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491 Selinexor and Low Dose Dexamethasone (Sd) in Patients with Lenalidomide, Pomalidomide, Bortezomib, Carfilzomib and Anti-CD38 Ab Refractory Multiple Myeloma (MM): STORM Study

Myeloma: Therapy, excluding Transplantation
Program: Oral and Poster Abstracts
Type: Oral
Session: 653. Myeloma: Therapy, excluding Transplantation: New Agents for Multiple Myeloma
Sunday, December 4, 2016: 5:30 PM
Hall AB (San Diego Convention Center)

Dan T. Vogl, MD1, David Dingli, MD, PhD, FRCP2, R. Frank Cornell, MD, MS3, Carol Ann Huff, M.D.4, Sundar Jagannath, MD5, Divaya Bhutani6, Rachid Baz, MD7, Ajay K Nooka, MD, MPH8, Joshua Richter, MD9, Craig E. Cole, MD10, Ravi Vij11, Andrzej Jakubowiak, MD12*, Rafat Abonour, MD13, Gary J. Schiller, MD14, Terri L. Parker, MD15*, Luciano J. Costa, MD, PhD16, David Kaminetzky, MD17, James Hoffman, MD18*, Andrew J. Yee, MD19, Ajai Chari, MD5, David S. Siegel, MD, PhD9, Rafael Fonseca, MD20, Scott VanWier21*, Gregory Ahmann21, Ilsel Lopez21*, Michael Kauffman, MD, PhD22, Sharon Shacham, PhD, MBA22*, Jean-Richard Saint-Martin22*, Carla Picklesimer22*, Sharon Friedlander, PhD22*, Cassandra Choe-Juliak, MD22* and A. Keith Stewart, MBChB20

1Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA
2Division of Hematology, Mayo Clinic, Rochester, MN
3Department of Medicine, Division of Hematology-Oncology, Vanderbilt-Ingram Cancer Center, Nashville, TN
4Johns Hopkins University, Baltimore, MD
5Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY
6Division of Oncology, Karmanos Cancer Institute/Wayne State University School of Medicine, Detroit, MI
7Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
8Winship Cancer Institute, Emory University, Atlanta, GA
9John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, NJ
10Division of Hematology/Oncology, University of Michigan School of Medicine, Ann Arbor, MI
11Washington University School of Medicine, St. Louis, MO
12University of Chicago, Chicago, IL
13Indiana University Simon Cancer Center, Indianapolis, IN
14University of California Los Angeles, Los Angeles, CA
15Yale University, New Haven, CT
16Division of Hematology/Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL
17NYU Perlmutter Cancer Center, NYU School of Medicine, New York, NY
18Division of Hematology-Oncology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL
19Massachusetts General Hospital Cancer Center, Boston, MA
20Mayo Clinic Cancer Center, Phoenix, AZ
21Mayo Clinic, Scottsdale, AZ
22Karyopharm Therapeutics Inc, Newton, MA

Introduction­ - With over 12,000 deaths from MM anticipated in 2016, nearly all patients (pts) with multiple myeloma (MM) will become “quad refractory” to IMIDs (lenalidomide and pomalidomide) and proteasome inhibitors (bortezomib and carfilzomib), and eventually “penta refractory” to anti-CD38 Abs (daratumumab and isatuximab), defining high unmet need populations. Selinexor, an oral selective XPO1 inhibitor, induces nuclear accumulation and activation of tumor suppressor proteins, inhibition of NF-kB, and inhibition of translation of several oncoprotein mRNAs such as c-myc and cyclin D. Selinexor showed potent induction of apoptosis of MM cells independent of p53 signaling. In phase 1 clinical studies, selinexor with low dose dexamethasone (Sd) demonstrated potent anti MM activity in pts with MM.

Methods – This phase II clinical trial evaluated Sd in pts with MM refractory to bortezomib, carfilzomib, lenalidomide, and pomalidomide (“quad”), with a subset also refractory to an anti-CD38 Ab (“penta”). Inclusion required CrCL≥20 mL/min, ANC≥1000/µL, platelets ≥50K/µL (≥30K if plasma cells were ≥50% of marrow cellularity). Pts were treated twice weekly (BIW) with oral selinexor 80 mg for 6 or 8 doses per 28 day cycle and dexamethasone (dex) 20 mg BIW. All pts received 5-HT3 antagonists. The primary objective was to determine the overall response rate (ORR) per IMWG criteria and duration of response (DOR), both adjudicated by an independent review committee (IRC). Secondary endpoints include progression free survival (PFS) and overall survival (OS). FISH analyses and gene expression profiling were performed on bone marrow aspirates.

