DARZALEX + DARZALEX FASPRO - Use in Combination with Cyclophosphamide and Bortezomib and Dexamethasone in Multiple Myeloma

SUMMARY

• Johnson & Johnson does not recommend the use of DARZALEX or DARZALEX FASPRO in a manner that is inconsistent with the approved labeling.
• LYRA is a phase 2 study evaluating the safety and efficacy of DARZALEX when administered in combination with cyclophosphamide, bortezomib, and dexamethasone (Dara-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.^1-3
  • Yimer et al (2022)^3,4 reported the end-of-study analysis of LYRA. At the end of cycle 4, very good partial response or better (≥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 most frequent any-grade treatment-emergent adverse event (TEAE) was fatigue (68.6%). Grade 3/4 TEAEs occurred in 62.8% patients, with the most frequent being neutropenia (12.8%).
• Beksac et al (2026)⁵ reported efficacy and safety results from the phase 2 EMN19 study evaluating DARZALEX in combination with CyBorD in patients with NDMM or first-relapse MM and confirmed extramedullary disease (EMD). Complete response or better (≥CR) was achieved by 47.5% of patients. The most common grade 3/4 TEAEs were pneumonia (12.5%) and COVID-19 infection (7.5%).
• Mollee et al (2024)⁶ conducted a phase 2 study evaluating induction with DARZALEX in combination with CyBorD followed by DARZALEX maintenance in transplant-ineligible (TIE) patients with NDMM. The median PFS was 21.7 months overall, 25.8 months in the Dara-CyBorD arm, and 16.8 months in the CyBorD arm. A total of 89% of patients from the Dara-CyBorD arm vs 82% of patients from the CyBorD arm experienced ≥1 adverse event (AE). At 6 months after randomization, early deaths were reported in 5 patients from the Dara-CyBorD arm vs 1 patient from the CyBorD arm.
• Swan et al (2022)⁷ reported the results of a phase 1b clinical study evaluating the efficacy and safety of DARZALEX in combination with CyBorD in patients with NDMM eligible for autologous stem cell transplant (ASCT). Overall, 77.8% of patients achieved CR/stringent complete response (sCR). The most common grade ≥3 AEs were lymphopenia, 16.7%; diarrhea, 11.1%; fatigue, 5.6%; and back pain, 11.1%.

PRODUCT LABELING

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

CLINICAL DATA

Phase 2 Study of DARZALEX in Combination with CyBorD in NDMM or RMM

LYRA (MMY2012; NCT02951819) 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.^1-3

Study Design/Methods

• Key eligibility criteria: patients ≥18 years of age with documented MM as per the International Myeloma Working Group (IMWG) criteria, Eastern Cooperative Oncology Group performance status (ECOG PS) 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
• Key exclusion criteria: refractory to a proteasome inhibitor (PI) or a combination of PI and immunomodulatory drug.¹
• Patients received 4-8 cycles (28 days per cycle) of the following induction treatment¹:
  • DARZALEX: 8 mg/kg intravenously (IV) on days 1 and 2, followed by 16 mg/kg IV weekly (QW) in cycle 1; 16 mg/kg IV QW in cycle 2, every 2 weeks (Q2W) in cycles 3-6, and every 4 weeks (Q4W) in cycles 7-8.
  • Bortezomib: 1.5 mg/m² subcutaneously (SC) QW on days 1, 8, and 15 in all cycles.
  • Cyclophosphamide: 300 mg/m² orally (PO) QW on days 1, 8, 15, and 22 in all cycles.
  • Dexamethasone: 20 mg IV on days 1 and 2, followed by 40 mg QW in cycle 1, 40 mg IV/PO QW in cycles 2-8.
• 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 Q4W.
  • Dexamethasone: 12 mg IV/PO on DARZALEX dosing days.
• Patients underwent high-dose therapy and ASCT at the discretion of the investigator after the induction phase.³
• Primary endpoint: ≥VGPR after 4 induction cycles.³
• Key secondary endpoints: overall response rate (ORR), time to ≥VGPR, time to ≥PR, PFS, overall survival (OS), safety, and tolerability.³

Final Analysis of the LYRA Study

Yimer et al (2022)³ reported the end-of-study results of the LYRA study at a median follow-up of 35.7 months for the NDMM arm and 35.3 months for the RMM arm.

