Sebastian Grosicki1, Maryana Simonova2, Ivan Spicka3, Ludek Pour4, Iryrna Kriachok5, Maria Gavriatopoulou6, Halyna Pylypenko7, Holger W Auner8, Xavier Leleu9, Vadim Doronin10, Ganna Usenko11, Nizar J Bahlis12, Roman Hajek13, Reuben Benjamin14, Tuphan K Dolai15, Dinesh K Sinha16, Christopher P Venner17, Mamta Garg18, Mercedes Gironella19, Artur Jurczyszyn20, Pawel Robak21, Monica Galli22, Craig Wallington-Beddoe23, Atanas Radinoff24, Galina Salogub25, Don A Stevens26, Supratik Basu27, Anna M Liberati28, Hang Quach29, Vesselina S Goranova-Marinova30, Jelena Bila31, Eirini Katodritou32, Hanna Oliynyk33, Sybiryna Korenkova34, Jeevan Kumar35, Sundar Jagannath36, Phillipe Moreau37, Moshe Levy38, Darrell White39, Moshe E Gatt40, Thierry Facon41, Maria V Mateos42, Michele Cavo43, Donna Reece44, Larry D Anderson45, Jean-Richard Saint-Martin46, Jacqueline Jeha46, Anita A Joshi46, Yi Chai46, Lingling Li46, Vishnuvardhan Peddagali46, Melina Arazy46, Jatin Shah46, Sharon Shacham46, Michael G Kauffman46, Meletios A Dimopoulos47, Paul G Richardson48, Sosana Delimpasi49. 1. Medical University of Silesia, Katowice, Poland. Electronic address: sgrosicki@wp.pl. 2. Institute of Blood Pathology and Transfusion Medicine, National Academy of Medical Sciences of Ukraine, Lviv, Ukraine. 3. Charles University and General Hospital, Prague, Czech Republic. 4. Clinic of Internal Medicine-Hematology and Oncology, University Hospital Brno, Brno, Czech Republic. 5. National Cancer Institute Ukraine, Kiev, Ukraine. 6. Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece. 7. Department of Hematology, Cherkassy Regional Oncological Center, Cherkassy, Ukraine. 8. Imperial College London, London, UK. 9. Department of Hematology, CHU la Miletrie and Inserm CIC 1402, Poitiers, France. 10. City Clinical Hospital No. 40, Moscow, Russia. 11. City Clinical Hospital 4 of Dnipro City Council, City Hematology Center, Dnipro, Ukraine. 12. Charbonneau Cancer Research Institute, University of Calgary, Calgary, AB, Canada. 13. Department of Hemato-oncology, University Hospital Ostrava and Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic. 14. Kings College NHS Foundation Trust, Kings College London, London, UK. 15. Nil Ratan Sircar Medical College and Hospital, Kolkata, India. 16. State Cancer Institute, Indira Gandhi Institute of Medical Sciences, Patna, India. 17. Cross Cancer Institute, University of Alberta, Edmonton, AB, Canada. 18. University Hospitals of Leicester NHS Trust, Leicester, UK. 19. Vall d'Hebron University Hospital, Barcelona, Spain. 20. Department of Hematology, Jagiellonian University Medical College, Kraków, Poland. 21. Department of Hematology, Copernicus Memorial Hospital, Medical University of Lodz, Lodz, Poland. 22. Department of Oncology and Hematology, Papa Giovanni XXIII Hospital, Bergamo, Italy. 23. Flinders Medical Centre and Flinders University, Adelaide, SA, Australia. 24. University Hospital "St Ivan Rilski" EAD, Sofia, Bulgaria. 25. Chemotherapy of Oncology Diseases-Bone Marrow Transplantation Department 1, Almazov National Medical Research Centre, Ministry of Health of Russia, St Petersburg, Russia. 26. Norton Cancer Institute, St Matthews Campus, Louisville, KY, USA. 27. New Cross Hospital, Royal Wolverhampton NHS Trust and University of Wolverhampton, Wolverhampton, UK. 28. Oncohematology Hospital S Maria Terni, University of Perugia, Terni, Italy. 29. University of Melbourne, St Vincent's Hospital, Melbourne, VIC, Australia. 30. University Hospital "Sv Georgi" EAD, Clinic of Clinical Hematology, Medical University of Plovdiv, Plovdiv, Bulgaria. 31. Clinic for Hematology, Clinical Centre of Serbia, Belgrade, Serbia. 32. Hematology Department, Theagenion Cancer Hospital, Thessaloniki, Greece. 33. Department of Hematology, Vinnytsia M I Pyrohov Regional Clinical Hospital, Vinnytsia, Ukraine. 34. Bone Marrow Transplantation Department, Kyiv Bone Marrow Transplantation Center, Kyiv, Ukraine. 35. Tata Medical Center, Kolkata, India. 36. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. 37. University Hospital, Hotel-Dieu, Nantes, France. 38. Baylor University Medical Center, Dallas, TX, USA. 39. Queen Elizabeth II Health Sciences Centre, Dalhousie University, Halifax, NS, Canada. 40. Hadassah Hebrew University Medical Center, Jerusalem, Israel. 41. CHU Lille Service des Maladies du Sang F-59000, Lille, France. 42. Hospital Universitario de Salamanca, Salamanca, Spain. 43. Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy; Istituto di Ematologia "Seràgnoli", Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Università degli Studi, Bologna, Italy. 44. University Health Network-Princess Margaret Cancer Centre, Toronto, ON, Canada. 45. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA. 46. Karyopharm Therapeutics, Newton, MA, USA. 47. School of Medicine, National and Kapodistrian University of Athens, Athens, Greece. 48. Dana-Farber Cancer Institute, Boston, MA, USA. 49. General Hospital Evangelismos, Athens, Greece.
