Pharmacokinetics-directed Intravenous Busulfan Combined With High-dose Melphalan and Bortezomib as a Conditioning Regimen for Patients With Multiple Myeloma

Stefan K. Barta, Rishi Jain, Amithaba Mazumder, Jason Carter, Lawrence Almanzar, Roy Browne, Samira Shahnaz, Richard Elkind, David Kaminetzky, Ramakrishna Battini, Olga Derman, Noah Kornblum, Amit K. Verma, Ira Braunschweig

Research output: Contribution to journalArticle

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Abstract

Background: High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) has a well-established role in the treatment of patients with multiple myeloma. Melphalan 200 mg/m2 (Mel200) is the most commonly used preparative regimen. Several studies have provided evidence for potential synergism and safety when combining bortezomib (Btz) or busulfan (Bu) with melphalan (Mel). Patients and Methods: We conducted a prospective phase II study to investigate the safety and efficacy of conditioning with pharmacokinetics (PK)-directed intravenous (IV) Bu with Btz and Mel. Bu dosing was adjusted to target a total area under the curve (AUC) of 20,000 μM × min. Patients received Btz (1 mg/m2 × 4 doses) and Mel (140 mg/m2). Results: A total of 19 subjects were enrolled. Their median age was 55 years, and the median follow-up period was 23.7 months. PK testing resulted in 86% of patients achieving an estimated total AUC of 20,000 ± 2500 μM × min. The overall response rate (ORR) at day +100 after ASCT was 100% in the evaluable patients, with 11% of patients achieving a complete response. The 2-year progression-free survival rate was 57.9% (95% confidence interval [CI], 38%-89%), and the 2-year overall survival rate was 88.5% (95% CI, 76%-100%). The most common grade 3 and 4 toxicities were febrile neutropenia, dysphagia/odynophagia, and oral mucositis. No case of hepatic sinusoidal obstruction syndrome developed. One treatment-related mortality occurred before day +100. Conclusion: A preparative regimen of PK-directed IV Bu with Btz and Mel led to an ORR of 100% with acceptable toxicity and should be considered for direct comparison with the Mel200 regimen in future trials.

Original languageEnglish (US)
JournalClinical Lymphoma, Myeloma and Leukemia
DOIs
StateAccepted/In press - 2017

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Busulfan
Melphalan
Multiple Myeloma
Pharmacokinetics
Stem Cell Transplantation
Area Under Curve
Survival Rate
Hepatic Veno-Occlusive Disease
Confidence Intervals
Safety
Febrile Neutropenia
Stomatitis
Deglutition Disorders
Disease-Free Survival
Bortezomib
Drug Therapy
Mortality
Liver
Therapeutics

Keywords

  • Autologous stem cell transplant
  • High-dose chemotherapy
  • Personalized medicine
  • Proteasome inhibition
  • Targeted therapy

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Cite this

Pharmacokinetics-directed Intravenous Busulfan Combined With High-dose Melphalan and Bortezomib as a Conditioning Regimen for Patients With Multiple Myeloma. / Barta, Stefan K.; Jain, Rishi; Mazumder, Amithaba; Carter, Jason; Almanzar, Lawrence; Browne, Roy; Shahnaz, Samira; Elkind, Richard; Kaminetzky, David; Battini, Ramakrishna; Derman, Olga; Kornblum, Noah; Verma, Amit K.; Braunschweig, Ira.

In: Clinical Lymphoma, Myeloma and Leukemia, 2017.

Research output: Contribution to journalArticle

Barta, Stefan K. ; Jain, Rishi ; Mazumder, Amithaba ; Carter, Jason ; Almanzar, Lawrence ; Browne, Roy ; Shahnaz, Samira ; Elkind, Richard ; Kaminetzky, David ; Battini, Ramakrishna ; Derman, Olga ; Kornblum, Noah ; Verma, Amit K. ; Braunschweig, Ira. / Pharmacokinetics-directed Intravenous Busulfan Combined With High-dose Melphalan and Bortezomib as a Conditioning Regimen for Patients With Multiple Myeloma. In: Clinical Lymphoma, Myeloma and Leukemia. 2017.
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abstract = "Background: High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) has a well-established role in the treatment of patients with multiple myeloma. Melphalan 200 mg/m2 (Mel200) is the most commonly used preparative regimen. Several studies have provided evidence for potential synergism and safety when combining bortezomib (Btz) or busulfan (Bu) with melphalan (Mel). Patients and Methods: We conducted a prospective phase II study to investigate the safety and efficacy of conditioning with pharmacokinetics (PK)-directed intravenous (IV) Bu with Btz and Mel. Bu dosing was adjusted to target a total area under the curve (AUC) of 20,000 μM × min. Patients received Btz (1 mg/m2 × 4 doses) and Mel (140 mg/m2). Results: A total of 19 subjects were enrolled. Their median age was 55 years, and the median follow-up period was 23.7 months. PK testing resulted in 86{\%} of patients achieving an estimated total AUC of 20,000 ± 2500 μM × min. The overall response rate (ORR) at day +100 after ASCT was 100{\%} in the evaluable patients, with 11{\%} of patients achieving a complete response. The 2-year progression-free survival rate was 57.9{\%} (95{\%} confidence interval [CI], 38{\%}-89{\%}), and the 2-year overall survival rate was 88.5{\%} (95{\%} CI, 76{\%}-100{\%}). The most common grade 3 and 4 toxicities were febrile neutropenia, dysphagia/odynophagia, and oral mucositis. No case of hepatic sinusoidal obstruction syndrome developed. One treatment-related mortality occurred before day +100. Conclusion: A preparative regimen of PK-directed IV Bu with Btz and Mel led to an ORR of 100{\%} with acceptable toxicity and should be considered for direct comparison with the Mel200 regimen in future trials.",
keywords = "Autologous stem cell transplant, High-dose chemotherapy, Personalized medicine, Proteasome inhibition, Targeted therapy",
author = "Barta, {Stefan K.} and Rishi Jain and Amithaba Mazumder and Jason Carter and Lawrence Almanzar and Roy Browne and Samira Shahnaz and Richard Elkind and David Kaminetzky and Ramakrishna Battini and Olga Derman and Noah Kornblum and Verma, {Amit K.} and Ira Braunschweig",
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TY - JOUR

