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3793 Clinical Outcomes in Patients (Pts) with Dose Reduction of Selinexor in Combination with Bortezomib, and Dexamethasone (XVd) in Previously Treated Multiple Myeloma from the Boston Study

Program: Oral and Poster Abstracts
Session: 652. Multiple Myeloma and Plasma cell Dyscrasias: Clinical and Epidemiological: Poster III
Hematology Disease Topics & Pathways:
Clinical Research, Clinically Relevant, Diseases, Therapies, Adverse Events, Myeloid Malignancies
Monday, December 13, 2021, 6:00 PM-8:00 PM

Sundar Jagannath, MD1*, Thierry Facon, MD2*, Ashraf Z. Badros, MD3, Moshe Levy, MD4*, Philippe Moreau, MD, PhD5*, Sosana Delimpasi, MD6*, Maryana Simonova, MD7*, Ivan Spicka, MD, Prof, PhD8*, Iryna Kriachok9*, Maria Gavriatopoulou, MD10*, Halyna Pylypenko, MD11*, Holger W Auner, MD, PhD12, Xavier Leleu, MD13, Vadim Doronin, MD, PhD14*, Ganna Usenko, MD15*, Roman Hajek, MD, PhD16, Reuben Benjamin, MD17, Tuphan Kanti Dolai, MBBS, MD, DNB, DM18*, Dinesh Kumar Sinha, MD19*, Chris P. Venner20, Mamta Garg, MD, FRCP, FRCPath21*, Mercedes Gironella Mesa, MD22*, Artur Jurczyszyn, MD23*, Tadeusz Robak, MD, PhD24, Monica Galli, MD25*, Craig Thomas Wallington-Beddoe, BSc, MBBS, MBiostat, PhD, FRACP, FRCPA26*, Atanas Radinoff, MD27*, Galina Salogub, MD, PhD28*, Don Stevens, MD29, Supratik Basu30*, Anna Marina Liberati, MD31, Hang Quach, FRACP, FRCPA32, Veselina S Goranova Marinova, MD, PhD33, Jelena Sreten Bila, MD, PhD34*, Eirini Katodritou, MD35*, Andrew DeCastro, PhD36*, Yi Chai, PhD37*, Dane R. Van Domelen, PhD36*, Moran Mishal, MD37*, Ohad S. Bentur, MD MHA36*, Jatin Shah, MD37, Sharon Shacham, PhD, MBA36*, Michael G. Kauffman, MD, PhD36, Sebastian Grosicki, MD, PhD38 and Paul G. Richardson, MD39

1Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY
2University Hospital, Lille, France
3University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, MD
4Baylor University Medical Center, Dallas, TX
5University of Nantes, Nantes, France
6General Hospital Evangelismos, Athens, Greece
7Institute of Blood Pathology & Transfusion Medicine, National Academy of Medical Sciences of Ukraine, Lviv, MA, Ukraine
8Vseobecna Fakultni Nemocnice V Praze, I. Interni Klinika, Klinika Hematologie, Praha 2, Prague, Czech Republic
9National Cancer Institute, Kiev, Ukraine
10Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens,, Athens, Greece
11Department of Hematology, Cherkassy Regional Oncology Center, Cherkassy, Ukraine
12Imperial College Healthcare NHS Trust, London, United Kingdom
13Department of Oncology-Haematology and Cell Therapy, CHU Poitiers, INSERM, Inserm CIC 1402, Poitiers, France
14City Clinical Hospital #40, St. Petersburg, Russian Federation
15City Hematology Center, City Clinical Hospital No. 4 of Dnipro City Council, Dnipro, Ukraine
16Department of Hematooncology, University Hospital Ostrava and Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic
17Department of Haematology, Kings College Hospital NHS Foundation Trust, London, CA, United Kingdom
18Haematology, Nil Ratan Sircar Medical College and Hospital, Kolkata, India
19State Cancer Institute, Indira Gandhi Institute of Medical Sciences, Patna, India
20University of Alberta, Edmonton, Canada
21Leicester Royal Infirmary, Leicester, United Kingdom
22Haematology Department, Hospital Universitario Vall d'Hebron, Barcelona, Spain
23Plasma Cell Dyscrasia Center, Jagiellonian University Department of Hematology, Faculty of Medicine,, Kraków, Poland
24Medical University of Lodz, Lodz, Poland
25Hematology, Papa Giovanni XXIII Hospital, Bergamo, Italy
26Flinders Medical Centre Flinders University, Adelaide, Australia
27University Multiprofile Hospital for Active Treatment, Sofia, Bulgaria
28Almazov National Medical Research Centre, St. Petersburg, Russian Federation
29Norton Healthcare, Norton Cancer Institute, Louisville, KY
30The Royal Wolverhampton NHS Trust, Wolverhampton, United Kingdom
31Department of Onco-Hematology, University of Perugia, Santa Maria Hospital, Terni, Italy
32University of Melbourne, St. Vincent’s Hospital, Melbourne, VIC, Australia
33Clinic of Hematology, University Multiprofile Hospital for Active Treatment "Sv. Georgi", EAD, Plovdiv, Medical University of Plovdiv, Plovdiv, Bulgaria
34Clinic for Hematology, Clinical Center of Serbia, University of Belgrade, Belgrade, SRB
35Department of Hematology, Theagenio Cancer Hospital, Thessaloniki, Greece
36Karyopharm Therapeutics Inc., Newton, MA
37Karyopharm Therapeutics, Newton, MA
38Medical University of Silesia, Katowice, Poland
39Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA

Introduction:

Treatment of multiple myeloma (MM) has greatly improved over the last two decades. However, most pts will relapse and develop refractory disease. Most anti-cancer regimens require dose modifications (interruption, reduction, or discontinuation) during the treatment course in order to optimize the therapeutic window; appropriate modifications improve tolerability while maintaining anti-cancer activity.

Selinexor, an oral selective inhibitor of XPO1-mediated nuclear export (SINE) compound, enforces the nuclear retention and functional activation of tumor suppressor proteins within the nucleus and prevents the translation of oncoproteins. The combination of once weekly (QW) selinexor, QW bortezomib, and dexamethasone (XVd) is FDA approved for previously treated MM. Compared to standard twice weekly (BIW) bortezomib plus dexamethasone (Vd) and using 40% less bortezomib and 25% less dexamethasone, XVd demonstrated significantly prolonged median progression-free survival (PFS) and time-to-next-treatment (TTNT), increased the overall response rate (ORR), reduced rates of peripheral neuropathy, and showed a trend towards improved overall survival (OS) in the Phase 3 randomized BOSTON study (NCT03110562). The recommended starting dose of selinexor in XVd is 100mg QW, but the median dose administered in BOSTON was 80 mg QW. Here, we analyzed the efficacy outcomes and adverse events (AEs) in pts whose dose was reduced compared to those where it was not.

Methods:

The BOSTON study consisted of two arms: pts treated with selinexor QW (100mg), bortezomib QW (1.3mg/m2) and dexamethasone BIW (20 mg) (XVd; n=195 in the intention-to-treat [ITT] population) compared to standard BIW Vd.

Results:

Of the XVd pts in the BOSTON study, 126 had a dose reduction of selinexor and 69 did not. The median age was 66.0 in both groups (range: with reduction, 47-87; without, 40-84) and the median number of prior therapies was 1.0 (range, 1-3) for both groups (Table 1). The median time to dose reduction in these pts was 68 days (range, 8-561 days). The median duration of study treatment for these pts was 34.5 weeks (range, 3-120 weeks) compared to 20.0 weeks (range, 1-118) in pts with no dose reduction. In the group with dose reduction, the median dose of selinexor received per week was 71.3 mg (range, 29.7, 101.4) compared to 100 mg (range, 33.3, 136.7) in pts with no reduction.

