SUMMARY

• PAVO is an ongoing, phase 1b, open-label, multicenter, dose-finding, proof-of-concept study evaluating the safety, pharmacokinetics (PK), and efficacy of DARZALEX FASPRO for subcutaneous (SC) use in patients with relapsed or refractory multiple myeloma (RRMM) who have received ≥2 prior therapy.¹
  • Chari et al (2017)¹ presented (at the 59th American Society of Hematology [ASH] Annual Meeting & Exposition) the initial results from the part 1 and part 2 of the PAVO study. In part 1, in the daratumumab-MD 1200 mg vs 1800 mg dosage group, all-grade hematologic treatment-emergent adverse events (TEAEs) included thrombocytopenia (38% vs 18%), anemia (25% vs 33%), and lymphopenia (0% vs 18%). In part 2, in the DARZALEX FASPRO 1800 mg dosage group, all-grade hematologic TEAEs included thrombocytopenia (20%), anemia (12%), and lymphopenia (28%).
  • San-Miguel et al (2021)² published the updated results from the part 2 of the PAVO study. The overall response rate (ORR) was 52% and complete response (CR) rate was 4%. The most common grade 3/4 TEAE (≥10%) was lymphopenia (20%; n=5).
  • Nahi et al (2023)³ published the updated safety and efficacy results from the part 3 of the PAVO study evaluating the tapering of pre- and post-dose corticosteroids during DARZALEX FASPRO administration. The ORR was 40.5% in the entire population, 40.0% in both the 3week and 2-week corticosteroid tapering groups and 41.7% in the 1week corticosteroid tapering group. Infusion-related reactions (IRR) were reported in 5 (11.9%) patients (2-week corticosteroid tapering group, n=3; 1week corticosteroid tapering group, n=2). The most common any grade TEAEs by corticosteroid tapering groups were nausea (3-week corticosteroid tapering group, n=8 [53.3%]), nasopharyngitis (2-week corticosteroid tapering group, n=5 [33.3%]), and anemia, diarrhea, asthenia, and peripheral edema (1-week corticosteroid tapering group, n=4 [33.3%] each).
• Clemens et al (2018)⁴ presented (at the 60th ASH Annual Meeting & Exposition) population pharmacokinetic study (PPK) of the PAVO study. Results from the PPK analysis are summarized below.
• Shibayama et al (2021)⁵ reported the safety and efficacy results from MMY1008, a phase 1 study evaluating the safety, PK, and efficacy of DARZALEX FASPRO in Japanese patients with RRMM who had received ≥2 prior therapies. Safety, PK, and response findings were generally consistent with those from the PAVO study.

PRODUCT LABELING

• DARZALEX FASPRO (daratumumab and hyaluronidase-fihj) [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc.; https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/DARZALEX+Faspro-pi.pdf

CLINICAL DATA

PAVO (MMY1004; clinicaltrials.gov identifier: NCT02519452) is an ongoing, open-label, multicenter, dose-finding, proof-of-concept, phase 1b study evaluating the safety, PK, and efficacy of DARZALEX FASPRO in patients with RRMM who had received ≥2 prior therapies.^6,7

• Part 1 and 2: Chari et al (2017)¹ presented the initial results from the part 1 and part 2 of the PAVO study at a median follow-up of 5.2 months for the 1200 mg dose group (part 1), 8.3 months for the 1800 mg dose group (part 1), and 4.6 months for the 1800 mg dose group (part 2). Further updated results from part 1 have not been published.
• Part 2: Chari et al (2018)⁸ presented the results from the part 2 of the PAVO study at a median follow-up of 6.5 months. Chari et al (2018)⁶ presented the results from the part 2 of the PAVO study at a median follow-up of 12.0 months. San-Miguel et al (2021)² published the updated results from the part 2 of the PAVO study at a median follow-up of 14.2 months.
• Part 3: Nahi et al (2020)⁹ presented the initial results from the part 3 of the PAVO study evaluating the safety of pre- and post-dose corticosteroid tapering during administration of DARZALEX FASPRO in patients with RRMM at a median follow-up of 7.7 months for the 3-week corticosteroid tapering group and 5.6 months for the 2-week corticosteroid tapering group. Nahi et al (2021)¹⁰ presented the safety and efficacy results from part 3 of the PAVO study at a median follow-up of 8.3 months. Nahi et al (2023)³ published the updated safety and efficacy results from part 3 of the PAVO study at a median follow-up of 8.3 months overall, 9.2 months for the 3-week corticosteroid tapering group, 11.1 months for the 2-week corticosteroid tapering group, and 8.3 months for the 1-week corticosteroid tapering group.

