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J. San-Miguel et al.
AB
Figure 1. Serum concentrations of daratumumab over time. The mean (± standard deviation) serum concentrations of daratumumab over time (A) after the first dose and (B) after the last weekly dose (eighth dose). DARA: daratumumab; Ctrough: trough concentration; C3D1: day 1 of cycle 3; IV: intravenous; SC: subcutaneous. aFrom the GEN501 study.16
Table 2. C trough
Study
PAVOa
GEN501 part 2
SIRIUS
for end of weekly daratumumab dosing (day 1 of cycle 3) for DARA SC 1,800 mg and historical data for daratumumab 16 mg/kg IV.
Dose/route
1,800 mg SC
16 mg/kg IV
16 mg/kg IV
n Mean
22 932
27 617
73 573b
Daratumumab cycle 3, day 1 C (mg/mL) trough
Median CV%
860 42%
714 51%
560 58%
C
bAs reported by Clemens et al.22
rHuPH20 antibodies during treatment, one patient experi- enced a mild IRR on day 1 of cycle 1, and best responses were partial response (1 patient), stable disease (2 patients), and progressive disease (1 patient).
Safety
The adverse event profile of DARA SC was consistent with the known safety and tolerability profile of IV daratu- mumab. The most frequently reported treatment-emergent adverse events (TEAE) were lymphopenia (32%), arthralgia (28%), back pain (28%), and thrombocytopenia, diarrhea, and nasopharyngitis (24% each) (Table 3). The most com- mon grade 3/4 TEAE was lymphopenia (20%) (Table 3). No treatment discontinuations due to TEAE were observed. Serious TEAE were reported in six (24%) patients who received DARA SC but were not considered related to the study drug. One patient died during part 2 of the study due to disease progression in the context of MM-related amy- loid light chain (AL) amyloidosis (clinically significant car- diac involvement was not present); this death was not con- sidered related to DARA SC. A secondary primary malig- nancy was observed in one patient (metastatic adenocarci- noma of prostate). There were no reports of tumor lysis syndrome or intravascular hemolysis.
The incidence and severity of IRR was low with DARA SC 1,800 mg. Among the 25 patients who received DARA SC 1,800 mg, four (16%) reported IRR, the majority of which occurred on day 1 of cycle 1. The median time to onset of an IRR was 70 (range, 9-80) min. Patient 1 experi- enced grade 3 hypertension, grade 2 chills, and grade 2 dys-
trough
: trough concentration; DARA: daratumumab; SC: subcutaneous; IV: intravenous; CV: coefficient of variation. aBased on the pharmacokinetic-evaluable population.
pnea. Patient 2 experienced grade 1 allergic rhinitis, patient 3 experienced grade 1 sneezing, and patient 4 experienced grade 3 hypertension. Patients 1, 2, and 3 experienced their IRR following the first injection (day 1 of cycle 1), whereas patient 4 experienced the IRR following the ninth injection (day 1 of cycle 3). The IRR of grade 3 hypertension were reversible, and both occurred in patients with a medical his- tory of hypertension. There were no grade 4 IRR and no discontinuations due to IRR.
Injection-site TEAE were observed in three (12%) patients; these included injection-site induration, injection- site discoloration, erythema, and hematoma (n=1 each; all grade 1 severity). Erythema and induration were objectively measured for all injections, regardless of attribution as a TEAE. Measurable erythema (24%) and measurable indura- tion (4%) at the injection site resolved within 1 h.
Efficacy
At a median follow-up of 14.2 months, the ORR with DARA SC 1,800 mg was 52%, which included a complete response in one (4%) patient, very good partial responses in seven (28%) patients, and partial responses in five (20%) patients (Figure 3A). The median time to best response was 1.02 (range, 1.0-12.1) months, and the median duration of response was 15.7 (range, 4.6-not estimable) months. Among 13 responders, three responses deepened over time (Figure 3B); one patient with an initial partial response at month 2 went on to achieve a complete response at month 12, and two patients who achieved initial partial responses at month 1 went on to achieve very good partial responses
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haematologica | 2021; 106(6)