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.

  • Article
  • Published:

Comparable outcomes using propylene glycol-free melphalan for autologous stem cell transplantation in multiple myeloma

Bone Marrow Transplantation volume 54, pages 587–594 (2019)Cite this article

Subjects

Abstract

Autologous stem cell transplantation (ASCT) remains a mainstay in the treatment of multiple myeloma (MM). While the procedure is generally safe, toxicities associated with high-dose melphalan conditioning are common and significantly affect patient quality of life. Recently, a propylene glycol-free melphalan formulation (PG-free MEL; Evomela®) was approved by the United States Food and Drug Administration as an ASCT-conditioning regimen for MM. PG-free MEL is more soluble and stable than propylene glycol-solubilized melphalan (PG-solubilized MEL; Alkeran®). As such, there is speculation that it could decrease toxicities and increase the efficacy of ASCT. We compared the outcomes of patients conditioned with PG-free MEL (n = 216) to PG-solubilized MEL (n = 200) at our institution. The baseline characteristics were similar between the two groups. After Day +0, there were no differences in terms of hospitalizations, neutropenic fevers, intravenous granisetron requirement, World Health Organization grade ≥ 2 oral/esophageal mucositis, intravenous fluid requirement, or narcotic requirement. However, PG-free MEL patients had a higher incidence of diarrhea, which was mostly C. difficile-negative (82% vs. 71%, P = 0.015*). Day + 100 hematologic responses and progression-free survival after ASCT were comparable. In summary, we demonstrate that switching to PG-free MEL did not significantly reduce short-term complications of ASCT or improve outcomes in MM.

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

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
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Rajkumar SV, Kumar S. Multiple myeloma: diagnosis and treatment. Mayo Clin Proc. 2016;91:101–19.

    Article  Google Scholar 

  2. Palumbo A, Anderson K. Multiple myeloma. New Engl J Med. 2011;364:1046–60.

    Article  CAS  Google Scholar 

  3. Kumar SK, Dispenzieri A, Lacy MQ, Gertz MA, Buadi FK, Pandey S, et al. Continued improvement in survival in multiple myeloma: changes in early mortality and outcomes in older patients. Leukemia. 2014;28:1122–8.

    Article  CAS  Google Scholar 

  4. Attal M, Harousseau JL, Stoppa AM, Sotto JJ, Fuzibet JG, Rossi JF, et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Francais du Myelome. N Engl J Med. 1996;335:91–7.

    Article  CAS  Google Scholar 

  5. Child JA, Morgan GJ, Davies FE, Owen RG, Bell SE, Hawkins K, et al. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. New Engl J Med. 2003;348:1875–83.

    Article  CAS  Google Scholar 

  6. Palumbo A, Cavallo F, Gay F, Di Raimondo F, Ben Yehuda D, Petrucci MT, et al. Autologous transplantation and maintenance therapy in multiple myeloma. New Engl J Med. 2014;371:895–905.

    Article  Google Scholar 

  7. Attal M, Lauwers-Cances V, Hulin C, Leleu X, Caillot D, Escoffre M, et al. Lenalidomide, Bortezomib, and Dexamethasone with Transplantation for Myeloma. New Engl J Med. 2017;376:1311–20.

    Article  CAS  Google Scholar 

  8. Mahajan S, Tandon N, Kumar S. The evolution of stem-cell transplantation in multiple myeloma. Ther Adv Hematol. 2018;9:123–33.

    Article  Google Scholar 

  9. Moreau P, Facon T, Attal M, Hulin C, Michallet M, Maloisel F, et al. Comparison of 200 mg/m2 melphalan and 8 Gy total body irradiation plus 140 mg/m2 melphalan as conditioning regimens for peripheral blood stem cell transplantation in patients with newly diagnosed multiple myeloma: final analysis of the Intergroupe Francophone du Myelome 9502 randomized trial. Blood. 2002;99:731–5.

