PRODUCT LABELING

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

DARZALEX vs DARZALEX FASPRO Non-Inferiority Study in Patients with RRMM

COLUMBA (MMY3012; clinicaltrials.gov identifier: NCT03277105) is an ongoing, phase 3, randomized, open-label, multicenter, non-inferiority study evaluating the efficacy, PK, and IRRs of DARZALEX vs DARZALEX FASPRO in patients with RRMM.^{2, 3} Mateos et al (2020)² reported primary analysis of efficacy and safety results of the COLUMBA study after a median follow-up of 7.5 months. Usmani et al (2022)³ reported final analysis of efficacy and safety results of the COLUMBA study after a median follow-up of 29.3 months.

Study Design/Methods

• The trial enrolled 522 patients from 19 countries, including the United States.
• Patients will be randomized to receive either DARZALEX (n=259) or DARZALEX FASPRO (n=263) over 4-week treatment cycles:
  • DARZALEX: daratumumab 16 mg/kg IV infusion weekly for cycles 1 and 2, every 2 weeks for cycles 3-6, and every 4 weeks thereafter, or
  • DARZALEX FASPRO: daratumumab 1800 mg (flat dose) in combination with recombinant human hyaluronidase PH20 (rHuPH20) 2000 units/mL administered by manual push (15 mL) over 3-5 minutes at alternating left/right abdominal sites, weekly for cycles 1 and 2, every 2 weeks for cycles 3-6, and every 4 weeks thereafter.
• Treatment will continue until disease progression or unacceptable toxicity.
• Pre-infusion medications to be administered are acetaminophen 650-1000 mg, diphenhydramine 25-50 mg, methylprednisolone 60-100 mg, and montelukast 10 mg (optional).
• Post-infusion medications to be administered are methylprednisolone 20 mg, and diphenhydramine, short-acting β2 adrenergic receptor agonist, and control medications for lung disease recommended for patients with higher risk of respiratory complications.
• Co-primary endpoints: ORR and maximum C_trough (serum pre-dose daratumumab concentration on cycle 3 day 1)

Results

• Median duration of follow-up was 29.3 months (additional 21.8 months after the primary analysis).
• A total of 522 patients were assigned to either the DARZALEX (n=259) or DARZALEX FASPRO (n=263) arm. Baseline demographics and clinical characteristics are summarized in Table: Key Baseline Demographics and Clinical Characteristics (Intention-to-Treat).

Treatment Exposure and Patient Disposition

• In patients who received ≥1 treatment dose, 90% in the DARZALEX FASPRO and 91.1% in the DARZALEX arm discontinued study treatment. Progressive disease (DARZALEX FASPRO, 75.4%; DARZALEX, 75.6%) was the most common reason for treatment discontinuation as present in Table: Treatment Exposure and Patient Disposition.
• At the clinical cutoff for the final analysis, 26 (10%) vs 23 (8.9%) patients continued treatment in the DARZALEX FASPRO vs DARZALEX arms, respectively.

Efficacy

• In the DARZALEX FASPRO arm, patients showed similar response rates across all weight subgroups (≤65 Kg, >65-85 kg, and >85 kg) as present in the Table: Efficacy Endpoints by Baseline Body Weight Subgroups.

Safety

• With the longer follow-up, the rates of any grade and grade 3/4 TEAEs across all body weight subgroups (≤65 Kg, >65-85 kg, and >85 kg) were similar to the overall population. See Table: Most Common Grade 3/4 (≥5%) TEAEs Across Body Weight Subgroups.
  • In ≤65 kg subgroup, incidence of neutropenia was higher in the DARZALEX FASPRO vs DARZALEX arms for any grade TEAEs (25.8% vs 14.1%) and grade 3/4 TEAEs (20.4% vs 8.7%), respectively.
  • In the ≤65 kg subgroup, there was no increase in the incidence of infections for any grade TEAEs (DARZALEX FASPRO, 57.0%; DARZALEX, 57.6%), and grade 3/4 TEAEs (DARZALEX FASPRO, 10.8%; DARZALEX, 17.4%).
  • In the ≤65 kg subgroup, incidence of serious infections was 10.8% vs 18.5% in the DARZALEX FASPRO vs DARZALEX arms, respectively.

DARZALEX FASPRO in Combination with Bortezomib, Cyclophosphamide, and Dexamethasone in Patients with Newly Diagnosed Systemic AL Amyloidosis

ANDROMEDA is an ongoing, prospective, randomized, active-controlled, multicenter, phase 3 study (AMY3001; clinicaltrials.gov identifier: NCT03201965) evaluating the efficacy and safety of D-VCd compared to VCd alone in newly diagnosed patients with systemic AL amyloidosis.⁵ Kastritis et al (2021)⁵ reported primary results of this study. Comenzo et al (2021)⁶ presented updated efficacy and safety results of the ANDROMEDA study, with a median follow-up of 25.8 months.

Study Design/Methods

• The study design is presented in Figure: ANDROMEDA Study Design.

Results - Body Weight Subgroup Analysis

Efficacy

• Complete hematologic response rates across body weight categories were consistent (≤65 kg, 54.8%; >65 kg to ≤85 kg, 52.1%; >85 kg, 54.1%) with the overall population (53.3%) of subjects in the D-VCd arm.⁷
• There was considerable overlap in C_trough values at PK sampling timepoints across body weight subgroups. However, as expected for a monoclonal antibody administered SC by flat dose, higher serum daratumumab concentrations were observed in subjects with lower body weight and lower serum daratumumab concentrations were observed in subjects with higher body weight at all PK sampling timepoints with measurable serum daratumumab concentrations.⁷
• For the lowest body weight subgroup (≤65 kg), the mean maximum C_trough of daratumumab at cycle 3 day 1 was approximately 15% higher compared with that of the total PK-evaluable analysis set.⁷
• For the highest body weight subgroup (>85 kg), the mean maximum C_trough of daratumumab at cycle 3 day 1 was approximately 17% lower compared with that of the total PK-evaluable analysis set.⁷
• For the middle body weight subgroup (>65 to 85 kg), the mean concentration of daratumumab at cycle 3 day 1 was comparable to that of the total PK-evaluable analysis set.⁷
• The inter-subject variability (%CV) for serum daratumumab concentrations in each body weight subgroup was within the range of variability observed for the total PK-evaluable analysis set following D-VCd treatment. Trough serum daratumumab concentrations at other timepoints with measurable serum daratumumab concentrations showed a similar pattern as for cycle 3 day 1. The flat-dose administration of DARZALEX FASPRO achieved adequate exposure for all body weight subgroups in the D-VCd arm.⁷

Safety

18-month Follow-up Update on Efficacy and Safety Results of ANDROMEDA

Comenzo et al (2021)⁶ presented updated efficacy and safety results of the ANDROMEDA study, with a median follow-up of 25.8 months.

Results - Body Weight Subgroup Analysis

Efficacy

• Improvement in hematologic complete response with D-VCd was consistent across subgroups, including those stratified by baseline weight. See Table: Hematologic Complete Response by Baseline Weight.

Safety

• Safety results were not stratified by baseline weight.

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 23 April 2024.