On September 11, the U.S. Food and Drug Administration (FDA) approved motixafortide (Aphexda) in combination with filgrastim to mobilize hematopoietic stem cells to the peripheral blood for collection and subsequent autologous transplantation in patients with multiple myeloma.
Motixafortide is administered by injection, for subcutaneous use.
Multiple myeloma is the second most-common hematologic malignancy. Autologous stem cell transplantation (ASCT) is part of the standard-of-care treatment paradigm for multiple myeloma and delivers prolonged survival for patients with this cancer type. The success of ASCT depends on adequate mobilization of stem cells during the treatment process. The American Society for Transplantation and Cellular Therapy guidelines recommend a collection target of 3 to 5 x 106 CD34+ cells/kg. Additionally, collection of a sufficient number of stem cells to perform two transplantations is recommended. Historically, depending on induction regimens and mobilization strategies, up to 47% of patients have had challenges collecting target numbers of hematopoietic stem cells for ASCT after one 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, primary investigator for the GENESIS trial and Professor of Medicine, Pathology, and Immunology, as well as Director of the Center for Gene and Cellular Immunotherapy at Washington University School of Medicine in St. Louis. "Innovation in this area of medicine has been needed, and [the] approval of [motixafortide] addresses the demand for new therapies that can meet today's challenges by delivering more reliability in stem cell mobilization, vs filgrastim alone, with fewer days of apheresis sessions and fewer doses of filgrastim for people living with this cancer."
GENESIS Trial
The FDA approval is based on results from the two-part, phase III GENESIS trial (ClinicalTrials.gov identifier NCT03246529), a randomized, double-blind, placebo-controlled study evaluating the safety and efficacy of motixafortide plus filgrastim compared to placebo plus filgrastim for the mobilization of hematopoietic stem cells for autologous transplantation in patients with multiple myeloma. Part 1 was a single-center, lead-in, open-label study involving 12 patients treated with motixafortide plus filgrastim designed to ascertain the dose; part 2 involved 122 patients who were randomly assigned 2:1 in a double-blind, placebo-controlled, multicenter study.
The assessment of CD34+ cells was performed by central and local laboratories: central laboratory assessments were used for the efficacy results, and local laboratory results were used for clinical treatment decisions. Motixafortide plus filgrastim enabled 67.5% of patients to achieve the stem cell collection goal of ≥ 6 × 106 CD34+ cells/kg within two apheresis sessions, vs 9.5% for the placebo plus filgrastim regimen, as measured by central laboratory. Additionally, 92.5% of patients reached the stem cell collection goal in up to two apheresis sessions in the motixafortide arm compared to 21.4% in the placebo arm, as measured by local laboratories. Local laboratory data were used for a sensitivity analysis.
In GENESIS, safety was evaluated in 92 patients with multiple myeloma who received motixafortide at 1.25 mg/kg subcutaneously plus filgrastim, and 42 patients who received placebo plus filgrastim. Serious adverse reactions occurred in 5.4% of patients receiving motixafortide plus filgrastim. These reactions included vomiting, injection site reaction, hypersensitivity reaction, injection site cellulitis, hypokalemia, and hypoxia. The most common adverse reactions occurring in GENESIS (incidence > 20%) were injection site reactions (pain, erythema, and pruritus), pruritus, flushing, and back pain.
Increased age, as well as exposure to lenalidomide-containing induction regimens, including three- or four-drug combination regimens, have been associated with impaired stem cell mobilization. The GENESIS study included patients considered representative of the typical multiple myeloma population undergoing ASCT, with a median age of 63 years and with approximately 70% of patients in both arms of the trial receiving lenalidomide-containing induction therapy. In this contemporary population, patients in the motixafortide plus filgrastim arm were able to mobilize more than four times the amount of stem cells with a single dose over a 24-hour period compared with placebo plus filgrastim.
