Written in
Featured research from recent issues of Blood
PAPER SPOTLIGHT
Can a Selinexor Combination
STOMP Out Relapsed/Refractory
Multiple Myeloma?
The combination of selinexor
plus low-dose bortezomib and
dexamethasone produced high
response rates in patients
with relapsed or refractory
multiple myeloma (MM), with
a “manageable” safety profile,
according to the phase Ib/II
Selinexor and Backbone Treatments
of Multiple Myeloma Patients
(STOMP) study. Findings from the
ongoing trial were published in
Blood.
“Selinexor represents a new
class of drugs targeting the
nuclear export protein XPO1 and
provides patients with myeloma
access to a therapeutic option
that does not include an immuno-
modulatory agent, proteasome
inhibitor, or anti-CD38 monoclonal
antibody,” lead study author Nizar
Jacques Bahlis, MD, from the
Charbonneau Cancer Research
Institute at the University of
Calgary, explained. “Of interest,
when selinexor was combined
with bortezomib, the gastro-
intestinal effects of selinexor were
much attenuated and, with the
weekly, low-dose subcutaneous
administration of bortezomib, the
neurotoxicity was minimal.”
The response
rates were
“encouraging”
considering
the large
portion of
patients
with heavily
pretreated
disease.
10
ASH Clinical News
In the dose-escalation and
dose-expansion phases of the
STOMP study, investigators
enrolled 42 adults with MM
whose disease had progressed
following at least one treatment
regimen. Patients who received
prior treatment with and were
refractory to bortezomib or a
proteasome inhibitor (PI) were
eligible for the trial; however,
patients who were refractory to
bortezomib as their most recent
line of therapy were excluded.
Patients with disease that was
refractory to carfilzomib or
ixazomib as the most recent line
of therapy were included.
Participants’ median age was
64 years (range = 43-75 years), and
the median number of prior lines
of therapy was three (range = 1-11).
Twenty-one patients (50%) had
disease that was refractory to a
PI and 19 (45%) had disease that
was refractory to both a PI and an
immunomodulatory agent.
During the dose-escalation
phase, patients were randomized
to receive once- or twice-weekly
selinexor at one of three doses
(60, 80, or 100 mg) in 21- or
35-day cycles. Patients also
received bortezomib 1.3 mg/m 2
and dexamethasone 20 mg (in
the 21-day cycle) or 40 mg (in the
35-day cycle).
As of data cutoff, patients had
received treatment for a median
of 225 days (range = 18-707 days).
Seven patients (17%) were still
receiving treatment: 22 (52%)
discontinued due to progressive
disease, eight (19%) due to
adverse events (AEs), and five
(12%) for other reasons.
The most commonly reported
non-hematologic AEs of any
grade included nausea (62%),
fatigue (60%), and decreased
appetite (60%); most of these
AEs were grade 1 or 2 and were
reversible with dose interruptions.
“Of particular interest, and
despite the fact that 86 percent
of the patients were previously
exposed to bortezomib, the
overall rate of peripheral
neuropathy was minimal with
only 5 percent of the patients
experiencing grade 2 neuropathy
and no grade 3 [events] reported,”
the authors wrote.
The most commonly reported
hematologic grade ≥3 AEs included:
• thrombocytopenia (50%)
• neutropenia (26%)
• anemia (19%)
“Clinical sequelae of these
hematologic AEs were low as
bleeding (5%, both cases grade
1) and febrile neutropenia (5%)
were uncommon,” the researchers
noted.
Six patients developed
pneumonia during the study but
all, including one death, were
considered unrelated or unlikely
related to selinexor treatment.
There were no dose-limiting
toxicities reported during the
dose-escalation phase, however,
the investigators found that the
side effects of treatment with
twice-weekly bortezomib “were
not sustainable for long-term
treatment and this dosing
schedule was abandoned.”
The recommended phase
II dose, therefore, was set at
once-weekly selinexor 100 mg,
dexamethasone 40 mg, and
bortezomib 1.3 mg/m 2 . The
dose-expansion phase enrolled
an additional 20 patients at the
once-weekly schedule to establish
the safety and efficacy profile.
For the 40 patients across the
dose-escalation and -expansion
cohorts who were evaluable for
response, the overall response
rate (ORR) was 63 percent,
which the researchers deemed
“encouraging” considering the
large portion of patients with
refractory and heavily pretreated
disease. The ORR included: three
complete responses (8%), nine
very good partial responses
(23%), and 13 partial responses
(33%). An additional seven
patients (18%) experienced a
minimal response, for a clinical
benefit of 80 percent.
Specifically, among patients
treated at the recommended
phase II dose, the ORR was 58
percent, and the authors observed
a higher ORR in PI-nonrefractory
patients compared with PI-refractory
patients (84% vs. 43%, respec-
tively). This higher ORR among
PI-nonrefractory patients
“supports the nonclinical synergy
observed between XPO1 inhibitors
and PIs,” the researchers added.
“Responses were sustained over
time with an overall median
progression-free survival (PFS) of
9.0 months [in the 40 evaluable
patients], including a median PFS
of 17.8 months in PI-relapsed/naïve
patients.”
The authors noted several
limitations of the study, including
its small number of participants
and the lack of a comparator or
control group.
Additionally, while the results
of this study are encouraging, Dr.
Bahlis stated that the findings
require further validation in a
future randomized trial. One such
study, the ongoing Bortezomib,
Selinexor, and Dexamethasone in
Patients With Multiple Myeloma
(BOSTON) trial, compares once-
weekly selinexor, bortezomib,
and dexamethasone with the
combination of bortezomib and
dexamethasone in patients
with relapsed and/or refractory
myeloma. “This randomized phase
III trial will confirm the [selinexor
and bortezomib] combination’s
efficacy, and establish it as an
anti-myeloma regimen,” Dr. Bahlis
explained. “Additional combination
studies of selinexor and pomali-
domide or daratumumab also are
ongoing.”
The authors report financial
relationships with Karyopharm
Therapeutics, which sponsored the
trial.
REFERENCE
Bahlis NJ, Sutherland H, White D, et al. Selinexor plus
low-dose bortezomib and dexamethasone for patients
with relapsed or refractory multiple myeloma. Blood.
2018;132:2546-54.
January 2019 Annual Meeting Edition