SELINEXOR COMBINED WITH POMALIDOMIDE AND LOW DOSE DEXAMETHASONE (SPD) IN A RELAPSED / REFRACTORY MULTIPLE MYELOMA PATIENT POPULATION
Author(s): ,
Christine Chen
Affiliations:
Princess Margaret Cancer Center,Toronto,Canada
,
Heather Sutherland
Affiliations:
Vancouver General Hospital,Vancouver,Canada
,
Rami Kotb
Affiliations:
Cancer Care Manitoba,Manitoba,Canada
,
Michael Sebag
Affiliations:
Royal Victoria Hospital,Montreal,Canada
,
Darrell White
Affiliations:
Dalhousie University and QEII Health Sciences Center,Halifax,Canada
,
William Bensinger
Affiliations:
Swedish Cancer Center,Seattle,United States
,
Cristina Gasparetto
Affiliations:
Duke University Cancer Center,Durham,United States
,
Richard LeBlanc
Affiliations:
Hôpital Maisonneuve-Rosemont,Montreal,Canada
,
Chris Venner
Affiliations:
Cross Cancer Institute,Edmonton,Canada
,
Suzanne Lentzsch
Affiliations:
Columbia University,New York,United States
,
Gary Schiller
Affiliations:
UCLA Ronald Reagan Medical Center,Los Angeles,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
Nizar Bahlis
Affiliations:
Southern Alberta Cancer Research Institute,Calgary,Canada
EHA Library. Chen C. 06/15/18; 215036; PF586
Christine Chen
Christine Chen
Contributions
Abstract

Abstract: PF586

Type: Poster Presentation

Presentation during EHA23: On Friday, June 15, 2018 from 17:30 - 19:00

Location: Poster area

Background
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 cell cycle regulators such as p53, IkB, and Rb. Pomalidomide/dexamethasone (Pd) is approved in relapsed/refractory MM (RRMM) with an overall response rate (ORR) of 30% and progression-free survival (PFS) rate of 3.6 months in patients (pts) having received a prior proteasome inhibitor (PI) and IMiD.  Strategies to improve the ORR and PFS are needed.  In murine MM models, the combination of selinexor with IMiDs shows synergistic anti-MM activity and good tolerability.

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, pomalidomide, and low dose dex (SPd) in pts with RRMM.

Methods
Pts with RRMM who received ≥ 2 prior therapies including lenalidomide (len) and a PI were enrolled. Selinexor was evaluated in 2 different dosing schedules of once-weekly (QW, 60; 80 mg) or twice-weekly (BIW, 60; 80 mg), with pomalidomide (pom) 4 mg PO daily, and dexamethasone (dex) 20 mg BIW or 40 mg QW.

Results
As of Feb 27th 2018, 33 pts (16 male / 17 female) have been enrolled.The median age is 61 years, with a median of 4 (range, 2 – 9) prior treatment regimens. Thirty-one patients were IMiD refractory (20 len, 11 pom/len). Six dose limiting DLTs were observed: G3 fatigue (60 mg BIW, pom 4 mg), G3 febrile neutropenia (FN) (60 mg BIW, pom 3 mg), G3 FN and G4 neutropenia (ANC) (80 mg QW, pom 4), G3 thrombocytopenia (PLT) (80 mg QW, pom 3 mg) and 4 missed doses in Cycle 1 due to symptomatic hyponatremia (80 mg BIW, pom 4 mg). Enrollment on selinexor 80 mg QW, pom 3 mg is ongoing. Common treatment related Grade 1/2 adverse events (AEs) include: nausea (48%), fatigue (42%), anorexia (45%) and diarrhea (30%). Grade 3/4 AEs include: ANC (55%), PLT (30%), and anemia (27%). Twenty-seven pts were evaluable for response. Responses rates can be seen in Table 1. Median PFS is 11.6 months with a median follow up of 7.7 months. 

