Safety and efficacy of targeted-dose busulfan and bortezomib as a conditioning regimen for patients with relapsed multiple myeloma undergoing a second autologous blood progenitor cell transplantation

César O. Freytes, Juan J. Toro, Rosa F. Yeh, Edward A. Stadtmauer, Voravit Ratanatharathorn, Görgün Akpek, Entezam Sahovic, Guido J. Tricot, Paul J. Shaughnessy, Darrell J. White, Tulio E. Rodriguez, Scott R. Solomon, Louie H. Yu, Cathy Zhao, Shiva Patil, Elizabeth Armstrong, Angela Smith, Agnes Elekes, Kazunobu Kato, Donna E. Reece

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

Patients with multiple myeloma (MM) who relapse after autologous transplantation have limited therapeutic options. We conducted a prospective, multicenter, phase IIa study to investigate the safety and efficacy of i.v. busulfan (Bu) in combination with bortezomib as a conditioning regimen for a second autotransplantation. Because a safe Bu exposure was unknown in patients receiving this combination, Bu was initially targeted to a total area under the concentration-time curve (AUC) of 20,000μM× minute. As no concentration-limiting toxicity was observed in 6 patients, this Bu exposure was utilized in the following treatment cohort (n=24). Individualized Bu dose, based on test dose .8mg/kg pharmacokinetics (PK), was administered daily for 4 consecutive days starting 5days before transplantation, followed by a single dose of bortezomib (1.3mg/m2) 1day before transplantation. The total mean dose of i.v. Bu (including the test dose and 4-day administration) was 14.2mg/kg (standard deviation=2.48; range, 8.7 to 19.2). Confirmatory PK demonstrated that only 2 of 30 patients who underwent transplantation were dosed outside the Bu AUC target and dose adjustments were made for the last 2 doses of i.v. Bu. The median age was 59years (range, 48 to 73). Median time from first to second transplantation was 28.0months (range, 12 to 119). Of 26 evaluable patients, 10 patients attained a partial response (PR) or better at 3months after transplantation, with 2 patients attaining a complete response. At 6months after transplantation, 5 of 12 evaluable patients had maintained or improved their disease status. Median progression-free survival was 191days, whereas median overall survival was not reached during the study period. The most common grade 3 and 4 toxicities were febrile neutropenia (50.0%) and stomatitis (43.3%). One transplantation-related death was observed. A combination of dose-targeted i.v. Bu and bortezomib induced PR or better in one third of patients with MM who underwent a second autotransplantation, with acceptable toxicity.

Original languageEnglish (US)
Pages (from-to)1949-1957
Number of pages9
JournalBiology of Blood and Marrow Transplantation
Volume20
Issue number12
DOIs
StatePublished - Dec 1 2014

Keywords

  • Autologous transplantation
  • Bortezomib
  • Busulfan
  • Multiple myeloma

ASJC Scopus subject areas

  • Hematology
  • Transplantation

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    Freytes, C. O., Toro, J. J., Yeh, R. F., Stadtmauer, E. A., Ratanatharathorn, V., Akpek, G., Sahovic, E., Tricot, G. J., Shaughnessy, P. J., White, D. J., Rodriguez, T. E., Solomon, S. R., Yu, L. H., Zhao, C., Patil, S., Armstrong, E., Smith, A., Elekes, A., Kato, K., & Reece, D. E. (2014). Safety and efficacy of targeted-dose busulfan and bortezomib as a conditioning regimen for patients with relapsed multiple myeloma undergoing a second autologous blood progenitor cell transplantation. Biology of Blood and Marrow Transplantation, 20(12), 1949-1957. https://doi.org/10.1016/j.bbmt.2014.08.007