Study Design/Methods - Part 1 and 2

• Key inclusion criteria: RRMM with measurable disease; ≥2 previous lines of treatment; no previous anti-cluster of differentiation 38 (CD38) therapy.^1,2
• Exclusion criteria: received anti-myeloma treatment within 2 weeks; received an allogeneic stem cell transplant or autologous stem cell transplantation (ASCT) within 12 weeks; history of malignancy (other than multiple myeloma [MM]) within 5 years; meningeal involvement of MM.⁷
• The study had 2 parts: a mixed formulation of daratumumab and recombinant human hyaluronidase PH20 (rHuPH20; daratumumab-MD) was used in part 1, and a second generation premixed concentrated coformulation of daratumumab and rHuPH20 (DARZALEX FASPRO) was used in part 2.¹
• In part 1 of the study, patients were assigned to sequential cohorts and received 28day cycles of the following until disease progression¹:
  • Daratumumab-MD 1200 mg: daratumumab 1200 mg with rHuPH20 30,000 Units SC infusion over 20 to 30 minutes (60 mL) once weekly (QW) in cycles 1 and 2, every 2 weeks in cycles 3-6, and every 4 weeks in subsequent cycles, or
  • Daratumumab-MD 1800 mg: daratumumab 1800 mg with rHuPH20 45,000 Units SC infusion over 30 minutes (90 mL) QW in cycles 1 and 2, every 2 weeks in cycles 3-6, and every 4 weeks in subsequent cycles, or
• In part 2 of the study, patients received 28-day cycles of the following until disease progression or unacceptable toxicity²:
  • DARZALEX FASPRO: daratumumab 1800 mg with rHuPH20 30,000 Units SC injection over 3-5 minutes (15 mL) QW in cycles 1 and 2, every 2 weeks in cycles 3-6, and every 4 weeks in subsequent cycles
• Pre- and/or post-infusion medications included acetaminophen, diphenhydramine, montelukast, and methylprednisolone.¹
• Primary endpoints: Trough plasma concentration (C_trough) of daratumumab at cycle 3 day 1 (C3D1); safety^1,2
• Select secondary endpoints: percentage of patients with CR; percentage of patients with ORR; duration of response; time to response^1,2

Evaluation of DARZALEX FASPRO in RRMM with ≥2 Prior Therapy in Part 1 and 2 of the PAVO Study

Chari et al (2017)¹ presented the initial results from the part 1 and part 2 of the PAVO study.

Results

Baseline Characteristics and Patient Disposition

• In part 1, a total of 53 patients were treated at the following daratumumab dose levels:
  • Daratumumab-MD 1200 mg, n=8
  • Daratumumab-MD 1800 mg, n=45
• In part 2, a total of 25 patients were treated with DARZALEX FASPRO 1800 mg.
• In part 1, the median duration of follow-up was 5.2 months (range, 1.6-13.9) and 8.3 months (range, 1.819.5) in the 1200 and 1800 mg dosing groups, respectively.
  • In part 1, in the daratumumab-MD 1200 vs 1800 mg dosing group, the treatment was discontinued in a total of 100% vs 78% of patients due to progressive disease (PD; 63% vs 62%), withdrawal by patient (13% vs 2%), decision by physician (13% vs 11%), and death (13% vs 2%), respectively.
• In part 2, the median duration of follow-up in was 4.6 months (range, 2.4-5.5).
  • In part 2, treatment was discontinued in 20% of patients in the DARZALEX FASPRO group due to PD (16%) and physician decision (4%).
• The baseline patient and disease characteristics are summarized in Table: Baseline Patient and Disease Characteristics.

