Abstract
Successful autologous stem cell transplantation (ASCT) in newly diagnosed multiple myeloma (NDMM) patients relies on the efficient mobilization of hematopoietic stem cells following induction therapy. While the efficacy of etoposide for stem cell mobilization has been demonstrated in numerous studies, a randomized comparison of the efficacy of cyclophosphamide versus etoposide has previously been lacking. This randomized, open-label, multicenter trial enrolled NDMM patients eligible for ASCT. The inclusion criteria were patients with a diagnosis of NDMM who required stem cell mobilization prior to ASCT. Patients were randomly assigned to receive either high-dose etoposide (VP16; 1.2 g/m2) or high-dose cyclophosphamide (CTX; 3.0 g/m2) before mobilization. Granulocyte colony-stimulating factor (G-CSF) was administered after chemotherapy to promote stem cell mobilization. The primary endpoint was the proportion of patients achieving CD34 + cell counts ≥ 2 × 10⁶/kg and ≥ 5 × 10⁶/kg. A total of 62 patients were enrolled, with 31 patients in each group. The VP16 group significantly outperformed the CTX group in CD34 + cell collection across all thresholds: ≥2 × 10⁶/kg (100% vs. 77%, p = 0.011), ≥ 5 × 10⁶/kg (90% vs. 55%, p = 0.002), and ≥ 8 × 10⁶/kg (71% vs. 32.3%, p = 0.023). The VP16 group also showed superior success rates in the first apheresis session and achieved higher CD34 + percentages in the collection. Additionally, the VP16 group required fewer apheresis sessions, fewer platelet transfusions, and experienced less nausea during the mobilization period. High-dose etoposide (1.2 g/m2) demonstrated superior efficacy and safety compared to high-dose cyclophosphamide (3.0 g/m2) for stem cell mobilization in NDMM patients. Based on these findings, etoposide may be considered a more effective and safer option for stem cell mobilization in clinical practice.
The clinical trial was registered on 24/08/2022 (clinical trial identifier NCT05517213).
Similar content being viewed by others
Data availability
Data will be made available upon request to the corresponding author (XBX).
References
Malard, F. et al. Multiple myeloma. Nat. Rev. Dis. Primers. 10 https://doi.org/10.1038/s41572-024-00529-7 (2024).
Rajkumar, S. V. Multiple myeloma: 2024 update on diagnosis, risk-stratification, and management. Am. J. Hematol. 99, 1802–1824. https://doi.org/10.1002/ajh.27422 (2024).
Belisário, A. R. et al. Influence of laboratory procedures on postthawing cell viability and hematopoietic engraftment after autologous peripheral blood stem cell transplantation. Transfusion 61, 1202–1214. https://doi.org/10.1111/trf.16289 (2021).
Pulsipher, M. A. et al. Donor, recipient, and transplant characteristics as risk factors after unrelated donor PBSC transplantation: beneficial effects of higher CD34 + cell dose. Blood 114, 2606–2616. https://doi.org/10.1182/blood-2009-03-208355 (2009).
Lee, H. S. et al. Predictive factors for rapid neutrophil and platelet engraftment after allogenic peripheral blood stem cell transplantation in patients with acute leukemia. Ann. Hematol. 92, 1685–1693. https://doi.org/10.1007/s00277-013-1847-5 (2013).
Zhu, J. et al. Plerixafor and granulocyte-colony-stimulating factor for mobilization of hematopoietic stem cells for autologous transplantation in Chinese patients with non-Hodgkin’s lymphoma: a randomized Phase 3 study. Transfusion 58, 81–87. https://doi.org/10.1111/trf.14426 (2018).
Mahindra, A. et al. Etoposide plus G-CSF priming compared with G-CSF alone in patients with lymphoma improves mobilization without an increased risk of secondary myelodysplasia and leukemia. Bone Marrow Transplant. 47, 231–235. https://doi.org/10.1038/bmt.2011.73 (2012).
Wang, L. et al. Comparison of the efficiency, safety, and survival outcomes in two stem cell mobilization regimens with cyclophosphamide plus G-CSF or G-CSF alone in multiple myeloma: a meta-analysis. Ann. Hematol. 100, 563–573. https://doi.org/10.1007/s00277-020-04376-w (2021).
Jeker, B. et al. Comparing stem cell mobilization with chemotherapy and cytokine (G-CSF) versus cytokine alone in myeloma patients (MOCCCA): a randomized phase II, open-label, non-inferiority trial. Bone Marrow Transplant. 60, 270–276. https://doi.org/10.1038/s41409-024-02468-z (2025).
