children’s Hospital at Westmead, Westmead, NSW, Australia

    C. E. Nath, L. Zeng & P. J. Shaw

  2. University of Sydney, Sydney, NSW, Australia

    C. E. Nath, J. Trotman, H. Gurney, D. Joshua, A. J. McLachlan & P. J. Shaw

  3. Concord Hospital, Concord, NSW, Australia

    J. Trotman

  4. Australasian Bone Marrow Transplant Recipient Registry, Darlinghurst, NSW, Australia

    I. Nivison-Smith

  5. Westmead Hospital, Westmead, NSW, Australia

    H. Gurney

  6. Wollongong Hospital, Wollongong, NSW, Australia

    P. Presgrave

  7. University of Wollongong, Wollongong, NSW, Australia

    P. Presgrave

  8. Gosford Hospital, Gosford, NSW, Australia

    C. Tiley

  9. Royal Prince Alfred Hospital, Camperdown, NSW, Australia

    D. Joshua

  10. Royal North Shore Hospital, St Leonards, NSW, Australia

    I. Kerridge

Authors
  1. C. E. Nath
    View author publications

    Search author on:PubMed Google Scholar

  2. J. Trotman
    View author publications

    Search author on:PubMed Google Scholar

  3. I. Nivison-Smith
    View author publications

    Search author on:PubMed Google Scholar

  4. H. Gurney
    View author publications

    Search author on:PubMed Google Scholar

  5. L. Zeng
    View author publications

    Search author on:PubMed Google Scholar

  6. P. Presgrave
    View author publications

    Search author on:PubMed Google Scholar

  7. C. Tiley
    View author publications

    Search author on:PubMed Google Scholar

  8. D. Joshua
    View author publications

    Search author on:PubMed Google Scholar

  9. I. Kerridge
    View author publications

    Search author on:PubMed Google Scholar

  10. A. J. McLachlan
    View author publications

    Search author on:PubMed Google Scholar

  11. P. J. Shaw
    View author publications

    Search author on:PubMed Google Scholar

Contributions

Principal investigators: CEN, PJS, JT. Conception, design and protocol development: CEN, PJS, JT. Statistical analysis: CEN, IN-S. Melphalan concentration measurement: CEN, LZ. Pharmacokinetic analysis: CEN, LZ, AJM. Provision of patients: JT, YLK, PP, CT, DJ, IK. Principal writers of manuscript: CEN, PJS, JT. Contributing to manuscript: IN-S, H, LZ, PP, CT, DJ, IK, AJM. All authors approved the final version of the manuscript.

Corresponding author

Correspondence to C. E. Nath.

Ethics declarations

Conflict of interest

AJM has received research funding from GlaxoSmithKline to support a postgraduate research student under his supervision. The remaining authors declare no competing financial interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nath, C.E., Trotman, J., Nivison-Smith, I. et al. Melphalan exposure and outcome in obese and non-obese adults with myeloma. A study of pharmacokinetics and pharmacodynamics. Bone Marrow Transplant 55, 1862–1864 (2020). https://doi.org/10.1038/s41409-020-0832-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Version of record:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41409-020-0832-6

This article is cited by

Search

Advanced search

Quick links