SUMMARY

• PAVO was a 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)² presented the initial results from part 1 and part 2 of the PAVO study. In part 1, the overall response rate (ORR) in the daratumumab mix-and-deliver (MD) 1200 mg group was 25% vs 38% in the daratumumab-MD 1800 mg group.³ In the daratumumab-MD 1200 mg vs 1800 mg dosage groups, 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, the ORR was 44% in the DARZALEX FASPRO 1800 mg dosage group and all-grade hematologic TEAEs included thrombocytopenia (20%), anemia (12%), and lymphopenia (28%).
  • San-Miguel et al (2021)⁴ published the updated results from part 2 of the PAVO study. The ORR was 52% and complete response (CR) rate was 4%. The most common (≥10%) grade 3/4 TEAE was lymphopenia (20%).
  • Nahi et al (2023)⁵ 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 (IRRs) 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, 53.3%), nasopharyngitis (2-week corticosteroid tapering group, 33.3%), and anemia, diarrhea, asthenia, and peripheral edema (1-week corticosteroid tapering group, 33.3% each).
  • Other relevant analyses of the PAVO study have been included in the References section for your information.^6-9 

CLINICAL DATA

Phase 1b Study of DARZALEX FASPRO in Patients with RRMM

PAVO (MMY1004; NCT02519452) was an 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.¹

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
• 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 2.²
• In part 1 of the study, patients were assigned to sequential cohorts and received 28day cycles of the following until disease progression²:
  • 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 (Q2W) in cycles 3-6, and every 4 weeks (Q4W) 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, Q2W in cycles 3-6, and Q4W in subsequent cycles.
• In part 2 of the study, patients received 28-day cycles of the following until disease progression or unacceptable toxicity⁴:
  • DARZALEX FASPRO: daratumumab 1800 mg with rHuPH20 30,000 Units SC injection over 3-5 minutes (15 mL) QW in cycles 1 and 2, Q2W in cycles 3-6, and Q4W in subsequent cycles.
• Pre- and/or post-infusion medications included acetaminophen, diphenhydramine, montelukast, and methylprednisolone.²
• Primary endpoints: Trough plasma concentration (C_trough) of daratumumab at cycle 3 day 1 (C3D1); safety^2,4
• Key secondary endpoints: percentage of patients with CR; percentage of patients with ORR; duration of response; time to response^2,4

Study Design/Methods – Part 3

• Key eligibility criteria: measurable RRMM, ≥2 prior lines of therapy (including a proteasome inhinitor [PI] and an immunomodulatory drug), and Eastern Cooperative Oncology Group performance status (ECOG PS) score of ≤2.⁵ 
• Patients received DARZALEX FASPRO QW during cycle 1 and 2, Q2W during cycle 3 through cycle 6, and Q4W thereafter (28 days/cycle). A 1-, 2-, or 3-week corticosteroid tapering schedule was applied during the first cycle, as described below^5,8:
  • 3-week taper: methylprednisolone (MP) given orally (PO)/IV pre-dose (100mg on C1D1; 60 mg on cycle 1 day 8 [C1D8]; 30 mg on cycle 1 day 15 [C1D15]) and PO post-dose (20 mg on C1D1 for 2 days, on C1D8 for 1 day, on C1D15 for 1 day).⁸ 
  • 2-week taper: MP given PO/IV pre-dose (100 mg on C1D1; 60 mg on C1D8) and PO post-dose (20 mg on C1D1 for 2 days, on C1D8 for 1 day).⁸ 
  • 1-week taper: dexamethasone IV given pre-dose (20 mg on C1D1).⁵
  • Dose limiting toxicities (DLTs) were assessed from C1D1 to cycle 2 day 4 for the 3week taper schedule, from C1D1 to cycle 1 day 25 for the 2-week taper schedule, and from C1D1 to cycle 1 day 11 for the 1-week taper schedule.^5,8 
• Primary endpoint: safety of pre- and post-dose steroid tapering
• Key secondary endpoints: ORR and CR

Initial Results from Parts 1 and 2 of the PAVO Study

Chari et al (2017)² presented the initial results from 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).

