SUMMARY

• MAIA is a phase 3 study evaluating the safety and efficacy of DARZALEX for intravenous (IV) use in combination with lenalidomide and dexamethasone (D-Rd) compared to lenalidomide plus dexamethasone (Rd) in transplant-ineligible newly diagnosed multiple myeloma (NDMM) patients.^1,2 Facon et al (2019)¹ reported the pre-specified interim results of this ongoing study.
  • Facon et al (2024)³ presented (at the European Hematology Association [EHA] Hybrid Congress) the results of the updated efficacy and safety analysis of the MAIA study. At a median follow-up of 89.3 months, a 33% reduction in the risk of death was observed with the D-Rd vs Rd arms. Median overall survival (OS) was reached for the D-Rd arm and was prolonged for patients in the D-Rd vs Rd arms (90.3 vs 64.1 months [hazard ratio, or HR, 0.67; 95% confidence interval, or CI, 0.55-0.82; nominal P<0.0001]). The median time to subsequent antimyeloma therapy was 42.4 months in the Rd arm and not reached (NR) in the D-Rd arm (HR, 0.51; 95% CI, 0.41-0.63; nominal P<0.0001). Deaths were reported for 47.5% (n=173) of patients in the D-Rd arm and 59.7% (n=218) of patients in the Rd arm, mostly due to disease progression.
  • Other relevant subgroup analysis from MAIA Study have been referenced below.^4-15
• POLLUX was a phase 3 study evaluating the safety and efficacy of Rd and D-Rd in patients with relapsed or refractory multiple myeloma (RRMM).¹⁶
  • Dimopoulos et al (2023)¹⁷ reported updated efficacy and safety results from POLLUX at a median follow-up of 79.7 months. Median OS in the intent-to-treat (ITT) population with D-Rd was 67.6 months (95% CI, 53.1-80.5) with D-Rd and
    51.8 months (95% CI, 44.0-60.0) with Rd (HR, 0.73; 95% CI, 0.58-0.91; P=0.0044). The most common grade 3/4 (≥10%) TEAEs were neutropenia (D-Rd, 57.6%; Rd, 41.6%), anemia (D-Rd, 19.8%; Rd, 22.4%), pneumonia (D-Rd, 17.3%; Rd, 11%), thrombocytopenia (D-Rd, 15.5%; Rd, 15.7%), and diarrhea (D-Rd, 10.2%; Rd, 3.9%).
  • Other relevant subgroup analysis from POLLUX Study have been referenced below.^18-23
• Wang et al (2022)²⁴ conducted a pooled analysis of data from the POLLUX, CASTOR, and MAIA studies, evaluating the survival outcomes of DARZALEX-based therapies according to early or late response. For streamlining purposes, this has been referenced below.
• Moreau et al (2020)²⁵ presented (at the 8^th Annual Meeting of the Society of Hematologic Oncology [SOHO]) safety and efficacy results of patients on DARZALEX who discontinued lenalidomide with or without dexamethasone (R±d) in the POLLUX and MAIA studies. For streamlining purposes, this presentation is referenced below.
• AURIGA is an ongoing, phase 3 study evaluating the conversion rate of MRD-negativity after maintenance treatment with DARZALEX FASPRO for subcutaneous (SC) use plus lenalidomide (D-R) vs lenalidomide alone in patients with NDMM who are MRD-positive after autologous stem cell transplantation (ASCT).²⁶ Results are not available at this time.
• PLEIADES is an ongoing, phase 2 study evaluating the clinical benefit of DARZALEX FASPRO administered in combination with 4 standard-of-care treatment regimens in patients with multiple myeloma (MM).^27-31 Results from patients in the D-Rd cohort are summarized below.

PRODUCT LABELING

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

Clinical studies

DARZALEX in Combination with Lenalidomide and Dexamethasone in Patients with NDMM

MAIA (MMY3008; clinicaltrials.gov identifier: NCT02252172) is an international, phase 3, randomized, open-label, active-controlled, multicenter study in patients with NDMM not eligible for high dose chemotherapy and ASCT (N=737).^1,2 Facon et al (2021)³² reported the updated safety and efficacy results in the MAIA study at the pre-specified interim OS analysis with a median follow-up of 56.2 months. Kumar et al (2022)³³ presented the results of the updated efficacy and safety analysis (median follow-up, 64.5 months), including updated OS results (median follow-up, 73.6 months), of the MAIA study in patients with NDMM who were ineligible for high-dose chemotherapy and ASCT. Facon et al (2024)³ presented updated efficacy and safety results at a median follow-up of 89.3 months. The updated analysis is summarized below.