Luo, C. et al. Efficacy of hematopoietic stem cell mobilization regimens in patients with hematological malignancies: a systematic review and network meta-analysis of randomized controlled trials. Stem Cell Res. Ther. 13 https://doi.org/10.1186/s13287-022-02802-6 (2022).
Sureda, A., Corbacioglu, S., Greco, R., Kröger, N. & Carreras, E. The EBMT Handbook: Hematopoietic Cell Transplantation and Cellular Therapies (2024).
Nakasone, H. et al. Retrospective comparison of mobilization methods for autologous stem cell transplantation in multiple myeloma. Am. J. Hematol. 84, 809–814. https://doi.org/10.1002/ajh.21552 (2009).
Güner, Ş., Yanmaz, I., Selvi, M. T., Usul, C. & A. & The High Effect of Chemomobilization with High-Dose Etopside + Granulocyte-Colony Stimulating Factor in Autologous Hematopoietic Peripheral Blood Stem Cell Transplantation: A Single Center Experience. Hematol. Rep. 8, 6319. https://doi.org/10.4081/hr.2016.6319 (2016).
Wood, W. A. et al. Chemomobilization with Etoposide is Highly Effective in Patients with Multiple Myeloma and Overcomes the Effects of Age and Prior Therapy. Biology blood marrow transplantation: J. Am. Soc. Blood Marrow Transplantation. 17, 141–146. https://doi.org/10.1016/j.bbmt.2010.06.021 (2011).
Song, G. Y. et al. Optimal chemo-mobilization for the collection of peripheral blood stem cells in patients with multiple myeloma. BMC cancer. 19 https://doi.org/10.1186/s12885-019-5285-1 (2019).
Park, S. S. et al. Prospective Comparative Study of Etoposide plus G-CSF versus G-CSF Alone, Followed by Risk-Adapted Plerixafor for Peripheral Blood Stem Cell Mobilization in Patients with Newly Diagnosed Multiple Myeloma: CAtholic REsearch Network for Multiple Myeloma Study (CAREMM-2001). Cancers 15 https://doi.org/10.3390/cancers15194783 (2023).
Li, J. et al. [Comparison of etoposide combined with G-CSF and cyclophosphamide combined with G-CSF in mobilization of autologous peripheral hematopoietic stem cells in patients with newly diagnosed multiple myeloma]. Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi. 43, 781–784. https://doi.org/10.3760/cma.j.issn.0253-2727.2022.09.012 (2022).
Wang, G. R. et al. [Comparison of etoposide combined with G-CSF and cyclophosphamide combined with G-CSF in the mobilization of autologous peripheral blood stem cells in patients with multiple myeloma]. Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi. 45, 351–356. https://doi.org/10.3760/cma.j.cn121090-20231124-00274 (2024).
[Consensus of Chinese experts on the mobilization. and collection of autologous hematopoietic stem cells in lymphoma (2020)]. Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi 41, 979–983, (2020). https://doi.org/10.3760/cma.j.issn.0253-2727.2020.12.002
Khan, S. et al. First Line Treatment of Newly Diagnosed Transplant Eligible Multiple Myeloma Recommendations From a Canadian Consensus Guideline Consortium. Clin. lymphoma myeloma Leuk. 25, e151–e172. https://doi.org/10.1016/j.clml.2024.10.012 (2025).
Kanfer, E. J. et al. High-dose etoposide with granulocyte colony-stimulating factor for mobilization of peripheral blood progenitor cells: efficacy and toxicity at three dose levels. Br. J. Cancer. 78, 928–932. https://doi.org/10.1038/bjc.1998.603 (1998).
Park, Y. et al. Single-dose etoposide is an effective and safe protocol for stem cell mobilization in patients with multiple myeloma. J. Clin. Apheresis. 34, 579–588. https://doi.org/10.1002/jca.21734 (2019).
Duong, H. K. et al. Peripheral blood progenitor cell mobilization for autologous and allogeneic hematopoietic cell transplantation: guidelines from the American Society for Blood and Marrow Transplantation. Biology blood marrow transplantation: J. Am. Soc. Blood Marrow Transplantation. 20, 1262–1273. https://doi.org/10.1016/j.bbmt.2014.05.003 (2014).
Al Hamed, R., Bazarbachi, A. H., Malard, F., Harousseau, J. L. & Mohty, M. Current status of autologous stem cell transplantation for multiple myeloma. Blood cancer J. 9, 44. https://doi.org/10.1038/s41408-019-0205-9 (2019).