T1 - Pharmacokinetics-directed Intravenous Busulfan Combined With High-dose Melphalan and Bortezomib as a Conditioning Regimen for Patients With Multiple Myeloma

AU - Barta, Stefan K.

AU - Jain, Rishi

AU - Mazumder, Amithaba

AU - Carter, Jason

AU - Almanzar, Lawrence

AU - Browne, Roy

AU - Shahnaz, Samira

AU - Elkind, Richard

AU - Kaminetzky, David

AU - Battini, Ramakrishna

AU - Derman, Olga

AU - Kornblum, Noah

AU - Verma, Amit K.

AU - Braunschweig, Ira

PY - 2017

Y1 - 2017

N2 - Background: High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) has a well-established role in the treatment of patients with multiple myeloma. Melphalan 200 mg/m2 (Mel200) is the most commonly used preparative regimen. Several studies have provided evidence for potential synergism and safety when combining bortezomib (Btz) or busulfan (Bu) with melphalan (Mel). Patients and Methods: We conducted a prospective phase II study to investigate the safety and efficacy of conditioning with pharmacokinetics (PK)-directed intravenous (IV) Bu with Btz and Mel. Bu dosing was adjusted to target a total area under the curve (AUC) of 20,000 μM × min. Patients received Btz (1 mg/m2 × 4 doses) and Mel (140 mg/m2). Results: A total of 19 subjects were enrolled. Their median age was 55 years, and the median follow-up period was 23.7 months. PK testing resulted in 86% of patients achieving an estimated total AUC of 20,000 ± 2500 μM × min. The overall response rate (ORR) at day +100 after ASCT was 100% in the evaluable patients, with 11% of patients achieving a complete response. The 2-year progression-free survival rate was 57.9% (95% confidence interval [CI], 38%-89%), and the 2-year overall survival rate was 88.5% (95% CI, 76%-100%). The most common grade 3 and 4 toxicities were febrile neutropenia, dysphagia/odynophagia, and oral mucositis. No case of hepatic sinusoidal obstruction syndrome developed. One treatment-related mortality occurred before day +100. Conclusion: A preparative regimen of PK-directed IV Bu with Btz and Mel led to an ORR of 100% with acceptable toxicity and should be considered for direct comparison with the Mel200 regimen in future trials.

AB - Background: High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) has a well-established role in the treatment of patients with multiple myeloma. Melphalan 200 mg/m2 (Mel200) is the most commonly used preparative regimen. Several studies have provided evidence for potential synergism and safety when combining bortezomib (Btz) or busulfan (Bu) with melphalan (Mel). Patients and Methods: We conducted a prospective phase II study to investigate the safety and efficacy of conditioning with pharmacokinetics (PK)-directed intravenous (IV) Bu with Btz and Mel. Bu dosing was adjusted to target a total area under the curve (AUC) of 20,000 μM × min. Patients received Btz (1 mg/m2 × 4 doses) and Mel (140 mg/m2). Results: A total of 19 subjects were enrolled. Their median age was 55 years, and the median follow-up period was 23.7 months. PK testing resulted in 86% of patients achieving an estimated total AUC of 20,000 ± 2500 μM × min. The overall response rate (ORR) at day +100 after ASCT was 100% in the evaluable patients, with 11% of patients achieving a complete response. The 2-year progression-free survival rate was 57.9% (95% confidence interval [CI], 38%-89%), and the 2-year overall survival rate was 88.5% (95% CI, 76%-100%). The most common grade 3 and 4 toxicities were febrile neutropenia, dysphagia/odynophagia, and oral mucositis. No case of hepatic sinusoidal obstruction syndrome developed. One treatment-related mortality occurred before day +100. Conclusion: A preparative regimen of PK-directed IV Bu with Btz and Mel led to an ORR of 100% with acceptable toxicity and should be considered for direct comparison with the Mel200 regimen in future trials.

KW - Autologous stem cell transplant

KW - High-dose chemotherapy

KW - Personalized medicine

KW - Proteasome inhibition

KW - Targeted therapy

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U2 - 10.1016/j.clml.2017.06.005

DO - 10.1016/j.clml.2017.06.005

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JO - Clinical Lymphoma, Myeloma and Leukemia

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SN - 2152-2669

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