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598 Results of the Pivotal STORM Study (Part 2) in Penta-Refractory Multiple Myeloma (MM): Deep and Durable Responses with Oral Selinexor Plus Low Dose Dexamethasone in Patients with Penta Exposed and Triple Class-Refractory MM

Program: Oral and Poster Abstracts
Type: Oral
Session: 653. Myeloma: Therapy, excluding Transplantation: Antibodies and Targeted Therapies
Hematology Disease Topics & Pathways:
Diseases, multiple myeloma, Adult, Therapies, Plasma Cell Disorders, Study Population, Lymphoid Malignancies, Clinically relevant
Monday, December 3, 2018: 7:45 AM
Room 6F (San Diego Convention Center)

Ajai Chari, MD1, Dan T. Vogl, MD2, Meletios A Dimopoulos, MD3, Ajay K Nooka, MD, MPH4,5, Carol Ann Huff, MD6, Philippe Moreau7*, Craig E. Cole, MD8, Joshua Richter9*, David Dingli, MD, PhD10, Ravi Vij11, Sascha A Tuchman, MD12, Marc S Raab, MD, PhD13*, Katja Weisel, MD14*, Michel Delforge, MD PhD15, David Kaminetzky, MD16*, Robert Frank Cornell, MD17, A Keith Stewart18*, James Hoffman19*, Kelly N. Godby, MD20*, Terri L Parker, MD21, Moshe Levy, MD22*, Martin Schreder, MD23*, Nathalie Meuleman, PhD, MD24*, Laurent Frenzel, MD, PhD25*, Mohamad Mohty, MD, PhD26, Choquet Sylvain, MD27*, Andrew J. Yee, MD28*, Maria Gavriatopoulou, MD29*, Luciano J Costa, MD, PhD30, Jatin J. Shah, MD31*, Carla Picklesimer31*, Jean-Richard Saint-Martin31*, Lingling Li31*, Michael G. Kauffman, MD, PhD31, Sharon Shacham, PhD, MBA31*, Paul Richardson32 and Sundar Jagannath33

1Mount Sinai School of Medicine, New York, NY
2Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA
3National and Kapodistrian University of Athens, Athens, Greece
4Winship Cancer Institute / Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA
5Winship Cancer Institute, Department of Hematology and Medical Oncology, Emory University, Atlanta, GA
6Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD
7University Hospital Hôtel-Dieu, Nantes, France
8Division of Hematology/Oncology, University of Michigan, Ann Arbor, MI
9Icahn School of Medicine at Mount Sinai, New York, NY
10Division of Hematology, Mayo Clinic, Rochester, MN
11Siteman Cancer Center, Washington University in St. Louis, St. Louis, MO
12University of North Carolina, Chapel Hill, NC
13Department of Medicine V, University Hospital Heidelberg, Heidelberg, Germany
14Department of Hematology, Oncology and Immunology, University Hospital Tuebingen, Tuebingen, Germany
15Department of Hematology, University Hospitals (UZ) Leuven, Leuven, Belgium
16NYU Langone Health, New York, NY
17Department of Medicine, Division of Hematology & Oncology, Vanderbilt Univ. Medical Center, Nashville, TN
18Mayo Clinic, Scottsdale, AZ
19University of Miami Cancer Center, Miami, FL
20University of Alabama at Birmingham, Birmingham, AL
21Hematology, Yale University School of Medicine, New Haven, CT
22Baylor University, Dallas, TX
23Department of Internal Medicine II, University Hospital Würzburg, Wuerzburg, Germany
24Institut Jules Bordet, Brussels, BEL
25Necker Children's Hospital, Paris, France
26Service d'Hématologie Clinique et de Thérapie Cellulaire, Saint Antoine Hospital, Paris, France
27Département d’Hématologie, Hôpital de la Pitié Salpêtriere, Paris, France
28Massachusetts General Hospital, Boston, MA
29Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
30University of Alabama at Birmingham, Vestavia, AL
31Karyopharm Therapeutics, Newton, MA
32Dept. of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
33Mount Sinai Hospital, New York, NY

Introduction: Selinexor is a novel, oral Selective Inhibitor of Nuclear Export (SINE) compound that blocks exportin 1 (XPO1). Selinexor treatment results in nuclear accumulation and activation of tumor suppressor proteins, inhibition of NF-kB, and translational suppression of several oncoprotein mRNAs (e.g., c-myc, cyclin D).Multiple myeloma (MM) remains incurable, and most patients (pts) eventually progress through standard drug classes of proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), anti-CD38 mAbs and others. The increased use of combinations in MM treatment, (PIs/IMiDs/mAbs), has led to a growing number of pts with penta-refractory MM (pts that have been treated with bortezomib (bort), carfilzomib (carfil), lenalidomide (len), pomalidomide (pom) and daratumumab (dara)). Active novel therapies with different mechanisms of actions are needed to address this unmet medical need. Part 1 of STORM enrolled pts with both quad- (bort, carfil, len, pom, treated MM) or penta-refractory MM and demonstrated an overall response rate (ORR) of 21% (Vogl et al, JCO 2018). Based on these findings, the Pivotal Part 2 of STORM was initiated, enrolling an additional cohort of 122 patients with penta-refractory MM.

Methods: Pts with penta-refractory MM were treated with 80 mg selinexor plus 20 mg dexamethasone (Sd) twice weekly. Pts must have received an alkylator, bort, carfil, len, pom and dara, and had MM refractory to ≥1 PI, ≥1 IMiD, dara, a glucocorticoid, and their last therapy. Pts must have a total ANC ≥1000 mm3,platelets ≥50k/mm3 (or ≥75k if marrow plasma cells <50%), and creatinine clearance ≥20 mL/min. The primary endpoint was ORR. Secondary endpoints: duration of response (DOR), clinical benefit rate (CBR), progression free survival (PFS), and overall survival (OS). Efficacy was assessed by an Independent Review Committee (IRC) based on IMWG criteria. OS was also compared to a cohort of pts with PI, IMiD, dara refractory MM from the Flatiron Health Analytic Database (FHAD), (ref: ASH 2018 abs ID: 116493),who met all the inclusion criteria for STORM.