[Guidelines for the diagnosis and management of multiple myeloma in China. Zhonghua nei ke za zhi 63, 1186–1195, (2024). revision)] https://doi.org/10.3760/cma.j.cn112138-20240928-00616 (2024).
Kumar, S. et al. Mobilization in myeloma revisited: IMWG consensus perspectives on stem cell collection following initial therapy with thalidomide-, lenalidomide-, or bortezomib-containing regimens. Blood 114, 1729–1735. https://doi.org/10.1182/blood-2009-04-205013 (2009).
[Guidelines for the diagnosis and management of multiple myeloma in China. Zhonghua nei ke za zhi 61, 480–487, (2022). revision)] https://doi.org/10.3760/cma.j.cn112138-20220309-00165 (2022).
Chhabra, S. et al. Stem cell mobilization yields with daratumumab- and lenalidomide-containing quadruplet induction therapy in newly diagnosed multiple myeloma: Findings from the MASTER and GRIFFIN trials. Transplant. Cell. Ther. 29 174.e171–174.e110 (2023).
Arora, S., Majhail, N. S. & Liu, H. Hematopoietic Progenitor Cell Mobilization for Autologous Stem Cell Transplantation in Multiple Myeloma in Contemporary Era. Clin. lymphoma myeloma Leuk. 19, 200–205. https://doi.org/10.1016/j.clml.2018.12.010 (2019).
Popat, U. et al. Impairment of filgrastim-induced stem cell mobilization after prior lenalidomide in patients with multiple myeloma. Biology blood marrow transplantation: J. Am. Soc. Blood Marrow Transplantation. 15, 718–723. https://doi.org/10.1016/j.bbmt.2009.02.011 (2009).
Cavallo, F. et al. Stem cell mobilization in patients with newly diagnosed multiple myeloma after lenalidomide induction therapy. Leukemia 25, 1627–1631. https://doi.org/10.1038/leu.2011.131 (2011).
Paripati, H. et al. Compromised stem cell mobilization following induction therapy with lenalidomide in myeloma. Leukemia 22, 1282–1284. https://doi.org/10.1038/sj.leu.2405100 (2008).
Thurlapati, A. et al. Stem cell mobilization for multiple myeloma patients receiving daratumumab-based induction therapy: A real- world experience. Transplant. Cell. Ther. 29 https://doi.org/10.1016/j.jtct.2023.02.013 (2023). 340.e341-340.e344.
Zhang, W., Gou, P., Dupret, J. M., Chomienne, C. & Rodrigues-Lima, F. Etoposide, an anticancer drug involved in therapy-related secondary leukemia: Enzymes at play. Translational Oncol. 14, 101169. https://doi.org/10.1016/j.tranon.2021.101169 (2021).
Ng, A. K., Kenney, L. B., Gilbert, E. S. & Travis, L. B. Secondary malignancies across the age spectrum. Semin. Radiat. Oncol. 20, 67–78. https://doi.org/10.1016/j.semradonc.2009.09.002 (2010).
Acknowledgements
NA.
Author information
Authors and Affiliations
Contributions
Conceptualization; X-B. X.; W-R. H. Formal analysis: X-B. X.; W-R. H.; Y. S.; Y-Q. W. Methodology: X-B. X.; W-R. H.; Y-Q. W; Y. S. Project management, X-B. X.; W-R. H.; Y-Q. W.; J-P. L.; Y-J. D.; X-L. C.; S-Z. Y.; Y. L.; Y. M.; J-L. C.; W. G.; Y. L.; M. L. Writing—original draft: X-B. X.; Y. S. Writing—review and editing: X-B. X.; W-R. H.; Y. S. All authors have read and agreed to the published version of the manuscript.
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing interests.
Ethical approval
This study was conducted in accordance with the tenets of the Declaration of Helsinki and approved by the Institutional Review Boards of PLA General Hospital. The study adheres to the CONSORT guidelines for reporting randomized controlled trials.
Informed consent
All enrolled patients provided written informed consent prior to randomization.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Sun, Y., Li, J., Dong, Y. et al. A randomized comparison of etoposide and cyclophosphamide for stem cell mobilization in newly diagnosed multiple myeloma. Sci Rep (2026). https://doi.org/10.1038/s41598-026-46787-1
Received:
Accepted:
Published:
DOI: https://doi.org/10.1038/s41598-026-46787-1
