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Selinexor: A Nuclear Export Inhibitor for Treating Relapsed or Refractory Multiple Myeloma

Sara Moran Smith, PharmD BCOP
Oncology Clinical Pharmacist
M Health Fairview Maple Grove Cancer Center
Maple Grove, MN

Despite significant advances in therapy for multiple myeloma (MM) in recent years, it continues to be an incurable hematologic malignancy. MM primarily affects the elderly, with a median age of diagnosis of 69 and an estimate of 32,000 new diagnoses in 2019.1 MM is characterized by uncontrolled proliferation of clonal plasma cells. Treatment generally includes an induction regimen, autologous transplant for eligible patients, and maintenance therapy. Although transplant gives patients the best chance for overall survival, all patients are expected ultimately to relapse. In the relapse setting, agents include proteasome inhibitors (bortezomib, carfilzomib, ixazomib), immunomodulatory agents (thalidomide, lenalidomide, pomalidomide), alkylating agents (cyclophosphamide, bendamustine), and/or monoclonal antibodies (daratumumab, elotuzumab).1,2 Daratumumab is an anti-CD38 monoclonal antibody approved for use in newly diagnosed patients and relapsed or refractory patients.3 Elotuzumab is a SLAMF7-directed monoclonal antibody approved for use in the relapsed setting.4 Despite these treatments, development of resistance continues.

A cell has various proteins moving in and out of the nucleus to and from the cytoplasm. Exportin-1 (XPO-1) is a karyopherin, a family of proteins that transport molecules between the nucleus and cytoplasm.5,6 In normal cells, XPO-1 is essential in maintaining homeostatic levels of proteins and messenger RNAs (mRNAs).6 These proteins include tumor suppressor proteins (TSPs) and oncogenic mRNAs. Overexpression of XPO-1 in cancer cells inactivates TSPs by excluding them from the nucleus.6 In addition, this overexpression leads to increased transport of oncogenic mRNAs to the cytoplasm where translation and oncogenic protein production occurs.7 XPO-1 is highly expressed in patients with MM, particularly in patients resistant to bortezomib.8 Furthermore, high expression of XPO-1 is associated with a poor prognosis.8

Clinical Trial

Selinexor (Xpovio) is an oral small-molecule nuclear export inhibitor that targets XPO-1 and is approved for use in patients who have received at least two proteasome inhibitors, two immunomodulatory agents, and an anti-CD38 monoclonal antibody.9 Selinexor inhibits XPO-mediated nuclear export of TSPs and oncogenic mRNAs, resulting in G1/G2 arrest and apoptosis.10

Selinexor received accelerated approval in combination with dexamethasone following its evaluation in the STORM trial. STORM was a multicenter single-arm open-label study of patients with relapsed or refractory MM. STORM part 2 included 122 patients who had previously received three or more antimyeloma treatment regimens. Patients who were enrolled had to be documented as refractory (not intolerable) to at least three treatment regimens—including an alkylating agent, glucocorticoids, bortezomib, carfilzomib, lenalidomide, pomalidomide, and daratumumab—and to their last line of therapy.9 Of the 122 patients, 83 patients had relapsed or refractory MM that was documented as being refractory to bortezomib, carfilzomib, lenalidomide, pomalidomide, and daratumumab.9 These patients were dosed with selinexor 80 mg and dexamethasone 20 mg on days 1 and 3 of each week.9,11 The major efficacy outcome was overall response rate (ORR). The accelerated approval granted for selinexor was based on this prespecified subgroup of 83 patients who were documented as pentarefractory because the benefit-risk ratio appeared greater in this more heavily pretreated population compared to the overall trial population.9 Median time to first response was 4 weeks, and median duration of treatment was nearly 4 months.9,11

Safety

Many people in the relapsed or refractory MM population struggle with side effects from previous therapy, particularly peripheral neuropathy. Selinexor is not associated with any peripheral neuropathy, making it a particularly attractive option for these patients. Selinexor does have side effects that can be managed with dose reductions and supportive therapies.

The overall incidence of nausea was 72%, with 10% of patients experiencing grade 3 or 4 nausea.9,11 It is important to take prophylactic measures with a 5-HT3 antagonist because the median time of onset for nausea is 3 days, and for vomiting, 5 days.9 If nausea continues, an additional antinausea agent should be added, such as an NK-1 receptor antagonist like rolapitant. Fosaprepitant and aprepitant should be avoided, given the significant interaction with high-dose dexamethasone, which can cause additional side effects, including hyperglycemia and edema. Another successful antinausea agent is olanzapine, an atypical antipsychotic, which can be initiated at low doses, 2.5–5 mg daily, and can be increased to  up to 10 mg daily. If patients experience grade 3 nausea despite these interventions, the dose should be interrupted and the medication restarted at the next dose level after nausea has decreased to grade 1 or better.9