Abstract
BACKGROUND: Selinexor combined with dexamethasone has shown activity in patients with heavily pre-treated multiple myeloma. In a phase 1b/2 study, the combination of oral selinexor with bortezomib (a proteasome inhibitor) and dexamethasone induced high response rates with low rates of peripheral neuropathy, the main dose-limiting toxicity of bortezomib. We aimed to evaluate the clinical benefit of weekly selinexor, bortezomib, and dexamethasone versus standard bortezomib and dexamethasone in patients with previously treated multiple myeloma. METHODS: This phase 3, randomised, open-label trial was done at 123 sites in 21 countries. Patients aged 18 years or older, who had multiple myeloma, and who had previously been treated with one to three lines of therapy, including proteasome inhibitors, were randomly allocated (1:1) to receive selinexor (100 mg once per week), bortezomib (1·3 mg/m2 once per week), and dexamethasone (20 mg twice per week), or bortezomib (1·3 mg/m2 twice per week for the first 24 weeks and once per week thereafter) and dexamethasone (20 mg four times per week for the first 24 weeks and twice per week thereafter). Randomisation was done using interactive response technology and stratified by previous proteasome inhibitor therapy, lines of treatment, and multiple myeloma stage. The primary endpoint was progression-free survival in the intention-to-treat population. Patients who received at least one dose of study treatment were included in the safety population. This trial is registered at ClinicalTrials.gov, NCT03110562. The trial is ongoing, with 55 patients remaining on randomised therapy as of Feb 20, 2020. FINDINGS: Of 457 patients screened for eligibility, 402 were randomly allocated-195 (49%) to the selinexor, bortezomib, and dexamethasone group and 207 (51%) to the bortezomib and dexamethasone group-and the first dose of study medication was given between June 6, 2017, and Feb 5, 2019. Median follow-up durations were 13·2 months [IQR 6·2-19·8] for the selinexor, bortezomib, and dexamethasone group and 16·5 months [9·4-19·8] for the bortezomib and dexamethasone group. Median progression-free survival was 13·93 months (95% CI 11·73-not evaluable) with selinexor, bortezomib, and dexamethasone and 9·46 months (8·11-10·78) with bortezomib and dexamethasone (hazard ratio 0·70 [95% CI 0·53-0·93], p=0·0075). The most frequent grade 3-4 adverse events were thrombocytopenia (77 [39%] of 195 patients in the selinexor, bortezomib, and dexamethasone group vs 35 [17%] of 204 in the bortezomib and dexamethasone group), fatigue (26 [13%] vs two [1%]), anaemia (31 [16%] vs 20 [10%]), and pneumonia (22 [11%] vs 22 [11%]). Peripheral neuropathy of grade 2 or above was less frequent with selinexor, bortezomib, and dexamethasone (41 [21%] patients) than with bortezomib and dexamethasone (70 [34%] patients; odds ratio 0·50 [95% CI 0·32-0·79], p=0·0013). 47 (24%) patients in the selinexor, bortezomib, and dexamethasone group and 62 (30%) in the bortezomib and dexamethasone group died. INTERPRETATION: A once-per-week regimen of selinexor, bortezomib, and dexamethasone is a novel, effective, and convenient treatment option for patients with multiple myeloma who have received one to three previous lines of therapy. FUNDING: Karyopharm Therapeutics.
