In phase I trials , the first-in-class selective inhibitor of XPO1 selinexor ( with or without low-dose dexamethasone ) showed clinical activity against several types of hematologic malignancies , including multiple myeloma ( MM ). Based on these results , Dan T . Vogl , MD , of the Perelman School of Medicine at the University of Pennsylvania , and researchers evaluated the selinexor combination in a phase II study of heavily pretreated patients with MM .

About one-fifth of participants responded to treatment , suggesting that “ selinexor plus dexamethasone has significant potential to be a new treatment option for patients with refractory MM ,” the authors wrote of their findings , which were published in The Journal of Clinical Oncology .

The multicenter , open-label study included 79 patients ( median age = 63 years ; range = 34-78 years ). Participants were previously treated with at least three anti-myeloma agents ( including an alkylating agent , glucocorticoids , bortezomib , carfilzomib , lenalidomide , and pomalidomide ) and had disease that was refractory to the most recent regimen ( defined as ≤25 % response to therapy or progression during or within 60 days of completion of therapy ).

Patients received a median of seven prior regimens ( range = 3-17 regimens ), and many ( 77 %) had undergone autologous hematopoietic cell transplantation .

More than half of participants ( n = 48 ) had disease that was quadrefractory ( refractory to bortezomib , carfilzomib , lenalidomide , and pomalidomide ) and 31 had disease that was penta-refractory ( refractory

to the previously listed agents , as well as an anti-CD38 antibody ).

Among the patients with pentarefractory disease , 25 ( 81 %) received single-agent daratumumab ( n = 15 ) or isatuximab ( n = 10 ), while six ( 19 %) received an anti-CD38 antibody combination including lenalidomide or pomalidomide . “ The relatively short median time since diagnosis of the patients [ median = 4 years ; range = < 1-35 years ], coupled with their quad- and penta-refractory status , suggests that this population had particularly aggressive MM ,” the researchers commented . Patients received :

• oral selinexor 80 mg twice-weekly on days 1 , 3 , 8 , 10 , 15 , and 17 of each 28-day cycle

• oral dexamethasone 20 mg at time of selinexor administration

Once 23 patients were enrolled , the protocol was amended to allow for continuous dosing of twice-weekly selinexor and dexamethasone on days one , three , eight , 10 , 15 , 17 , 22 , and 24 of each 28-day cycle ( 8 cycles vs . 6 cycles ). Patients with stable disease who tolerated selinexor could increase to a 100 mg dose .

Sixteen patients responded to treatment , for an overall response rate ( ORR ; primary endpoint ; defined as a partial response [ PR ] or better ) of 21 percent ; the ORR was 21 percent ( n = 10 ) in those with quad-refractory disease and 20 percent ( n = 6 ) in those with penta-refractory disease . The

ORR “ was numerically higher than the prespecified minimally acceptable threshold of 15 percent , although the difference was not statistically significant ( p = 0.17 ),” the authors wrote .

See TABLE 1 for ORR according to refractory status and cytogenetic risk .

Responses were “ rapid ,” the authors noted , with 85 percent of patients who achieved a minimal response or better ( n = 22 / 26 ) responding within the first cycle . The median duration of response for those with a PR or better was five months ( range not reported ), with at least one response lasting 8.4 months .

Median progression-free and overall survival ( OS ) were 2.3 months and 9.3 months , respectively ( ranges not reported ). Patients who achieved at least a minimal response after one cycle had significantly better OS than those with stable or progressive disease ( median = not reached vs . 7.2 months , respectively ; p = 0.01 ) among 60 patients who were alive and evaluable at last follow-up .

Although the observed ORR was not statistically significantly higher than the prespecified study threshold , “ we believe that this evidence of efficacy is sufficient to warrant further study ,” the authors noted .

The most common any-grade adverse events ( AEs ) were nausea ( n = 58 ; 73 %), thrombocytopenia ( n = 58 ; 73 %), fatigue ( n = 50 ; 63 %), anemia ( n = 39 ; 49 %), decreased appetite ( n = 39 ; 49 %), and vomiting ( n = 35 ; 44 %). The most common grade 3 AEs were anemia ( n = 21 ; 27 %), thrombocytopenia ( n = 20 ; 25 %), and hyponatremia ( n = 17 ; 22 %).

More than half of patients required

dose interruptions ( n = 41 ; 52 %) or reductions ( n = 29 ; 37 %) because of AEs , and 14 ( 18 %) discontinued treatment . Dose reductions and interruptions appeared to occur more frequently among patients treated with the amended eight-dose protocol than with the sixdose protocol ( 71 % vs . 43 %; p value not reported ). The selinexor 100 mg dose was also associated with increased AEs .

Twenty-two serious AEs reported in 19 patients were deemed “ at least possibly related to study treatment ,” the authors wrote . One patient had fatal intracranial bleeding that was attributed to MM , prior myelotoxic therapy , and possibly selinexor , according to the report .

“ Selinexor is the first anti-myeloma agent to show clear activity in pentarefractory MM ,” the researchers wrote . “ Combining selinexor with dexamethasone has a mechanistic rationale and is associated with higher response rates than single-agent selinexor .”

The study is limited by its lack of a comparator arm and small patient population .

Karyopharm Therapeutics provided support for the study .

The corresponding authors report financial support from Celgene , Amgen , Karyopharm Therapeutics , Teva , Janssen , Millennium , Acetylon , GlaxoSmithKline , Calithera Biosciences , Constellation Pharmaceuticals , and Takeda .

REFERENCE

Vogl DT , Dingli D , Cornell RF , et al . Selective inhibition of nuclear export with oral selinexor for treatment of relapsed or refractory multiple myeloma . J Clin Oncol . 2018 January 30 . [ Epub ahead of print ]

Patient Cohort

Number of

Patients *

Overall

78

16

( 21 %)

Quad-refractory

48

10

( 21 %)

Penta-refractory

30

6

( 20 %)

Cytogenetic Risk

Standard risk

22

4

( 18 %)

High risk

17

6

( 35 %)