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Adding daratumumab to bortezomib and
dexamethasone improves outcomes of relapsed
or refractory multiple myeloma significantly
Daratumumab improved progression-free survival, time to progression, and objective response rates
significantly in combination with bortezomib and dexamethasone versus bortezomib and dexamethasone
alone, reports an interim outcome of the phase 3, randomised, controlled CASTOR trial.
A
ntonio Palumbo, MD, of the University of Turin, Italy, explained
that daratumumab, a human anti-CD38 immune globulin G
κ
monoclonal antibody, induces deep and durable responses
with a favourable safety profile in patients with relapsed or refractory
multiple myeloma.
Dr Palumbo and colleagues are performing the first randomised con-
trolled study of daratumumab (CASTOR). Their aim is to compare the
efficacy and safety of daratumumab + bortezomib and dexamethasone
versus bortezomib and dexamethasone alone in patients with relapsed
or refractory multiple myeloma.
Patients who received at least one prior line of therapy were ran-
domised 1:1 to eight cycles every 3 weeks of bortezomib 1.3 mg/m
2
subcutaneously on days 1, 4, 8, and 11; and dexamethasone 20 mg
orally on days 1, 2, 4, 5, 8, 9, 11, and 12 with or without daratumumab
(16 mg/kg intravenously once weekly in cycles 1–3, day 1 of cycles
4–8, then every 4 weeks until progression). The primary endpoint was
progression-free survival.
A total of 498 patients (daratumumab + bortezomib + dexametha-
sone, n=251; bortezomib + dexamethasone, n=247) were randomised.
Baseline demographics and disease characteristics were well balanced
between the two groups.
Patients received a median of two prior lines of therapy (range one
to ten). Sixty-six percent received prior bortezomib; 76% received
a prior immunomodulatory drug; 48% received a prior proteasome
inhibitor and an immunomodulatory drug; 33% were refractory to an
immunomodulatory drug; and 32% were refractory to their last line
of prior therapy.
After a median follow-up of 7.4 months, daratumumab significantly
improved median progression-free survival (61% reduction in risk of
progression/death) for daratumumab + bortezomib +dexamethasone
versus bortezomib + dexamethasone.
Addition of daratumumab to bortezomib + dexamethasone also delayed
median time to disease progression significantly versus bortezomib +
dexamethasone (not reached vs 7.3 months; hazard ratio 0.30; 95%
CI 0.21–0.43; P < 0.0001).
Daratumumab increased overall response rate significantly (objec-
tive response rate 83% vs 63%, P < 0.0001), in addition to doubling
the rates of very good partial responses or better (59% vs 29%, P <
0.0001) and complete responses or better (19% vs 9%, P = 0.0012)
for daratumumab + bortezomib + dexamethasone vs bortezomib +
dexamethasone, respectively.
The median duration of response was not reached for daratumumab
+ bortezomib + dexamethasone versus 7.9 months for bortezomib +
dexamethasone. All planned sensitivity analyses demonstrated that
daratumumab + bortezomib + dexamethasone was better than borte-
zomib + dexamethasone, which was consistent with results from the
primary analysis.
In addition, prespecified subgroup analyses on progression-free
survival demonstrated that the treatment effect of daratumumab +
bortezomib + dexamethasone over bortezomib + dexamethasone was
consistent across all selected subgroups.
Most common (>25%) treatment-emergent adverse events with
daratumumab + bortezomib + dexamethasone and bortezomib +
dexamethasone were thrombocytopenia (59%/44%), peripheral
sensory neuropathy (47%/ 38%), diarrhoea (32%/22%), and anaemia
(26%/31%), respectively.
Most common (>10%) grade 3/4 treatment-emergent adverse events
with daratumumab + bortezomib + dexamethasone and bortezomib
+ dexamethasone were thrombocytopenia (45%/33%), anaemia
(14%/16%), and neutropenia (13%/4%), respectively. Seven percent
of patients who received daratumumab + bortezomib + dexameth-
asone and 9% of those who received bortezomib + dexamethasone
discontinued due to a treatment-emergent adverse event.
Daratumumab-associated infusion-related reactions (45% of patients)
occurred mostly during the first infusion (98% of patients with an infu-
sion-related reaction). Most were
grade 1/2 (grade 3/4, 9%/0%).
Dr Palumbo concluded that
daratumumab improved pro-
gression-free survival, time to
progression, and objective re-
sponse rate in combination with
bortezomib and dexamethasone
significantly versus bortezomib +
dexamethasone alone.
Daratumumab + bortezomib +
dexamethasone doubled rates of
both very good partial response
or better and stringent complete
response/complete response ver-
sus bortezomib + dexamethasone
alone.
The safety of daratumumab +
bortezomib + dexamethasone
is consistent with the known
safety profile of daratumumab,
bortezomib, and dexamethasone.
The addition of daratumumab to
bortezomib and dexamethasone
should be considered a new
standard of care for patients with
relapsed or refractory multiple
myeloma receiving bortezomib +
dexamethasone alone.
© EHA 2016
EUROPEAN HEMATOLOGY ASSOCIATION 2016 CONGRESS
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PRACTICEUPDATE HAEMATOLOGY & ONCOLOGY