Motixafortide Mobilization Yields Greater Number of Stem Cells for Transplant in Multiple Myeloma

The investigational drug motixafortide was associated with increased yield and speed of the mobilization of hematopoietic stem and progenitor cell (HSPC) in advance autologous hematopoietic stem cell transplantation (ASCT) in patients with multiple myeloma (MM), when added to standard mobilization protocols. The findings come from a phase III randomized placebo-controlled trial published April 17 in Nature Medicine.

The addition of motixafortide (Aphexda, BioLineRx) to granulocyte-colony stimulating factor (G-CSF) enabled 92.5% of patients to meet the primary endpoint of collecting at least 6 × 10⁶ CD34⁺ cells/kg within two apheresis procedures compared with 26.2% for those who received G-CSF plus placebo. In addition, 88.8% of patients in the motixafortide group achieved the secondary endpoint of collection of the same number of cells in one apheresis procedure compared with 9.5% in the placebo group. The median number of CD34⁺ HSPCs mobilized in one apheresis day with motixafortide was 10.8 × 10⁶ versus 2.25 × 10⁶ cells/kg^/ with placebo. The drug was generally safe and well tolerated.

“Thus it appears, based on these data, that a single injection of motixafortide added to G-CSF substantially improves on currently approved mobilization regimens in terms of the rapidity, robustness and reliability of HSPC mobilization for ASCT in patients newly diagnosed with MM following modern induction therapy in the current era,” the researchers wrote.

Treatment-emergent adverse events (TEAEs) were comparable for the two groups — 93.8% of patients in the motixafortide group versus 83.3% with placebo + G-CSF. The most common TEAEs related to motixaforatide were transient and primarily limited to grade 1/2 local injection site reactions and systemic reactions.

In a post hoc pooled analysis of all patients, the researchers found that infusions with increasing cell numbers were associated with shorter median time to platelet engraftment.

Motixafortide blocks C-X-C chemokine receptor type 4 (CXCR4), which is important in keeping HSPCs in the bone marrow. Blockade of CXCR4 allows mobilization.

The GENESIS trial included 122 patients, who were randomized 2:1 to receive either G-CSF with motixafortide (80 patients) or placebo (42 patients) for HSPC mobilization.

Previous research has identified distinct subsets of CD34+ that include primitive hematopoietic stem cells (HSCs) that are capable of long-term self-renewal and have the potential to differentiate into different types of cells to those that are multilineage potential to relatively differentiated and committed to a cell type of cell. Additionally, CXCR4 expression has been found to vary on subsets of CD34+ HSPCs.

Based on a small sample of 18 with cell numbers ranging from 2,000 to 20,000, the researchers determined that use of long-acting motixafortide resulted in preferentially mobilized primitive HSPC subsets, which are less strongly positive for CXCR4. In comparison, mobilization using short-acting CXCR4 inhibitor plerixafor (commonly added to G-CSF for mobilization). The findings suggest that with optimal CXCR4 blockade, different types of HSPC subsets may be “selected” for mobilization.

While the clinical effect of different mobilization regimens on heterogeneous CD34+ HSPC is unclear, the findings set the stage for additional research into improving ASCT results for patients with multiple myeloma.