Study Design/Methods

• Eligible patients were randomized 1:1 to receive 28-day cycles of D-Rd or Rd until PD or unacceptable toxicity at the following dosage:
  • D-Rd arm:
    • DARZALEX: 16 mg/kg IV weekly during cycles 1-2, every 2 weeks during cycles 3-6, then every 4 weeks during cycle 7+
    • Lenalidomide: 25 mg PO daily on days 1-21
    • Dexamethasone: 40 mg PO on days 1, 8, 15, and 22
  • Rd arm:
    • Lenalidomide and dexamethasone at the same dosage as the D-Rd arm.
• Primary endpoint: PFS
• Key secondary endpoints: complete response (CR) rate, very good partial response or better (≥VGPR) rate, stringent complete response (sCR), duration of response (DOR), MRD-negativity rate, ORR, OS, time from randomization to disease progression on the next line of therapy or death (PFS2), time to next (2nd-line) treatment, time to response, time to progression (TTP), and safety

Results

Patient Characteristics

• A total of 737 (D-Rd, n=368; Rd, n=369) patients were randomized in this study.
• The median duration of follow-up was around 7.5 years (89.3 months [range, 0-102.2]).
• Baseline characteristics of the ITT population are summarized in Table: Demographic and Baseline Disease Characteristics of the ITT Population.

Efficacy

• At a median follow-up of 89.3 months (range, 0-102.2), the 7-year OS rate was 53.1% for the D-Rd arm and 39.3% for the Rd arm.
• Median OS was reached for the D-Rd group and was prolonged for patients in the D-Rd vs Rd arm (90.3 vs 64.1 months [HR, 0.67; 95% CI, 0.55-0.82; nominal P<0.0001]). See Table: Analysis of OS in Pre-Specified Patient Subgroups.
• Median time to subsequent antimyeloma therapy was 42.4 months in the Rd arm and NR in the D-Rd arm (HR, 0.51; 95% CI, 0.41-0.63; nominal P<0.0001). See Table: Summary of First Subsequent Antimyeloma Therapy in the Safety Population.
  • In the D-Rd vs Rd arm, 10.7% (15/140) vs 24.4% (49/201) of patients received DARZALEX-containing regimens as their first subsequent therapy.
  • Among treated patients, 38.5% (140/364) vs 55.1% (201/365) of patients in the D-Rd vs Rd arm received ≥1 subsequent antimyeloma therapy.
  • Across subsequent therapy lines, the most common antineoplastic agents in the D-Rd vs Rd arms were bortezomib (27.7% vs 41.9%), DARZALEX (6.3% vs 28.8%), and carfilzomib (7.7% vs 12.3%).
  • In patients evaluable for best response to first subsequent antimyeloma therapy, CR or better (≥CR) was achieved by 4.6% (6/130) vs 4.1% (8/193) in the D-Rd vs Rd arm, and ≥VGPR was achieved by 13.8% (18/130) vs 23.8% (46/193) of patients in the D-Rd vs Rd arm.
  • No patient in either group reported the use of B-cell maturation antigen (BCMA)- or G protein-coupled receptor class C group 5 member D (GPRC5D)-targeted therapy.
  • Investigational drug was given to 2 patients in the D-Rd group and 2 patients in the Rd group in subsequent therapy lines.

Safety and Tolerability

• Among the safety population, 78.3% (n=285) of patients in the D-Rd arm and 94.5% (n=345) in the Rd arm discontinued study treatment.
  • Progressive disease was the primary reason for discontinuation in both the D-Rd (32.7%) and Rd arms (38.6%).
  • A lower proportion of patients in the D-Rd (16.5%) and Rd arms (25.8%) discontinued study treatment due to AEs.
• In the D-Rd vs Rd arm, 33% reduction in the risk of death was reported.
  • Deaths were reported for 47.5% (n=173) of patients in the D-Rd arm and 59.7% (n=218) of patients in the Rd arm, mostly due to disease progression. See Table: Summary of Death and Causes of Death in the Safety Population.