    Article  CAS  Google Scholar 

  10. Bayraktar UD, Bashir Q, Qazilbash M, Champlin RE, Ciurea SO. Fifty years of melphalan use in hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2013;19:344–56.

    Article  CAS  Google Scholar 

  11. Lazarus HM, Herzig RH, Graham-Pole J, Wolff SN, Phillips GL, Strandjord S, et al. Intensive melphalan chemotherapy and cryopreserved autologous bone marrow transplantation for the treatment of refractory cancer. J Clin Oncol. 1983;1:359–67.

    Article  CAS  Google Scholar 

  12. Grazziutti ML, Dong L, Miceli MH, Krishna SG, Kiwan E, Syed N, et al. Oral mucositis in myeloma patients undergoing melphalan-based autologous stem cell transplantation: incidence, risk factors and a severity predictive model. Bone Marrow Transplant. 2006;38:501–6.

    Article  CAS  Google Scholar 

  13. Gabriel DA, Shea T, Olajida O, Serody JS, Comeau T. The effect of oral mucositis on morbidity and mortality in bone marrow transplant. Semin Oncol. 2003;30:76–83.

    Article  CAS  Google Scholar 

  14. Fleming S, Harrison SJ, Blombery P, Joyce T, Stokes K, Seymour JF, et al. The choice of multiple myeloma induction therapy affects the frequency and severity of oral mucositis after melphalan-based autologous stem cell transplantation. Clin Lymphoma, Myeloma Leuk. 2014;14:291–6.

    Article  Google Scholar 

  15. Vera-Llonch M, Oster G, Ford CM, Lu J, Sonis S. Oral mucositis and outcomes of autologous hematopoietic stem-cell transplantation following high-dose melphalan conditioning for multiple myeloma. J Support Oncol. 2007;5:231–5.

    PubMed  Google Scholar 

  16. Jones JA, Qazilbash MH, Shih YC, Cantor SB, Cooksley CD, Elting LS. In-hospital complications of autologous hematopoietic stem cell transplantation for lymphoid malignancies: clinical and economic outcomes from the Nationwide Inpatient Sample. Cancer. 2008;112:1096–105.

    Article  Google Scholar 

  17. Sonis ST, Oster G, Fuchs H, Bellm L, Bradford WZ, Edelsberg J, et al. Oral mucositis and the clinical and economic outcomes of hematopoietic stem-cell transplantation. J Clin Oncol. 2001;19:2201–5.

    Article  CAS  Google Scholar 

  18. Koltun M, Morizzi J, Katneni K, Charman SA, Shackleford DM, McIntosh MP. Preclinical comparison of intravenous melphalan pharmacokinetics administered in formulations containing either (SBE)7 m-beta-cyclodextrin or a co-solvent system. Biopharm Drug Dispos. 2010;31:450–4.

    Article  CAS  Google Scholar 

  19. Singh R, Chen J, Miller T, Bergren M, Mallik R. Solution stability of Captisol-stabilized melphalan (Evomela) versus Propylene glycol-based melphalan hydrochloride injection. Pharm Dev Technol. 2016;14:1–6.

  20. Aljitawi OS, Ludlow A, Ganguly S, Abhyankar S, Lin T, Pipkin JD, et al. Propylene glycol-free melphalan induces higher remission rates in multiple myeloma patients undergoing autologous transplantation. Blood. 2012;120:4551.

    Article  Google Scholar 

  21. Hari P, Aljitawi OS, Arce-Lara C, Nath R, Callander N, Bhat G, et al. A Phase IIb, Multicenter, Open-Label, Safety, and Efficacy Study of High-Dose, Propylene Glycol-Free Melphalan Hydrochloride for Injection (EVOMELA) for Myeloablative Conditioning in Multiple Myeloma Patients Undergoing Autologous Transplantation. Biol Blood Marrow Transplant. 2015;21:2100–5.

