Phase I/II trial of the CXCR4 inhibitor plerixafor in combination with bortezomib as a chemosensitization strategy in relapsed/refractory multiple myeloma

Autor: Edie Weller, Kaitlen Reyes, James J. Vredenburgh, Adam Boruchov, Kimberly Noonan, Paul G. Richardson, Rachid Baz, Jacob P. Laubach, Abdel Kareem Azab, Houry Leblebjian, Robert L. Schlossman, Irene M. Ghobrial, Frank G. Basile, Pamela A. Crilley, Kenneth C. Anderson, Patrick Henrick, Michael Constantine, Stacey Chuma, Nikhil C. Munshi, Kenneth H. Shain, Kalvis Hornburg, Claudia E. Paba-Prada, Philippe Armand, Diane Warren, Yuji Mishima, Lorenzo Trippa, Chia Jen Liu, Oksana Zavidij
Rok vydání: 2019
Předmět:
Male
Oncology
Benzylamines
Gastrointestinal Diseases
Phases of clinical research
Apoptosis
Kaplan-Meier Estimate
Cyclams
CXCR4
Bortezomib
0302 clinical medicine
Bone Marrow
Heterocyclic Compounds
Recurrence
Antineoplastic Combined Chemotherapy Protocols
Tumor Microenvironment
Multiple myeloma
Aged
80 and over
Hematopoietic Stem Cell Transplantation
Hematology
Middle Aged
Combined Modality Therapy
Neoplasm Proteins
medicine.anatomical_structure
030220 oncology & carcinogenesis
Neoplastic Stem Cells
Female
Stem cell
Multiple Myeloma
medicine.drug
Adult
Receptors
CXCR4
medicine.medical_specialty
Maximum Tolerated Dose
Disease-Free Survival
03 medical and health sciences
Refractory
Internal medicine
medicine
Humans
Aged
Salvage Therapy
Dose-Response Relationship
Drug
business.industry
Plerixafor
medicine.disease
Hematologic Diseases
Drug Resistance
Neoplasm
Bone marrow
business
030215 immunology
Zdroj: American Journal of Hematology. 94:1244-1253
ISSN: 1096-8652
0361-8609
DOI: 10.1002/ajh.25627
Popis: We tested the hypothesis that using CXCR4 inhibition to target the interaction between the tumor cells and the microenvironment leads to sensitization of the tumor cells to apoptosis. Eligibility criteria included multiple myeloma (MM) patients with 1-5 prior lines of therapy. The purposes of the phase I study were to evaluate the safety and maximal-tolerated dose (MTD) of the combination. The treatment-related adverse events and response rate of the combination were assessed in the phase II study. A total of 58 patients were enrolled in the study. The median age of the patients was 63 years (range, 43-85), and 78% of them received prior bortezomib. In the phase I study, the MTD was plerixafor 0.32 mg/kg, and bortezomib 1.3 mg/m2 . The overall response rate for the phase II study was 48.5%, and the clinical benefit rate 60.6%. The median disease-free survival was 12.6 months. The CyTOF analysis demonstrated significant mobilization of plasma cells, CD34+ stem cells, and immune T cells in response to plerixafor. This is an unprecedented study that examines therapeutic targeting of the bone marrow microenvironment and its interaction with the tumor clone to overcome resistance to therapy. Our results indicate that this novel combination is safe and that the objective response rate is high even in patients with relapsed/refractory MM. ClinicalTrials.gov, NCT00903968.
Databáze: OpenAIRE
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