475 Motixafortide (BL-8040) and G-CSF Versus Placebo and G-CSF to Mobilize Hematopoietic Stem Cells for Autologous Stem Cell Transplantation in Patients with Multiple Myeloma: The Genesis Trial
Program: Oral and Poster Abstracts Type: Oral Session: 711. Cell Collection and Processing: Advances in Mobilization, Collection, Manipulation and Engineering of HSCs and T Cells Hematology Disease Topics & Pathways: Clinical Trials, Biological, Adults, Clinical Research, Plasma Cell Disorders, Clinically Relevant, Diseases, Therapies, Lymphoid Malignancies, Study Population, Transplantation Sunday, December 12, 2021: 12:00 PM Zachary D. Crees, MD1, Keith E. Stockerl-Goldstein, MD2, Sarah Larson, MD3, Árpád Illés4*, Giuseppe Milone, MD, Prof5, Massimo Martino6*, Patrick Stiff, MD7, Douglas W. Sborov, MD, MSc8, Denise L. Pereira, MD9*, Ivana N. Micallef, MD10, Gemma Moreno Jiménez, MD11*, Gábor Mikala, MD, PhD12*, Maria liz paciello Coronel13*, Udo Holtick, MD, PhD14*, John W. Hiemenz, MD15*, Muzaffar H. Qazilbash, MD16, Nancy M. Hardy, MD17, Tahir Latif, MD18, Irene García-Cadenas, MD19*, Abi Vainstein, MD20*, Ella Sorani, PhD21*, Irit Gliko-Kabir22*, Inbal Goldstein22*, Shaul Kadosh22* and John F. DiPersio, MD, PhD1
1Division of Oncology, Washington University School of Medicine, Saint Louis, MO 2BMT and Leukemia Program, Department of Medicine, Washington University School of Medicine, Saint Louis, MO 3David Geffen School of Medicine at UCLA, Los Angeles, CA 4University of Debrecen, Faculty of Medicine, Department of Hematology, Debrecen, Hungary 5Hematology and BMT Unit, Azienda Policlinico Vittorio Emanuele, Catania, Italy 6Stem Cell Transplant and Cellular Therapies Unit, "BMM" Hospital, Reggio Calabria, Italy, Reggio Calabria, ITA 7Loyola University Medical Center, Maywood, IL 8Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT 9University of Miami Sylvester Cancer Ctr., Miami, FL 10Division of Hematology, Mayo Clinic, Rochester, MN 11Department of Hematology, Hospital Ramón y Cajal, Madrid, Spain 12Center Hospital of Southern Pest, Budapest, Hungary 13Hospital University 12 De Octubre, Madrid, Spain 14Department of Internal Medicine I, Leukapheresis and Stem Cell Transplant Unit, University Hospital of Cologne, Cologne, Germany 15Division of Hematology-Oncology, Department of Medicine, University of Florida, Gainesville, FL 16M.D. Anderson Cancer Center, Houston, TX 17Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, MD 18University of Cincinatti College of Medicine, Cincinnati, OH 19Department of Hematology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain 20BiolineRx Ltd., Modi'In, Israel 21BioLineRx Ltd., Modi'in, Israel 22BioLineRx, Ltd., Modi'In, Israel
Background: Autologous stem cell transplantation (ASCT) in multiple myeloma (MM) has been shown to improve survival compared to conventional chemotherapy alone. However, the ability to perform ASCT relies, in part, on collecting a sufficient number (#) of CD34+ hematopoietic stem cells (HSCs), typically from peripheral blood. The ideal HSC mobilization regimen would enable collection of optimal #s of HSCs (5-6x106 CD34+ cells/kg) within the minimum # of apheresis sessions possible. Yet, despite currently available G-CSF (G) based mobilization regimens and multiple apheresis days, many remain unable to collect optimal #s of HSCs. Motixafortide (M) is a novel CXCR4 inhibitor, with high affinity (IC50 0.54-4.5 nM) and long receptor occupancy (>48 hours). Methods: In this prospective, phase 3, double blind, placebo controlled, multicenter trial, 122 patients were randomized (2:1) to receive either M+G or placebo (P)+G for HSC mobilization prior to ASCT for MM. All patients received G (10 mcg/kg) on days 1-5 (and 6-8, if needed). Patients received either M (1.25 mg/kg, subcutaneous injection) or P on day 4 (and 6, if needed). Apheresis began day 5, with the primary (PEP) and secondary (SEP) endpoints of collecting ≥6x106 CD34+ cells/kg in up to 2 apheresis days or 1 day, respectively. Apheresis continued on days 6-8 if needed. Total CD34+ cells/kg were analyzed on site to determine if patients mobilized to the goal and all samples were subsequently sent for assessment by central laboratory. Patients that did not collect ≥2x106 CD34+ cells/kg by day 8 proceeded to rescue mobilization. The # of CD34+ cells infused was determined independently by each investigator according to local practice (minimum ≥2x106 CD34+ cells/kg). Analyses of the PEP/SEPs were performed on an intent-to-treat basis.
