Patients with multiple myeloma are more likely to mobilize sufficient numbers of hematopoietic stem cells (HSCs) when plerixafor (AMD3100) is given with G-CSF (Neupogen) than with G-CSF alone.
ATLANTAPatients with multiple myeloma are more likely to mobilize sufficient numbers of hematopoietic stem cells (HSCs) when plerixafor (AMD3100) is given with G-CSF (Neupogen) than with G-CSF alone. John F. DiPersio, MD, PhD, of Washington University School of Medicine, presented interim results of a phase III study evaluating this regimen at ASH 2007 (abstract 445).
Plerixafor is a small-molecule competitive antagonist of CXCR4, a receptor that normally binds to the SDF-1 ligand expressed on bone marrow stromal cells and osteoblasts. By inhibiting the interaction between CXCR4 and SDF-1, plerixafor triggers the rapid release of stem cells out of the bone marrow and into the circulating blood (mobilization). This agent works in concert with G-CSF to rapidly expand the pool of available HSCs that can be collected by apheresis for subsequent transplantation.
The multicenter, randomized double-blind, placebo-controlled phase III trial included adults with myeloma who required an autologous HSC transplant and who were in first or second complete or partial remission.
Patients on both arms received G-CSF (10 μg/kg/d) subcutaneously for 4 days. On the evening of day 4 they were given either plerixafor (240 μg/kg) or placebo. Following a morning dose of G-CSF on day 5 and 10 to 11 hours after treatment with study drug, patients underwent apheresis.
This cycle of evening treatment with study drug, morning G-CSF, and apheresis continued for up to four apheresis sessions or until the target cell number (at least 6 106 CD34+ cells/kg) was harvested.
Those patients who were not able to achieve more than 2 106 cells/kg were allowed to receive plerixafor plus G-CSF without unblinding of the study.
Following myeloablative chemotherapy and HSC transplantation, patients were followed for at least 12 months to assess engraftment and survival.
The primary endpoint of the trial was the proportion of patients who achieved the target cell number in 2 or fewer apheresis days.
The interim analysis reported by Dr. DiPersio included 302 patients who had completed at least 100 days of follow-up. In intent-to-treat analysis, 106 of 148 patients (72%) in the plerixafor/G-CSF group achieved the primary endpoint, compared with 53 of 154 (34%) in the placebo/G-CSF group (P < .0001).
More than half (54%) of the plerixafor/G-CSF patients reached the collection target in 1 day of apheresis, whereas it took 4 apheresis days for 56% of those in the placebo group to reach the target.
Of the 7 patients in the placebo arm who required rescue therapy, all were able to collect at least 2 106 CD34+ cells/kg following plerixafor/G-CSF therapy.
Transplantation occurred in 142 patients (96%) in the plerixafor/G-CSF arm and 136 patients (88%) in the placebo arm, with tandem transplants in 32 and 24 patients, respectively. Median time to engraftment was similar for both groups, and grafts were durable through day 100 post-transplant in both patient groups.
Toxicities observed with plerixafor and G-CSF were generally mild. "Plerixafor is a very well tolerated drug, with primarily low-level (grade 1-2) toxicities," Dr. DiPersio said. Common adverse effects included nausea (17%), diarrhea (17%), injection site erythema (19.7%), and vomiting (5.4%).
Dr. DiPersio concluded that treatment with plerixafor/G-CSF produces reliable and rapid stem cell mobilization in patients with myeloma, allowing for fewer apheresis sessions and a greater proportion of patients able to undergo transplantation.
"Most important," he said, "an optimal stem cell product is more frequently achieved with the combination regimen than with G-CSF alone, so more patients will have fewer complications with transplantation."
Future studies will evaluate the potential of this regimen in other settings, such as allogeneic transplants and chemosensitization.