    Article  CAS  Google Scholar 

  22. Aljitawi OS, Ganguly S, Abhyankar SH, Ferree M, Marks R, Pipkin JD, et al. Phase IIa cross-over study of propylene glycol-free melphalan (LGD-353) and alkeran in multiple myeloma autologous transplantation. Bone Marrow Transplant. 2014;49:1042–5.

    Article  CAS  Google Scholar 

  23. Badar T, Hari P, Chhabra S, Dhakal B, Drobyski WR, Fenske TS, et al. Use of propylene glycol-free melphalan conditioning in light-chain amyloidosis patients undergoing autologous hematopoietic cell transplantation is well tolerated and effective. Bone Marrow Transplant. 2018. https://doi.org/10.1038/s41409-018-0178-5.

    Article  PubMed  Google Scholar 

  24. Dhakal B, D’Souza A, Lakshman A, Hamadani M, Chhabra S, Thompson R, et al. Pharmacokinetics of high-dose propylene glycol free melphalan in multiple myeloma patients undergoing autologous hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2018. https://doi.org/10.1016/j.bbmt.2018.04.028.

    Article  PubMed  Google Scholar 

  25. Rajkumar SV, Dimopoulos MA, Palumbo A, Blade J, Merlini G, Mateos M-V, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014;15:e538–48.

    Article  Google Scholar 

  26. Gertz MA, Buadi FK, Hayman SR, Lacy MQ, Dispenzieri A, Dingli D, et al. Safety outcomes for autologous stem cell transplant in multiple myeloma. Mayo Clin Proc. 2018;93:56–58.

    Article  Google Scholar 

  27. Kyle RA, Rajkumar SV. Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma. Leukemia. 2009;23:3–9.

    Article  CAS  Google Scholar 

  28. Greipp PR, San Miguel J, Durie BG, Crowley JJ, Barlogie B, Blade J, et al. International staging system for multiple myeloma. J Clin Oncol. 2005;23:3412–20.

    Article  Google Scholar 

  29. Kumar SK, Rajkumar SV. The multiple myelomas — current concepts in cytogenetic classification and therapy. Nat Rev Clin Oncol. 2018;15:409–21.

    Article  CAS  Google Scholar 

  30. Hewan B, J. BL, Ryan S, Manju N, Brian M, Aleksandr L, et al. Transplantation related toxicity and mortality in older autologous hematopoietic cell transplantation recipients. Am J Hematol. 2017;92:e529–e533.

    Article  Google Scholar 

  31. Khera N, Zeliadt SB, Lee SJ. Economics of hematopoietic cell transplantation. Blood. 2012;120:1545–51.

    Article  CAS  Google Scholar 

  32. Chintan P, Shahrukh H, Nandita K, A. GM, Angela D, William H, et al. Cost‐effectiveness analysis of early vs. late autologous stem cell transplantation in multiple myeloma. Clin Transplant. 2014;28:1084–91.

    Article  Google Scholar 

  33. Moreau P, Milpied N, Mahé B, Juge-Morineau N, Rapp MJ, Bataille R, et al. Melphalan 220 mg/m2 followed by peripheral blood stem cell transplantation in 27 patients with advanced multiple myeloma. Bone Marrow Transplant. 1999;23:1003.

    Article  CAS  Google Scholar 

  34. Feliz V, Saiyad S, Ramarao SM, Khan H, Leonelli F, Guglin M. Melphalan-induced supraventricular tachycardia: incidence and risk factors. Clin Cardiol. 2011;34:356–9.

    Article  Google Scholar 

  35. Mileshkin LR, Seymour JF, Wolf MM, Gates P, Januszewicz EH, Joyce P, et al. Cardiovascular toxicity is increased, but manageable, during high-dose chemotherapy and autologous peripheral blood stem cell transplantation for patients aged 60 years and older. Leuk Lymphoma. 2005;46:1575–9.

    Article  CAS  Google Scholar 

  36. Zar T, Graeber C, Perazella MA. Recognition, treatment, and prevention of propylene glycol toxicity. Semin Dial. 2007;20:217–9.

