A Phase I/II, Open-Label, Prospective, Multicenter Study to Evaluate the Efficacy and Safety of Lower Doses of Bortezomib Plus Busulfan and Melphalan as a Conditioning Regimen in Patients with Multiple Myeloma Undergoing Autologous Peripheral Blood Stem Cell Transplantation: The KMM103 Study

the Korean Multiple Myeloma Working Party

doi:10.1016/j.bbmt.2019.03.016

A Phase I/II, Open-Label, Prospective, Multicenter Study to Evaluate the Efficacy and Safety of Lower Doses of Bortezomib Plus Busulfan and Melphalan as a Conditioning Regimen in Patients with Multiple Myeloma Undergoing Autologous Peripheral Blood Stem Cell Transplantation: The KMM103 Study

the Korean Multiple Myeloma Working Party

Department of Internal Medicine

Research output: Contribution to journal › Article › peer-review

9 Scopus citations

Abstract

A phase I/II trial was conducted to explore the safety and activity of the addition of bortezomib on days -6, -3, and +1 relative to the day of autologous stem cell transplantation (ASCT) to a conditioning regimen with busulfan and melphalan (BuMel; 3.2 mg/kg/day busulfan on days -5 to -3 and 140 mg/m²/day melphalan on day -2) in patients with multiple myeloma (MM) following bortezomib-based induction chemotherapy. In phase I, doses of bortezomib (.7, 1.0, and 1.3 mg/m²) with BuMel were administered to groups of 3 patients each. No dose-limiting toxicities were observed. The maximum tolerated dose of bortezomib was 1.3 mg/m²/day. A subsequent cohort with 41 patients was analyzed in a phase II trial to identify safety and efficacy. The phase II trial showed a 75% response rate, including very good partial response (VGPR) or better, and a 55% rate of complete response (CR) at 3 months; For post-transplantation best response, an 83% rate of VGPR or better (68% CR) was observed. With a median follow-up of 31.4 months, the median progression-free survival (PFS) was 26.8 months. The probability of 2 year-PFS was 56.5%, and median overall survival (OS) could not calculated. Specifically, high-risk cytogenetics were associated with adverse survival outcomes compared with standard-risk cytogenetics (median PFS, 12.2 months versus 35.7 months, P = .039; median OS, 26.7 months versus 73.3 months; P = .086). With a median of 11 days to neutrophil engraftment and 10 days for platelet engraftment, no graft failure or delayed engrafting were observed. The most common grade 3 or severe nonhematologic adverse events included neutropenic fever (73.2%) and stomatitis (14.6%). Except for 3 patients with transplantation-related mortality due to sepsis, other adverse events were manageable. These findings demonstrate that bortezomib is safe and has a potential role in conditioning regimens in combination with BuMel for patients with transplantation-eligible MM.

Original language	English
Pages (from-to)	1312-1319
Number of pages	8
Journal	Biology of Blood and Marrow Transplantation
Volume	25
Issue number	7
DOIs	https://doi.org/10.1016/j.bbmt.2019.03.016
State	Published - Jul 2019

Bibliographical note

Funding Information:
The authors are grateful to all members of the Korean Multiple Myeloma Working Party. Financial disclosure: The authors have nothing to disclose. Conflict of interest statement: There are no conflicts of interest to report. Authorship statement: S.S.P. analyzed the clinical data and wrote the manuscript. J.S.K. and C.K.M. designed the study. K.K. S.J.K. J.H.L. S.S.Y. Y.C.M. J.J.L. H.S.E. and members of the Korean Multiple Myeloma Working Party contributed to the study design and analyzed the clinical data. J.S.K. and C.K.M. were involved in critically revising the manuscript for intellectual content and approved the final manuscript for submission. Financial disclosure: See Acknowledgments on page 1319.

Publisher Copyright:
© 2019 American Society for Blood and Marrow Transplantation

Keywords

Autologous transplantation
Bortezomib
Busulfan
Melphalan
Myeloma

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the Korean Multiple Myeloma Working Party (2019). A Phase I/II, Open-Label, Prospective, Multicenter Study to Evaluate the Efficacy and Safety of Lower Doses of Bortezomib Plus Busulfan and Melphalan as a Conditioning Regimen in Patients with Multiple Myeloma Undergoing Autologous Peripheral Blood Stem Cell Transplantation: The KMM103 Study. Biology of Blood and Marrow Transplantation, 25(7), 1312-1319. https://doi.org/10.1016/j.bbmt.2019.03.016

the Korean Multiple Myeloma Working Party. / A Phase I/II, Open-Label, Prospective, Multicenter Study to Evaluate the Efficacy and Safety of Lower Doses of Bortezomib Plus Busulfan and Melphalan as a Conditioning Regimen in Patients with Multiple Myeloma Undergoing Autologous Peripheral Blood Stem Cell Transplantation : The KMM103 Study. In: Biology of Blood and Marrow Transplantation. 2019 ; Vol. 25, No. 7. pp. 1312-1319.