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
• 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).^3,4

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.^3,4
  • 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.^3,4
• The median duration of response (DOR) was 20.7 months (95% CI, 5.9-NE) in the RMM arm and NR in both the transplant and non-transplant NDMM arms.^3,4
• 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. See Table: Most Common TEAEs of Any Grade (≥25%) and Grade 3/4 (≥10%) in the Safety Analysis Set (LYRA).^3,4

• TEAEs leading to treatment discontinuation occurred in 1 patient in the RMM arm and 7 patients in the NDMM arm.^3,4
  • 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.^3,4
• 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.^3,4
  • 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) ^3,4

Phase 2 Study Evaluating Dara-CyBorD in NDMM or First-Relapse MM with EMD

Beksac et al (2026)⁵ reported efficacy results from the EMN19 trial, a phase 2, open-label, single-arm, multinational study evaluating Dara-CyBorD in patients with NDMM or first-relapse MM and confirmed EMD.

Study Design/Methods

• Key eligibility criteria: NDMM or first-relapsed MM with EMD, measurable disease, ECOG PS score 0-2.⁵
• Key exclusion criteria: solitary plasmacytoma, previous therapy with anti-CD38 monoclonal antibody, refractory to bortezomib-based regimens.⁵
• Patients received the following treatment until progression or unacceptable toxicity (maximum 36 months)⁵:
  • DARZALEX was given 16 mg/kg IV initially but was switched to DARZALEX FASPRO 1800 mg SC after July 2020, administered QW during cycles 1-2, Q2W during cycles 3-6, and Q4W during cycles 7+.
  • Bortezomib 1.5 mg/m² SC QW.
  • Cyclophosphamide 300 mg/m² PO or IV QW.
  • Dexamethasone 20 mg PO or IV on days 1, 2, 8, 9, 15, 16, 22, and 23.
• Treatment was discontinued if patients failed to achieve a confirmed ≥PR by the end of cycle 3.⁵
• ASCT was permitted for patients who successfully completed 4-6 cycles of Dara-CyBorD.⁵
• Primary endpoint: CR.⁵
• Key secondary endpoints: ORR, PFS, OS, DOR, safety.⁵

Results

Patient Characteristics

• Overall, 40 patients were enrolled, including 29 patients (72.5%) with NDMM and 11 patients (27.5%) with RMM. Baseline patient and disease characteristics are summarized in Table: Baseline Patient and Disease Characteristics.⁵
• The median follow-up was 30.0 months (range, 2.0-52.4).⁵
• At data cut-off, the median Dara-CyBorD treatment duration was 18.4 months (range, 0.8-52.4) and 11/29 patients (37.9%) with NDMM received ASCT.⁵

Efficacy

• The ORR was 80.0% (NDMM, 89.7% [n=26/29]; RMM, 54.5% [n=6/11]).⁵
• Best hematologic responses are summarized in Table: Treatment Responses.⁵

• Of 19 minimal residual disease (MRD)-evaluable patients, 15 (78.9%) achieved MRD-negativity (10^-5; NDMM, n=13; RMM, n=2).⁵
• The median PFS for all patients was 25.8 months (95% CI, 10.2-NR).⁵
• For all patients, the median OS was NR; for patients with NDMM, median OS was NR (95% CI, 29.3-NR) vs 25.8 months (95% CI, 2.4-NR) in patients with RMM.⁵

Safety

• Thirty-nine patients (97.5%) experienced one or more TEAE.⁵
  • The most common any grade hematologic TEAEs were thrombocytopenia (37.5%), anemia (35.0%), and neutropenia (30.0%)
  • The most common any grade non-hematologic TEAEs were upper respiratory tract infection (42.5%), COVID-19 (37.5%), and hypogammaglobulinemia (37.5%).
• Thirteen patients (32.5%) experienced one or more grade 3/4 TEAE, most commonly pneumonia (12.5%) and COVID-19 infection (7.5%).⁵
• Serious AEs occurred in 18 patients (45.0%).⁵
• Serious AEs leading to death occurred in 4 patients (10.0%) and included myocardial infarction, COVID-19, myocarditis infectious, and pneumonia cytomegaloviral (n=1 each).⁵
  • Pneumonia cytomegaloviral was the only grade 5 event related to study treatment.