Results: As of 1-Jun-2018, 122 pts (71 M/ 51 F) were enrolled in 38 sites (US and EU). Pt characteristics were [medians (range)]: age 65 yrs (40–85); 7 (3 – 18) prior treatment regimens, 6.6 yrs (<1 – 23.4) from initial MM diagnosis.65 pts (53%) had high risk cytogenetics, 86 pts (70%) had prior dara in combination, 102 pts (84%) had prior stem cell transplantation, 2 pts had prior CAR-T therapy. All pts enrolled with progressive disease (PD), 72% of pts had increases (3% – 792%) in MM markers from screening to C1D1 (median 11 days). Frequently reported Sd treatment related adverse events (AEs) included (all grades, grades 3/4): thrombocytopenia (67%, 53%), nausea (67%, 10%), fatigue (68%, 21%), anorexia (50%, 2%), anemia (46%, 28%), and weight loss (46%, 0%). Eight pts remain on study and 114 pts discontinued treatment (most commonly for PD). There were 4 deaths on treatment: sepsis, respiratory failure, pulmonary embolism, and an unrelated, unspecified cardiac event. IRC determined ORR (≥PR) was 26.2%, with 6.5% ≥ very good partial response, including 2 stringent complete responses (sCRs; MRD negative at 1:10-6 and at 1:10-4sensitivity). Both pts who relapsed after CAR-T achieved PRs. The CBR (≥minimal response, [MR]) was 39.3%, and 79% of pts achieved ≥stable disease (SD). Responses typically occurred within the first month. Medians: DOR 4.4 months (mo) (range <1 – 10 mo), PFS 3.7 mo, and OS 8.0 mo. Pts with ≥MR had significantly longer OS than pts with PD/NE (median not reached vs 1.9 mo, p=<0.0001). Compared to the FHAD cohort, STORM cohort had longer OS (Figure 1, HR 0.41, p=0.0001).

Conclusions: Results of the pivotal STORM Part 2 in penta (PI, IMiD, dara)-refractory MM demonstrated that oral selinexor plus low-dose dexamethasone (Sd) was highly active with an ORR of 26.2%. Importantly, responses were rapid and deep with 2 patients achieving sCRs (both MRD negative) in these heavily pre-treated penta-refractory MM pts (median 7 prior regimens, 53% high risk). AEs are a function of dose/schedule/disease severity and can be managed with dose modifications and supportive care. No major organ toxicity was observed and AEs were typically transient and reversible. Sd is an all-oral, first in class mechanism with novel MOA and represents a potential therapeutic option to the growing number of pts with penta-refractory MM who have exhausted approved therapies.

Disclosures: Chari: Bristol Myers Squibb: Consultancy; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Vogl: Karyopharm Therapeutics: Consultancy. Dimopoulos: Takeda: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Nooka: GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive technologies: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Spectrum Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Moreau: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Cole: University of Michigan: Employment; Cancer Support Community myeloma advisory board: Membership on an entity's Board of Directors or advisory committees. Dingli: Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding. Vij: Jazz Pharmaceuticals: Honoraria; Karyopharm: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Takeda: Honoraria, Research Funding; Bristol Myer Squibb: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Raab: BMS: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Weisel: Celgene: Consultancy; Angeb: Consultancy, Honoraria, Research Funding; Juno: Consultancy; Bristol Myers SquibbMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Research Funding; Takeda: Consultancy, Honoraria. Delforge: Celgene and Janssen: Research Funding; Amgen, Celgene, Janssen and Takeda: Consultancy. Stewart: Amgen Inc., BMS, Celgene, Takeda, Roche, Seattle Genetics, Janssen, Ono: Consultancy; Amgen Inc., Celgene, Roche, Seattle Genetics: Research Funding. Mohty: Amgen: Consultancy, Honoraria; Molmed: Consultancy; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Servier: Consultancy; Jazz Pharmaceuticals: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Research Funding, Speakers Bureau; MaaT Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria; Takeda: Honoraria, Speakers Bureau; Bristol Myers: Consultancy, Research Funding. Sylvain: Gilead: Other: scientific advisor board. Costa: Celgene: Honoraria, Research Funding; Abbvie: Research Funding; Karyopharm: Research Funding; Janssen: Research Funding; Amgen: Honoraria, Research Funding; Sanofi: Honoraria; BMS: Research Funding. Shah: Karyopharm Therapeutics: Employment. Picklesimer: Karyopharm Therapeutics: Employment. Saint-Martin: Karyopharm Therapeutics: Employment. Li: Karyopharm Therapeutics: Employment. Kauffman: Karyopharm Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Shacham: Karyopharm Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Richardson: Amgen: Other: Advisory Committee Member; Janssen: Other: Advisory Committee Member; Karyopharm: Other: Advisory Committee Member; BMS: Other: Advisory Committee Member, Research Funding; Oncopeptides: Other: Advisory Committee Member; Jazz Pharmaceuticals: Other: Advisory Committee Member, Research Funding; Takeda: Other: Advisory Committee Member, Research Funding; Celgene: Other: Advisory Committee Member, Research Funding. Jagannath: Novartis: Consultancy; Medicom: Speakers Bureau; Multiple Myeloma Research Foundation: Speakers Bureau; Bristol-Myers Squibb: Consultancy; Merck: Consultancy; Celgene: Consultancy.

*signifies non-member of ASH