Thrombocytopenia is a common side effect of selinexor used in relapsed or refractory MM patients. Any-grade thrombocytopenia was 74%, with 61% of those patients having grade 3 or 4.9,11 Median time to onset is 22 days, with bleeding occurring in 23% of patients.9,11 Platelet counts should be monitored at baseline and throughout therapy. If the platelet count drops to <75,000/mcL, selinexor should be reduced by one dose level. If bleeding is present, selinexor should be withheld and restarted at the next dose level.9 Many MM patients starting therapy may have grade 2 or higher thrombocytopenia due to their disease. It’s important to distinguish these patients from the cases addressed in the dose-modification guidelines. Dose modifications contained in the package insert pertain to platelet counts while the patient is on therapy, not at the start of therapy. Any patient who starts treatment with a platelet count of <75,000/mcL should begin treatment at the full dose to receive the maximum benefit. Before dose modifications are made for patients with a low platelet count while on therapy, a conversation about risk versus benefit and the extent of the patient’s disease should be held with the oncologist.

An atypical side effect of this oral targeted agent is hyponatremia. Median time to onset is 8 days; thus it is important to monitor sodium levels at baseline and during treatment. It is important to correct sodium levels for concurrent hyperglycemia.9 Hyponatremia should be treated per institutional guidelines. Some patients may benefit from taking 1 gram of sodium three times per day to maintain appropriate sodium levels while they are on therapy.

Other reported side effects (all grades) include fatigue (73%), anemia (59%), anorexia (53%), weight decrease (47%), diarrhea (44%), constipation (25%), and upper respiratory tract infections (21%).9

The rate of treatment discontinuation because of adverse events was 27%.9 Fifty-three percent of patients had a reduction in selinexor dose, and 65% had a dose interruption.9 It is therefore common for patients to require a dose reduction or interruption (or both) while on therapy. It is important to note, however, that patients benefit most from therapy when they start at the full dose. Because their disease is pentarefractory and is progressing rapidly, full doses of selinexor will provide the best chance for the patient to achieve a response. If the patient experiences side effects, the dose can be adjusted for better tolerability.

Currently, no drug interactions have been reported with selinexor.

How Xpovio Is Supplied

Xpovio comes in dose packs for each dose level.9 The starting dose is 80 mg twice weekly. The first dose reduction is 100 mg weekly, the second reduction is 80 mg weekly, and the last recommended dose reduction is 60 mg weekly.9 Further dose reductions are not recommended because patients would likely not benefit from therapy. All dose packs contain 20-mg tablets. Therefore, if a patient starts on a full dose of 80 mg twice weekly and requires a dose reduction, the patient can continue to use the current dose pack with instructions of how many 20-mg tablets to take before getting a new dose pack of 100-mg dosed weekly.

Future Directions

Selinexor is currently undergoing clinical trials for use in a number of other disease states, including gastrointestinal stromal tumor, soft tissue sarcomas, non-small-cell lung cancer, non-Hodgkin lymphoma, acute myeloid leukemia, breast cancer, diffuse large B-cell lymphoma, and a number of other malignancies.12 

Disclosure

Sara Moran Smith is a speaker for Karyopharm Therapeutics.

References

  1. Peterson TJ, Orozco J, Buege M. Selinexor: a first-in-class nuclear export inhibitor for management of multiply relapsed multiple myeloma. Ann Pharmacother. December 2, 2019. doi:10.1177/1060028019892643. [Epub ahead of print]
  2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Multiple Myeloma. Version 2.2020 (October 9, 2019). Available at https://www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf. Accessed December 8, 2019.
  3. Darzalex [package insert]. Horsham, PA: Janssen Biotech, Inc.; 2019.
  4. Empliciti [package insert]. Princeton, NJ: Bristol-Myers Squibb Co.; 2015.
  5. Das A, Wei G, Parikh K, Liu D. Selective inhibitors of nuclear export (SINE) in hematological malignancies. Exp Hematol Oncol. 2015;4:7.
  6. Sun Q, Chen X, Zhou Q, Burstein E, Yang S, Jia D. Inhibiting cancer cell hallmark features through nuclear export inhibition. Signal Transduct Target Ther. 2016;1:16010.
  7. Culjkovic-Kraljacic B, Borden KL. Aiding and abetting cancer: mRNA export and the nuclear pore. Trends Cell Biol. 2013;23:328-335.
  8. Tai YT, Landesman Y, Acharya C, et al. CRM1 inhibition induces tumor cell cytotoxicity and impairs osteoclastogenesis in multiple myeloma: molecular mechanisms and therapeutic implications. Leukemia. 2014; 28(1):155-165.
  9. Xpovio [package insert]. Newton, MA: Karyopharm Therapeutics Inc.; 2019
  10. Gandhi UH, Senapedis W, Baloglu E, et al. Clinical implications of targeting XPO1-mediated nuclear export in multiple myeloma. Clin Lymphoma Myeloma Leuk. 2018;18:335-345.
  11. Chari A, Vogl DT, Gavriatopoulou M, et al. Oral selinexor-dexamethasone for triple-class refractory multiple myeloma. N Engl J Med. 2019;381:727-738.
  12. U.S. National Library of Medicine. ClinicalTrials.gov. Available at https://www.clinicaltrials.gov/. Accessed December 8, 2019.
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