Phase 2 Study of Induction Therapy Using DARZALEX in Combination with CyBorD Followed by DARZALEX Maintenance

Mollee et al (2024)⁶ is a phase 2, prospective randomized, openlabel, multicenter study evaluating induction with DARZALEX in combination with CyBorD followed by DARZALEX maintenance in transplant-ineligible patients with NDMM at a median follow-up of 44.7 months.

Study Design/Methods

• Patients were randomized 1:1 to receive nine 5-week cycles of either of the following treatment regimens⁶:
  • CyBorD arm:
    • Bortezomib: 1.3 mg/m² SC on days 1, 8, 15, and 22.
    • Cyclophosphamide: 300 mg/m² PO on days 1, 8, 15, and 22.
    • Dexamethasone: 20 mg PO on days 1, 8, 15, and 22.
  • Dara-CyBorD arm:  
    • DARZALEX: 16 mg/kg IV on days 1, 8, 15, and 22 of cycles 1 and 2; days 1 and 15 of cycles 3-6; and day 1 of cycles 7-9, followed by maintenance with 16 mg/kg IV Q4W until progressive disease (PD).
    • CyBorD as described above.
• Patients received the below medications within 1 hour of DARZALEX administration to mitigate the risk of IRRs.⁶
  • Paracetamol: 1000 mg PO.
  • Diphenhydramine: 25-50 mg or equivalent PO or IV.
  • Dexamethasone: 20 mg PO.
  • Montelukast: 10 mg PO (optional).
• Primary endpoint: PFS.⁶
• Secondary endpoints: ORR, MRD, OS, safety, toxicity, and global health status.⁶

Results

Patient Characteristics

• Overall, 121 patients were included (Dara-CyBorD arm, n=64; CyBorD arm, n=57) in the study. The baseline patient and disease characteristics are summarized in Table: Baseline Characteristics.⁶
• A total of 78%, 13%, and 8% of patients from the Dara-CyBorD arm vs 61%, 26%, and 12% of patients from the CyBorD arm completed 9 cycles, ≤4 cycles, and
  5-8 cycles of induction, respectively.⁶

Efficacy

• Median PFS was 21.7 months (95% CI, 17.7-26.3) overall, 25.8 months (95% CI,
  19.9-33.5) in the Dara-CyBorD arm, and 16.8 months (95% CI, 15.3-21.7) in the CyBorD arm (hazard ratio [HR], 0.67; log rank test, P=0.066).⁶
• Proportion of patients who were progression-free (Dara-CyBorD vs CyBorD arm)⁶:
  • At 18 months: 68% vs 48%; P=0.0002.
  • At 24 months: 52% vs 36%; P=0.0001.
  • At 30 months: 41% vs 27%; P<0.0001.
• A significant difference in median PFS favoring the Dara-CyBorD arm was reported for younger patients.⁶
  • Younger patients (<75 years old): 29.8 months vs 16.3 months (95% CI,
    0.265-0.975; HR, 0.508; P=0.042).
  • Older patients (≥75 years old): 23.0 months vs 19.0 months (95% CI, 0.474-1.470; HR, 0.834; P=0.533).
• A difference in PFS favoring the Dara-CyBorD arm was reported for patients with revised international staging system (R-ISS) stage II (95% CI, 0.308-0.851; HR, 0.512; P=0.010) and R-ISS stage III (95% CI, 0.040-1.024; HR, 0.202; P=0.053).⁶
• The treatment response rates are summarized in Table: Treatment Responses.⁶
• The follow-up period was not long enough to adequately assess OS differences between the arms. Hence, median OS was estimated to be NR (95% CI, 41.7-not available) in the Dara-CyBorD arm and 58.7 months (95% CI, 47.0-not available) in the CyBorD arm (P=0.392).⁶

Safety

• A total of 89% patients from the Dara-CyBorD arm vs 82% patients from the CyBorD arm experienced ≥1 AE. See Table: Summary of AEs.⁶
• The most common any-grade AEs that occurred in the Dara-CyBorD arm vs CyBorD arm included pain (48% vs 47%), nausea and vomiting (25% vs 26%), diarrhea (25% vs 21%), peripheral neuropathy (28% vs 18%), fatigue and lethargy (20% vs 23%), lower limb edema (22% vs 16%), and upper respiratory tract infections (27% vs 11%).⁶
• At 6 months after randomization, early deaths (n=6) were reported in 5 patients from the Dara-CyBorD arm (PD, n=2; infection, n=3) vs 1 patient from the CyBorD arm (respiratory failure, n=1).⁶

Phase 1b Study of DARZALEX in Combination with CyBorD in Patients with NDMM Eligible for ASCT

Swan et al (2022)⁷ reported the results of a phase 1b clinical study evaluating the efficacy and safety of DARZALEX in combination with CyBorD in patients with NDMM eligible for ASCT at a median follow-up of 2.9 years.

