On September 11, 2023, the FDA approved motixafortide (Aphexda; BioLineRx) subcutaneous injection, a hematopoietic stem cell (HSC) mobilizer, for use in combination with the granulocyte colony-stimulating factor filgrastim (Neupogen; Amgen), to mobilize HSCs to the peripheral blood for collection and subsequent autologous stem cell transplantation (ASCT) in patients with multiple myeloma. Motixafortide is the first novel stem cell mobilizer in a decade to receive FDA approval for multiple myeloma.
The approval was based on the results of the GENESIS study, a randomized, double-blind, placebo-controlled, phase 3 clinical trial that evaluated the safety and efficacy of motixafortide plus filgrastim versus placebo plus filgrastim for the mobilization of HSCs for ASCT in patients with multiple myeloma.
ASCT is part of the standard of care for patients with multiple myeloma. The success of ASCT in prolonging patient survival depends on the adequate mobilization of the stem cells used. Historically, many patients have had difficulty collecting enough HSCs for ASCT after 1 apheresis session.
“Greater numbers of patients with multiple myeloma are candidates for autologous stem cell therapy; however, achieving target collection goals can be difficult in some patients given modern barriers, including the treatment of older patients and use of contemporary induction regimens,” said John DiPersio, MD, PhD, Director, Center for Gene and Cellular Immunotherapy, and Professor, Medicine, Pathology and Immunology, Washington University School of Medicine, St. Louis, and lead investigator of the GENESIS study, in a press release. “Innovation in this area of medicine has been needed, and today’s approval of Aphexda addresses the demand for new therapies that can meet today’s challenges by delivering more reliability in stem cell mobilization, versus filgrastim alone, with fewer days of apheresis sessions and fewer doses of filgrastim for people living with this cancer,” he added.
The American Society for Transplantation and Cellular Therapy guidelines recommend a stem cell collection target of 3 × 106 to 5 × 106 CD34+ cells/kg, as well as the collection of enough stem cells to perform 2 transplants.
The GENESIS study was divided into 2 parts: a single-center, lead-in, open-label study of 12 patients who received motixafortide plus filgrastim to confirm the appropriate dose of motixafortide, and a double-blind, placebo-controlled, multicenter trial that randomized (2:1) 122 patients to motixafortide plus filgrastim or to placebo plus filgrastim. The CD34+ cells were assessed by central and local laboratories, with the central laboratory results used for the efficacy results and the local laboratory results used for treatment decisions.
Of the patients who received motixafortide plus filgrastim, 67.5% achieved the stem cell collection goal of ≥6 × 106 CD34+ cells/kg in ≤2 apheresis sessions compared with only 9.5% of the patients who received placebo plus filgrastim (measured by central laboratory). In addition, 92.5% of patients achieved the stem cell collection goal in ≤2 apheresis sessions in the motixafortide arm versus 21.4% in the placebo arm (measured by local laboratories). The local laboratory data were used for a sensitivity analysis, and the data are descriptive and were not statistically powered nor prespecified.
Older patient age and previous exposure to lenalidomide (Revlimid; Bristol-Myers Squibb)-containing induction regimens (including 3-4 drug combination regimens) are associated with impaired stem cell mobilization. The GENESIS study included individuals who represented typical patients with multiple myeloma undergoing ASCT, with a median age of 63 years and approximately 70% of the patients in both study arms receiving lenalidomide-containing induction therapy. The patients who received motixafortide plus filgrastim mobilized >4 times the amount of stem cells with a single dose over 24 hours than those who received placebo plus filgrastim. Overall, 1 dose of motixafortide plus filgrastim enabled most of the patients to achieve the collection goal of ≥6 million HSCs.
The safety profile of motixafortide was based on the results of the GENESIS study, which included 92 patients who received at least 1 dose of motixafortide 1.25 mg/kg subcutaneously plus filgrastim and 42 patients who received placebo plus filgrastim. The premedication regimen changed during the study when evidence of hypersensitivity reactions was noted.
Of the 92 patients who received at least 1 dose of motixafortide, 14 received the triple-drug premedication regimen of an H1 antihistamine, an H2 blocker, and a leukotriene inhibitor, and 78 did not receive the premedication regimen or received another regimen. Serious adverse events occurred in 5.4% of patients who received motixafortide plus filgrastim, including vomiting, injection-site reaction, hypersensitivity reaction, injection-site cellulitis, hypokalemia, and hypoxia.
The most common (>20%, and ≥2% higher than in the filgrastim plus placebo arm) adverse reactions with motixafortide treatment were injection-site reactions, injection-site pain, injection-site erythema, injection-site pruritus, pruritus, flushing, and back pain. In addition, 1 patient did not receive the fifth dose of filgrastim because of an elevated white blood cell count after receiving motixafortide.
Treatment with motixafortide should be initiated after filgrastim has been administered daily for 4 days. A second dose of motixafortide can be administered 10 to 14 hours before a third apheresis.
The recommended dose of motixafortide is 1.25 mg/kg (actual body weight), by subcutaneous injection, 10 to 14 hours before the initiation of apheresis. More than 1 vial of motixafortide may be needed for a full dose. A second dose of motixafortide can be administered 10 to 14 hours before a third apheresis if necessary.
Because of the risks for anaphylactic shock and hypersensitivity reactions with motixafortide treatment, all patients should receive a 3-drug premedication regimen that includes an H1 antihistamine, an H2 blocker, and a leukotriene inhibitor.