Results – 79 pts were enrolled: 48 quad (24 M/24 F, median age 62 yrs) and 31 penta (13 M / 18 F, median age 68 yrs). Both groups had a median of 7 prior treatment regimens including multiple dex-containing regimens. Baseline laboratory abnormalities included grade (Gr)≥3 anemia in 13% and Gr≥3 thrombocytopenia in 8%. Most penta pts received 8 doses / cycle (65%); most quad pts received 6 doses / cycle (83%). Common treatment-related adverse events (TRAEs) hematological: thrombocytopenia (72%, Gr 3/4 58%), anemia (48%, Gr 3 25%) and neutropenia (29%, Gr≥3 21%). TRAEs non-hematological: nausea (72%, Gr 3 6%), fatigue (62%, Gr 3 14%) anorexia (49%, Gr 3 3%), vomiting (43%, Gr3 4%), asymptomatic hyponatremia (42%. Gr 3 20%), diarrhea (42%, Gr 3 5%) and weight loss (33%, Gr 3 1%). There was one case of febrile neutropenia (1%) and one case of clinically significant bleeding related to thrombocytopenia (1%). Seventy pts have discontinued therapy: PD (73%), AEs (17%), physician/pt preference (1%) and 6 deaths (one case related to selinexor, intracranial bleed in pt with Gr4 thrombocytopenia). Nine pts remain on study. Efficacy was evaluated in 78 pts (1 pt did not have measurable disease). The IRC-determined ORR (≥PR) for all pts was 21%, including 5% VGPR. ORR was 21% for quad pts and 20% for penta pts. Clinical benefit rates (≥MR) were 32% (all), 29% (quad), and 37% (penta). Median OS was 9.3 months (mo) for all pts, >11 mo (median not reached) for responders (≥PR), and 5.7 mo for non-responders. Median DOR in responding pts was 5 mo, and median PFS in all pts was 2.1 mo. Baseline cytogenetics were assessed in 41 pts. The ORR in 18 pts with high-risk FISH abnormalities was 33% (Table 1). Notably, 3 of the 13 pts with a 17p abnormality responded (ORR 23%). Transcriptomic profiling revealed differentially expressed genes (DEGs) between responders and non-responders in both whole blood RNA and CD138+ bone marrow cells. Pathways enriched in responders included IL-6, IL-8 and IGF-1 pathways.

Conclusions – Oral Sd is active in heavily pretreated pts with refractory MM, including those with MM refractory to anti-CD38 Ab and those with high-risk cytogenetic abnormalities. Response was associated with longer survival. The main toxicities of Sd are thrombocytopenia, nausea, anorexia, and fatigue. AEs were manageable with supportive care and dose interruptions/reductions. To our knowledge, this is the first report of anti-tumor activity in the penta-refractory MM population. This population of MM pts has exhausted all currently available treatment options and has an extremely poor prognosis and therefore requires new therapies. Expansion of this trial in this high unmet medical need, penta refractory population is planned.

Table 1: Activity of Sd in Patients with High Risk MM Cytogenetics

Disclosures: Vogl: Celgene: Consultancy; Millennium/Takeda: Consultancy, Research Funding. Jagannath: Bristol-Myers Squibb: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Merck: Consultancy; Celgene: Consultancy. Baz: Bristol-Myers Squibb: Research Funding; Takeda/Millennium: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Signal Genetics: Research Funding; Novartis: Research Funding; Karyopharm: Research Funding; Merck: Research Funding. Nooka: Spectrum, Novartis, Onyx pharmaceuticals: Consultancy. Richter: Takeda: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Janssen: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau. Vij: Karyopharm: Honoraria; Amgen: Honoraria, Research Funding; Celgene: Consultancy; Takeda: Honoraria, Research Funding; Novartis: Honoraria; Bristol-Myers Squibb: Honoraria; Janssen: Honoraria. Schiller: Incyte Corporation: Research Funding. Costa: Sanofi: Honoraria, Research Funding. Chari: Array Biopharma: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Pharmacyclics: Research Funding; Janssen: Consultancy, Research Funding; Amgen Inc.: Honoraria, Research Funding; Novartis: Consultancy, Research Funding. Siegel: Novartis: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Merck: Honoraria; Amgen: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau. Fonseca: Janssen: Consultancy; AMGEN: Consultancy; Millennium, a Takeda Company: Consultancy; Bayer: Consultancy; Sanofi: Consultancy; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; AMGEN: Consultancy; Novartis: Consultancy; Millennium, a Takeda Company: Consultancy; Sanofi: Consultancy; AMGEN: Consultancy; Janssen: Consultancy; BMS: Consultancy; Celgene: Consultancy; BMS: Consultancy; Millennium, a Takeda Company: Consultancy; Millennium, a Takeda Company: Consultancy; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; Bayer: Consultancy; Novartis: Consultancy; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms; AMGEN: Consultancy; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms; Celgene: Consultancy. Kauffman: Karyopharm Therapeutics Inc: 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. Saint-Martin: Karyopharm: Employment. Picklesimer: Karyopharm: Employment. Friedlander: Karyopharm Therapeutics: Employment. Choe-Juliak: Karyopharm Therapeutics: Employment.

*signifies non-member of ASH