Literature Scan
BCMA-Targeting CAR T-Cell Therapy Shows High
Response Rate in Pretreated Myeloma
Multiple myeloma (MM) is a potential target
for chimeric antigen receptor (CAR) T-cell
therapies, according to final results from
a first-in-human trial of B-cell maturation
antigen (BCMA)–targeting CAR (CAR-
BCMA) T cells published in the Journal of
Clinical Oncology. Eighty-one percent of
patients with heavily pretreated MM enrolled
in this small trial responded to treatment
with CAR-BCMA T cells; however, “toxic-
ity was substantial,” noted the authors, led
by Jennifer Brudno, MD, from the National
Cancer Institute. BCMA, a member of the
tumor necrosis factor receptor superfamily, is
expressed on malignant plasma cells in most
patients with MM.
“The infrequent [administration schedule]
nature of CAR T-cell therapy allows some pa-
tients treatment-free intervals when they often
enjoy a high quality of life without therapy-
related toxicities,” the investigators wrote.
“However, the short-term [cytokine release
syndrome (CRS)] toxicities after CAR T-cell
infusions are a disadvantage of [this modality].”
The trial included 24 patients with relapsed/
refractory MM who received CAR-BCMA T
cells at doses ranging from 0.3×10 6 cells/kg to
9×10 6 cells/kg. The article reports results from
the 16 patients who were treated at the highest
dose (9×10 6 cells/kg).
The participants had received a median of
9.5 therapies (range = 3-19) prior to enroll-
ment, and most (63%) were refractory to their
last treatment regimen. Six patients had high-
risk cytogenetics, including del17p or t(4;14).
From 5 to 3 days prior to CAR-BCMA
T-cell infusion, patients underwent condition-
ing with cyclophosphamide 300 mg/m 2 and
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fludarabine 30 mg/m 2 daily; antimyeloma che-
motherapy also was administered to enhance
the activity of adoptively transferred T cells. Pa-
tients were monitored monthly until 6 months
after infusion, then every 6 months afterward.
Thirteen of the 16 patients responded to
treatment, including:
• partial response (PR): 3 patients (duration
of anti-MM response range = 2-24+
weeks)
the subsequent patients treated at this dose were
required to have lower MM burdens (<30% MM
plasma cells). “Patients with CRS of grade 3 or
4 had higher levels of bone marrow plasma cells
compared with patients who had less than grade
3 CRS, which indicates an increased chance of
severe CRS in patients with high MM burdens,”
the authors added.
Five patients received tocilizumab and four
received corticosteroids to manage adrenal
insufficiency or CRS-related toxicities.
• very good PR: 8 patients (range = 11-66
weeks)
• stringent complete response: 2 patients
(range = 17-37+ weeks)
The median event-free survival (EFS) was 31
weeks (range not reported), and six patients had
ongoing responses at the time of publication.
The remaining 10 patients experienced MM
progression.
Nine patients had evaluable bone marrow
biopsies and immunohistochemistry staining for
CD138 before and after CAR-BCMA infusion.
By 2 months after infusion, all patients had a
decrease in bone marrow plasma cells. Among
the 11 patients who were evaluated for minimal
residual disease (MRD) by flow cytometry, all 11
were determined to be
MRD-negative.
“All but [one pa-
tient] had a substan-
tial decrease in their
serum MM marker,”
the authors added.
They also noted
several factors that
appeared to be associ-
ated with response
to CAR-BCMA
T-cell therapy: Serum
BCMA declined in
responders, while
nonresponders expe-
rienced only minor
changes in their
serum BCMA levels
(p<0.001), and peak
levels of CAR-positive
cells were higher in
responders than non-
responders (p=0.013).
All but one patient
experienced CRS, in-
cluding six with grade
3/4 CRS, which led to “substantial CRS-related
toxicities,” the researchers noted.
The first two patients who were treated with
CAR-BCMA T-cells at the 9×10 6 cells/kg dose
developed CRS and experienced severe CRS
toxicities, and each had high MM burdens (90%
and 80%, respectively, of bone marrow cells were
MM plasma cells). Based on this observation,
“This trial has
demonstrated
anti-myeloma
activity by CAR-
BCMA T cells
against myeloma
resistant to other
therapies.”
—JENNIFER BRUDNO, MD
Six patients (38%) required vasopressors
for hypotension, and one patient required
mechanical ventilation. The other most com-
mon grade 3/4 toxicities included leukopenia
(n=15), neutropenia (n=14), and thrombocy-
topenia (n=10).
“CAR T cells have the advantage of being
mechanistically different from all other MM
modalities, and this trial has demonstrated
anti-MM activity by CAR-BCMA T cells
against MM resistant to other therapies,” the
authors concluded. They added, though, that
this early-phase study was limited by lack of
a comparator arm and the small number of
enrolled patients.
The researchers also noted several areas
for improving the use of CAR-BCMA T-cell
therapies in patients with MM. These include
enhancing in vivo CAR T-cell proliferation
and survival, combining CAR T cells with
other anti-MM therapies, and the prevention
and management of toxicities.
The authors report no relevant conflicts of
interest.
REFERENCE
Brudno JN, Maric I, Hartman SD, et al. T Cells genetically modified to express an
anti–B-cell maturation antigen chimeric antigen receptor cause remissions of
poor-prognosis relapsed multiple myeloma. J Clin Oncol. 2018;36:2267-80.
December 2018