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

Am J Hematol. 2019 Nov;94(11):1244-1253. doi: 10.1002/ajh.25627. Epub 2019 Oct 4.

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.

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Apoptosis / drug effects
  • Bone Marrow / drug effects
  • Bone Marrow / pathology
  • Bortezomib / administration & dosage
  • Bortezomib / adverse effects
  • Combined Modality Therapy
  • Disease-Free Survival
  • Dose-Response Relationship, Drug
  • Drug Resistance, Neoplasm / drug effects*
  • Female
  • Gastrointestinal Diseases / chemically induced
  • Hematologic Diseases / chemically induced
  • Hematopoietic Stem Cell Transplantation
  • Heterocyclic Compounds / administration & dosage
  • Heterocyclic Compounds / adverse effects
  • Humans
  • Kaplan-Meier Estimate
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Multiple Myeloma / drug therapy*
  • Multiple Myeloma / genetics
  • Multiple Myeloma / therapy
  • Neoplasm Proteins / antagonists & inhibitors*
  • Neoplastic Stem Cells / cytology
  • Neoplastic Stem Cells / drug effects
  • Receptors, CXCR4 / antagonists & inhibitors*
  • Recurrence
  • Salvage Therapy*
  • Tumor Microenvironment / drug effects

Substances

  • CXCR4 protein, human
  • Heterocyclic Compounds
  • Neoplasm Proteins
  • Receptors, CXCR4
  • Bortezomib
  • plerixafor

Associated data

  • ClinicalTrials.gov/NCT00903968