Pts who dose reduced had a median PFS of 16.6 months compared to 9.2 months in pts who did not (one-sided p value, <0.01), with a median follow up of 14.1 months with reduction and 10.6 months without. The ORR in the dose reduced group compared to pts who did not dose reduce was 81.7% vs 66.7% (one-sided p value, <0.01), and the rate of VGPR or better was 51.6% vs 31.8% (Table 2). Duration of response (DOR) was NR in the dose reduced group and was 12.0 months in the group without reduction. TTNT was 22.6 months in the dose reduced group and 10.5 months in pts with no dose reductions (one-sided p value, <0.001).

The most common adverse events (AEs; dose reduction and without dose reduction) of any grade were thrombocytopenia (69.8% and 42.0%), nausea (55.6% and 40.6%), and fatigue (49.2% and 29.0%). The rate of treatment discontinuation in the dose reduced group was 24.6% and 14.5% without dose reductions. In the dose reduced group, there were 6 (4.8%) deaths and 6 (8.7%) in the group with no dose reduction.

As pts with a dose reduction stayed on therapy for a prolonged period of time, to best understand the impact of dose reduction on the AE, we present the duration-adjusted incidence rates of AEs of clinical interest. The duration-adjusted incidence rates of AE were considerably lower after dose reduction of selinexor compared to the rates on or before dose reduction: thrombocytopenia (62.5% vs 47.6%), nausea (31.6% vs 7.3%), fatigue (28.1% vs 9.9%), decreased appetite (21.5% vs 6.4%), anemia (17.9% vs 10.3%), and diarrhea (12.9% vs 5.2) (Table 3).

Conclusions:

While all pts on XVd initiated therapy at 100mg selinexor QW, and it was associated with very low rates of progressive disease (1 in 195 pts), appropriate dose reductions of selinexor were associated with a longer PFS, DOR, and TTNT, and significantly reduced AE with improved tolerability, highlighting dose reductions as an important tool to personalize and optimize the therapeutic window for pts with RRMM.

