Selinexor (XPOVIO™) is a first-in-class, oral, small molecule Exportin-1 (XPO1) inhibitor that is being developed by Karyopharm Therapeutics for the treatment of cancer. Selinexor (in combination with dexamethasone) received accelerated approval in the USA in July 2019 for the treatment of adult patients with relapsed or refractory multiple myeloma (RRMM). Selinexor is also undergoing clinical development in a wide range of haematological and solid cancers. This article summarizes the milestones in the development of selinexor leading to this first approval for RRMM.

Selinexor: First Global Approval.

Introduction: Despite unprecedented advances in the treatment of multiple myeloma (MM), almost all patients develop a disease that is resistant to the five most commonly used and active anti-MM agents. The prognosis for this patient population is particularly poor resulting in an unmet need for additional therapeutic options. Exportin-1 (XPO-1) is a major nuclear export protein of macromolecular cargo frequently overexpressed in MM. Selinexor is a first-in-class, oral Selective-Inhibitor-of-Nuclear-Export (SINE) compound that impedes XPO-1. Based on results of the STORM-trial, selinexor in combination with dexamethasone was granted accelerated FDA approval for patients with penta-refractory MM in July 2019.Areas covered: This article summarizes our up-to-date knowledge on the pathophysiologic role of XPO-1 in MM. Furthermore, it reviews the most recent clinical data on selinexor in combination with dexamethasone and other anti-MM agents; and discusses its safety profile, management strategies; and potential future developments.Expert opinion: Selinexor represents a next-generation-novel agent with an innovative mechanism of action that marks a significant advance in the treatment of heavily pretreated MM patients. Ongoing studies investigate its therapeutic potential also in earlier lines of therapy. Additional data is needed to confirm that selinexor and other SINE compounds are a valuable addition to our current therapeutic armamentarium.

Selinexor for the treatment of multiple myeloma.

Patients with relapsed and refractory multiple myeloma (RRMM) who are triple-class exposed (to an immunomodulatory agent, proteasome inhibitor, and anti-CD38 antibody) have limited treatment options and there is no standard of care. Idecabtagene vicleucel (ide-cel, bb2121), a BCMA-directed CAR T-cell therapy, demonstrated efficacy in triple-class exposed RRMM patients in the KarMMa trial (NCT03361748). In this retrospective study (KarMMa-RW), patient-level data from triple-class exposed RRMM patients were merged into a single data model and compared with KarMMa using trimmed stabilized inverse probability of treatment weighting. Endpoints included overall response rate (ORR; primary), rate of very good partial response or better (≥VGPR), progression-free survival (PFS), and overall survival (OS). Of 1949 real-world triple-class exposed RRMM patients, 190 received subsequent (index) line of therapy and met KarMMa eligibility criteria (Eligible RRMM cohort). With a median follow-up of 13.3 months in KarMMa and 10.2 months in Eligible RRMM, ORR, and ≥VGPR were significantly improved in KarMMa versus Eligible RRMM (ORR, 76.4% vs 32.2%; ≥VGPR, 57.9% vs 13.7%; both P < 0.0001) as were PFS (11.6 vs 3.5 months; P = 0.0004) and OS (20.2 vs 14.7 months; P = 0.0006). This study demonstrated that ide-cel significantly improved responses and survival compared with currently available therapies in triple-class exposed RRMM.

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KarMMa-RW: comparison of idecabtagene vicleucel with real-world outcomes in relapsed and refractory multiple myeloma

