Haematology+Oncology_News

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Heavily pretreated myeloma responds to
pembrolizumab combo
BY PATRICE WENDLING
Frontline Medical News
The one-two punch of combining the pro-
grammed cell death-1 (PD-1) inhibitor pem-
brolizumab with the immunomodulatory drug
lenalidomide and low-dose dexamethasone pro-
duced responses in 76% of 17 heavily pretreated
patients with relapsed or refractory multiple
myeloma in the KEYNOTE-023 study.
This included four very good partial responses
(24%) and nine partial responses (53%).
In nine lenalidomide-refractory patients, the
overall response rate was 56%, including two very
good partial responses (22%) and three partial
responses (33%).
The efficacy results are preliminary, but support
the continued development of pembrolizumab
in patients with multiple myeloma, Dr Jesús San
Miguel of Clinica Universidad de Navarra, Pam-
plona, Spain, said at the annual meeting of the
American Society of Hematology.
He closed his presentation with two illustra-
tive cases highlighting a rapid response lasting
more than a year and a half in a 49-year-old man
with myeloma triple-refractory to autologous
stem cell transplant (ASCT), lenalidomide, and
dexamethasone.
The second case involved a patient with double-
refractory myeloma and extramedullary disease
who achieved a stringent complete response after
two cycles of fourth-line pembrolizumab that was
associated with a “striking” reduction in lesion
volume on computed tomography scans, he said.
The median duration of response among the
17 evaluable patients was 9.7 months.
The median time to first response was 1.2
months (range 1.0 months to 6.5 months). But
some patients require more time and, interestingly,
the quality of the response was upgraded in 11%
with continued treatment, Dr San Miguel said.
The rationale for combining PD-1 inhibitors with
immunomodulatory drugs (IMiD) lies in recent
research showing that lenalidomide reduces PD-
ligand 1 and PD-1 expression on multiple myeloma
cells as well as on T and myeloid-derived suppres-
sor cells, he explained. In addition, lenalidomide
enhances checkpoint blockade-induced effector
cytokine production inmultiplemyeloma bonemar-
row and induces cytotoxicity against myeloma cells.
“Lenalidomide will increase the number of
T cells and the T-cell activation and anti-PD-1
will release the brake in order to allow these
activated T cells to interact with the tumour,”
Dr San Miguel said.
Patients enrolled in KEYSTONE-023 were
heavily pretreated, with 26% previously exposed
to pomalidomide, 76% refractory to lenalidomide,
80% refractory to their last line of therapy, and
86% having undergone prior ASCT. Half the pa-
tients were double, triple, or quadruple refractory,
he noted.
The study (Abstract 505) was designed to iden-
tify the maximum tolerated dose (MTD) of pem-
brolizumab and to assess its safety and tolerability
when given with lenalidomide and dexamethasone
in patients with multiple myeloma failing at least
two prior lines of therapy including a proteasome
inhibitor and an IMiD. Their median age was 62
years; 64% were male.
In the dose-determination stage, three of six
patients treated with pembrolizumab 2 mg/kg plus
lenalidomide 25 mg and dexamethasone 40 mg
experienced dose-limiting toxicities that resolved
without treatment discontinuation.
After dose adjustments, a “flat dose” of pem-
brolizumab 200 mg given every other week in a
rapid 30-minute intravenous infusion without
premedication with lenalidomide 25 mg on days
1–21 and dexamethasone 40 mg weekly did not
cause any dose-limiting toxicities and was identi-
fied as the final MTD, Dr San Miguel said.
The regimen is to continue for 24 months or
until tumour progression or excessive side effects
and was carried forward into the dose-expansion
stage in 33 additional patients with a median
follow-up of 48 days.
Among all 50 patients evaluable for safety, 72%
experienced at least one treatment-related adverse
event of any grade and 46% (23/50 patients) had
grade 3/4 adverse events including neutropenia
(22%), thrombocytopenia and anaemia (8% each),
hyperglycaemia (6%), and fatigue, muscle spasms,
and diarrhoea (2% each).
The adverse events were consistent with the
individual drug safety profiles, but “the incidence
may be underestimated due to the limited drug
exposure,” Dr San Miguel cautioned.