Safety

• TEAEs are summarized in Table: All-Grade and Grade 3/4 Treatment-Emergent Adverse Events.
• The median duration of treatment was 2.6 months in the daratumumabMD 1200 mg group, 5.4 months in the daratumumabMD 1800 mg group, and 4.6 months in the DARZALEX FASPRO group.
• There were no TEAE-related treatment discontinuations.
• In part 2, IRRs reported in a total of 3 (12%) patients (all within 6 hours of the first injection) were:
  • Grade 3 hypertension, grade 2 chills, and grade 2 dyspnea in 1 patient, grade 1 allergic rhinitis in 1 patient, and grade 1 sneezing in 1 patient.
  • There were no grade 4 IRRs, delayed occurrences of IRRs, or treatment discontinuations due to IRRs.
• In part 2, the injection-site reactions (ISRs) were induration (1 [4%]), erythema (1 [4%]), injection-site discoloration (1 [4%]), and hematoma (1 [4%]); all of grade 1 in severity. Measurable erythema was reported in a total of 5 (20%) patients, which was reversible within 1 hour.

Pharmacokinetics (Part 2 Only)

• Administration of DARZALEX FASPRO resulted in a slower systemic absorption compared with DARZALEX for intravenous (IV) use.
• The maximum C_trough of daratumumab was similar or higher for DARZALEX FASPRO compared with DARZALEX IV.
• In a mean concentration-time profile simulation:
  • The C_trough of daratumumab remained higher for DARZALEX FASPRO than DARZALEX IV throughout the dosing regimen.
  • The mean maximum plasma concentration (C_max) of daratumumab was initially lower for DARZALEX FASPRO during the early QW dosing period and subsequently increased to be higher at the end of the QW dosing period and during the once every 2 weeks (Q2W) dosing period, compared with DARZALEX IV.
  • During the once every 4 weeks (Q4W) dosing period, the C_max for DARZALEX FASPRO was similar to DARZALEX IV overall.

Efficacy

• At a median follow-up of 4.3 months, the ORR was 38% (partial response [PR], 29%; very good partial response [VGPR], 7%; stringent complete response [sCR], 2%; ≥VGPR, 9%) in the daratumumab-MD 1200 mg group (part 1).
• At a median follow-up of 8.3 months, the ORR was 42% (PR, 22%; VGPR, 11%; sCR, 9%; ≥VGPR, 20%) in the daratumumab-MD 1800 mg group (part 1).
• At a median follow-up of 4.6 months, the ORR was 44% (PR, 16%; VGPR, 28%; ≥VGPR, 28%) in the DARZALEX FASPRO group (part 2).

Updated Analysis of the Part 2 of the PAVO Study

San-Miguel et al (2021)² published the updated results from the part 2 of the PAVO study at a median follow-up of 14.2 months.

Results

Baseline Characteristics and Patient Disposition

• A total of 25 patients were treated with DARZALEX FASPRO.
• The baseline patient and disease characteristics are summarized in Table: Baseline Patient and Disease Characteristics.
• The median duration of follow-up was 14.2 months (range, 2.4-18.5).
  • Treatment was discontinued in 76% (n=19) of patients in the DARZALEX FASPRO group due to PD (68% [n=17]) and physician decision (unconfirmed PD; 8% [n=2]).

Safety

• TEAEs are summarized in Table: All-Grade and Grade 3/4 Treatment-Emergent Adverse Events (Updated Analysis of Part 2).
• The adverse event profile of DARZALEX FASPRO was consistent with that of DARZALEX IV.²
• No TEAE-related treatment discontinuations were reported.

