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

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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.

Original languageEnglish
Pages (from-to)1312-1319
Number of pages8
JournalBiology of Blood and Marrow Transplantation
Volume25
Issue number7
DOIs
StatePublished - 1 Jul 2019

Fingerprint

Peripheral Blood Stem Cell Transplantation
Busulfan
Melphalan
Multiple Myeloma
Multicenter Studies
Prospective Studies
Safety
Disease-Free Survival
Transplantation
Cytogenetics
Survival
Stomatitis
Induction Chemotherapy
Maximum Tolerated Dose
Stem Cell Transplantation
Sepsis
Neutrophils
Fever
Blood Platelets
Bortezomib

Keywords

  • Autologous transplantation
  • Bortezomib
  • Busulfan
  • Melphalan
  • Myeloma

Cite this

@article{0c41a82104514222af7ecbe5490ae72a,
title = "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",
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 Sung-Soo Yoon and Eom, {Hyeon Seok} and Kim, {Jin Seok} and Min, {Chang Ki}",
year = "2019",
month = "7",
day = "1",
doi = "10.1016/j.bbmt.2019.03.016",
language = "English",
volume = "25",
pages = "1312--1319",
journal = "Biology of Blood and Marrow Transplantation",
issn = "1083-8791",
publisher = "Elsevier Inc.",
number = "7",

}

TY - JOUR

T1 - 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

T2 - The KMM103 Study

AU - The Korean Multiple Myeloma Working Party

AU - Park, Sung Soo

AU - Kim, Kihyun

AU - Kim, Seok Jin

AU - Lee, Jae Hoon

AU - Yoon, Sung Soo

AU - Mun, Yeung Chul

AU - Yoon, Sung-Soo

AU - Eom, Hyeon Seok

AU - Kim, Jin Seok

AU - Min, Chang Ki

PY - 2019/7/1

Y1 - 2019/7/1

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.

KW - Autologous transplantation

KW - Bortezomib

KW - Busulfan

KW - Melphalan

KW - Myeloma

UR - http://www.scopus.com/inward/record.url?scp=85064497371&partnerID=8YFLogxK

U2 - 10.1016/j.bbmt.2019.03.016

DO - 10.1016/j.bbmt.2019.03.016

M3 - Article

VL - 25

SP - 1312

EP - 1319

JO - Biology of Blood and Marrow Transplantation

JF - Biology of Blood and Marrow Transplantation

SN - 1083-8791

IS - 7

ER -