Immune-mediated adverse events included
two cases each of hyper- and hypothyroidism,
one case of thyroiditis, and one grade 2 adrenal
insufficiency. No cases of colitis or pneumonitis
were reported. No dose modifications or treat-
ment discontinuations were required to mange
the immune-related side effects, he said. No
treatment-related deaths occurred.
In a second study reported during the same oral
myeloma session, pneumonitis cropped up in 10%
of heavily pretreated patients with relapsed multi-
ple myeloma receiving a slightly different regimen
of pembrolizumab plus the IMiD pomalidomide
and dexamethasone. The overall response rate in
the phase II study was 60% among 27 evaluable
patients and 55% in those double-refractory to
IMiDs and proteasome inhibitors.
Genes affecting risk, severity of chronic ITP are identified
BY MARY JO DALES
Frontline Medical News
Children with chronic immune thrombocy-
topenia (ITP) have an increased frequency
of damaging variants in genes associated
with cellular immunity, notably IFNA17 and
IFNLR1, based on the results of whole ge-
nome sequencing.
The links to IFNA17 and IFNLR1 genes,
which are involved in T cell pathways, re-
main significant when patients are stratified
according to disease severity, Dr Jenny M.
Despotovic reported at the annual meeting
of the American Sociey of Haematology. The
finding is further evidence for the role of T
cell abnormalities in the pathophysiology of
chronic ITP.
These may be important candidate genes
involved in immune regulation and in sus-
tained autoimmunity, which appears to be
due to generalised immune dysregulation that
includes altered T cell balance with a shift
toward immune activation (increased Th1/
Th2 ratio) as well as decreased number and
impaired function of regulatory T cells, said
Dr Despotovic, of Texas Children’s Cancer
and Haematology Centres, Baylor College of
Medicine, Houston.
In their study, Dr Despotovic and her col-
leagues performed whole exome sequencing
on 262 samples with robust phenotype data
from children with chronic ITP in the North
American Chronic ITP Registry and the
Platelet Disorders Centre at the Weill-Cornell
Medical Centre. All but three patients were
less than 20 years old at diagnosis; 83% had
primary ITP, 10% had Evans syndrome, and
7% had other autoimmune disorders.
To identify candidate genes associated
with ITP susceptibility, sequencing data were
compared for 172 ITP cases of European
American ancestry and 5664 controls of Eu-
ropean American ancestry with platelet levels
over 150 x 109 /L in the Atherosclerosis Risk
in Communities (ARIC) Study. In a separate
analysis, phenotype data for ITP cases were
reviewed and cases were stratified by disease
severity according to the need for second line
treatment.
A significant increase in the frequency of
several damaging variants were identified in
genes in the ITP cohort. The most significant
associations were detected in the IFNA17
gene, which is involved in transforming growth
factor beta secretion and could affect number
and function of regulatory T cells.
IFNA17 rs9298814 was identified in 26%
of cases in the ITP cohort compared to less
than 0.01% of controls. In all, 43% of ITP pa-
tients had at a presumed deleterious variant
of IFNA17.
IFNA17 gene variants remained significant
in the most severely affected patients, spe-
cifically those requiring second line therapy,
providing further evidence for this gene’s
functional relevance in the pathogenesis and
pathophysiology of ITP, Dr Despotovic said.
Other genes with known impact on T cell
number or function, including DGCR14,
SMAD2 and CD83 also contained an in-
creased frequency of variants in the European
American ITP cohort. IFNLR1 and REL genes
were also significantly associated with need for
second line ITP therapy.
Analysis of this large cohort did not vali-
date any of over 20 variants that have been
previously published as candidates for ITP
susceptibility or evolution to chronic ITP, she
added.
American Society
of Haematology
5–8 December • Orlando, Florida
The 57th American Society of
Hematology annual meeting, the
premier haematology event in
malignant and non-malignant
haematology, presented the
year’s most significant scientific
discoveries and relevant key
updates in the field, some of
which we feature here in our
coverage of the meeting. Further
in-depth coverage and expert
commentaries can be found on
© 2015 American Society of Hematology.
The most significant associations
were detected in the IFNA17 gene,
which is involved in transforming
growth factor beta secretion and
could affect number and function of
regulatory T cells.
Haematology & O ncology News • Vol. 9 • No. 1 • 2016 12
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