• Serious TEAEs were reported in 24% (n=6) of patients but were not considered related to study drug.
  • One patient died due to disease progression in context of MM-related amyloid light chain (AL) amyloidosis; this death was not considered related to DARZALEX FASPRO.
  • A secondary primary malignancy of metastatic adenocarcinoma of the prostate was reported in 1 patient.
• IRRs with DARZALEX FASPRO occurred in 4 of 25 (16%) patients, the majority of which occurred on cycle 1 day 1 (C1D1).
  • Patient 1: grade 3 hypertension, grade 2 chills, and grade 2 dyspnea
  • Patient 2: grade 1 allergic rhinitis
  • Patient 3: grade 1 sneezing
  • Patient 4: grade 3 hypertension
• Patients 1, 2, and 3 experienced their IRR after the first injection (C1D1), and patient 4 experienced their IRR after the ninth injection (C3D1).
• The IRRs of grade 3 hypertension were reversible and occurred in patients with a history of hypertension.
• There were no grade 4 IRRs or treatment discontinuations due to IRRs.
• Injection-site TEAEs included induration, erythema, injection-site discoloration, and hematoma (n=1 each; all were of grade 1).
• Measurable erythema (24%) and measurable induration (4%) at the injection site were reversible within 1 hour.
• Median (range) time to onset of IRRs was 70 (9-80) minutes.

Pharmacokinetics and Immunogenicity

• Administration of DARZALEX FASPRO resulted in a slower systemic absorption of daratumumab compared with DARZALEX IV.
• The maximum C_trough of daratumumab was similar or higher for DARZALEX FASPRO than that generally observed with DARZALEX IV and the C_trough values remained higher throughout the dosing regimen.
• The mean C_max of daratumumab for DARZALEX FASPRO was lower than DARZALEX IV initially during the early QW dosing but was higher than DARZALEX IV towards the end of the QW dosing and when dosed Q2W. When dosed Q4W, C_max of daratumumab for DARZALEX FASPRO was similar to that achieved with DARZALEX IV 16 mg/kg.
• The mean and median C_trough of daratumumab at C3D1 was 932 and 860 µg/mL, respectively, for DARZALEX FASPRO. See Table: Daratumumab Dosing Cycle 3 Day 1 in GEN501, SIRIUS, and PAVO.
• One (4%) patient reported positive for anti-daratumumab antibodies. The antibodies were detected 4 weeks after treatment and were neutralizing and transient. No IRR was reported in this patient and a best response of stable disease was achieved.
• One (4%) patient reported positive for anti-rHuPH20 antibodies at baseline and 4 (16%) patients during treatment; all antibodies were non-neutralizing. Among the 4 patients with anti-rHuPH20 antibodies during treatment, 1 patient experienced a mild IRR on C1D1, and the best responses were PR (n=1), stable disease (n=2), and PD (n=1).

Efficacy

• The ORR was 52% in the DARZALEX FASPRO group (CR, 4%; PR, 20%; VGPR, 28%; sCR, 0%).
• The median progression-free survival (PFS) was 12 months (95% confidence interval [CI], 5.6-16.6) in all treated patients (n=25) and 11.7 months (95% CI, 2.8-13.8) in patients refractory to both a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD; n=14).
• The median duration of response with DARZALEX FASPRO was 15.7 months (range, 4.6not estimable).
• The median time to best response was 1.02 months (range, 1.0-12.1).

Evaluation of Pre- and Post-Dose Corticosteroid Tapering in Part 3 of the PAVO Study

Nahi et al (2020)⁹ presented the initial results from the part 3 of the PAVO study evaluating the safety of pre- and post-dose corticosteroid tapering during administration of DARZALEX FASPRO in patients with RRMM.

