SUMMARY  

• DARZALEX for intravenous use (IV) is not approved by the regulatory agencies for use in combination with cyclophosphamide, bortezomib, and dexamethasone for the treatment of multiple myeloma. Janssen does not recommend the use of DARZALEX in a manner that is inconsistent with the approved labeling.
• LYRA is a phase 2, single-arm, open-label, multicenter study evaluating the safety and efficacy of DARZALEX when administered in combination with cyclophosphamide, bortezomib, and dexamethasone (CyBorD) for the treatment of multiple myeloma (MM) in patients who have not received previous treatment or have relapsed after receiving only 1 line of treatment.^1,2
  • Yimer et al (2022)³ reported the end-of-study analysis of LYRA. At the end of cycle 4, ≥very good partial response (VGPR) was achieved by 57.1% patients in the relapsed multiple myeloma (RMM) arm and 44.2% patients in the newly diagnosed multiple myeloma (NDMM) arm. The median progression-free survival (PFS) was 21.7 months in the RMM arm and not reached (NR) in the NDMM arm (both in patients who received and did not receive transplant). The overall response rate (ORR) was 86% in the RMM arm, 97% in the NDMM transplant arm, and 83% in the NDMM non-transplant arm. The most frequent any-grade TEAE was fatigue (68.6%). Grade 3/4 TEAEs occurred in 62.8% patients, with the most frequent being neutropenia (12.8%).

PRODUCT LABELING

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

CLINICAL DATA

LYRA (clinicaltrials.gov identifier: NCT02951819)¹ is a phase 2, single-arm, open-label, multicenter study evaluating the safety and efficacy of DARZALEX when administered in combination with CyBorD for the treatment of MM in patients who have not received previous treatment or have relapsed after receiving only 1 line of treatment. Yimer et al (2019)¹ published results with a median follow-up of 7.9 months for RMM and 8.8 months for NDMM. Rifkin et al (2019)⁴ presented updated safety and efficacy results at the 61st American Society of Hematology (ASH) Annual Meeting & Exposition in December 2019 with a median PFS follow-up of 25.8 months for NDMM and 26.6 months for RMM. Yimer et al (2022)³ reported the end-of-study analysis of the LYRA study.

Study Design/Methods

• Key eligibility criteria: Patients of ≥18 years of age with documented MM as per the International Myeloma Working Group (IMWG) criteria, Eastern Cooperative Oncology Group (ECOG) performance status score of 0-2, and previously untreated NDMM or RMM with 1 prior line of therapy were eligible. Patients with RMM were included only if they achieved partial response or better (≥PR) with prior therapy before disease progression.¹
• Patients refractory to a proteasome inhibitor (PI) or a combination of PI and immunomodulatory drug (IMiD) were excluded.¹
• Patients received 4-8 cycles (28 days per cycle) of the following induction treatment¹:
  • DARZALEX: 16 mg/kg intravenous (IV)
    • Cycle 1: 8 mg/kg IV on days 1 and 2, followed by 16 mg/kg weekly
    • Cycle 2: weekly
    • Cycles 3-6: every 2 weeks
    • Cycles 7-8: every 4 weeks
  • Bortezomib: 1.5 mg/m² subcutaneous (SC) weekly on days 1, 8, and 15 in all cycles
  • Cyclophosphamide: 300 mg/m² orally (PO) weekly on days 1, 8, 15, and 22 in all cycles
  • Dexamethasone: 40 mg
    • Cycle 1: 20 mg IV on days 1 and 2, followed by 40 mg weekly
    • Cycles 2-8: 40 mg IV/PO weekly
• After the induction phase, all patients received up to 12 cycles (28 days per cycle) of the following maintenance treatment¹:
  • DARZALEX: 16 mg/kg IV every 4 weeks
  • Dexamethasone: 12 mg IV/PO on DARZALEX dosing days
• Patients underwent high-dose therapy (HDT) and autologous stem cell transplant (ASCT) at the discretion of the investigator after the induction phase.³
• Primary endpoint: Very good partial response or better (≥VGPR) after 4 induction cycles³
• Key secondary endpoints: ORR, time to ≥VGPR, time to ≥PR, PFS, overall survival (OS), safety, and tolerability³

Results

Patient Characteristics

• Overall, 101 patients were included (NDMM, n=87; RMM, n=14), of whom 100 received ≥1 dose of study treatment (NDMM, n=86; RMM, n=14).³
• The median follow-up duration was 35.7 months for the NDMM arm and 35.3 months for the RMM arm.³
• In total, 39 patients with NDMM and 1 patient with RMM received ASCT.³
• Demographic and baseline characteristics are summarized in Table: Patient Characteristics (LYRA).

