SUMMARY  

• GEN501 was a phase 1/2 dose-escalation (Part 1) and dose-expansion (Part 2) study primarily assessing the safety of DARZALEX monotherapy in multiple myeloma (MM) patients who had relapsed after or were refractory to ≥2 prior lines of therapy. In Part 2 of the study, the most commonly occurring adverse events (AEs, >25%) were fatigue, allergic rhinitis, pyrexia, diarrhea, upper respiratory tract infection, and dyspnea. Infusion-related reactions (IRRs) were observed in 71% of patients across the DARZALEX 8 mg/kg and 16 mg/kg cohorts in Part 2 and were mostly grades 1/2 in severity. Patients who received DARZALEX 16 mg/kg (n=42) had an overall response rate (ORR) of 36% (95% confidence interval [CI], 22-52) and 65% (95% CI, 28-86) of responders remained in remission at 12 months.¹
• A combined analysis of the safety and efficacy of DARZALEX 16 mg/kg used as monotherapy in patients with relapsed or refractory MM in the GEN501 and SIRIUS² studies is referenced.³
• An exploratory analysis of the influence of disease and patient characteristics on DARZALEX exposure and clinical outcomes in patients with relapsed or refractory multiple myeloma in the GEN501 and SIRIUS² studies is referenced.⁴

CLINICAL DATA

GEN501 (clinicaltrials.gov identifier: NCT00574288) was an open-label, multicenter, dose-escalating (Part 1) and dose expansion (Part 2) phase 1/2 study assessing the safety of DARZALEX monotherapy in patients with MM who had relapsed after or were refractory to ≥2 prior lines of therapy, including proteasome inhibitors, immunomodulatory agents, chemotherapy, and autologous stem-cell transplantation (ASCT) (N=72). Lokhorst et al (2015)¹ reported results from this study.

Study Design/Methods

• Part 1: patients received DARZALEX 0.0005 to 24 mg/kg in 10 dose cohorts over an 8week treatment period
  • 3-week washout period after first full dose with 6 doses administered weekly thereafter
  • Predoses (10% of full dose and ≤10 mg) administered prior to the first 2 full doses
• Part 2: patients received DARZALEX 8 mg/kg or DARZALEX 16 mg/kg
  • DARZALEX 8 mg/kg (schedules A, B, and C): once weekly for 8 weeks, then twice monthly for 16 additional weeks
  • DARZALEX 16 mg/kg (schedules D and E): 1 infusion followed by a 3-week washout period, then once weekly for 7 weeks, twice monthly for 14 additional weeks, and monthly thereafter
• Planned infusion rates and volumes:
  • Schedule A: DARZALEX 8 mg/kg in 500 mL over 4 hours for first infusion; 500 mL over 3.25 to 4 hours for second infusion
  • Schedule B: DARZALEX 8 mg/kg in 500 mL over 6 hours for first infusion; 500 mL over 3.25 to 4 hours for second infusion
  • Schedule C: DARZALEX 8 mg/kg in 1000 mL over 6 hours for first infusion; 500 mL over 3.25 to 4 hours for second infusion
  • Schedules D and E: DARZALEX 16 mg/kg in 1000 mL over 6 hours for first and second infusions
  • Subsequent infusions for all schedules were 500 mL over 3.25 to 4 hours
• Inclusion criteria: life expectancy ≥3 months, an Eastern Cooperative Oncology Group (ECOG) performance status ≤2, and a measurable level of M protein or free light chains
• Select exclusion criteria: absolute neutrophil count ≤1000/m³, platelet count ≤75 x 10⁹/L, and hemoglobin ≤7.5 g/Dl
• Primary endpoint: safety
• Secondary endpoints: pharmacokinetics, relative reductions in levels of M protein and free light chains, objective response per the International Myeloma Working Group (IMWG) uniform response criteria for myeloma, time to disease progression, duration of response, progression-free survival (PFS), and overall survival (OS)

Results

Patient Characteristics

• Results from the dose-expansion (Part 2) study are summarized.
• Baseline patient demographics and disease characteristics from the DARZALEX 16 mg/kg cohort in phase 2 are presented in Table: Baseline Patient Demographics and Disease Characteristics and baseline refractory status in the same patient population is presented in Table: Baseline Refractory Status.

Safety

• The most common AEs (>25%) in Part 2 are presented in Table: Most Common (>25%) Adverse Events in Dose-Expansion Study.
• Serious AEs (SAEs) were reported in 40% and 30% of patients in the DARZALEX 8 mg/kg and DARZALEX 16 mg/kg cohorts, respectively.
  • Infection-related events were the most commonly reported SAEs and were reported in 17% of DARZALEX 8 mg/kg and 10% of DARZALEX 16 mg/kg patients.

• Neutropenia, the most frequent hematologic AE, was observed in 5 patients (12%) who received DARZALEX 16 mg/kg.
• Grade 3/4 AEs were reported in 26% of patients in the DARZALEX 16 mg/kg cohort, with pneumonia (n=5) and thrombocytopenia (n=4) as the most common across both the DARZALEX 8 mg/kg and 16 mg/kg cohorts.
• IRRs were observed in 71% of patients across the DARZALEX 8 mg/kg and 16 mg/kg cohorts in Part 2 and were mostly grades 1/2 in severity.
  • One patient experienced a grade 3 IRR.
  • No grade 4 IRRs or discontinuations due to IRRs were reported.
  • 67% and 71% of patients in the DARZALEX 8 mg/kg and DARZALEX 16 mg/kg cohorts, respectively, had an IRR during the 1st infusion.
  • The incidence of IRRs was lower in patients who received DARZALEX 8 mg/kg in 1000 mL for 6 hours compared to DARZALEX 8 mg/kg in 500 mL for 4-6 hours and DARZALEX 16 mg/kg in 1000 mL for 6 hours.

Duration of Infusion

• In the cohort of patients who received DARZALEX 16 mg/kg in the dose expansion part, the median (range) of full infusions was 13.5 (1-24). Median (range) durations of full infusions were:
  • First infusion: 7.7 (6.3-11.3) hours
  • Second infusion: 6.7 (5.4-8.2) hours
  • Subsequent infusions: 3.3 (3.0-7.2) hours

Efficacy

• The ORR in the DARZALEX 16 mg/kg group was 36% (95% CI, 22-52; confirmed complete response in 2 patients; very good partial response in 2 patients; partial response in 11 patients).
  • Median (range) time to first response: 0.9 (0.5-3.2) months
  • Median duration of response was not reached
  • Median PFS: 5.6 months (95% CI, 4.2-8.1), with 65% of responding patients remaining progression-free at 12 months
  • OS at 12 months: 77% (95% CI, 58-88)
• A reduction of at least 50% in the level of M protein or free light chains was observed in 46% (19/41) of patients in the DARZALEX 16 mg/kg group and 15% (4/27) in the DARZALEX 8 mg/kg group. Individual results for M-protein or free light chain reductions were not reported.

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) was conducted on 07 October 2024.