Study Design/Methods

• Key eligibility criteria: Adult (≥18 years old) patients with measurable RRMM, ≥2 prior lines of therapy (including a PI and an IMiD), Eastern Cooperative Oncology Group (ECOG) performance status score of ≤2, and no prior treatment with DARZALEX or other anti-CD38 therapies.
• Patients received DARZALEX FASPRO QW during cycle 1 and 2, Q2W during cycle 3 through cycle 6, and Q4W thereafter (28 days/cycle). A 2- or 3-week corticosteroid tapering schedule was applied during the first cycle, as described below:
  • 3-week taper: methylprednisolone (MP) given orally (PO)/IV pre-dose (on C1D1, 100mg; cycle 1 day 8 [C1D8], 60 mg; cycle 1 day 15 [C1D15], 30 mg) and PO post-dose (on C1D1, 20 mg for 2 days; C1D8, 20 mg for 1 day; C1D15, 20 mg for 1 day).
  • 2-week taper: MP given PO/IV pre-dose (on C1D1, 100 mg; C1D8, 60 mg) and PO post-dose (on C1D1, 20 mg for 2 days; C1D8, 20 mg for 1 day)
  • Dose limiting toxicities (DLTs) were assessed from C1D1 to cycle 2 day 4 (C2D4) for the 3week taper schedule and from C1D1 to cycle 1 day 25 (C1D25) for the 2-week taper schedule.
• Primary endpoint: safety of pre- and post-dose steroid tapering
• Key secondary endpoints: ORR and CR

Results

Patient Characteristics

• Overall, 30 patients were included (3-week corticosteroid tapering group, n=15; 2-week corticosteroid tapering group, n=15).
• The baseline patient and disease characteristics are presented in Table: Baseline Patient and Disease Characteristics.
• The median duration of follow-up was 7.7 months (range, 1.9-14.8) in the 3-week corticosteroid tapering group and 5.6 months (range, 1.7-11.1) in the 2-week corticosteroid tapering group.
• Patients in the 3-week corticosteroid tapering group received a median of 14.0 (range, 2-22) doses of DARZALEX FASPRO without corticosteroids.
• Patients in the 2-week corticosteroid tapering group received a median of 12.0 (range, 3-19) doses of DARZALEX FASPRO without corticosteroids.

Safety

• Grade 3/4 TEAEs were reported in 53% (n=8) of patients in both the 3-week and 2week corticosteroid tapering group.
• Serious TEAEs were reported in 33% (n=5) and 40% (n=6) of patients in the 3-week and 2-week corticosteroid tapering group, respectively.
• The most common TEAEs in the 3-week and 2-week corticosteroid tapering group are presented in Table: Most Common TEAEs.
• No IRRs were reported in the 3-week corticosteroid tapering group.
• IRRs reported in a total of 3 (20%) patients in the 2-week corticosteroid tapering group (all occurring on the first DARZALEX FASPRO administration) were:
  • Grade 1 pyrexia in 1 patient, grade 1 sore throat in 1 patient, and grade 3 increased blood pressure, grade 2 chills, and grade 1 tachycardia in 1 patient.
• The median time to onset of IRRs was 65 minutes (range, 31-79) after the first DARZALEX FASPRO administration.

Efficacy

• Response rates in the overall population and in the 3-week and 2-week corticosteroid tapering groups are as follows:
  • At a median follow-up of 6.5 months, in all treated patients, the ORR was 40%, ≥VGPR 20%, and CR 3%.
  • At median follow-up of 7.7 months, in the 3-week corticosteroid tapering group, the ORR was 40%, ≥VGPR 27%, and CR 7%.
  • At a median follow-up of 5.6 months, in the 2-week corticosteroid tapering group, the ORR was 40%, ≥VGPR 27%, and CR 0%.
• Among responders (n=6 in each group), the median time to first response was 0.97 (range 0.9-1.1) months for the 3-week corticosteroid tapering group and 0.97 (range 0.9-1.9) months for the 2-week corticosteroid tapering group.
• The median duration of response was not reached in either group.
• For all treated patients (n=30), the median PFS was 5.6 months, with an estimated 9-month PFS of 36.8%.

Updated Analysis of Part 3 of the PAVO Study

Nahi et al (2023)³ published the updated safety and efficacy results from the part 3 of the PAVO study.

