SUMMARY  

• SIRIUS was a phase 2 study evaluating the efficacy and safety of DARZALEX monotherapy in patients with multiple myeloma (MM) who have received ≥3 prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent or have disease refractory to both a PI and an immunomodulatory agent (N=106). The overall response rate (ORR) was 29.2% (95% CI, 20.8-38.9). Treatment-emergent adverse events (TEAEs) that occurred in ≥20% of patients included fatigue, anemia, nausea, thrombocytopenia, neutropenia, back pain, and cough. Infusion-related reactions (IRRs) occurred in 42% of patients.¹
• Vorhees et al (2015)² presented management of IRRs in the SIRIUS study. The incidence of IRRs for DARZALEX 8 mg/kg and 16 mg/kg were 38% and 44%, respectively. Most IRRs occurred during the first infusion and no patients discontinued treatment due to an IRR.
• Usmani et al (2020)³ reported a combined analysis of the safety and efficacy of DARZALEX 16 mg/kg used as monotherapy in patients with relapsed or refractory MM in the GEN501⁴ and SIRIUS¹ studies. This analysis is referenced below.
• Yan et al (2018)⁵ reported an exploratory analysis of the influence of disease and patient characteristics on daratumumab exposure and clinical outcomes in patients with relapsed or refractory MM in the GEN501⁴ and SIRIUS¹ studies. This analysis is referenced below.

product labeling

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

CLINICAL DATA

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)¹ 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. Vorhees et al (2015)² further described the management of IRRs in this study.

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.²
  • In the absence of 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:²
  • 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.²
• Additional inclusion criteria were Eastern Cooperative Oncology Group performance status ≤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: progression-free survival (PFS), overall survival (OS), duration of response, and clinical benefit rate (ORR + minimal response [MR])

Results

Patient Characteristics

• At baseline, 95% of patients were refractory to both PI and immunomodulatory drug and 66% were refractory to 3 of 4 therapies (bortezomib, lenalidomide, carfilzomib, and pomalidomide).
• Refractory status of patients at baseline is detailed in Table: Baseline Refractory Status.

Efficacy

• Reasons for study discontinuation were progressive disease (n=82; 77%), withdrawal of consent due to symptoms related to disease progression (n=3; 3%), and adverse events (AEs) not related to DARZALEX therapy (n=5; 5%).
• The ORR was 29.2% (n=31; 95% CI, 20.8-38.9) as presented in the Table: Overall Best Responses.
  • A total of 29 of 31 responders were alive at the time of data cutoff.
  • A listing of ORR by subgroup is noted in Table: Overall Response Rate by Subgroup.
• The median duration of follow-up was 9.3 months (range, 0.5-14.4 months).
• The median time to first response was 1.0 month (range, 0.9-5.6 months).
• The median duration of response was 7.4 months (95% CI, 5.5-not estimable [NE]).

• The median PFS was 3.7 months (95% CI, 2.8-4.6).
• The median OS was NE (95% CI, 13.7-NE).
• The 12-month OS was 64.8% (95% CI, 51.2-75.5).
• At a subsequent cutoff, median OS was 17.5 months (95% CI, 13.7-NE).

Safety

• TEAEs with ≥20% frequency are presented in the Table: Most Common (≥20%) TEAEs.
• Grade ≥3 anemia and thrombocytopenia occurred more frequently in non-responders (32% and 24%, respectively) than responders (3% and 6%, respectively).
• Grade ≥3 neutropenia rates were similar in non-responders (12%) and responders (13%).
• Serious TEAEs occurred in 32 (30%) patients. A total of 24 (23%) patients had grade 3/4 serious TEAEs.
• There were no discontinuations due to AEs related to DARZALEX.
• Supportive care administered during the trial included: red blood cell transfusion (38%), platelet transfusion (13%), and granulocyte colony-stimulating factor (8%).

• IRRs occurred in 38% of patients in the DARZALEX 16 mg/kg group and 44% in the DARZALEX 8 mg/kg group and were mostly grade 1/2.²
  • The most common IRRs in the DARZALEX 8 mg/kg group included: chills (28%); cough (17%); nasal congestion, dyspnea, pruritus, vomiting, and wheezing (6% each).
  • The most common IRRs in the DARZALEX 16 mg/kg group included: nasal congestion (12%); throat irritation (7%); cough, dyspnea, chills, and vomiting (6% each); nausea (5%); bronchospasm (4%); and pruritus and wheezing (2% each).
  • Grade 3 IRRs consisted of: bronchospasm (DARZALEX 16 mg/kg, n=2); dyspnea (DARZALEX 16 mg/kg, n=1); chills and cytokine release syndrome (DARZALEX 8 mg/kg, n=1 each); and hypertension (DARZALEX 8 mg/kg, n=1).
  • There were no instances of grade 4 IRRs.
  • Most IRRs occurred during the first infusion, and the median infusion duration decreased with each cycle. See Table: Onset of IRRs and Duration of Infusions for Each Treatment Cycle (DARZALEX 16 mg/kg).
  • In the DARZALEX 16 mg/kg group, treatment modifications in patients who experienced IRRs were: infusion interrupted (30/106, 28%), infusion rate decreased (10/106, 9%), and infusion aborted (2/106, 2%). An additional infusion was aborted in 1 patient in the DARZALEX 8 mg/kg group.
  • No patients discontinued treatment due to an IRR.
  • Cytokine changes from baseline to 4 hours after the first DARZALEX infusion did not correlate with IRRs.

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 17 July 2024.