Motixafortide and G-CSF to mobilize hematopoietic stem cells for autologous transplantation in multiple myeloma: a randomized phase 3 trial

• Published in: Nature medicine Vol. 29; no. 4; pp. 869 - 879
• Main Authors: Crees, Zachary D., Rettig, Michael P., Jayasinghe, Reyka G., Stockerl-Goldstein, Keith, Larson, Sarah M., Arpad, Illes, Milone, Giulio A., Martino, Massimo, Stiff, Patrick, Sborov, Douglas, Pereira, Denise, Micallef, Ivana, Moreno-Jiménez, Gemma, Mikala, Gabor, Coronel, Maria Liz Paciello, Holtick, Udo, Hiemenz, John, Qazilbash, Muzaffar H., Hardy, Nancy, Latif, Tahir, García-Cadenas, Irene, Vainstein-Haras, Abi, Sorani, Ella, Gliko-Kabir, Irit, Goldstein, Inbal, Ickowicz, Debby, Shemesh-Darvish, Liron, Kadosh, Shaul, Gao, Feng, Schroeder, Mark A., Vij, Ravi, DiPersio, John F.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-04-2023; Nature Publishing Group
• Subjects: 631/532/1542; 631/532/2063; 631/67/1990/804; 692/308/2171; 692/308/2779/777; Adult; Antigens, CD34 - metabolism; Apheresis; Autografts; Biomedical and Life Sciences; Biomedicine; Cancer Research; CD34 antigen; Cell survival; Colony-stimulating factor; CXCR4 protein; Erythema; Granulocyte colony-stimulating factor; Granulocyte Colony-Stimulating Factor - pharmacology; Granulocyte Colony-Stimulating Factor - therapeutic use; Hematopoietic Stem Cell Mobilization - methods; Hematopoietic Stem Cell Transplantation - adverse effects; Hematopoietic stem cells; Hematopoietic Stem Cells - metabolism; Heterocyclic Compounds - pharmacology; Heterocyclic Compounds - therapeutic use; Humans; Immunologic Factors - therapeutic use; Infectious Diseases; Inhibitors; Leukocytes (granulocytic); Metabolic Diseases; Molecular Medicine; Multiple myeloma; Multiple Myeloma - drug therapy; Neurosciences; Placebos; Progenitor cells; Prospective Studies; Stem cell transplantation; Stem cells; Transplantation; Transplantation, Autologous
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/s41591-023-02273-z

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
The phase 3 GENESIS trial reports the superiority of the novel CXCR4 inhibitor motixafortide with G-CSF in mobilizing hematopoietic progenitor cells for autologous stem cell transplantation in multiple myeloma.