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abstract = "A phase I/II trial was conducted to explore the safety and activity of the addition of bortezomib on days -6, -3, and +1 relative to the day of autologous stem cell transplantation (ASCT) to a conditioning regimen with busulfan and melphalan (BuMel; 3.2 mg/kg/day busulfan on days -5 to -3 and 140 mg/m2/day melphalan on day -2) in patients with multiple myeloma (MM) following bortezomib-based induction chemotherapy. In phase I, doses of bortezomib (.7, 1.0, and 1.3 mg/m2) with BuMel were administered to groups of 3 patients each. No dose-limiting toxicities were observed. The maximum tolerated dose of bortezomib was 1.3 mg/m2/day. A subsequent cohort with 41 patients was analyzed in a phase II trial to identify safety and efficacy. The phase II trial showed a 75% response rate, including very good partial response (VGPR) or better, and a 55% rate of complete response (CR) at 3 months; For post-transplantation best response, an 83% rate of VGPR or better (68% CR) was observed. With a median follow-up of 31.4 months, the median progression-free survival (PFS) was 26.8 months. The probability of 2 year-PFS was 56.5%, and median overall survival (OS) could not calculated. Specifically, high-risk cytogenetics were associated with adverse survival outcomes compared with standard-risk cytogenetics (median PFS, 12.2 months versus 35.7 months, P = .039; median OS, 26.7 months versus 73.3 months; P = .086). With a median of 11 days to neutrophil engraftment and 10 days for platelet engraftment, no graft failure or delayed engrafting were observed. The most common grade 3 or severe nonhematologic adverse events included neutropenic fever (73.2%) and stomatitis (14.6%). Except for 3 patients with transplantation-related mortality due to sepsis, other adverse events were manageable. These findings demonstrate that bortezomib is safe and has a potential role in conditioning regimens in combination with BuMel for patients with transplantation-eligible MM.",

keywords = "Autologous transplantation, Bortezomib, Busulfan, Melphalan, Myeloma",

author = "{the Korean Multiple Myeloma Working Party} and Park, {Sung Soo} and Kihyun Kim and Kim, {Seok Jin} and Lee, {Jae Hoon} and Yoon, {Sung Soo} and Mun, {Yeung Chul} and Lee, {Je Jung} and Eom, {Hyeon Seok} and Kim, {Jin Seok} and Min, {Chang Ki}",

note = "Funding Information: The authors are grateful to all members of the Korean Multiple Myeloma Working Party. Financial disclosure: The authors have nothing to disclose. Conflict of interest statement: There are no conflicts of interest to report. Authorship statement: S.S.P. analyzed the clinical data and wrote the manuscript. J.S.K. and C.K.M. designed the study. K.K. S.J.K. J.H.L. S.S.Y. Y.C.M. J.J.L. H.S.E. and members of the Korean Multiple Myeloma Working Party contributed to the study design and analyzed the clinical data. J.S.K. and C.K.M. were involved in critically revising the manuscript for intellectual content and approved the final manuscript for submission. Financial disclosure: See Acknowledgments on page 1319. Publisher Copyright: {\textcopyright} 2019 American Society for Blood and Marrow Transplantation",

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the Korean Multiple Myeloma Working Party 2019, 'A Phase I/II, Open-Label, Prospective, Multicenter Study to Evaluate the Efficacy and Safety of Lower Doses of Bortezomib Plus Busulfan and Melphalan as a Conditioning Regimen in Patients with Multiple Myeloma Undergoing Autologous Peripheral Blood Stem Cell Transplantation: The KMM103 Study', Biology of Blood and Marrow Transplantation, vol. 25, no. 7, pp. 1312-1319. https://doi.org/10.1016/j.bbmt.2019.03.016

A Phase I/II, Open-Label, Prospective, Multicenter Study to Evaluate the Efficacy and Safety of Lower Doses of Bortezomib Plus Busulfan and Melphalan as a Conditioning Regimen in Patients with Multiple Myeloma Undergoing Autologous Peripheral Blood Stem Cell Transplantation: The KMM103 Study. / the Korean Multiple Myeloma Working Party.
In: Biology of Blood and Marrow Transplantation, Vol. 25, No. 7, 07.2019, p. 1312-1319.

