SUMMARY

• DARZALEX for intravenous (IV) use and DARZALEX FASPRO for subcutaneous (SC) use are not approved by the regulatory agencies for use in patients with extramedullary disease (EMD). Janssen does not recommend the administration of DARZALEX or DARZALEX FASPRO in a manner that is inconsistent with the approved labeling.
• Kumar et al (2024)¹ presented (at the European Hematology Association [EHA] 2024 Hybrid Congress) results from a retrospective, descriptive analysis involving secondary use of historical data from 7 clinical trials in patients with relapsed/refractory multiple myeloma (RRMM) with and without EMD. Across the 7 trials, overall response rates (ORRs) were numerically lower for patients with EMD vs patients without EMD (range, 0%-50.0% vs 42.7-92.8%, respectively). Over the first year of treatment, patients with EMD generally had higher rates of progression and/or death vs patients without EMD (range; progression: 33.3%-100% vs 14.8%-69.5%, respectively; death: 0%-66.7% vs 6.9%-29.2%, respectively).
• MAIA is a phase 3 study evaluating the efficacy and safety of DARZALEX in combination with lenalidomide and dexamethasone (D-Rd) compared with lenalidomide in combination with dexamethasone (Rd) in transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM). At a median follow-up of 64.5 months, the median progression-free survival (PFS) was 57.5 months in the D-Rd arm and 19.4 months in the Rd arm of the extramedullary plasmacytoma subgroup. Additional efficacy outcomes evaluated in this subgroup were ORR (D-Rd, 86.7%; Rd, 33.3%), minimal residual disease (MRD)-negativity (D-Rd, 33.3%; Rd, 0%), and sustained MRD-negativity (DRd, 13.3%; Rd, 0%).²
• SIRIUS was a phase 2 study that evaluated the efficacy and safety of DARZALEX monotherapy in patients with multiple myeloma (MM; N=106) who had received ≥3 prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent, or had disease refractory to both a PI and an immunomodulatory agent. At baseline, there were 14 (13%) patients with ≥1 extramedullary plasmacytoma. The ORR was achieved by 21.4% (n=3) patients with extramedullary plasmacytoma (95% confidence interval [CI], 4.750.8).³
• Beksac et al (2023)^4,5 presented (at the American Society of Hematology [ASH] 2023 Annual Meeting) efficacy results from a phase 2, open-label, single-arm, multinational study evaluating DARZALEX in combination with bortezomib, cyclophosphamide, and dexamethasone (D-VCd) in patients with NDMM or first-relapse MM. Overall, complete response (CR) or more was achieved by 18 (45.0%) patients (CR, n=16 [40.0%]; stringent complete response [sCR], n=2 [5.0%]). The ORR was 80.0% in the entire study population.
• Jelinek et al (2022)⁶ conducted a retrospective study to evaluate the efficacy of DARZALEX monotherapy and in combination with lenalidomide and dexamethasone (D-Rd) in patients with RRMM and EMD.
  • Of the 41 patients with RRMM who were administered DARZALEX monotherapy, 34% (n=14) had EMD. In patients with EMD (n=14) vs without EMD (n=27), the ORR was 21.4% vs 50.0%, median PFS was 1.4 months vs 6.2 month (P=0.002), and median overall survival (OS) was 4.6 months vs 15.4 months (P=0.042), respectively.
  • Of the 186 patients with RRMM who were administered D-Rd, 22% (n=41) had EMD. In patients with EMD (n=41) vs without EMD (n=145), the ORR was 57.7% vs 84.5% (P=0.0048), and median PFS was 7.8 months vs 27.3 months (P=0.002), respectively.
• Several case reports have been identified which discuss the use of DARZALEX monotherapy or in combination in patients with EMD. The reports are included in the References section for your information.^7-16

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 DATA

Retrospective Analysis of 7 Clinical Trials in Patients With RRMM With and Without EMD

Kumar et al (2024)¹ presented results from a retrospective, descriptive analysis involving secondary use of historical data from 7 clinical trials in patients with RRMM with and without EMD.

Study Design/Methods

• The 7 historical clinical trials in this analysis included the Phase 1 trials: MMY1003 and PAVO and the Phase 3 trials: COLUMBA, POLLUX, APOLLO, CASTOR, and LEPUS.
• Patients were categorized based on EMD at baseline (0=no, ≥1=yes).
• Primary endpoint: ORR based on International Myeloma Working Group (IMWG) criteria.
• Time-to-event endpoints: progression and death.

Results

Patient Characteristics

• A total of 2274 patients with RRMM were analyzed, of whom 5.3% (n=121) of patients had EMD. The ranges of baseline characteristics for all treatment cohorts have been presented in Table: Ranges of Baseline Characteristics for All Treatment Cohorts.

