Dr Mascarenhas on the Use of Selinexor in Myelofibrosis

John Mascarenhas, MD, professor, medicine, Icahn School of Medicine, Mount Sinai, director, Center of Excellence for Blood Cancers and Myeloid Disorders, member, The Tisch Cancer Institute, Mount Sinai, discusses the use of selinexor in patients with JAK inhibitor–naive myelofibrosis, highlighting the phase 2 XPORT-MF-044 trial (NCT05980806) evaluating the safety and efficacy of selinexor monotherapy in this patient population.

Selinexor is indicated for use in patients with various hematologic malignancies, such as multiple myeloma, Mascarenhas begins. In the context of myelofibrosis, however, the agent has been developed at a lower dose administered less frequently, once a week rather than the twice-weekly dosing schedule for patients with multiple myeloma, he says. Initial phase 1 data from the XPORT-MF-034 trial (NCT04562389) of selinexor plus ruxolitinib (Jakafi) in patients with myelofibrosis, especially in the JAK inhibitor–naive setting in combination regimens, has demonstrated the promising activity of the agent, particularly regarding spleen and symptom improvement, Mascarenhas emphasizes. Although the patient population was relatively small in this trial, the outcomes are still impressive, and show benefits with selinexor in the form of deep responses, safety, and tolerability, he adds.

The agent is now advancing into the phase 3 portion of the XPORT-MF-034 study, which is currently recruiting and builds upon the combination approach that has shown efficacy with other drugs, Mascarenhas expands. Despite the encouraging aspects of this combination and trial design, it is essential to acknowledge the expected toxicities associated with selinexor, notably potential gastrointestinal issues, dysgeusia, and myelosuppression, he emphasizes. Monitoring these potential AEs will be crucial as the drug progresses through development. Mechanistically, selinexor aligns with relevant pathways in myelofibrosis, including XPO1 inhibition and activation of proteins within the JAK/STAT signaling pathways, along with non-signaling pathways like p53, which play a pivotal role in mediating NSC-34 cell survivability, Mascarenhas says.

Selinexor has also been evaluated as a monotherapy in in patients with JAK inhibitor–naive myelofibrosis and moderate thrombocytopenia in the XPORT-MF-044 trial. Although the agent exhibits activity as a monotherapy, the preferred strategy for its development involves combination approaches, he continues. Combining selinexor with other drugs, whether upfront or as a salvage therapy for suboptimal responders, seems to offer a balanced approach between efficacy and safety, Mascarenhas imparts. Different treatment strategies, such as starting with one approach and potentially pivoting to salvage therapy with another drug, can be complementary, he notes. The ongoing XPORT-MF-034 study and the exploration of various combination approaches highlight the promising trajectory of selinexor in myelofibrosis management, Mascarenhas concludes.