Selinexor Shows Synergy in Combination with Pomalidomide and Low Dose Dexamethasone in Patients with Relapsed / Refractory Multiple Myeloma

Abstract

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 tumor suppressor proteins (TSPs; NF-kB, p53 and FOXO) and reduction of many proto-oncogenes, including MDM2, MYC and Cyclin D. In murine MM models, the combination of selinexor with IMIDs shows synergistic anti-MM activity with good tolerability. Methods - This phase 1b/2 dose escalation study (NCT02343042) using the standard 3+3 design, is designed to determine the tolerability, maximum tolerated dose (MTD), recommended phase 2 dose (RP2D) and preliminary efficacy of selinexor in combination with pomalidomide and dexamethasone (SdP). Patients (pts) with relapsed/refractory MM who received ≥ 2 prior therapies including lenalidomide and a proteasome inhibitor (PI) were enrolled. Selinexor is dose escalated once-weekly (QW, starting at 80 mg) or twice-weekly (BIW, starting at 60 mg), pomalidomide 4 mg PO daily, days 1 -21 and dexamethasone (dex) 40 mg PO weekly in a 28 day cycle. Results - As of 25-Jul-2016, 11 pts (7 male / 4 female) have been enrolled. The median age is 58 years (range, 43 - 76), with a median of 5 (range, 2 - 9) prior treatment regimens. Eight pts had MM refractory to lenalidomide and 7 pts to bortezomib; including 5 pts with MM refractory to both. For the once-weekly selinexor cohort, the 80 mg dose level has been cleared and the 100 mg dose level is on going. For the twice-weekly cohort, the 60 mg dose level has been cleared and 80 mg dose level is on going. Common related grade 1/2 adverse events (AEs) include: nausea 7pts (64%), altered taste 5pts (45%), anorexia 3pts (27%), and diarrhea 3pts (27%). Grade 3/4 AEs include: neutropenia 8pts (73%), thrombocytopenia 4pts (36%), and leukopenia 3pts (27%). There was no febrile neutropenia or bleeding reported to date. No dose limiting toxicities have been observed and MTD has not been reached. Ten pts were evaluable for response including, 1 complete response (CR), 5 partial responses (PR), 3 minor responses (MR), and 1 stable disease (SD). The overall response rate (ORR) is 60% with a clinical benefit rate of 90% (ORR + MR). Responses are rapid in onset, with at least MR achieved by cycle 2 day 1. In lenalidomide and bortezomib refractory patients the ORR was 50%. One pt was deemed not evaluable due to non-compliance with study procedures. Eight pts are still on study, (range <1 - 7+ months) including 4 pts maintaining their response for > 3 months. Conclusions - The all oral combination of selinexor, pomalidomide and low dose dex (SdP) has significant clinical activity (ORR 60%) in pts with heavily pretreated MM. Responses are rapid in onset even with the lower dose cohorts tested thus far, CR can be achieved. No additive toxicities over monotherapy of either pomalidomide or selinexor have been observed. This novel treatment regimen therefore holds promise in addressing the urgent need to induce meaningful and durable responses in patients with IMiD and PI relapsed/refractory MM. Disclosures Chen: Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Takeda: Research Funding. Sebag:Celgene: Honoraria; Janssen: Honoraria; Novartis: Honoraria. Sutherland:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. White:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Venner:Takeda: Honoraria; Celgene: Honoraria, Research Funding; J+J: Research Funding; Janssen: Honoraria; Amgen: Honoraria. Kouroukis:Karyopharm: Research Funding; Amgen: Research Funding; Janssen: Research Funding. McCurdy:Celgene: Honoraria. Lalancette:BMS: Honoraria; Celgene: Honoraria. Bensinger:Sanofi: Consultancy, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Acetylon: Research Funding; Bayer: Research Funding; Takeda: Honoraria, Research Funding. Lentzsch:Celgene: Consultancy, Honoraria; BMS: 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. Jeha:Karyopharm: Employment. Picklesimer:Karyopharm: Employment. Saint-Martin:Karyopharm: Employment. Choe-Juliak:Karyopharm Therapeutics: Employment. Bahlis:BMS: Honoraria; Janssen: Consultancy, Honoraria, Other: Travel Expenses, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Other: Travel Expenses, Research Funding, Speakers Bureau; Onyx: Consultancy, Honoraria; Amgen: Consultancy, Honoraria.

Clinical Implications of Targeting XPO1-mediated Nuclear Export in Multiple Myeloma

“…The preliminary results of the combination arm of selinexordexamethasone with pomalidomide in patients previously treated with lenalidomide and ! 1 PI (another arm of the phase Ib/II STOMP trial) were reported by Chen et al 83 Selinexor was dose escalated, starting QW at 80 mg or BIW at 60 mg, with all patients receiving pomalidomide (4 mg/d orally for days 1-21) and dexamethasone (40 mg QW in a 28-day cycle). Eleven patients were enrolled at the time of reporting, including five with MM refractory to both lenalidomide and bortezomib.…”

“…Also, the constitutional and gastrointestinal side effects appear to be reduced when selinexor is given QW (as opposed to BIW) in combination with other anti-MM drugs. 83,85 Eltanexor, the second-generation SINE compound, has demonstrated a broad therapeutic window with reduced penetration of the bloodebrain barrier across species (mouse, rat, monkey) compared with selinexor. 51 After oral administration, animals treated with eltanexor showed a lower percentage of body weight loss and improved food consumption than animals similarly treated with selinexor.…”

Pomalidomide in the treatment of multiple myeloma: design, development and place in therapy

“…The all-oral combination of selinexor, a first-in-class selective inhibitor of nuclear export, with POMd has demonstrated in a phase 1/2 trial 61 a 60% ORR. Responses were rapid in onset, and 10% CR was achieved.…”

Pomalidomide, bortezomib, and dexamethasone at first relapse in lenalidomide‐pretreated myeloma: A subanalysis of OPTIMISMM by clinical characteristics

“…Pomalidomide, an oral immunomodulatory agent, has demonstrated antimyeloma activity in the context of lenalidomide resistance and is the only agent that has been extensively studied in patients previously treated with lenalidomide, including those who received pomalidomide immediately after lenalidomide 14‐17 . Pomalidomide has also demonstrated antimyeloma activity synergistic with multiple agents, supporting its integration into novel triplet regimens 16,18‐23 . The combination of pomalidomide, bortezomib, and dexamethasone (PVd) was approved in the European Union and other countries on the basis of the findings of the registrational phase 3 OPTIMISMM study in lenalidomide‐pretreated patients (70% with lenalidomide‐refractory disease) with relapsed or refractory MM (RRMM) in early lines of therapy (median of two prior lines of therapy) 17,24,25 .…”