    Article  Google Scholar 

  37. 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 

  38. Shah GL, Landau H, Sarubbi C, Schofield R, Lin A, Bhatt V, et al. Pharmacokinetics and Toxicities after Evomela; (Propylene Glycol Free Melphalan) with Hematopoietic Stem Cell Transplant (HCT) for Multiple Myeloma (MM), AL Amyloidosis (AL), Lymphoma, Acute Myeloid Leukemia (AML), and Myelodysplastic Syndrome (MDS). Biol Blood Marrow Transplant. 2018;24:S79–80.

    Article  Google Scholar 

  39. Shah GL, Lin A, Schofield R, Sarubbi C, Preston EV, Devlin SM, et al. Feasibility and Toxicity of Pharmacokinetic (PK)-Directed Dosing of Evomela; (propylene glycol free melphalan, PGF-MEL) for Multiple Myeloma (MM) and AL Amyloidosis (AL) Patients Undergoing Autologous Hematopoietic Stem Cell Transplant (AHCT). Biol Blood Marrow Transplant. 2018;24:S129–30.

    Article  Google Scholar 

Download references

Acknowledgements

SKK is supported in part by US National Cancer Institute grants CA 107476, CA 168762, and CA186781.

Author information

Authors and Affiliations

  1. Mayo Clinic School of Medicine, Rochester, MN, USA

    Kevin C. Miller

  2. Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, USA

    Morie A. Gertz, Francis K. Buadi, Suzanne R. Hayman, Robert C. Wolf, Martha Q. Lacy, Angela A. Dispenzieri, David Dingli, Prashant Kapoor, Wilson I. Gonsalves, Taxiarchis Kourelis, William J. Hogan & Shaji K. Kumar

Authors
  1. Kevin C. Miller
    View author publications

    Search author on:PubMed Google Scholar

  2. Morie A. Gertz
    View author publications

    Search author on:PubMed Google Scholar

  3. Francis K. Buadi
    View author publications

    Search author on:PubMed Google Scholar

  4. Suzanne R. Hayman
    View author publications

    Search author on:PubMed Google Scholar

  5. Robert C. Wolf
    View author publications

    Search author on:PubMed Google Scholar

  6. Martha Q. Lacy
    View author publications

    Search author on:PubMed Google Scholar

  7. Angela A. Dispenzieri
    View author publications

    Search author on:PubMed Google Scholar

  8. David Dingli
    View author publications

    Search author on:PubMed Google Scholar

  9. Prashant Kapoor
    View author publications

    Search author on:PubMed Google Scholar

  10. Wilson I. Gonsalves
    View author publications

    Search author on:PubMed Google Scholar

  11. Taxiarchis Kourelis
    View author publications

    Search author on:PubMed Google Scholar

  12. William J. Hogan
    View author publications

    Search author on:PubMed Google Scholar

  13. Shaji K. Kumar
    View author publications

    Search author on:PubMed Google Scholar

Corresponding author

Correspondence to Shaji K. Kumar.

Ethics declarations

Conflict of interest

SKK has been a non-paid consultant or advisory board member for AbbVie, Celgene, Janssen, Kite Pharma, Merck, and Takeda and is the principal investigator in clinical trials supported by Bristol-Myers Squibb, Celgene, Janssen, Kite Pharma, Roche/Genentech, Sanofi, and Takeda.

Additional information

Parts of this manuscript were presented in abstract form at the 23rd European Hematology Association Congress in Stockholm, Sweden on 17 June 2018.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Miller, K.C., Gertz, M.A., Buadi, F.K. et al. Comparable outcomes using propylene glycol-free melphalan for autologous stem cell transplantation in multiple myeloma. Bone Marrow Transplant 54, 587–594 (2019). https://doi.org/10.1038/s41409-018-0302-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Version of record:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41409-018-0302-6

This article is cited by

Search

Advanced search

Quick links