Research output: Contribution to journal › Article › peer-review

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T2 - The KMM103 Study

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AU - Park, Sung Soo

AU - Kim, Kihyun

AU - Kim, Seok Jin

AU - Lee, Jae Hoon

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AU - Mun, Yeung Chul

AU - Lee, Je Jung

AU - Eom, Hyeon Seok

AU - Kim, Jin Seok

AU - Min, Chang Ki

N1 - Funding Information: The authors are grateful to all members of the Korean Multiple Myeloma Working Party. Financial disclosure: The authors have nothing to disclose. Conflict of interest statement: There are no conflicts of interest to report. Authorship statement: S.S.P. analyzed the clinical data and wrote the manuscript. J.S.K. and C.K.M. designed the study. K.K. S.J.K. J.H.L. S.S.Y. Y.C.M. J.J.L. H.S.E. and members of the Korean Multiple Myeloma Working Party contributed to the study design and analyzed the clinical data. J.S.K. and C.K.M. were involved in critically revising the manuscript for intellectual content and approved the final manuscript for submission. Financial disclosure: See Acknowledgments on page 1319. Publisher Copyright: © 2019 American Society for Blood and Marrow Transplantation

PY - 2019/7

Y1 - 2019/7

N2 - A phase I/II trial was conducted to explore the safety and activity of the addition of bortezomib on days -6, -3, and +1 relative to the day of autologous stem cell transplantation (ASCT) to a conditioning regimen with busulfan and melphalan (BuMel; 3.2 mg/kg/day busulfan on days -5 to -3 and 140 mg/m2/day melphalan on day -2) in patients with multiple myeloma (MM) following bortezomib-based induction chemotherapy. In phase I, doses of bortezomib (.7, 1.0, and 1.3 mg/m2) with BuMel were administered to groups of 3 patients each. No dose-limiting toxicities were observed. The maximum tolerated dose of bortezomib was 1.3 mg/m2/day. A subsequent cohort with 41 patients was analyzed in a phase II trial to identify safety and efficacy. The phase II trial showed a 75% response rate, including very good partial response (VGPR) or better, and a 55% rate of complete response (CR) at 3 months; For post-transplantation best response, an 83% rate of VGPR or better (68% CR) was observed. With a median follow-up of 31.4 months, the median progression-free survival (PFS) was 26.8 months. The probability of 2 year-PFS was 56.5%, and median overall survival (OS) could not calculated. Specifically, high-risk cytogenetics were associated with adverse survival outcomes compared with standard-risk cytogenetics (median PFS, 12.2 months versus 35.7 months, P = .039; median OS, 26.7 months versus 73.3 months; P = .086). With a median of 11 days to neutrophil engraftment and 10 days for platelet engraftment, no graft failure or delayed engrafting were observed. The most common grade 3 or severe nonhematologic adverse events included neutropenic fever (73.2%) and stomatitis (14.6%). Except for 3 patients with transplantation-related mortality due to sepsis, other adverse events were manageable. These findings demonstrate that bortezomib is safe and has a potential role in conditioning regimens in combination with BuMel for patients with transplantation-eligible MM.

AB - A phase I/II trial was conducted to explore the safety and activity of the addition of bortezomib on days -6, -3, and +1 relative to the day of autologous stem cell transplantation (ASCT) to a conditioning regimen with busulfan and melphalan (BuMel; 3.2 mg/kg/day busulfan on days -5 to -3 and 140 mg/m2/day melphalan on day -2) in patients with multiple myeloma (MM) following bortezomib-based induction chemotherapy. In phase I, doses of bortezomib (.7, 1.0, and 1.3 mg/m2) with BuMel were administered to groups of 3 patients each. No dose-limiting toxicities were observed. The maximum tolerated dose of bortezomib was 1.3 mg/m2/day. A subsequent cohort with 41 patients was analyzed in a phase II trial to identify safety and efficacy. The phase II trial showed a 75% response rate, including very good partial response (VGPR) or better, and a 55% rate of complete response (CR) at 3 months; For post-transplantation best response, an 83% rate of VGPR or better (68% CR) was observed. With a median follow-up of 31.4 months, the median progression-free survival (PFS) was 26.8 months. The probability of 2 year-PFS was 56.5%, and median overall survival (OS) could not calculated. Specifically, high-risk cytogenetics were associated with adverse survival outcomes compared with standard-risk cytogenetics (median PFS, 12.2 months versus 35.7 months, P = .039; median OS, 26.7 months versus 73.3 months; P = .086). With a median of 11 days to neutrophil engraftment and 10 days for platelet engraftment, no graft failure or delayed engrafting were observed. The most common grade 3 or severe nonhematologic adverse events included neutropenic fever (73.2%) and stomatitis (14.6%). Except for 3 patients with transplantation-related mortality due to sepsis, other adverse events were manageable. These findings demonstrate that bortezomib is safe and has a potential role in conditioning regimens in combination with BuMel for patients with transplantation-eligible MM.

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the Korean Multiple Myeloma Working Party. A Phase I/II, Open-Label, Prospective, Multicenter Study to Evaluate the Efficacy and Safety of Lower Doses of Bortezomib Plus Busulfan and Melphalan as a Conditioning Regimen in Patients with Multiple Myeloma Undergoing Autologous Peripheral Blood Stem Cell Transplantation: The KMM103 Study. Biology of Blood and Marrow Transplantation. 2019 Jul;25(7):1312-1319. doi: 10.1016/j.bbmt.2019.03.016