DARZALEX in Combination with Lenalidomide and Dexamethasone in Patients with RRMM

POLLUX (MMY3003; clinicaltrials.gov identifier: NCT02076009) is a phase 3, randomized, open-label, multicenter study to evaluate the safety and efficacy of D-Rd and Rd in patients with RRMM (N=569).¹⁶ Dimopoulos et al (2023)¹⁷ reported updated results of the POLLUX study, including OS, at a median follow-up of 79.7 months.

Study Design/Methods

• Primary endpoint: PFS
• In addition to safety assessments, secondary endpoints included: TTP, ORR, rate of ≥VGPR, OS, DOR, and MRD

Results

Patients and Treatments

• The median duration of follow-up was 79.7 (range, 0-86.5) months.
• Baseline characteristics are summarized in Table: Baseline Demographics and Clinical Characteristics (POLLUX; ITT Population).

Efficacy

• At a median follow-up of 79.7 months, D-Rd arm provided a 27% reduction in the risk of death compared to Rd arm (HR, 0.73; 95% CI, 0.58-0.91; P=0.0044).
  • Median OS in the ITT population with D-Rd was 67.6 months (95% CI, 53.1-80.5) vs 51.8 months (95% CI, 44.0-60.0) with Rd.
• MRD-negativity rate at a 10^-5 sensitivity threshold was 33.2% vs 6.7% in the D-Rd vs Rd arms, respectively (P<0.0001).
• In the ITT population, median PFS2 was significantly prolonged in D-Rd vs Rd arms, respectively, at 57.9 months vs 32.0 months (HR, 0.54; 95% CI, 0.43-0.67; P<0.0001).
• OS benefit of D-Rd vs Rd was generally consistent across pre-specified patient subgroups as presented in Table: OS in Pre-specified Patient Subgroups in the ITT Population (POLLUX).
• In total, 44.9% (127 of 283) of patients vs 74.7% (210 of 281) of patients in the D-Rd vs Rd arms, respectively, received subsequent therapy. See Table: Most Common Subsequent Anticancer Therapies in the D-Rd and Rd arms.
  • Of the patients in the Rd arm who received subsequent therapy, 122 (58.1%) patients received DARZALEX in any subsequent line of therapy.
  • Median number of subsequent lines of therapy was 2 (range, 1-13) vs 2 (range, 1-12) in the D-Rd vs Rd arms, respectively.
• Median time to subsequent treatment was significantly increased with D-Rd vs Rd (69.3 vs 23.1 months; HR, 0.40; 95% CI, 0.32-0.50; P<0.0001).
• The most common first line subsequent anticancer therapy was pomalidomide and dexamethasone (12.5%) or bortezomib and dexamethasone (10.2%) in the D-Rd arm and DARZALEX monotherapy (22.4%) in the Rd arm.

Safety

• With the longer follow-up, no new safety concerns were reported.
• The most common TEAEs are presented in Table: Most common (>15% of Patients) and Grade 3/4 (>5% of Patients) TEAEs in the Safety Population (POLLUX) and TEAEs Leading to Treatment Discontinuation or Deaths (POLLUX).
• Grade 3/4 infections were reported in 44.5% vs 28.1% patients in the D-Rd vs Rd arms, respectively.
• No deaths because of COVID-19 disease occurred during the study.
• With the longer follow-up, second primary malignancies (cutaneous, invasive, and hematologic) were reported in 40 (14.1%) vs 30 (10.7%) patients in the D-Rd vs Rd arm, respectively.

DARZALEX FASPRO in Combination with 4 Standard-of-Care Regimens

PLEIADES (MMY2040; clinicaltrials.gov identifier: NCT03412565) is an ongoing, phase 2, non-randomized, open-label, multicenter study evaluating the clinical benefit of DARZALEX FASPRO administered in combination with various treatment regimens in patients with MM. Chari et al (2020)³⁰ presented updated safety and efficacy results of the DARZALEX FASPRO + bortezomib + lenalidomide + dexamethasone (D-VRd), D-VMP, and D-Rd arms in the PLEIADES study. Results specifically to the D-Rd cohort are summarized below.