1. Makani J, Tluway F, Makubi A, et al. A ten year review of the sickle cell program in Muhimbili National Hospital, Tanzania. BMC Hematol. 2018;18:33. https://doi.org/10.1186/s12878-018-0125-0. 2. Steinberg MH. Treating sickle cell anemia: a new era dawns. Am J Hematol. 2020;95:338–342. https://doi.org/10.1002/ajh.25724. 3. Tshilolo L, Tomlinson G,Williams TN, et al. Hydroxyurea for children with sickle cell anemia in sub-SaharanAfrica.NEngl JMed. 2019;380:121-131. 4. World Health Organization and Health Action International, . Measuring Medicine Price, Availability, Affordability and Price Component. 2nd ed. Geneva: World Health Organization; 2008 http://www.who.int/ medicines/areas/access/OMS_Medicine_prices.pdf. Accessed June 15, 2020. 5. Government of the United Republic of Tanzania, Gazette of the United Republic of Tanzania, Supplement No. 24. Dar es Salaam: United Republic of Tanzania; 2013, 94, 26, 8, ISSN: 0856-034X. https:// www.ilo.org/dyn/natlex/natlex4.detail?p_lang=en&p_isn=94094. Accessed June 15, 2020 6. National Association of Boards of Pharmacy, Good compounding practices applicable to state-licensed pharmacies. Model State Pharmacy Act and Model Rules of the National Association of Boards of Pharmacy. Park Ridge, IL: National Association of Boards of Pharmacy; 1993:C.1-C.5. 7. Fischelis RP. Combating war prices by the use of galenicals. J Pharm Sci. 1916;5(4):411-414. 8. Luzzatto L, Makani J. Hydroxyurea: an essential medicine for sickle cell disease in Africa. N Engl J Med. 2019;380:187-189. 9. McNeil DG. In Desperately Poor Rwanda, Most Have Health Insurance. Section D. 15 June. New York, NY: The New York Times; 2010:1. https://www.nytimes.com/2010/06/15/health/policy/15rwanda.html. Accessed June 15, 2020. 10. Report of the United Nations. Secretary-General's High Level Panel on Access to Medicines. https://static1.squarespace.com/static/ 562094dee4b0d00c1a3ef761/t/57d9c6ebf5e231b2f02cd3d4/ 1473890031320/UNSG+HLP+Report+FINAL+12+Sept+2016.pdf. Accessed June 15, 2020 Received: 15 July 2020 Revised: 16 September 2020 Accepted: 22 September 2020

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Overall survival of patients with triple-class refractory multiple myeloma treated with selinexor plus dexamethasone vs standard of care in MAMMOTH.

The progression of multiple myeloma is accompanied by complex cytogenetic and epigenetic alterations that include mutation or functional inactivation of tumor suppressor proteins and overexpression of oncoproteins. Patients whose myeloma is refractory to the three major classes of drugs including immunomodulatory agents, proteasome inhibitors and anti-CD38 monoclonal antibodies have a very poor prognosis. Drugs with novel mechanisms of action that can bypass resistance mechanisms are sorely needed for this group of patients. Selinexor represents a novel, oral agent with an innovative mechanism of action that offers a significant therapeutic advance in this group of heavily treated patients. Moreover, this novel mechanism may provide additional options for patients with less refractory disease.

Selinexor: a first-in-class SINE compound for treatment of relapsed refractory multiple myeloma.

8014Background: TCR-MM is defined as being refractory to immunomodulatory agents, proteasome inhibitors, and anti-CD38 mAbs, representing an urgent unmet medical need with a median OS of 3-5 months...

Overall survival (OS) with oral selinexor plus low dose dexamethasone (Sd) in patients with triple class refractory-multiple myeloma (TCR-MM).

197Background: Overexpression of exportin 1 (XPO1) in malignant cells increases the nuclear export/inactivation of tumor suppressor proteins (eg. p53), and promotes the translation of eIF4E-bound o...

Eltanexor (KPT-8602), a second-generation selective inhibitor of nuclear export (SINE) compound, in patients with metastatic castration-resistant prostate cancer (mCRPC).

William Reichman

Papers

Overall survival (OS) with oral selinexor plus low dose dexamethasone (Sd) in patients with triple class refractory-multiple myeloma (TCR-MM).

Eltanexor (KPT-8602), a second-generation selective inhibitor of nuclear export (SINE) compound, in patients with metastatic castration-resistant prostate cancer (mCRPC).