KPT-8602: A Promising XPO1 Inhibitor for Overcoming Drug Resistance in Multiple Myeloma

KPT-8602, a novel XPO1 inhibitor, has demonstrated potent activity against multiple myeloma (MM) cells, both as a single agent and in combination with various drugs. The compound showed low IC50 values and acted synergistically with bortezomib, carfilzomib, doxorubicin, melphalan, topotecan, and VP16, as indicated by CI values less than 1.0. This synergistic effect was less pronounced when KPT-8602 was combined with dexamethasone or lenalidomide.

In tests on multiple myeloma cell lines, including drug-resistant ones, KPT-8602 induced apoptosis as evidenced by caspase 3 cleavage and flow cytometry. In a NOD/SCID-gamma mouse model, KPT-8602 in combination with melphalan reduced tumor growth and increased survival rates compared to single-agent treatments. Moreover, a treatment regimen of KPT-8602 administered five times per week resulted in significantly reduced tumor growth and improved survival in mice, with no observed toxicity as measured by weight loss.

Ex vivo tests on bone marrow samples from MM patients revealed that the combination of KPT-8602 with bortezomib, carfilzomib, doxorubicin, melphalan, topotecan, and VP16 was more effective at inducing apoptosis in CD138+/LC+ MM cells than single agents, in both newly diagnosed and relapsed/refractory patient samples.

The study concluded that KPT-8602 sensitizes MM cells to several drugs, as demonstrated by increased apoptosis and reduced cell viability. The drug was effective as a monotherapy and in combination with melphalan in a mouse model of human MM tumors. KPT-8602 also showed promise when combined with multiple MM drugs in both MM cell lines and patient bone marrow aspirates. With its minimal brain penetration and reduced toxicities in rodents and primates, KPT-8602 is a potential candidate for future clinical trials in MM treatment.