Background CXCR4 mediates retention of hematopoietic stem cells (HSCs) in the bone marrow (BM) niche. BL-8040, a novel, high affinity CXCR4 antagonist is a potent mobilizer of HSCs to the peripheral blood with numerous potential clinical applications, including mobilization of CD34+ cells for autologous HSC transplantation (auto-HSCT) in Multiple Myeloma (MM). This study aims to evaluate the efficacy of single dose BL-8040 plus G-CSF in mobilization of ≥6.0 × 106 CD34+ cells/kg in up to 2 apheresis sessions for auto-HSCT in MM. Methods A Phase III study composed of an open-label, single-arm lead-in Part1 followed by a randomized, double-blinded, placebo-controlled Part2. Eligible MM patients age 18-78 will receive G-CSF (10 µg/kg; SC) daily for up to 8 days and one dose of BL-8040 (1.25 mg/kg; SC) or placebo on day 4 followed by up to 2 apheresis sessions; and if needed a second dose of BL-8040 or placebo on day 6 followed by up to 2 apheresis sessions. Part1 included up to 3 cohorts (∼10 patients/cohort), with Data Monitoring Committee (DMC) review after each cohort. Part2 will include 177 patients randomized 2:1. Results Part1 enrolled 11 patients, median age 61 (57-70). 9/11 patients (82%) reached the primary endpoint of ≥6 × 106 CD34+ cells/kg with one dose of BL-8040 and up to 2 apheresis sessions. 7/11 patients (64%) collected ≥6 × 106 CD34+ cells/kg in one apheresis session. Administration of BL-8040 resulted in a 7.86-fold average increase in circulating peripheral CD34+ cells (range 1.62-15.75, median 7.5, n=9). Additional CD34+ immunophenotyping/subset analyses are currently underway. BL-8040 plus G-CSF was found to be safe and well tolerated. Following these promising results, DMC recommended early continuation to Part2 of the Phase III trial. Conclusions The GENESIS lead-in results demonstrate BL-8040 is a potent mobilizer of HSCs, with potential to improve mobilization rates while minimizing mobilization-related healthcare costs.
Abstract Autologous hematopoietic stem cell transplantation (ASCT) improves survival in multiple myeloma (MM). However, many individuals are unable to collect optimal CD34 + hematopoietic stem and progenitor cell (HSPC) numbers with granulocyte colony-stimulating factor (G-CSF) mobilization. Motixafortide is a novel cyclic-peptide CXCR4 inhibitor with extended in vivo activity. The GENESIS trial was a prospective, phase 3, double-blind, placebo-controlled, multicenter study with the objective of assessing the superiority of motixafortide + G-CSF over placebo + G-CSF to mobilize HSPCs for ASCT in MM. The primary endpoint was the proportion of patients collecting ≥6 × 10 6 CD34 + cells kg –1 within two apheresis procedures; the secondary endpoint was to achieve this goal in one apheresis. A total of 122 adult patients with MM undergoing ASCT were enrolled at 18 sites across five countries and randomized (2:1) to motixafortide + G-CSF or placebo + G-CSF for HSPC mobilization. Motixafortide + G-CSF enabled 92.5% to successfully meet the primary endpoint versus 26.2% with placebo + G-CSF (odds ratio (OR) 53.3, 95% confidence interval (CI) 14.12–201.33, P < 0.0001). Motixafortide + G-CSF also enabled 88.8% to meet the secondary endpoint versus 9.5% with placebo + G-CSF (OR 118.0, 95% CI 25.36–549.35, P < 0.0001). Motixafortide + G-CSF was safe and well tolerated, with the most common treatment-emergent adverse events observed being transient, grade 1/2 injection site reactions (pain, 50%; erythema, 27.5%; pruritis, 21.3%). In conclusion, motixafortide + G-CSF mobilized significantly greater CD34 + HSPC numbers within two apheresis procedures versus placebo + G-CSF while preferentially mobilizing increased numbers of immunophenotypically and transcriptionally primitive HSPCs. Trial Registration: ClinicalTrials.gov , NCT03246529