Efficacy

• Across the 7 trials, ORRs were numerically lower for patients with EMD than in patients without EMD (range, 0%-50.0% vs 42.7%-92.8%).
• Patients with EMD generally had higher rates of progression and/or death over the first year of treatment vs patients without EMD (range, 33.3–100% vs 14.8–69.5%, respectively; death: 0–66.7% vs 6.9–29.2%, respectively).
• A summary of ORR, disease progression, and deaths in patients with EMD in the first year of treatment in 7 historical clinical trials has been presented in Table: Summary of ORR, Disease Progression, and Deaths in Patients with EMD in the First Year of Treatment in 7 Historical Clinical Trials.

Phase 3 Study Comparing D-Rd vs Rd in Patients with RRMM

MAIA (MMY3008; clinicaltrials.gov identifier: NCT02252172) is an ongoing, international, phase 3, randomized, open-label, active-controlled, multicenter study in patients with NDMM not eligible for high-dose chemotherapy and autologous stem cell transplantation (ASCT).¹⁷ Moreau et al (2022)² presented the efficacy and safety results in clinically important subgroups of patients from the MAIA study at a median follow-up of 64.5 months.

Study Design/Methods

• Patients were randomized 1:1 to receive D-Rd or Rd until progressive disease (PD) or unacceptable toxicity (28 days/cycle):
  • Rd arm:
    • Lenalidomide: 25 mg orally (PO) daily on days 1-21 (10 mg daily if creatinine clearance [CrCl] between 30-50 mL/min)
    • Dexamethasone: 40 mg PO on days 1, 8, 15, and 22 (20 mg in patients with >75 years of age or with a body mass index [BMI] of <18.5 kg/m²)
  • D-Rd arm:
    • DARZALEX: 16 mg/kg IV weekly during cycles 1-2, every 2 weeks during cycles 36, then every 4 weeks during cycle 7+
• Efficacy and safety outcomes were evaluated in clinically important subgroups, including a subgroup of patients with extramedullary plasmacytomas.
• Primary endpoint: PFS
• Key secondary endpoints: ORR and MRD-negativity rate (10^-5 sensitivity)

Results

Patient Characteristics

• Overall, 737 patients (D-Rd, n=368; Rd, n=369) were included in the intent-to-treat (ITT) population, of whom 15 patients in the DRd arm and 9 patients in the Rd arm had extramedullary plasmacytomas.
• The median duration of follow-up was 64.5 months.

Efficacy

• At data cut-off, 7 of 15 and 5 of 9 patients with extramedullary plasmacytomas in the DRd and Rd arm, respectively, were alive without progression. The median PFS was 57.5 months in the D-Rd arm and 19.4 months in the Rd arm of the extramedullary plasmacytoma subgroup (HR, 0.47; 95% CI, 0.15-1.50).
• Other efficacy outcomes in the extramedullary plasmacytoma subgroup are summarized in Table: Efficacy Outcomes in Patients with Extramedullary Plasmacytoma.

Phase 2 Study with DARZALEX Monotherapy in Patients with Heavily Pretreated RRMM

SIRIUS (MMY2002; clinicaltrials.gov identifier: NCT01985126) was an open-label, multicenter, international, phase 2 study evaluating the efficacy and safety of DARZALEX monotherapy in patients with MM who have received ≥3 prior lines of therapy including a PI and an immunomodulatory agent or have disease refractory to both a PI and an immunomodulatory agent. Lonial et al (2016)³ evaluated the efficacy and safety of DARZALEX monotherapy in patients with MM (N=106) who were refractory to both a PI and an immunomodulatory agent.

Study Design/Methods

• Patients were initially randomized 1:1 to receive DARZALEX 8 mg/kg every 4 weeks (n=18); or DARZALEX 16 mg/kg every week for 8 weeks, DARZALEX 16 mg/kg every 2 weeks for 16 weeks, then DARZALEX 16 mg/kg every 4 weeks thereafter (n=16).
• Response was evaluated and the DARZALEX 16 mg/kg dose was established as the recommended dose for further evaluation. An additional 90 patients were enrolled in the DARZALEX 16 mg/kg group.
• The DARZALEX infusion was initiated in 1000 mL at 50 mL/hr.¹⁸
  • In the absence of infusion-related reactions (IRRs), the rate increased to 200 mL/hr at 50 mL/hr intervals.
  • Second and subsequent infusions (in 500 mL) began at 50 mL/hr and 100 mL/hr, respectively, and increased to 200 mL/hr.
• Pre-medications for the management of IRRs, administered 1 hour (±15 minutes) prior to the DARZALEX infusion, included:¹⁸
  • Methylprednisolone 100 mg (or equivalent) intravenously for the first 2 infusions, and 60 mg with subsequent infusions
  • Acetaminophen 650-1000 mg
  • Diphenhydramine 25-50 mg (or equivalent)
• A corticosteroid (methylprednisolone 20 mg or equivalent) was given on the 2 consecutive days following DARZALEX infusions.¹⁸
• Additional inclusion criteria were Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2, absolute neutrophil count >1 x 10⁹/L, hemoglobin >7.5 g/dL, platelet count ≥50 x 10⁹/L, and creatinine clearance >20 mL/min/1.73 m².
• Primary endpoint: ORR
• Secondary endpoints: PFS, OS, duration of response (DOR), and clinical benefit rate (ORR + minimal response [MR])

Results

Patient Characteristics

• Baseline patient and disease characteristics are presented in Table: Key Baseline Patient Demographics and Disease Characteristics.