BACKGROUND: Selinexor combined with dexamethasone has shown activity in patients with heavily pre-treated multiple myeloma. In a phase 1b/2 study, the combination of oral selinexor with bortezomib (a proteasome inhibitor) and dexamethasone induced high response rates with low rates of peripheral neuropathy, the main dose-limiting toxicity of bortezomib. We aimed to evaluate the clinical benefit of weekly selinexor, bortezomib, and dexamethasone versus standard bortezomib and dexamethasone in patients with previously treated multiple myeloma. METHODS: This phase 3, randomised, open-label trial was done at 123 sites in 21 countries. Patients aged 18 years or older, who had multiple myeloma, and who had previously been treated with one to three lines of therapy, including proteasome inhibitors, were randomly allocated (1:1) to receive selinexor (100 mg once per week), bortezomib (1·3 mg/m2 once per week), and dexamethasone (20 mg twice per week), or bortezomib (1·3 mg/m2 twice per week for the first 24 weeks and once per week thereafter) and dexamethasone (20 mg four times per week for the first 24 weeks and twice per week thereafter). Randomisation was done using interactive response technology and stratified by previous proteasome inhibitor therapy, lines of treatment, and multiple myeloma stage. The primary endpoint was progression-free survival in the intention-to-treat population. Patients who received at least one dose of study treatment were included in the safety population. This trial is registered at ClinicalTrials.gov, NCT03110562. The trial is ongoing, with 55 patients remaining on randomised therapy as of Feb 20, 2020. FINDINGS: Of 457 patients screened for eligibility, 402 were randomly allocated-195 (49%) to the selinexor, bortezomib, and dexamethasone group and 207 (51%) to the bortezomib and dexamethasone group-and the first dose of study medication was given between June 6, 2017, and Feb 5, 2019. Median follow-up durations were 13·2 months [IQR 6·2-19·8] for the selinexor, bortezomib, and dexamethasone group and 16·5 months [9·4-19·8] for the bortezomib and dexamethasone group. Median progression-free survival was 13·93 months (95% CI 11·73-not evaluable) with selinexor, bortezomib, and dexamethasone and 9·46 months (8·11-10·78) with bortezomib and dexamethasone (hazard ratio 0·70 [95% CI 0·53-0·93], p=0·0075). The most frequent grade 3-4 adverse events were thrombocytopenia (77 [39%] of 195 patients in the selinexor, bortezomib, and dexamethasone group vs 35 [17%] of 204 in the bortezomib and dexamethasone group), fatigue (26 [13%] vs two [1%]), anaemia (31 [16%] vs 20 [10%]), and pneumonia (22 [11%] vs 22 [11%]). Peripheral neuropathy of grade 2 or above was less frequent with selinexor, bortezomib, and dexamethasone (41 [21%] patients) than with bortezomib and dexamethasone (70 [34%] patients; odds ratio 0·50 [95% CI 0·32-0·79], p=0·0013). 47 (24%) patients in the selinexor, bortezomib, and dexamethasone group and 62 (30%) in the bortezomib and dexamethasone group died. INTERPRETATION: A once-per-week regimen of selinexor, bortezomib, and dexamethasone is a novel, effective, and convenient treatment option for patients with multiple myeloma who have received one to three previous lines of therapy. FUNDING: Karyopharm Therapeutics.
Authors: Husain Yar Khan; Misako Nagasaka; Yiwei Li; Amro Aboukameel; Md Hafiz Uddin; Rachel Sexton; Sahar Bannoura; Yousef Mzannar; Mohammed Najeeb Al-Hallak; Steve Kim; Rafic Beydoun; Yosef Landesman; Hirva Mamdani; Dipesh Uprety; Philip A Philip; Ramzi M Mohammad; Anthony F Shields; Asfar S Azmi Journal: Cancer Res Commun Date: 2022-05-10
Authors: Shaji Kumar; Lawrence Baizer; Natalie S Callander; Sergio A Giralt; Jens Hillengass; Boris Freidlin; Antje Hoering; Paul G Richardson; Elena I Schwartz; Anthony Reiman; Suzanne Lentzsch; Philip L McCarthy; Sundar Jagannath; Andrew J Yee; Richard F Little; Noopur S Raje Journal: Blood Cancer J Date: 2022-06-29 Impact factor: 9.812