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1993 Selinexor Plus Pomalidomide and Low Dose Dexamethasone (SPd) in Patients with Relapsed or Refractory Multiple Myeloma

Program: Oral and Poster Abstracts
Session: 653. Myeloma: Therapy, excluding Transplantation: Poster I
Hematology Disease Topics & Pathways:
Adult, multiple myeloma, Diseases, Therapies, Study Population, Plasma Cell Disorders, Clinically relevant, Lymphoid Malignancies
Saturday, December 1, 2018, 6:15 PM-8:15 PM
Hall GH (San Diego Convention Center)

Christine I Chen, MD1, Heather J. Sutherland, MD, PhD2, Rami Kotb, MD3*, Michael Sebag, MD, PhD4, Darrell J. White, MD5, William Bensinger, MD6*, Cristina J Gasparetto, MD7, Richard Leblanc, MD, FRCPC8, Christopher P. Venner, MD, FRCPC9, Suzanne Lentzsch, MD10*, Gary J. Schiller, MD11, Brea Lipe, MD12, Aldo Del Col13*, Jatin J. Shah, MD14*, Jacqueline Jeha14*, Jean-Richard Saint-Martin14*, Michael G. Kauffman, MD, PhD14, Sharon Shacham, PhD, MBA14* and Nizar Bahlis, MD15

1Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, ON, Canada
2Vancouver General Hospital, Vancouver, BC, Canada
3Cancer Care Manitoba, Winnipeg, MB, Canada
4Royal Victoria Hospital, Montreal, QC, Canada
5Queen Elizabeth II Health Sciences Ctr. Dalhousie University, Halifax, NS, Canada
6Center for Blood Disorders and Stem Cell Transplantation, Swedish Cancer Institute, Seattle, WA
7Duke University Medical Center, Durham, NC
8Hopital Maisonneuve-Rosemont, Montreal, QC, Canada
9Cross Cancer Institute, Edmonton, AB, Canada
10Columbia University, New York, NY
11Ronald Regan University of California Los Angeles Medical Center, Santa Monica, CA
12University of Rochester Medical College, Rochester, NY
13Myeloma Canada, Montreal, QC, Canada
14Karyopharm Therapeutics, Newton, MA
15Tom Baker Cancer Center, Department of Hematology, University of Calgary, Calgary, AB, Canada

Introduction­ – The nuclear export protein exportin 1 (XPO1) is overexpressed in a wide variety of cancers including multiple myeloma (MM). Selinexor is a first-in-class Selective Inhibitor of Nuclear Export (SINE) compound that binds and inactivates XPO1. Selinexor forces nuclear retention and reactivation of cell cycle regulators such as p53, IkB, and Rb. Pomalidomide/dexamethasone (Pd) is approved in relapsed/refractory MM (RRMM)with an overall response rate (ORR) of 30% and progression-free survival (PFS) rate of <4 months in patients (pts) having received a prior proteasome inhibitor (PI) and IMiD. Strategies to improve the ORR and PFS are needed. In murine MM models, the combination of selinexor with IMiDs shows synergistic anti-MM activity and good tolerability.

Methods– Pts with RRMM who received ≥ 2 prior therapies including lenalidomide (len) and a PI were enrolled. Selinexor was evaluated in 2 different dosing schedules of once-weekly (QW, 60 or 80 mg) or twice-weekly (BIW, 60 or 80 mg), with pomalidomide (pom)3 or 4 mg PO daily, and dexamethasone (dex) 20 mg BIW or 40 mg QW. The primary objectives were to determine the maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), safety, and preliminary efficacy of the combination of selinexor, pomalidomide, and low dose dex (SPd) in pts with RRMM.

Results– As of July 20th2018, 34 pts (16 male / 18 female) have been enrolled. The median age is 61 years and patients received a median of 4 (range, 2 – 9) prior treatment regimens. Thirty-two patients were IMiD refractory (21 len, 11 pom/len). Six dose limiting toxicities (DLTs) were observed: G3 fatigue (60 mg BIW, pom 4 mg), G3 febrile neutropenia (FN) (60 mg BIW, pom 3 mg), G3 FN and G4 neutropenia (80 mg QW, pom 4), G3 thrombocytopenia (80 mg QW, pom 3 mg) and 4 missed doses in Cycle 1 due to symptomatic hyponatremia (80 mg BIW, pom 4 mg). Enrollment on selinexor 80 mg QW, pom 3 mg is ongoing. Common SPd treatment related adverse events included (all grades, grades 3/4): neutropenia (62%, 56%), thrombocytopenia (59%, 32%), anemia (53%, 29%), anorexia (56%, 0%), fatigue (50%, 9%), nausea (47%, 0% ). Thirty pts were evaluable for response, which is outlined in Table 1. Median PFS is 10.3 months with a median follow up of 9.4 months.

Conclusions– Enrollment is ongoing to evaluate once weekly selinexor in combination with Pd , (SPd). This all-oral SPd combination has clinical activity with an ORR 55% in pom-naive pts with heavily pretreated MM compared to previously published data of 30% ORR for Pd alone. Similarly, the PFS on SPd is 10.3 months vs. <4 months for Pd alone. No unexpected adverse events were noted. Phase 1 dose escalation of the combination of SPd is ongoing to define the optimal RP2D.

Disclosures: Chen: Amgen: Honoraria. Sebag: Janssen Inc.: Membership on an entity's Board of Directors or advisory committees; Amgen Canada: Membership on an entity's Board of Directors or advisory committees; Takeda Canada: Membership on an entity's Board of Directors or advisory committees; Celgene Canada: Membership on an entity's Board of Directors or advisory committees. White: Amgen, Celgene, Janssen, Takeda: Honoraria. Bensinger: Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Speakers Bureau; celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; amgen: Speakers Bureau. Gasparetto: Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel; Janssen: Consultancy, Honoraria, Other: Travel; Takeda: Honoraria; Celgene: Consultancy, Honoraria, Other: Travel, Research Funding. Leblanc: Amgen Canada: Membership on an entity's Board of Directors or advisory committees; Janssen Inc.: Membership on an entity's Board of Directors or advisory committees; Celgene Canada: Membership on an entity's Board of Directors or advisory committees; Takeda Canada: Membership on an entity's Board of Directors or advisory committees. Venner: Takeda: Honoraria; Amgen: Honoraria; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Schiller: Pharmacyclics: Research Funding; Celator/Jazz Pharmaceuticals: Research Funding. Lipe: Celgene: Consultancy. Shah: Karyopharm Therapeutics: Employment. Jeha: Karyopharm Therapeutics: Employment. Saint-Martin: 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. Bahlis: Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding.

*signifies non-member of ASH