S1606 SAFETY AND EFFICACY OF COMBINATION OF SELINEXOR, DARATUMUMAB, AND DEXAMETHASONE (SDD) IN PATIENTS WITH MULTIPLE MYELOMA (MM) PREVIOUSLY EXPOSED TO PROTEASOME INHIBITORS AND IMMUNOMODULATORY DRUGS
Authors: Gasparetto C. , Lentzsch S. , Schiller G. , Callander N. , Tuchman S. , Chen C. , White D. , Kotb R. , Sutherland H. , Sebag M. , Baljevic M. , Bensinger W. , LeBlanc R. , Venne C. , Bahlis N. , Rodriguez‐Lopez K. , Sheehan H. , Saint‐Martin J.‐R. , Shah J. , Shacham S. , Kauffman M. , Lipe B. 
Published: June 2019

Background:Selinexor is a first‐in‐class Selective Inhibitor of Nuclear Export (SINE) compound that binds and inactivates Exportin 1 (XPO1). Selinexor in combination with dexamethasone (dex) has demonstrated a 26.2% overall response rate (ORR) in patients (pts) with triple‐class refractory myeloma (defined as refractory to an immunomodulatory drug (IMiD), proteasome inhibitor (PI), and CD‐38 monoclonal antibody [mAb]) including deep responses with very good partial response (VGPR) and 2 pts in a stringent complete response (sCR) (minimal residual disease negative). Daratumumab (Dara), an anti‐CD38 mAb, is approved for the treatment of heavily pretreated MM is limited by short progression‐free survival (PFS) and an ORR of ∼21% in quad‐refractory MM.Aims:The objectives of the study were to determine the maximum tolerated dose (MTD), the recommended phase 2 dose (RP2D), and to assess the safety, tolerability, and preliminary efficacy of the combination of SDd in pts with PI/IMiD refractory MM.Methods:This is amulticenter, open‐label, phase 1/2b study with a dose escalation and expansion phase.Pts were eligible if they had received ≥3 prior lines of anti‐myeloma therapy, including a PI and an IMiD or whose MM is refractory to a PI and IMiD. In the expansion phase, pts’ prior dara therapy was exclusionary. Selinexor was dose‐escalated in 2 concurrent cohorts: once‐weekly (QW, at 100 mg) or twice‐weekly (BIW, at 60 mg). Dara was administered at 16 mg/kg IV (recommended schedule) and dex at 40 mg QW or 20 mg BIW. In the expansion phase, pts were to receive the RP2D.Results:As of February 20th2019, 30 pts (16 male/14 female) have been enrolled. Three pts have been enrolled into the 60 mg BIW and 27 pts in the 100 mg QW cohorts. The median age was 69 years and the median number of prior treatment regimens was 3 (range, 2 – 10). Common treatment‐related adverse events (all grades, Grades 3/4) included: thrombocytopenia (66%, 48%), nausea (66%, 3%), fatigue (55%, 14%), anemia (52%, 31%), leukopenia (48%, 31%), and neutropenia (48%, 24%). Two dose‐limiting toxicities (DLTs) were reported in the 60 mg BIW cohort: Grade 3 thrombocytopenia and Grade 2 fatigue requiring dose reduction in selinexor to 100 mg QW. In the 100 mg QW escalation cohort (n = 6), no DLTs occured.Based on tolerability and efficacy, the RP2D of SDd is selinexor 100 mg, dara 16 mg/kg, and dex 40 mg, administered QW. A total of 28 pts were evaluable for response.In dara naïve pts (n = 26), the ORR was 77% (9 VGPR, 8 partial response, 3 unconfirmed partial response). In the 2 pts with dara refractory MM, there was one progressive disease and one stable disease.Summary/Conclusion:Selinexor 100 mg QW can be combined safely with dara (per approved dosing) and dex to produce a deep and durable response warranting further investigation in pts with relapsed refractory MM. The ORR was 77% in pts who had not received prior dara or selinexor. Enrollment in the expansion arm is expected to be completed in March 2019 and full study results will be presented.