Table 1. SPd – Response Rates in Evaluable Patients 

Prior Therapy Status

 

N*

 

ORR

CBR

Pom Naïve & Len Refractory or Relapsed

19

12 (63%)

14 (74%)

Pom & Len Refractory

8

3 (38%)

5 (63%)

Overall Response Rate= VGPR + PR, Clinical Benefit Rate= VGPR + PR + MR (*Includes 1 unconfirmed PR and 1 unconfirmed MR)

Conclusion
Conclusions – Enrollment is ongoing to evaluating once weekly selinexor in combination with Pd. This all oral combination of selinexor, pom and dex (SPd) has significant clinical activity with an ORR 63% in pom naive pts with heavily pretreated MM compared to previously published data of 30% ORR. No unexpected adverse events were noted. Phase 1 dose escalation of the combination of SPd is ongoing to define the RP2D. SPd appears active and supports further clinical development in RRMM.

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

Keyword(s): Dexamethasone, Imids, Multiple Myeloma

Abstract: PF586

Type: Poster Presentation

Presentation during EHA23: On Friday, June 15, 2018 from 17:30 - 19:00

Location: Poster area

Background
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 cell cycle regulators such as p53, IkB, and Rb. Pomalidomide/dexamethasone (Pd) is approved in relapsed/refractory MM (RRMM) with an overall response rate (ORR) of 30% and progression-free survival (PFS) rate of 3.6 months in patients (pts) having received a prior proteasome inhibitor (PI) and IMiD.  Strategies to improve the ORR and PFS are needed.  In murine MM models, the combination of selinexor with IMiDs shows synergistic anti-MM activity and good tolerability.

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, pomalidomide, and low dose dex (SPd) in pts with RRMM.

Methods
Pts with RRMM who received ≥ 2 prior therapies including lenalidomide (len) and a PI were enrolled. Selinexor was evaluated in 2 different dosing schedules of once-weekly (QW, 60; 80 mg) or twice-weekly (BIW, 60; 80 mg), with pomalidomide (pom) 4 mg PO daily, and dexamethasone (dex) 20 mg BIW or 40 mg QW.

Results
As of Feb 27th 2018, 33 pts (16 male / 17 female) have been enrolled.The median age is 61 years, with a median of 4 (range, 2 – 9) prior treatment regimens. Thirty-one patients were IMiD refractory (20 len, 11 pom/len). Six dose limiting DLTs were observed: G3 fatigue (60 mg BIW, pom 4 mg), G3 febrile neutropenia (FN) (60 mg BIW, pom 3 mg), G3 FN and G4 neutropenia (ANC) (80 mg QW, pom 4), G3 thrombocytopenia (PLT) (80 mg QW, pom 3 mg) and 4 missed doses in Cycle 1 due to symptomatic hyponatremia (80 mg BIW, pom 4 mg). Enrollment on selinexor 80 mg QW, pom 3 mg is ongoing. Common treatment related Grade 1/2 adverse events (AEs) include: nausea (48%), fatigue (42%), anorexia (45%) and diarrhea (30%). Grade 3/4 AEs include: ANC (55%), PLT (30%), and anemia (27%). Twenty-seven pts were evaluable for response. Responses rates can be seen in Table 1. Median PFS is 11.6 months with a median follow up of 7.7 months. 

Table 1. SPd – Response Rates in Evaluable Patients 

Prior Therapy Status

 

N*

 

ORR

CBR

Pom Naïve & Len Refractory or Relapsed

19

12 (63%)

14 (74%)

Pom & Len Refractory

8

3 (38%)

5 (63%)

Overall Response Rate= VGPR + PR, Clinical Benefit Rate= VGPR + PR + MR (*Includes 1 unconfirmed PR and 1 unconfirmed MR)

Conclusion
Conclusions – Enrollment is ongoing to evaluating once weekly selinexor in combination with Pd. This all oral combination of selinexor, pom and dex (SPd) has significant clinical activity with an ORR 63% in pom naive pts with heavily pretreated MM compared to previously published data of 30% ORR. No unexpected adverse events were noted. Phase 1 dose escalation of the combination of SPd is ongoing to define the RP2D. SPd appears active and supports further clinical development in RRMM.

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

Keyword(s): Dexamethasone, Imids, Multiple Myeloma

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