Study Design/Methods

• After a protocol amendment, a 1-week corticosteroid tapering group was added to the study.¹¹ Patients included in this group received DARZALEX FASPRO at the same dosage and schedule as the 3-week and 2-week corticosteroid tapering groups, along with IV dexamethasone given pre-dose (C1D1, 20 mg).³
• DLTs were assessed from C1D1 to C2D4 for the 3week taper schedule, from C1D1 to C1D25 for the 2-week taper schedule, and from C1D1 to C1D11 for the 1-week taper schedule.

Results

Patient Characteristics

• A total of 42 patients were enrolled in part 3 of the PAVO study (3-week corticosteroid tapering group, n=15; 2-week corticosteroid tapering group, n=15; and 1-week corticosteroid tapering group, n=12). See Table: Patient Demographics and Baseline Characteristics.
• The median duration of follow-up was 8.3 months overall, 9.2 months (range, 1.9-25.5) for the 3-week corticosteroid tapering group, 11.1 months (range, 1.7-24.0) for the 2-week corticosteroid tapering group, and 8.3 months (range, 0.4-13.1) for the 1-week corticosteroid tapering group.
• The median number of DARZALEX FASPRO doses was 18 (range, 2-38).
• Treatment discontinuation was reported in 13 (86.7%) patients in the 3-week corticosteroid tapering group, in 13 (86.7%) patients in the 2-week corticosteroid tapering group, and in 7 (58.3%) patients in the 1-week corticosteroid tapering group. Most discontinuations were due to PD (3-week corticosteroid tapering group, 10 [66.7%] patients; 2-week corticosteroid tapering group, 12 [80.0%] patients; and 1-week corticosteroid tapering group, 5 [41.7%] patients).

Safety

• IRRs were reported in 5 (11.9%) patients during the first administration only (3-week corticosteroid tapering group, n=0; 2-week corticosteroid tapering group, n=3 [20.0%]; 1week corticosteroid tapering group, n=2 [16.7%]).
• The median time to onset of IRRs was 79.0 minutes (range, 31-555). All IRRs resolved on the same day.
• The most common (≥5%) IRRs were chills and pyrexia (n=3 [7.1%] each). Additional IRRs included tachycardia, increased blood pressure, and oropharyngeal pain (n=1 [2.4%] each).
• All IRRs were generally mild, except for one grade 3 IRR (increased blood pressure) reported in the 2-week corticosteroid tapering group.
• IRRs of grade 4, IRRs meeting DLT definition, or IRRs leading to treatment discontinuation were not reported.
• All patients experienced ≥1 TEAEs, 16 (38.1%) patients experienced serious TEAEs, and 21 (50.0%) patients experienced grade ≥3 TEAEs.
• The most common TEAEs are presented in Table: Most Common TEAEs (Updated Analysis of Part 3).
• TEAEs led to death in 6 patients (3-week corticosteroid tapering group, n=2 [complications from diffuse large B-cell lymphoma and PD]; 2-week corticosteroid tapering group, n=1 [PD]; 1-week corticosteroid tapering group, n=3 [staphylococcal pneumonia (grade 5), pulmonary embolism (grade 5), and PD]).

PK and Immunogenicity

• Within the PK-evaluable population (n=37), the mean serum daratumumab concentrations at C3D1 were 676 μg/mL (standard deviation [SD], 314) overall, 604 μg/mL (SD, 280) in the 3-week corticosteroid tapering group, 731 μg/mL (SD, 382) in the 2-week corticosteroid tapering group, and 706 μg/mL (SD, 270) in the 1-week corticosteroid tapering group.
• Of the immunogenicity evaluable patients (n=41), none tested positive for antidaratumumab antibodies. The reported anti-rHuPH20 antibodies (3-week corticosteroid tapering group, n=6 [40.0%]; 2week corticosteroid tapering group, n=3 [20.0%]; and 1week corticosteroid tapering group, n=1 [9.1%]) were not neutralizing.