Study Design/Methods

• All patients received 4 cycles of the following induction treatment (28 days/cycle)⁷:
  • DARZALEX: 16 mg/kg IV on days 1, 8, 15, and 22 during cycles 1 and 2 and on
    days 1 and 15 during cycles 3 and 4.
  • Cyclophosphamide: 150-300 mg/m² PO QW.
  • Bortezomib: 1.3-1.5 mg/m² SC QW.
  • Dexamethasone: 40 mg PO on days 1, 2, 8, 9, 15, 16, 22, and 23.
• After induction, patients underwent stem cell mobilization with cyclophosphamide, followed by melphalan therapy and ASCT.⁷
• Patients received 2 cycles of consolidation therapy after ASCT following the same schedule as cycles 3 and 4 of induction and proceeded to maintenance with DARZALEX on day 1 of each cycle (28 day) until PD, unacceptable toxicity, or withdrawal of consent (maximum 2 years). Patients with high-risk disease also received bortezomib 1.3 mg/m² on days 1 and 15 of each maintenance cycle.⁷
• Primary endpoints: Post-ASCT ≥CR rate, and the maximum tolerated dose of cyclophosphamide and bortezomib that can be safely delivered with DARZALEX.⁷

Results

Patient Characteristics

• The baseline patient and disease characteristics are summarized in Table: Baseline Patient and Disease Characteristics.⁷
• Three patients discontinued the study before consolidation due to hepatic toxicity, PD, and death after ASCT (1 patient each).⁷
• Fifteen patients proceeded to consolidation and maintenance therapy. The median duration of maintenance therapy was 23.7 months.⁷

Transplant Characteristics

• Patients underwent stem cell mobilization using cyclophosphamide and
  granulocyte-colony stimulating factor (G-CSF) as per institutional protocol. Plerixafor was required in 4 patients.⁷
• Successful harvesting was achieved in 93.8% of patients (15 of 16).⁷
• The median number of harvested cluster of differentiation 34 (CD34)+ cells was 6.46×10⁶ cells/kg (range, 0.7-13.36).⁷
• The median time to recovery of neutrophils to >0.5×10⁹ was 11 days (range, 9-13) and that of platelets to >20×10⁹ was 11 days (range, 7-14), after ASCT.⁷
• One patient who had received intensive spinal radiotherapy failed to mobilize and proceeded directly to consolidation and maintenance.⁷

Efficacy

• The ORR in the intent-to-treat (ITT) population was 94.1% after induction. Overall, 77.8% of patients achieved CR/sCR. The response outcomes are presented in Table: Response Outcomes (ITT Population).⁷
• At the end of maintenance therapy, the PFS rate was 81.3% and the estimated 2-year OS rate was 88.9%.⁷
• MRD (10^-5) was evaluated in 14 patients after induction, 13 after ASCT and consolidation each, and 10 at the end of treatment (EOT).⁷
  • Sustained MRD-negativity (ie, from ASCT to EOT) was reported in 37.5% of patients.
  • Seven patients were MRD-negative after both ASCT and consolidation, of whom all those who were evaluable at EOT (n=6) remained MRD-negative. One patient was not able to undergo MRD assessment due to Coronavirus Disease 2019 (COVID-19), but remained in CR.
• Among patients with high-risk cytogenetics (n=4) and high-risk gene expression profile (GEP; n=1), 1 patient discontinued study due to deranged liver function, and 1 patient died after ASCT.⁷
• One patient had PD during maintenance and 2 patients remained in MRD-negative CR/sCR at EOT.⁷

Safety

• The most common AEs are summarized in Table: Most Common Adverse Events.⁷
• Serious AEs occurred in 55.6% of patients (sepsis, influenza, urinary tract infection, and back pain; 2 cases each).⁷
• No neuropathic pain or peripheral neuropathy related to study treatment was observed.⁷

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 22 July 2026.