Literature Scan
New and noteworthy research from the medical literature landscape
Pomalidomide-Based Regimen Associated With Durable
Response in Lenalidomide-Refractory Myeloma
Treatment with a regimen consisting of pomalidomide,
low-dose dexamethasone, and daratumumab
as either second- or third-line therapy induced durable
responses in a high proportion of lenalidomidepretreated
patients with relapsed or refractory myeloma,
according to findings from the phase II MM-014 trial.
Clinical benefit was seen across all patient populations,
including those with high-risk cytogenetics.
According to the study authors, led by David
Siegel, MD, of Hackensack University Medical Center
in New Jersey, these findings could alter clinicians’
treatment decisions, as practitioners currently “may
be inclined to switch away from the immunomodulatory
agent drug class after lenalidomide-based treatment
failure.”
The study – conducted across 49 sites in the U.S.,
Canada, and Japan – included 3 treatment cohorts:
• cohort A: pomalidomide plus low-dose
dexamethasone
• cohort B: pomalidomide, low-dose dexamethasone,
and daratumumab (North American arm)
• cohort C: pomalidomide, low-dose dexamethasone,
and daratumumab (currently enrolling, Japaneseonly
arm)
Dr. Siegel and colleagues reported only on findings
from 112 patients enrolled in cohort B. Participants
in this treatment arm had a documented diagnosis of
myeloma, measurable disease (serum M-protein ≥0.5 g/
dL or urine M-protein ≥200 mg/24 hours), an Eastern
Cooperative Oncology Group performance status of ≤2,
and documented progressive disease; they had recently
received a lenalidomide-based regimen for ≥2 consecutive
cycles.
Participants received 28-day cycles of:
• oral pomalidomide 4 mg (administered on days
1-21)
• oral low-dose dexamethasone 40 mg (20 mg for
patients >75 years of age; administered on days 1,
8, 15, and 22)
• intravenous daratumumab 16 mg/kg (administered
on days 1, 8, 15, and 22 of cycles 1 and 2; days
1 and 15 of cycles 3-6; and day 1 for subsequent
cycles)
The median age of patients in cohort B was 66.5 years,
and the majority of patients (67.9%) were men. The
median time from myeloma diagnosis to study entry
was 3.4 years (range = 0.5-11.6).
Seventy participants had received 1 prior line of
therapy, and the remaining 42 had received 2. Per
study inclusion criteria, all 112 patients received
lenalidomide); other prior therapies included a proteasome
inhibitor (n=89), alkylating agents (n=89), hematopoietic
cell transplant (n=78), or other agents (n=8). The
median duration of most recent prior lenalidomidebased
regimen was 23.9 months (range = 0.4-116.8).
Most patients (59.8%) had an Eastern Cooperative
Oncology Group (ECOG) Performance Status (PS) of 1,
whereas more than one-third (39.3%) of patients had
an ECOG PS of 0. More than three-quarters of patients
(78.5%; n=73) were classified as standard cytogenetic
risk at study entry, whereas 21.5% of patients (n=20)
were classified as high risk.
“These findings [indicate]
that pomalidomide-based
regimens ... can overcome
early-line resistance or
refractoriness to
lenalidomide.”
Patients were followed for a median of 17.2 months,
during which 63 patients discontinued treatment. The
other 49 patients remained on active treatment as of
data cutoff (February 8, 2019). The most common cause
of treatment discontinuation was progressive disease
(n=33), followed by patient withdrawal (n=17), adverse
events (n=4), other reasons (n=4), death (n=2), and
transition to another therapy (n=1).
The median treatment durations for each drug in
the regimen were:
• pomalidomide: 14.6 months
• low-dose dexamethasone: 13.2 months
• daratumumab: 14.4 months
—David Siegel, MD
Infections were the most common treatment emergent
adverse events (TEAEs; 75.9%), and neutropenia was the
most common hematologic any-grade TEAE (66.1%).
The most common grade 3/4 hematologic TEAEs included
neutropenia (62.5%) and anemia (17.9%).
Approximately 77.7% of patients (n=87) in the
intent-to-treat population responded to treatment.
Half of responders (n=57; 50.9%) achieved at least a
very good partial response, while nearly one-quarter
(n=27; 24.1%) achieved a complete response. The
authors noted that the median time to best response
was 3.7 months (range = 0.9-20.7), and 42.5% of patients
did not achieve a best response until 6 months or later.
The median duration of response was not reached
as of last follow-up. At 1 year, 77.7% of participants
were responding to treatment. While the investigators
observed a higher overall response rate (ORR)
among patients with standard-risk cytogenetics compared
with those with high-risk cytogenetics (79.5% vs.
55.0%), they wrote that the fact that more than onehalf
of high-risk patients responded “indicates activity
with this pomalidomide-based regimen in this difficult-to-treat
population.”
Duration of prior lenalidomide treatment also
appeared to be associated with response rates: The
ORR was higher in patients who were treated with lenalidomide
for >24 months (90.9%) compared with those
treated with lenalidomide for ≤24 months (64.9%).
The median progression-free survival (PFS) was
not reached at last follow-up, but the 1-year PFS rate
was 75.1% for the entire population. For patients who
had relapsed disease following lenalidomide or who
had lenalidomide-refractory disease, the 1-year PFS
rates were 83.2% and 72.4%, respectively. The authors
reported that there were 20 documented deaths during
follow-up, but the data on overall survival were not yet
mature and were not included in this analysis, representing
a potential study limitation.
“The higher 1-year PFS rate and ORR reported in
patients who were treated with lenalidomide for >2
years versus those treated for ≤2 years, as well as the
fact that responses deepened over time, may be suggestive
of the benefits of uninterrupted treatment
with immunomodulatory agents and tolerance to their
related AEs,” the researchers concluded. “In clinical
practice, physicians may be inclined to change class
following progressive disease on or after lenalidomide.
However, these findings add to the growing body
of evidence indicating that pomalidomide-based regimens,
including pomalidomide with daratumumab,
can overcome early-line resistance or refractoriness to
lenalidomide.”
Study authors report relationships with Bristol-Myers
Squibb, which sponsored this trial.
Reference
Siegel DS, Schiller GJ, Samaras C, et al. Pomalidomide, dexamethasone, and daratumumab
in relapsed refractory multiple myeloma after lenalidomide treatment. Leukemia. 2020 May
6. [Epub ahead of print]
14 ASH Clinical News July 2020 Bonus Mid-Year Edition