Efficacy

• Efficacy outcomes are presented in table: Efficacy Outcomes (Updated Analysis of Part 3).

Population Pharmacokinetics Study

Clemens et al (2018)⁴ evaluated the clinical pharmacology of daratumumab-MD, daratumumab SC from the PAVO⁶ study, including a simulation of a combined IV and SC PPK model from the GEN501¹² and SIRIUS¹³ studies.

Study Design/Methods

• PK analysis was performed using the PAVO Study Design/Methods described above.
• Additional secondary endpoints included the evaluation of immunogenicity of daratumumab and rHuPH20.  
• Blood samples were obtained at a specified time point for PK evaluations:
  • Cycle 1: days 1 (pre-dose, end of infusion [EOI], EOI + 2 hours, EOI + 12 hours), 2, 3, 4, 8, 15, and 22.
  • Cycle 2: days 1, 8, 15, 22, (pre-dose, EOI, EOI + 2 hours), 23, and 25
  • Cycle 3: day 1 (pre-dose and EOI).
  • Cycle 4, 6, and 8: day 1.
  • Post-treatment: week 4 and week 8.
• Blood samples for anti-daratumumab and anti-rHuPH20 antibodies were collected on C1D1, C1D15, cycle 2 day 22 (C2D22), cycle 4 day 1, and post-treatment week 4 and 8.
• A total of 899 samples were analyzed from 53 patients in part 1 of PAVO (1200 mg group, n=8; 1800 mg group, n=45).
• A total of 2572 PK samples were obtained from 223 patients in GEN501 and SIRIUS study.

Results

• In part 1 of the PK analysis, administration of daratumumab-MD 1200 and 1800 mg resulted in a slower absorption into the systemic circulation (median time to C_max [T_max] was 72.6 and 71.8 hours, for the daratumumab-MD 1200 and 1800 mg group, respectively) compared with the daratumumab 16 mg/kg IV group.
• The mean C3D1 C_trough was similar or higher for daratumumab-MD 1800 mg group vs daratumumab 16 mg/kg IV group. See Table: Daratumumab Dosing Cycle 3 Day 1 in GEN501, SIRIUS, and PAVO.

PPK Simulations

• The model indicated approximately 88% of patients receiving daratumumab-MD 1800 mg to achieve the effective concentration of 274 μg/mL vs 73% of patients receiving daratumumab-MD 1200 mg and 80% receiving daratumumab 16 mg/kg IV dose.
• The C_troughs for daratumumab-MD 1200 mg and 1800 mg were lower than daratumumab 16 mg/kg IV group.
• Daratumumab-MD 1800 mg demonstrated higher C_troughs throughout the dosing period without increasing the C_max compared to daratumumab 16 mg/kg IV group.
• In part 2 of the PAVO study, the mean C3D1 C_trough was higher for daratumumab SC 1800 mg vs daratumumab-MD 1800 mg and daratumumab 16 mg/kg IV group.
• The range of C_max and C_trough of daratumumab SC 1800 mg group was similar to daratumumab 16 mg/kg IV group.
• In part 1 of fixed dose vs body weight-based dosing simulation, a fixed-dose of daratumumab 1800 mg was selected to be further evaluated for part 2 of the study as it demonstrated similar or higher PK values compared to daratumumab 16 mg/kg IV group.
• From part 1 and 2 of the PAVO study evaluating 78 patients, one (1%) patient was positive for anti-DARA antibodies, 6 (8%) patients had baseline samples positive for anti-rHuPH20 antibodies, and 10 (13%) patients were positive for anti-rHuPH20 antibodies. See Table: Immunogenicity Summary of Anti-daratumumab and Anti-rHuPH20 Antibodies.