Results

Baseline Characteristics and Patient Disposition

• In part 1, a total of 53 patients were treated (daratumumab-MD 1200 mg, n=8; daratumumab-MD 1800 mg, n=45).²
• In part 2, a total of 25 patients were treated with DARZALEX FASPRO 1800 mg.²
• In part 1, the median 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.²
  • In part 1, in the daratumumab-MD 1200 vs 1800 mg dosing group, 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 follow-up was 4.6 months (range, 2.4-5.5).²
  • In part 2, treatment was discontinued in 20% of patients in the DARZALEX FASPRO group due to PD (16%) and physician decision (4%).
• 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.²
• The baseline patient and disease characteristics are summarized in Table: Baseline Patient and Disease Characteristics (Parts 1 and 2).²

Safety

• TEAEs are summarized in Table: All-Grade and Grade 3/4 TEAEs (Parts 1 and 2).²

• There were no TEAE-related treatment discontinuations.²
• In part 2, IRRs reported in a total of 3 (12%) patients (all within 6 hours of the first injection) were²:
  • 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 (n=1 [4%]), erythema (n=1 [4%]), injection-site discoloration (n=1 [4%]), and hematoma (n=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.²

Pharmacokinetics (Part 2 Only)

• Administration of DARZALEX FASPRO resulted in a slower systemic absorption compared with DARZALEX for intravenous (IV) use.²
• The maximum C_trough of daratumumab was similar or higher for DARZALEX FASPRO compared with DARZALEX IV.²
• In a mean concentration-time profile simulation²:
  • 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 Q2W dosing period, compared with DARZALEX IV.
  • During the 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 or better [≥VGPR], 9%) in the daratumumab-MD 1800 mg group (part 1).²
• 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).²
• 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).²

Updated Analysis of Part 2 of the PAVO Study

San-Miguel et al (2021)⁴ published the updated results from the part 2 of the PAVO study at a median follow-up of 14.2 (range, 2.4-18.5) months.

Results

Baseline Characteristics and Patient Disposition

• A total of 25 patients were treated with DARZALEX FASPRO.⁴
• 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]).⁴

Safety

• TEAEs are summarized in Table: All-Grade and Grade 3/4 TEAEs (Part 2).⁴

• The adverse event profile of DARZALEX FASPRO was consistent with that of DARZALEX IV.⁴
• No TEAE-related treatment discontinuations were reported.⁴
• Serious TEAEs were reported in 24% (n=6) of patients but were not considered related to study drug.⁴
  • One patient died due to disease progression in context of multiple myeloma (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 C1D1.⁴
• There were no grade 4 IRRs or treatment discontinuations due to IRRs.⁴
• Injection-site TEAEs included induration, erythema, injection-site discoloration, and hematoma (n=1 each; all grade 1).⁴
• Measurable erythema (24%) and measurable induration (4%) at the injection site were reversible within 1 hour.⁴
• Median time to onset of IRRs was 70 minutes (range, 9-80).⁴

Pharmacokinetics and Immunogenicity

• Administration of DARZALEX FASPRO resulted in a slower systemic absorption of daratumumab compared with DARZALEX IV.⁴
• 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.⁴
• 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.⁴
• The mean and median C_trough of daratumumab at C3D1 was 932 and 860 µg/mL, respectively, for DARZALEX FASPRO.⁴
• 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.⁴
• 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).⁴

Efficacy

• The ORR was 52% in the DARZALEX FASPRO group (CR, 4%; PR, 20%; VGPR, 28%; sCR, 0%).⁴
• 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 PI and an immunomodulatory drug (n=14).⁴
• The median duration of response with DARZALEX FASPRO was 15.7 months (range, 4.6-not estimable).⁴
• The median time to best response was 1.02 months (range, 1.0-12.1).⁴

Updated Analysis of Part 3 of the PAVO Study

Nahi et al (2023)⁵ 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.

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 (Part 3).^5,8

• 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.⁵
• The median number of DARZALEX FASPRO doses was 18 (range, 2-38).⁵
• 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).⁵

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%]).⁵
  • 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.⁵
• The most common TEAEs are presented in Table: Most Common TEAEs (Part 3).⁵
• 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]).⁵

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.⁵
• 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%]; 2-week corticosteroid tapering group, n=3 [20.0%]; and 1-week corticosteroid tapering group, n=1 [9.1%]) were not neutralizing.⁵

Efficacy

• Efficacy outcomes are presented in table: Efficacy Outcomes (Part 3).⁵

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 04 February 2026.