Myeloma is a type of cancer that develops in the bone marrow, where different blood cells are produced. In myeloma, certain types of blood cells called B-cells start dividing and growing out of control.
Because myeloma can develop anywhere there is bone marrow, it often occurs at multiple sites throughout the body — this is called multiple myeloma. Myeloma cells produce abnormal antibodies and other proteins.
What is nuclear protein export?
In normal cells, proteins called tumor suppressors block the pathways that lead to cancer. These tumor suppressors move to the nucleus of the cell and prevent the activity of genes involved in cell growth and division.
One of the mechanisms by which cancer cells evade the tumor suppressors and remain cancerous is by exporting the tumor suppressors out of the nucleus before they can act to suppress gene activity. They do this by appropriating a protein called exportin 1 (also called XPO1), which orchestrates the shuttling of proteins, including tumor suppressors, out of the nucleus. Cancer cells have extra XPO1 to keep the nucleus clear of tumor suppressor proteins.
Inhibiting nuclear protein export
Selective inhibitors of nuclear export (also called SINEs or SINE compounds) are molecules that bind to XPO1 and inhibit it, thereby blocking the export of tumor suppressor proteins from the nucleus. Blocking XPO1 means that tumor suppressors accumulate in the nucleus and can kill cancerous cells.
The first SINE identified was a molecule called leptomycin B. Although it showed an ability to inhibit XPO1, it was too toxic to be used to treat patients.
Approved nuclear export inhibitors
The U.S. Food and Drug Administration granted Xpovio, in combination with dexamethasone, accelerated approval in July 2019 for the treatment of relapsed or refractory multiple myeloma. Under accelerated approval, the FDA may require further clinical trials to verify the efficacy of a therapy before awarding full approval.
The treatment is indicated for multiple myeloma patients who have received at least four previous treatments and are resistant to several other types of therapy.
This approval was based on the results of a Phase 3 clinical trial (NCT02336815) that assessed the safety and efficacy of the treatment in 122 patients with multiple myeloma. Participants received Xpovio and dexamethasone on the first and third days of every week throughout the study. In a subgroup of 83 heavily pretreated patients, the response rate was 25.3%; the median time to first response was four weeks, though some patients responded at one week, and some at 10 weeks. The median duration of response was 3.8 months.
Common symptoms reported included thrombocytopenia (low platelet count), fatigue, nausea, anemia (low red blood cell count), decreased appetite, weight loss, diarrhea, vomiting, low salt levels in the blood, constipation, and colds.
Xpovio was also granted fast-track designation from the FDA for the treatment of certain patients with diffuse large B-cell lymphoma.
Last updated: Nov. 8, 2019
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