Phase 1 Study Evaluating the Safety, PK, Efficacy in Japanese Patients with RRMM

Shibayama et al (2021)⁵ reported the safety and efficacy results from MMY1008 (clinicaltrials.gov identifier: NCT03242889), a phase 1 study evaluating the safety, PK, and efficacy of DARZALEX FASPRO 1800 mg in Japanese patients with RRMM who have received >2 prior therapies at a median duration of follow-up of 12.9 months. Safety, PK, and response findings were generally consistent with those from the PAVO study.

Study Design/Methods

• Phase 1, open label, multicenter study.
• Patients received DARZALEX FASPRO over 3-5 min (15 mL) QW in cycles 1 and 2, every 2 weeks in cycles 3-6, and monthly in subsequent cycles.
• Pre- and/or post-infusion medications included acetaminophen, diphenhydramine, montelukast, and methylprednisolone.
• Key inclusion criteria: RRMM with measurable disease; ≥2 previous lines of treatment, including a PI and IMiD; ECOG status of 0-1.
• Exclusion criteria: prior use of anti-CD38 therapy; received anti-myeloma treatment within 2 weeks; received an allogeneic stem cell transplant or ASCT within 12 weeks; history of malignancy (other than certain carcinomas considered cured) within 3 years; meningeal or central nervous system involvement of MM; clinically significant cardiac disease; plasma cell leukemia; Waldenström’s macroglobulinemia; polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin abnormalities (POEMS) syndrome; primary AL amyloidosis.
• Primary endpoint: safety, including DLTs (defined as: IRRs grade ≥3; hematologic toxicities and non-hematologic toxicities grade ≥3).
• Secondary endpoints: PK; immunogenicity; ORR (defined as >PR); duration of response; time to response.

Results

Patient Characteristics

• A total of 6 patients were enrolled. The baseline characteristics of these patients are listed in table: Baseline Characteristics.

Safety

• TEAEs are summarized in Table: Treatment-Emergent Adverse Events.
• DLTs, assessed by TEAEs, were evaluated from the first dose of DARZALEX FASPRO through the end of cycle 1, with a safety assessment prior to DARZALEX FASPRO administration on day 1, cycle 2.
• No DLTs, no grade 4 AEs, no IRRs, no serious TEAEs, and no TEAEs leading to modification or discontinuation were reported.
• Four patients had injection-site reactions. All four patients had injection-site erythema, with 1 patient also having injection-site induration.
• All injection-site reactions were grade 1, reversible, and lasted ≤2 hours post administration.
• One (16.7%) patient was positive for anti-daratumumab antibodies but had no symptoms and achieved clinical response after antibody detection.

Pharmacokinetics

• Daratumumab was detectable in the serum 2 hours after the first DARZALEX FASPRO injection.
• During weekly dosing, the mean C_trough of daratumumab increased from 155 μg/mL (SD, 29) at the first dose (C1D8) to 879 μg/mL (SD, 247) at the eighth dose (cycle 3 day 1).
• During monthly dosing (cycle 8 day 1), the mean C_trough decreased to 745 μg/mL (SD, 348) and stabilized thereafter.
• The mean C_max was 177 μg/mL (SD, 28) after the first dose and increased to 1092 μg/mL (SD, 318) after the last weekly dose (C2D22).
• The mean AUC_0-7d was 990 day×μg/mL (SD, 145) after the first dose and increased to 7015 day×μg/mL (SD, 1895) after the last weekly dose (C2D22).
• The median T_max following first dose was 3 days (range, 2.9-7.0) and approximately 1 day (range, 0.9-3.1) following the last weekly dose.

Efficacy

• The median (range) duration of treatment was 12.5 (4.6-12.9) months.
• The median (range) duration of follow-up was 12.9 (6.2-12.9) months.
• The ORR was 67% (1 [16.7%] patient achieved CR, 1 [16.7%] achieved VGPR, and 2 [33.3%] achieved PR).
• The median (range) time to response (≥PR) was 1.0 (0.9-1.9) months.
• The median duration was not able to be calculated at the time of clinical cutoff.

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File databases (and/or other resources, including internal/external databases) was conducted on 10 February 2025.