Study Design/Methods

• Primary endpoint: ORR
• Key secondary endpoints: maximum observed serum concentrations (C_max) and minimum observed serum concentrations (C_min) of daratumumab, immunogenicity, Percentage of Participants with IRR, ≥CR, DOR, MRD-negativity rate, ≥VGPR for the D-Rd cohort.

Results: D-Rd Cohort

Efficacy

• Median follow-up was 7.1 months for D-Rd cohort.
• Primary endpoints were met for the D-Rd cohort with available data and response rates were similar to the DARZALEX study, POLLUX³⁴.
  • In the D-Rd cohort:
    • ORR was 93.8% versus 92.9% in the POLLUX study³⁴.
    • VGPR was 40% versus 32.7%.
    • PR was 15.4% versus 17.1%.
    • CR was 20% versus 24.9%.
    • sCR was 18.5% versus 18.1%.
• MRD-negativity rates were evaluated via NGS at a sensitivity threshold of 10^-5.
  • MRD-negativity rate was 15.4% (90% CI, 8.6-24.7) in the D-Rd cohort.  

Pharmacokinetics

• Overall, serum trough concentrations (C_trough) and immunogenicity values were consistent with historical daratumumab IV data.
• C_max after the 1st dose was 108 ± 49.9 µg/mL in the D-Rd cohort
• Sixteen patients developed rHuPh20 antibodies (all were non-neutralizing).
• No patients developed anti-daratumumab antibodies.

Safety

• Treatment discontinuation due to TEAEs were 8% in the D-Rd cohort.
• A summary of TEAEs in each cohort is presented in Table: Safety Summary - D-Rd Cohort (PLEIADES).
• Any-grade IRRs occurred in 8% of patient across all cohorts.

• Across all 3 cohorts with available data any grade IRRs occurred in 8% (15/199) of patients
  • IRRs were mild (grade 1/2), one patient had grade 3 IRR and no patients reported grade 4 IRR.
• Median time to onset of IRRs was 5.5 hours in the D-Rd cohorts.
• Local injection site reactions occurred in 8% of patients in all cohorts (all grade 1/2).
• A summary of most common TEAEs is presented in Table: Most Common TEAEs in D-Rd Cohort (≥ 5%; PLEIADES).

Results: D-Rd Cohort with a Median Follow-up of 25.7 Months

Moreau et al (2020)³¹ presented updated safety and efficacy results of the PLEIADES study with a median follow-up of 9.2 months for DARZALEX FASPRO + carfilzomib + dexamethasone D-Kd (primary analysis), 25.7 months for D-Rd, and 25.2 months for D-VMP. Results specifically to the D-Rd cohort are summarized below.

Patient Characteristics

• Baseline demographics and patient characteristics in each cohort are detailed in Table: Baseline Demographics and Patient Characteristics - D-Rd Cohort (PLEIADES).

Efficacy

• Median duration of follow-up was 25.7 months for D-Rd cohort.
• Response rates were similar to DARZALEX studies in POLLUX³⁴.
  • In the D-Rd cohort (n=65):
    • ORR was 93.8% versus 92.9% in the POLLUX study³⁴.
    • sCR was 23.1% versus 29.5%.
    • CR was 26.2% versus 28.1%.
    • VGPR was 30.8% versus 23.5%.
    • PR was 13.8% versus 11.7%.
• MRD-negativity rates were evaluated via NGS at a sensitivity threshold of 10^-5.
  • MRD-negativity rate was 20.0% in the D-Rd cohort.
  • MRD-negative ≥CR rate was 20.0% in the D-Rd cohort.

Safety

• A summary of TEAEs reported is presented in Table: Summary of TEAEs in D-Rd Cohort (PLEIADES).
• Cardiac toxicities were infrequent (<5%) in D-Rd cohort.
• Most patients with IRRs experienced them on the first administration (D-Rd, 100%).
• IRRs were mild (grade 1/2).
• Median (range) time to onset of IRRs was 330 (254-330) minutes in the D-Rd cohort.
• Local injection site reactions occurred in 6% (11/198) of patients (all grade 1/2).

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 30 July 2024. For purposes of streamlining, this scientific response has been limited to phase 2/3 clinical studies.

In response to your specific request, summarized in this response is the relevant data from company-sponsored studies pertaining to this topic.