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599 Deep and Durable Responses with Selinexor, Daratumumab, and Dexamethasome (SDd) in Patients with Multiple Myeloma (MM) Previously Exposed to Proteasome Inhibitors and Immunomodulatory Drugs: Results of Phase 1b Study of Sdd

Program: Oral and Poster Abstracts
Type: Oral
Session: 653. Myeloma: Therapy, excluding Transplantation: Antibodies and Targeted Therapies
Hematology Disease Topics & Pathways:
Adult, Diseases, multiple myeloma, Therapies, Study Population, Plasma Cell Disorders, Lymphoid Malignancies, Clinically relevant
Monday, December 3, 2018: 8:00 AM
Room 6F (San Diego Convention Center)

Cristina J Gasparetto, MD1, Suzanne Lentzsch, MD2*, Gary J. Schiller, MD3, William Bensinger, MD4*, Nizar Bahlis, MD5, Heather J. Sutherland, MD, PhD6, Darrell J. White, MD7, Michael Sebag, MD, PhD8, Rami Kotb, MD9*, Christopher P. Venner, MD, FRCPC10, Richard Leblanc, MD, FRCPC11, Christine I Chen, MD12, Aldo Del Col13*, Jatin J. Shah, MD14*, Jacqueline Jeha14*, Jean-Richard Saint-Martin14*, Michael G. Kauffman, MD, PhD14, Sharon Shacham, PhD, MBA14*, Joel G. Turner, PhD15, Daniel M Sullivan, MD15 and Brea Lipe, MD16

1Duke University Medical Center, Durham, NC
2Columbia University, New York, NY
3Ronald Regan University of California Los Angeles Medical Center, Santa Monica, CA
4Center for Blood Disorders and Stem Cell Transplantation, Swedish Cancer Institute, Seattle, WA
5Tom Baker Cancer Center, Department of Hematology, University of Calgary, Calgary, AB, Canada
6Vancouver General Hospital, Vancouver, BC, Canada
7Queen Elizabeth II Health Sciences Ctr. Dalhousie University, Halifax, NS, Canada
8Royal Victoria Hospital, Montreal, QC, Canada
9Cancer Care Manitoba, Winnipeg, MB, Canada
10Cross Cancer Institute, Edmonton, AB, Canada
11Hopital Maisonneuve-Rosemont, Montreal, QC, Canada
12Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, ON, Canada
13Myeloma Canada, Montreal, QC, Canada
14Karyopharm Therapeutics, Newton, MA
15Department of Blood and Marrow Transplantation and Cellular Immunotherapy, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
16University of Rochester Medical College, Rochester, NY

Introduction – Selinexor is a first-in-class Selective Inhibitor of Nuclear Export (SINE) compound that binds and inactivates Exportin 1 (XPO1). Selinexor with low dose dexamethasone (Sd) or in with protesome inhibitors (PIs) or immunomodulatory drugs (IMiDs), has shown anti-MM activity in patients (pts) with relapsed or refractory MM. Daratumumab (Dara), an anti-CD38 mAb, is approved for the treatment of heavily pretreated MM is limited by short PFS and an ORR of ~21% in quad-refractory MM. Selinexor in combiniation with dara have shown preclinical synergistic killing of MM cells.

Methods – Pts were eligible if they had received ≥ 3 prior lines of anti-myeloma therapy, including a PI and an IMiD. Selinexor was dose-escalated in 2 concurrent cohorts: once-weekly (QW, at 100 mg) or twice-weekly (BIW, at 60 mg). Dara was 16 mg/kg IV (recommended schedule) and dexamethasone (dex) was 40 mg QW or 20 mg BIW. The objectives were to determine the maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), safety, tolerability and preliminary efficacy of the combination of this SDd combination in pts with PI/IMiD refractory MM

Results – As of Jul 20th2018, 25 pts (11 males / 14 females) have been enrolled. Three pts have been enrolled into the 60 mg BIW and 22 pts in the 100 mg QW cohorts. Pts have a median age of 68 years and a median of 3 (range, 2 – 10) prior treatment regimens. Common SDd treatment related adverse events included (all grades, grades 3/4): thrombocytopenia (58%, 42%), leukopenia (54%, 38%), anemia (46%, 29%), nausea (50%, 0%) and fatigue (46%, 8%). Two dose limiting toxicities (DLTs) were reported in the 60 mg BIW cohort: G3 thrombocytopenia and G2 fatigue requiring dose reduction in selinexor to 100 mg QW. In the 100 mg QW escalation cohort, 6 pts enrolled, 5 evaluable, with no DLTs. This cohort was expanded and enrollment is ongoing. A total of 21 pts were evaluable for response. In 19 dara-naïve pts, the ORR was 74% (5 VGPR, 9 PR, 2 MR, 2 SD, 1 PD), including 3 unconfirmed PRs, 1 unconfirmed MR. In the 2 pts with dara refractory MM, there was one PD and one SD. The longest duration of therapy is 13 months. Based on tolerability and efficacy, the RP2D of SDd is selinexor 100 mg, daratumumab 16 mg/kg and dex 40 mg, administered QW.

Conclusions – Selinexor 100 mg QW can be combined safely with dara (per approved dosing) and dex. The preliminary ORR of 74% with SDd in patients with PI/IMiD refractory MM who are dara naïve is promising and compares favorably to 21% ORR of Dara and Sd in quad refractory myeloma. This once weekly regimen is well tolerated with no major organ toxicities to date. Data from the full phase 1 dose expansion will be presented.

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

*signifies non-member of ASH