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

Irene M. Ghobrial, Chia Jen Liu, Oksana Zavidij, Abdel K. Azab, Rachid Baz, Jacob P. Laubach, Yuji Mishima, Philippe Armand, Nikhil C. Munshi, Frank Basile, Michael Constantine, James Vredenburgh, Adam Boruchov, Pamela Crilley, Patrick M. Henrick, Kalvis T.V. Hornburg, Houry Leblebjian, Stacey Chuma, Kaitlen Reyes, Kimberly NoonanDiane Warren, Robert Schlossman, Claudia Paba-Prada, Kenneth C. Anderson, Edie Weller, Lorenzo Trippa, Kenneth Shain, Paul G. Richardson

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Abstract

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.

Original languageEnglish
Pages (from-to)1244-1253
Number of pages10
JournalAmerican journal of hematology
Volume94
Issue number11
DOIs
StatePublished - Nov 1 2019

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    Ghobrial, I. M., Liu, C. J., Zavidij, O., Azab, A. K., Baz, R., Laubach, J. P., Mishima, Y., Armand, P., Munshi, N. C., Basile, F., Constantine, M., Vredenburgh, J., Boruchov, A., Crilley, P., Henrick, P. M., Hornburg, K. T. V., Leblebjian, H., Chuma, S., Reyes, K., ... Richardson, P. G. (2019). Phase I/II trial of the CXCR4 inhibitor plerixafor in combination with bortezomib as a chemosensitization strategy in relapsed/refractory multiple myeloma. American journal of hematology, 94(11), 1244-1253. https://doi.org/10.1002/ajh.25627