Posted on April 14, 2020 in: Professional Practice
By Polly Luo, Pharm.D. candidate 2020, University of Michigan, Ann Arbor
Patients with multiple myeloma often develop relapsed or refractory multiple myeloma (RRMM) and have a median overall survival rate of 1.3 to 3.5 months.1 Selinexor was approved July 3, 2019, for adults patients with RRMM who are penta-exposed and triple class refractory to at least two proteasome inhibitors, two immunomodulatory agents and an Anti-CD38 monoclonal antibody.2 Selinexor is a selective inhibitor of nuclear export that binds to the nuclear export protein (XP01) that mediates the nuclear export of proteins and upregulates certain malignancies.1,3 By binding to XP01, the accumulation of tumor suppressor proteins amplifies the tumor suppressor function, leading to apoptosis in cancer cells and sparing normal cells. The Food and Drug Administration (FDA) granted accelerated approval of selinexor based off part two of the Selinexor Treatment of Refractory Myeloma (STORM) trial which represents the largest, most heavily treated patient population to date.4 This approval, however, was not without controversy.
The STORM trial was a phase 2b, multicenter, single-arm, open-label study of 123 patients with RRMM.1,3 All patients were refractory to at least one immunomodulatory drug, one proteasome inhibitor, daratumumab and glucocorticoids. The study was permissive with the allowance of patients that had baseline thrombocytopenia, neutropenia and reduced renal function. All patients received oral selinexor (80 mg) and dexamethasone (20 mg) twice weekly for a 28-day cycle.1,3 The overall response rate was studied as the primary endpoint. The secondary endpoints included duration of response (DUR), overall survival (OS), progression free survival (PFS) and safety. A partial response or better was seen in 26 percent of patients and the median OS of these patients was 15.6 months.1,3 The overall median survival of the patient population was 8.6 months. The median DUR was 4.4 months and the median PFS was 3.7 months. During this study, 28 patients died from disease progression or an adverse event. The most common adverse events included thrombocytopenia (73 percent), fatigue (73 percent), nausea (72 percent) and anemia (67 percent).1,3 Serious adverse events occurred in 63 percent of the population with pneumonia and sepsis as the most common. Around 88.6 percent required at least one dose modification due to a treatment emergent adverse events (TEAEs).4 The efficacy and safety outcomes were similar across all evaluated subgroups, including the most treatment resistant group that included 83 patients who were refractory to bortezomib, carfilzomib, lenalidomide, pomalidomide and daratumumab.1,3
FDA’s Oncologic Drugs Advisory Committee (ODAC) voted to wait for the findings of the phase 3 trial before deciding on an approval.4 The recommendation of ODAC is considered but is non-binding. In a surprising turn of events, the FDA approved selinexor, but due to the severe toxicities and modest benefit seen in the STORM study, the drug was not approved for all RRMM patients. It is indicated only for adult patients who are refractory to at least two proteasome inhibitors, two immunomodulatory agents and an Anti-CD38 monoclonal antibody (ie, the characteristics of the most heavily pretreated 83-patient subset in the STORM trial). It was concluded that this group represents a population who, for all intents and purposes, has no available therapy, and therefore, the benefit-risk profile of selinexor is acceptable in this population. This indication was approved under an accelerated approval and continued FDA approval requires additional clinical trials to verify clinical benefits.5 The approval was controversial because there were several issues noted for this trial. Selinexor’s activity as a monotherapy in the phase 1 trial was not demonstrated and the isolated effects of selinexor is undetermined.4 All patients in the trial experienced at least one adverse event thus toxicity is a concern. The proposed starting dose in phase 2 was not well tolerated because 88.6 percent of patients required at least one dose modification due to TEAEs.4 Lastly, the time frame between previous treatments and selinexor was unknown. Medications can have a lingering effect in the body long after the patient is finished with their therapy. There is reason to question if there were lingering effects from previous therapies.
Several clinical trials are in progress for selinexor. Of note, the results of the phase 3 BOSTON study assessing the use of selinexor with bortezomib and low-dose dexamethasone versus bortezomib plus low-dose dexamethasone are set to be released in early 2020.6 In addition, a phase 2 trial assessing the safety and efficacy of at least two different doses of selinexor, a hepatic impairment trial and a drug interaction trial results are set to be available in late 2021.5
1. Chari, A., Vogl, D. T., Gavriatopoulou, M., et al (2019). Oral Selinexor–Dexamethasone for Triple-Class Refractory Multiple Myeloma. New England Journal of Medicine, 381(8), 727-738.
2. Food and Drug Administration. (2019). FDA grants accelerated approval to selinexor for multiple myeloma. Retrieved from https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-selinexor-multiple-myeloma
3. Karyopharm Therapeutics. (2018). Results of the Pivotal STORM Study (Part 2): Deep and Durable Responses with Oral Selinexor plus Low Dose Dexamethasone in Patients with Penta-Exposed and Triple Class Refractory MM [PDF file]. Retrieved from https://www.karyopharm.com/wp-content/uploads/2019/01/STORM-ASH2018-Final-2Dec18-1.pdf
4. Food and Drug Adminstration. (2019). FDA Briefing Document [PDF file]. Retrieved from https://www.fda.gov/media/121667/download
5. Food and Drug Adminstration. (2019). FDA approval letter [PDF file]. Retrieved from https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2019/212306Orig1s000ltr.pdf
6. Karyopharm Therapeutics. (2019). Clinical Trials. Retrieved from https://www.karyopharm.com/patient-resources/clinical-trials/