Results: Demographics between the 2 treatment arms were similar. Mobilization with M+G resulted in 92.5% of patients collecting ≥6x106 CD34+ cells/kg within 2 apheresis days vs 26.2% with P+G (Odds Ratio (OR) 53.3, 95% CI 14.12-201.33, p<0.0001). Furthermore, 88.8% of patients with M+G collected ≥6x106 CD34+ cells/kg in 1 apheresis day vs 9.5% with P+G (OR 118.0, 95% CI 25.36-549.35, p<0.0001); and 96.3% with M+G collected ≥2x106 CD34+ cells/kg within 1 apheresis day vs 64.3% with P+G (OR 18.9, 95% CI 4.47-80.04, p<0.0001). The PEP and SEPs were confirmed as statistically significant by central laboratory (all respective p-values <0.0001). The median # of HSCs mobilized in 1 apheresis day with M+G was 10.80x106 CD34+ cells/kg vs 2.14x106 CD34+ cells/kg with P+G. The # of cells infused was determined independently by each investigator according to local practice. Median time to neutrophil engraftment was 12 days in both arms (HR 0.94, 95% CI 0.62-1.41, p=0.75). Median time to platelet engraftment was 18 days (range: 17-19) with M+G and 17 days (range: 17-18) with P+G (HR 0.89, 95% CI 0.59-1.34, p=0.57). Graft durability at day 100 post-ASCT was 92.2% in the M+G arm and 91.9% in the P+G arm (OR 1.04, 95% CI 0.2-4.5, p=0.96). Overall, adverse events were reported in 98.8% (Grade 3/4: 68.8%) of patients with M+G vs 95.2% (Grade 3/4: 42.9%) with P+G, with cytopenias in the post-ASCT period prior to engraftment accounting for the majority of Grade 3/4 AEs in both arms, as expected. The most common AEs related to M included: local injection site reactions (any grade: 70.0%, Grade 3/4: 11.3%); and systemic reactions such as pruritis (33.8%), flushing (32.5%) and urticaria (12.5%). Additionally, mobilization with M+G resulted in a 10.5x increase in mean absolute # of CD34+CD45RA-CD123loCD38-CD90+CD49f+ primitive HSCs collected vs P+G (p<0.0001). Multicolor FACS and scRNA sequencing of CD34+ HSCs from both arms will be reported in a separate ASH abstract.
Conclusions: A single injection of M on top of G significantly increased the proportion of patients mobilizing ≥6x106 CD34+ cells/kg for ASCT (92.5%) vs G (26.2%) in up to 2 apheresis days (p<0.0001), while enabling 88.8% to collect ≥6x106 CD34+ cells/kg in just 1 apheresis (p<0.0001, Figure 1A). Despite the higher # of cells mobilized by M+G, the # of CD34+ cells/kg infused was determined independently by each investigator according to local practice with comparable engraftment kinetics and graft durability between the 2 arms. Finally, M+G mobilized 10.5x more immunophenotypically primitive CD34+ HSCs capable of durable multilineage hematopoietic engraftment vs P+G (p<0.0001, Figure 1B).
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