Efficacy

• Response outcomes are presented in Table: Overall Response Rate by Subgroup.

Phase 2 Study Evaluating D-VCd in NDMM or First-Relapse MM

Beksac et al (2023)^4,5 presented efficacy results from a phase 2, open-label, single-arm, multinational study evaluating D-VCd in patients with NDMM or first-relapse MM.

Study Design/Methods

• Key eligibility criteria: patients with NDMM or first-relapsed MM with EMD, measurable disease, not hypersensitive to bortezomib or refractory to bortezomib-based regimens, no ASCT ≤12 weeks before cycle 1 day 1, no previous allogeneic stem cell transplant.^4,5
• Patients received the following treatment until progression or unacceptable toxicity (maximum 36 months), unless refractory disease (PD or failure to achieve a confirmed partial response or better [≥PR]) was detected by the end of cycle 3.^4,5
  • DARZALEX was given 16 mg/kg IV initially but was switched to DARZALEX FASPRO 1800 mg/kg subcutaneous (SC) after July 2020, administered once a week (QW) during cycles 1-2, once every 2 weeks (Q2W) during cycles 3-6, and once every 4 weeks (Q4W) during cycles 7+.
  • Bortezomib was given at a dose of 1.5 mg/m² SC QW.
  • Cyclophosphamide was given at a dose of 300 mg/m² PO or IV QW (maximum 500 mg).
  • Dexamethasone was given at a dose of 20 mg PO or IV on days 1, 2, 8, 9, 15, 16, 22, and 23.
• Primary endpoint: CR⁴
• Key secondary endpoints: ORR, PFS, OS, DOR, safety⁴

Results

Patient Characteristics

• Overall, 40 patients were included. The baseline patient and disease characteristics are summarized in Table: Baseline Patient and Disease Characteristics.
• The median duration of follow-up was 23.0 months (range, 2.0-38.3).⁵
• At data cut-off, 17 patients (42.5%) were still on study treatment and 23 patients (57.5%) had discontinued study treatment (PD, n=13 [32.5%]; death, n=3 [7.5%]; inadequate response after cycle 3, n=5 [12.5%]; withdrawal, n=1 [2.5%]; physician’s decision, n=1 [2.5%]).⁵
• Eleven (27.5%) patients had received ASCT.⁵

Efficacy

• Hematologic treatment responses are summarized in Table: Hematologic Treatment Responses as per IMWG Criteria.
• Of the 40 patients included in the study, 28 (70.0%) had a concurrent hematologic and EMD response of ≥PR, and 4 (10.0%) had a ≥PR (sCR, n=1; CR, n=1; and VGPR, n=2) without achieving an EMD response.⁵
  • A total of 8 patients had discontinued treatment by cycle 4 and had not achieved hematologic or EMD response. See Table: Summary of Hematologic Response.
• The median duration of first concurrent hematologic CR and complete metabolic response (CMR) was 6 months (range, 3-15).⁵
• The median duration of first response for patients achieving only one type of response (hematologic CR or CMR) was 5 months (range, 1-11).⁵
• The median PFS and responses for hematologic CR and CMR have been presented in Table: Summary of PFS and Response for Hematologic CR and CMR.

Retrospective, Multicenter Study in Patients with RRMM and EMD

Jelinek et al (2022)⁶ conducted a retrospective study to evaluate the efficacy of DARZALEX monotherapy and D-Rd in patients with RRMM and EMD.

Study Design/Methods

• A retrospective, multicenter study in patients with RRMM who were administered DARZALEX monotherapy (N=41) or D-Rd (N=186) treatment regimen.
• The presence of EMD was evaluated according to institutional guidelines by positron emission tomography (PET)/computed tomography (CT), magnetic resonance imaging (MRI), or CT; both bone-related and soft tissue lesions were considered as EMD.

Results

Patient Characteristics

• Baseline patient and disease characteristics are presented in Table: Key Baseline Demographics and Disease Characteristics of Patients with EMD.

Efficacy

• Of the 41 patients with RRMM who were administered DARZALEX monotherapy, 34% (n=14) had EMD. See Table: Demographics and Characteristic of Patients Treated with DARZALEX Monotherapy.
  • In patients with EMD (n=14) vs without EMD (n=27), the ORR was 21.4% vs 50.0%, median PFS was 1.4 months vs 6.2 month (P=0.002), and median OS was 4.6 months vs 15.4 months (P=0.042), respectively.
• Of the 186 patients with RRMM who were administered D-Rd, 22% (n=41) had EMD. See Table: Demographics and Characteristic of Patients Treated with D-Rd.
  • In patients with EMD (n=41) vs without EMD (n=145), the ORR was 57.7% vs 84.5% (P=0.0048), and median PFS was 7.8 months vs 27.3 months (P=0.002), respectively.
• In patients with soft tissue EMD (n=10) vs bone-related EMD (n=31), PFS was 4.8 months vs 8.4 months (P=0.549), respectively.

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 27 June 2024.