Efficacy

• The median PFS was 21.7 months (95% confidence interval [CI], 6.8-not evaluable [NE]) in the RMM arm and NR in both the transplant and non-transplant NDMM arms.³
  • The estimated 36-month PFS rates were 31.7% (95% CI, 5.6-63.4) in the RMM arm, 69.3% (95% CI, 43.0-85.3) in the NDMM transplant arm, and 72.6% (95% CI, 54.084.7) in the NDMM non-transplant arm.
• Median OS was NR. The estimated 36-month OS rates were 50% (95% CI, 22.9-72.2) in the RMM arm, 94.9% (95% CI, 81.0-98.7) in the NDMM transplant arm, and 84.3% (95% CI, 69.892.2) in the NDMM non-transplant arm.³
• The median duration of response was 20.7 months (95% CI, 5.9-NE) in the RMM arm and NR in both the transplant and non-transplant NDMM arms.³
• For a summary of response rates over time in patients with RMM, transplant patients with NDMM, and non-transplant patients with NDMM, see Tables: Summary of Response Rates Over Time in Patients With RMM (LYRA), Summary of Response Rates Over Time in Transplant Patients With NDMM (LYRA), and Summary of Response Rates Over Time in Non-transplant Patients With NDMM (LYRA).

• In patients with NDMM achieving ≥CR vs those achieving ≤VGPR, estimated 36-month PFS rates were higher in both transplant (87.5% vs 51.2%) and non-transplant arms (100.0% vs 57.7%).³
• Among evaluable patients with NDMM and standard (n=52) vs high (n=31) cytogenetic risk³:
  • After induction, the rate of ≥VGPR was 61.5% vs 67.7% and the rate of ≥CR was 9.6% vs 16.1% for standard vs high risk, respectively.
  • By the end of the study, the rate of ≥VGPR was 75.0% vs 77.4% and the rate of ≥CR was 42.3% vs 29.0% for standard vs high risk, respectively.
• Among evaluable patients with NDMM and standard (n=53) vs high (n=31) cytogenetic risk³:
  • Median PFS was NR vs 33.1 months.
  • Estimated 36-month PFS rate was 87.5% vs 45.2% for standard vs high risk, respectively.

Safety

• In the RMM vs NDMM (both transplant and non-transplant) arm, grade 3/4 TEAEs occurred in 57.1% vs 62.8% of patients, serious TEAEs occurred in 35.7% vs 32.6% of patients, and cardiac TEAEs occurred in 0% vs 16.3% of patients. Grade 3 cardiac events (atrial fibrillation, n=4; atrial flutter, n=1) were reported in 4.7% (n=4) patients, all of which were serious and not related to study treatment.³ See Table: Most Common TEAEs of Any Grade (≥25%) and Grade 3/4 (≥10%) in the Safety Analysis Set (LYRA).
• TEAEs leading to treatment discontinuation occurred in 1 patient in the RMM arm and 7 patients in the NDMM arm.³
  • TEAEs leading to treatment discontinuation in the NDMM arm were anemia (n=2), atrial fibrillation, hip fracture, nephrotic syndrome, laryngeal edema, and rash (n=1 each).
  • In the NDMM arm, TEAEs leading to treatment discontinuation occurred in 5.6% (n=2) of patients who received transplants and 2.6% (n=1) of those who did not receive transplants.
• TEAEs leading to death was reported in 1 patient each in both the RMM and NDMM arms, all of which were unrelated to study treatment.³
• In the NDMM arm, serious TEAEs occurred in 16.7% (n=6) of patients who received transplant and 23.1% (n=9) of patients who did not receive transplant.³
• The incidence of infusion-related reactions (IRRs) was 57.1% in the RMM arm and 55.8% in the NDMM arm.³
  • In the RMM arm, all IRRs occurred during the induction phase and were of grade 1/2. No patient discontinued study treatment due to an IRR.
  • In the NDMM arm:
    • Grade 3 IRRs included anaphylactic reaction, chest discomfort, and hypertension (n=1 each). One patient reported laryngeal edema as a grade 4 IRR.
    • The majority of IRRs occurred during the first cycle of treatment.
      • Among patients who received transplants, 9 (25.0%) patients reported ≥1 IRR during the first maintenance cycle, with the majority being grade 1/2. Grade 3 (chest discomfort) and grade 4 (laryngeal edema) IRRs were reported in 1 patient each.
      • No IRRs were reported during maintenance treatment in patients who did not receive transplant.
    • One patient discontinued study treatment due to an IRR.
• TEAEs occurring in the maintenance phase are summarized in Tables: Most Common TEAEs of Any Grade (≥20%) and Grade 3/4 (≥5%) Occurring During the Maintenance Phase in the Safety Analysis Set (LYRA, RMM Arm) and Most Common TEAEs of Any Grade (≥20%) and Grade 3/4 (≥5%) Occurring During the Maintenance Phase in the Safety Analysis Set (LYRA, NDMM Arm).

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 17 June 2024.