Disclosures: Jagannath: Bristol Myers Squibb: Consultancy; Janssen Pharmaceuticals: Consultancy; Karyopharm Therapeutics: Consultancy; Legend Biotech: Consultancy; Sanofi: Consultancy; Takeda: Consultancy. Badros: Janssen: Research Funding; GlaxoSmithKline: Research Funding; J&J: Research Funding; BMS: Research Funding. Levy: Takeda, Celgene, Seattle Genetics, AbbVie, Jazz Pharmaceuticals, Gilead Sciences, Bristol-Myers Squibb, Amgen, Spectrum Pharmaceuticals,Janssen.: Consultancy. Moreau: Celgene BMS: Honoraria; Oncopeptides: Honoraria; Amgen: Honoraria; Sanofi: Honoraria; Abbvie: Honoraria; Janssen: Honoraria. Delimpasi: Takeda: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Kriachok: Takeda, Roche, Abbivie, Janssen, MSD: Consultancy; Takeda, Roche, Abbvie, Janssen, MSD, Pfizer: Honoraria, Speakers Bureau. Gavriatopoulou: Takeda: Honoraria; Sanofi: Honoraria; GSK: Honoraria; Janssen: Honoraria; Karyopharm: Honoraria; Genesis: Honoraria; Amgen: Honoraria. Auner: Janssen: Speakers Bureau; Amgen: Research Funding; Takeda, Karyopharm: Other: Advisory role. Leleu: Bristol-Myers Squibb: Honoraria; Carsgen Therapeutics Ltd: Honoraria; Celgene: Honoraria; Gilead Sciences: Honoraria; Janssen-Cilag: Honoraria; Karyopharm Therapeutics: Honoraria; Merck: Honoraria; Mundipharma: Honoraria; Novartis: Honoraria; Oncopeptides: Honoraria; Pierre Fabre: Honoraria; Roche: Honoraria; Sanofi: Honoraria; Amgen: Honoraria; AbbVie: Honoraria; Takeda: Honoraria, Other: Non-financial support. Usenko: Janssen: Consultancy, Honoraria, Other: Clinical Trials Investigator; AbbVie: Consultancy, Honoraria, Other: Clinical Trials Investigator; Pfizer: Consultancy, Honoraria; Acerta: Other: Clinical Trials Investigator; Ascentage: Other: Clinical Trials Investigator; Celgene: Other: Clinical Trials Investigator; Il-Yang: Other: Clinical Trials Investigator; Karyopharm: Other: Clinical Trials Investigator; Oncopeptides: Other: Clinical Trials Investigator; Rigel: Other: Clinical Trials Investigator; Takeda: Other: Clinical Trials Investigator; UCB: Other: Clinical Trials Investigator. Hajek: Janssen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria; Pharma MAR: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Venner: BMS: Honoraria; Amgen: Research Funding; Celgene: Research Funding; Amgen: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; Pfizer: Honoraria. Garg: University Hospital Leicester: Current Employment; Amgen Janssen Novartis Sanofi Takeda: Honoraria; Takeda Janssen Novartis Sanofi: Other: Travel Accommodations, Expenses. Gironella Mesa: BMS, Janssen: Honoraria. Jurczyszyn: Janssen-Cilag, Amgen: Honoraria, Speakers Bureau. Robak: Biogen, Abbvie, Octapharma, Janssen: Honoraria, Other: Advisory board; AstraZeneca, Abbvie, Janssen, Octapharma, Gilead,Oncopeptides AB, Pharmacyclics, Pfizer, GlaxoSmithKline, Biogen: Research Funding; Medical University of Lodz: Current Employment. Galli: BMS, Celgene, Janssen, Sanofi, Takeda: Honoraria. Radinoff: Janssen, Pfizer, Novartis, Servier etc.: Consultancy, Honoraria; Amgen, Bayer, Takeda, etc.: Research Funding; the Bulgarian Minister of Health: Membership on an entity's Board of Directors or advisory committees. Liberati: abbvie, amgen, archigen, beigene, BMS, celgene, DR REDDY’S LABORATORIES SPA, fibrogen, glaxo, Janssen, Karyopharm, Morphosys, Novartis, Onconova, Oncopeptides ab, Roche, Sanophi, Secura Bio, Takeda, Verastem,: Research Funding. Quach: Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Antengene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen/Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL: Consultancy, Membership on an entity's Board of Directors or advisory committees. Bila: Takeda, AMGEN, Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Katodritou: GSK, Amgen, Karyopharm, Abbvie, Janssen-Cilag, Genesis Pharma, Sanofi: Honoraria, Research Funding. DeCastro: Karyopharm: Current Employment, Current equity holder in publicly-traded company. Chai: Karyopharm: Current Employment. Van Domelen: Karyopharm: Current Employment, Current equity holder in publicly-traded company. Mishal: Karyopharm: Current Employment. Bentur: Karyopharm Therapeutics: Current Employment, Current equity holder in publicly-traded company. Shah: Karyopharm: Current Employment. Shacham: Karyopharm: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: (8999996, 9079865, 9714226, PCT/US12/048319, and I574957) on hydrazide containing nuclear transport modulators and uses, and pending patents PCT/US12/048319, 499/2012, PI20102724, and 2012000928) . Kauffman: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Richardson: GlaxoSmithKline: Consultancy; Sanofi: Consultancy; AstraZeneca: Consultancy; Regeneron: Consultancy; Karyopharm: Consultancy, Research Funding; Janssen: Consultancy; AbbVie: Consultancy; Protocol Intelligence: Consultancy; Secura Bio: Consultancy; Takeda: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; Oncopeptides: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding.

*signifies non-member of ASH