SELINEXOR COMBINED WITH LOW DOSE BORTEZOMIB AND DEXAMETHASONE (SVD) INDUCES A HIGH RESPONSE RATE IN PATIENTS WITH RELAPSED OR REFRACTORY MULTIPLE MYELOMA (MM)
Author(s): ,
Nizar Bahlis
Affiliations:
Southern Alberta Cancer Research Institute,Calgary,Canada
,
Heather Sutherland
Affiliations:
Vancouver General Hospital,Vancouver,Canada
,
Darrell White
Affiliations:
Dalhousie University and QEII Health Sciences Center,Halifax,Canada
,
Michael Sebag
Affiliations:
Royal Victoria Hospital,Montreal,Canada
,
Suzanne Lentzsch
Affiliations:
Columbia University,New York,United States
,
Rami Kotb
Affiliations:
Cancer Care Manitoba,Manitoba,Canada
,
Chris Venner
Affiliations:
Cross Cancer Institute,Edmonton,Canada
,
Cristina Gasparetto
Affiliations:
Duke University Cancer Center,Durham,United States
,
Gary Schiller
Affiliations:
UCLA Ronald Reagan Medical Center,Los Angeles,United States
,
Richard LeBlanc
Affiliations:
Hôpital Maisonneuve-Rosemont,Montreal,Canada
,
William Bensinger
Affiliations:
Swedish Cancer Center,Seattle,United States
,
Brea Lipe
Affiliations:
University of Rochester Medical College,New York,United States
,
Aldo Del Col
Affiliations:
Myeloma Canada,Laval,Canada
,
Michael Kauffman
Affiliations:
Karyopharm Therapeutics,Newton,United States
,
Sharon Shacham
Affiliations:
Karyopharm Therapeutics,Newton,United States
,
Jacqueline Jeha
Affiliations:
Karyopharm Therapeutics,Newton,United States
,
Jean-Richard Saint-Martin
Affiliations:
Karyopharm Therapeutics,Newton,United States
,
Jatin Shah
Affiliations:
Karyopharm Therapeutics,Newton,United States
Christine Chen
Affiliations:
Princess Margaret Cancer Center,Toronto,Canada
EHA Learning Center. Bahlis N. Jun 16, 2018; 215622
Nizar Bahlis
Nizar Bahlis

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Abstract: PS1322

Type: Poster Presentation

Presentation during EHA23: On Saturday, June 16, 2018 from 17:30 - 19:00

Location: Poster area

Background
Selinexor is a first-in-class Selective Inhibitor of Nuclear Export (SINE) compound that binds and inactivates Exportin 1 (XPO1). Twice weekly (BIW) bortezomib (bort) in combination with dexamethasone (Vd) is an established therapy in relapsed and refractory multiple myeloma (RRMM). While the activity of bort BIW in combination with other agents is efficacious, prolonged use is limited due to peripheral neuropathy (PN, 50-60%) as well as acquired resistance to bort. New dosing regimes with improved tolerability and the ability to overcome resistance are needed. Preclinical studies have shown that selinexor, in combination with bort, can restore sensitivity of bort-resistant MM, in murine MM xenografts.

Aims
This Ph 1b/2 (NCT02343042), dose escalation study was designed to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) for the safety, tolerability and efficacy of the combination of selinexor, bort and low dose dex (SVd) in patients (pts) with RRMM.

Methods
The study enrolled pts with RRMM after ≥ 1 prior therapy.  Pts with prior exposure or refractory to proteasome inhibitors (PI) were included, provided they were not refractory to bort as a last therapy. Selinexor was dosed escalated in once-weekly (QW, 80; 100 mg) or twice-weekly (BIW, 60; 80 mg) regimens. Bort (1.3 mg/m2 sc) was administered QW or BIW. Dex was given orally 40 mg per week.

Results
As of Feb 27th, 2018, 42 pts were enrolled; 22 pts in the dose escalation and 20 pts in the expansion (RP2D) cohort.  Median age was 64 years; 23 M 19 F, median of 3 (range, 1 – 11) prior trement regimens. The MTD was not reached. Three pts in the BIW bort cohort were dose reduced to QW bort after Cycle 1.  Common treatment related grade 1/2 adverse events (AEs) included: anorexia (57%), nausea (57%), fatigue (45%), and diarrhea (36%). Grade 3/4 AEs included: thrombocytopenia (45%), neutropenia (24%) and anemia (12%). Importantly, PN across all pts was limited to 6 patients (14%) (G1 4pts, G2 2 pts) of which 5 had prior bort exposure.  Based on tolerability and efficacy, the RP2D of SVd is selinexor 100 mg, bort 1.3 mg/m2 and dex 40 mg, all QW (40% less bort and 25% less dex compared to the standard, approved BIW schedule of Vd). Median PFS in PI relapsed or naïve pts is >13 months. Median PFS in PI refractory pts is 6.4 months. The median duration of response is ~12 months. Response rates can be seen in Table 1. Table 1: SVd Best Response in PI non-Refractory & PI-Refractory Patients

Category 

N 

ORR  (%) 

CBR 

(%) 

CR 

(%) 

VGPR (%) 

PR* 

(%)

MR

(%)

SD

(%)

PD

(%)

PI Relapsed or Naïve

19

16 (84%)

16 (95%)

2 (11%)

5 (26%)

9 (47%)

2 (11%)

1 (5%)

--

PI Refractory

21

9 (43%)

14 (67%)

1 (5%)

4 (19%)

4 (19%)

5 (24%)

6 (29%)

1 (5%)

PI Relapsed or Naïve, ≤ 3 Prior Treatments

18

15 (83%)

16 (89%)

2 (11%)

6 (33%)

7 (39%)

1 (6%)

2 (11%)

--

*1 PR unconfirmed

Conclusion
Selinexor in combination with weekly bort and dex is well tolerated and highly active in RRMM.  The high ORR with SVd is achieved with 40% less bort and 25% less dex and no overt major organ toxicities. Furthermore, in pts with PI refractory MM, the ORR of 43% and CBR of 67% which support preclinical findings that selinexor re-sensitizes and overcomes resistance to PIs. This data supports the ongoing Ph 3 BOSTON study examining SVd vs Vd.

Session topic: 14. Myeloma and other monoclonal gammopathies - Clinical

Keyword(s): bortezomib, Dexamethasone, Multiple Myeloma

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