Summary

• No formal studies of DARZALEX for intravenous (IV) use or DARZALEX FASPRO for subcutaneous (SC) use in patients with renal impairment have been conducted. Based on population pharmacokinetic (PK) analyses, no dosage adjustment is necessary in patients with renal impairment.^1,2
• As an IgG1κ monoclonal antibody, renal excretion and hepatic enzyme-mediated metabolism of intact daratumumab are unlikely to represent major elimination routes.²
• Patients with severe renal impairment were excluded from DARZALEX + DARZALEX FASPRO clinical studies^3-10 and no formal clinical or PK studies have been conducted in patients receiving hemodialysis or peritoneal dialysis.
• Moreau et al (2025)¹¹ reported the efficacy and safety results in clinically important subgroups of patients from the MAIA study. The progression-free survival (PFS) duration was longer in the DARZALEX in combination with lenalidomide and dexamethasone (DRd) vs lenalidomide in combination with dexamethasone (Rd) arm in the majority of subgroups. Treatment with DRd generally resulted in a greater improvement in the overall response rate (ORR), minimal residual disease (MRD)-negativity (10^-5) rate, and sustained MRD-negativity (10^-5) rate for ≥12 months across subgroups, compared with Rd. Among patients aged ≥75 years, grade 3/4 treatment-emergent adverse events (TEAEs) were reported in 95.5% vs 95.0% patients in the DRd vs Rd arm. The most common (≥10%) grade 3/4 TEAEs were neutropenia (DRd, 62.4%; Rd, 41.5%), lymphopenia (DRd, 21.0%; Rd, 12.6%), anemia (DRd, 20.4%; Rd, 25.2%), pneumonia (DRd, 20.4%; Rd, 14.5%), leukopenia (DRd, 12.1%; Rd, 7.5%), hypokalemia (DRd, 11.5%; Rd, 10.7%), hypertension (DRd, 10.8%; Rd, 5.0%), thrombocytopenia (DRd, 10.2%; Rd, 11.9%), and diarrhea (DRd, 10.2%; Rd, 5.0%).
• Facon et al (2022)¹² presented the results of a subgroup analysis of the phase 3 MAIA study that evaluated the efficacy and patient-reported outcomes (PROs) of DRd vs Rd in subgroups of patients with newly diagnosed multiple myeloma (NDMM) who had renal impairment and/or high-risk cytogenetics.
• Mateos et al (2022)¹³ presented the results of a post hoc subgroup analysis of the phase 3 CASTOR and POLLUX studies, evaluating the efficacy of DARZALEX in combination with bortezomib plus dexamethasone (DVd) vs bortezomib plus dexamethasone (Vd) along (CASTOR) and DRd vs Rd alone (POLLUX) in patients with relapsed and refractory multiple myeloma (RRMM). In the pooled intent-to-treat (ITT) population of CASTOR and POLLUX, PFS benefit of the DARZALEX (median, 24.2 months) vs control (median, 7.5 months) arm was observed (hazard ratio [HR], 0.39; 95% confidence interval [CI], 0.290.52) and overall survival (OS) benefit of the DARZALEX (median, 50.8 months) vs control (median, 28.8 months) arm was observed (HR, 0.65; 95% CI, 0.49-0.86) in patients with renal impairment. PFS benefit of the DARZALEX vs control arm was observed in patients with renal impairment in the ITT populations of each of the CASTOR and POLLUX studies.
• Harvey et al (2023)¹⁴ presented the phase 2 results of patients with NDMM and acute kidney injury (AKI; creatinine clearance [CrCl] <30 mL/min) treated with DARZALEX-based induction regimen. The ORR was 100% in the evaluable patients. The median baseline CrCl was 13.8 (range, 4.9-20.2) mL/min and end of study CrCl was 59 (range, 25-101) mL/min. The most common grade 3/4 TEAEs were anemia (n=10), lymphopenia (n=9), thrombocytopenia (n=4), neutropenia (n=1), and hyponatremia (n=1).
• Kastritis et al (2023)^15,16 reported the updated efficacy and safety results from the DARE study after a median follow-up of 11.3 months. The median PFS was 11.8 (95% CI, 2.8-20.8) months. The most frequent grade 3/4 adverse events (AEs) were anemia (15.8%), hyperglycemia (13.2%), and hypercalcemia (7.9%). The most common serious adverse event (SAE) was septic shock (10.5%), of which 3 cases were fatal.
• Other relevant literature has been identified in addition to the data summarized above.¹⁷

PRODUCT LABELING

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

clinical Data

MAIA - Phase 3 Study in Patients with NDMM

Moreau et al (2025)¹¹ presented the efficacy and safety results in clinically important subgroups of patients from the MAIA study.

Study Design/Methods

• Patients were randomized 1:1 to receive DRd 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 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)
  • DRd 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 outcomes (PFS, ORR, and MRD-negativity) were analyzed in subgroups based on renal insufficiency (baseline CrCl ≤60 mL/min).

Results

Patient Characteristics

• Overall, 737 (DRd, n=368; Rd, n=369) patients were included in the ITT population, of whom 162 patients in the DRd arm and 142 patients in the Rd arm had renal insufficiency.
• The median follow-up was 64.5 months.

Efficacy

• The PFS duration was longer in the DRd vs Rd arm in the majority of subgroups. See Table: Subgroup Analysis of PFS in the ITT Population of MAIA.
• A more favorable result was reported in the DRd vs Rd arm for the following endpoints across all subgroups:
  • ORR (See Table: Subgroup Analysis of ORR in the ITT Population of MAIA)
  • MRD-negativity (10^-5) rate (See Table: Subgroup Analysis of MRD-Negativity (10^-5) Rates in the ITT Population of MAIA)
  • Sustained MRD-negativity (10^-5) lasting ≥12 months (See Table: Subgroup Analysis of Rates of Sustained MRD-Negativity (10^-5) Lasting ≥12 Months in the ITT Population)

Safety (Patients Aged ≥75 Years)

• Among patients aged ≥75 years, grade 3/4 TEAEs were reported in 95.5% vs 95.0% of patients in the DRd vs Rd arm.
  • The most common (≥10%) grade 3/4 TEAEs are summarized in Table: Most Common (≥10%) Grade 3/4 TEAEs Among Patients Aged ≥75 Years in the Safety Population.
• Serious TEAEs were reported in 80.9% vs 79.2% of patients in the DRd vs Rd arm, the most common of which was pneumonia (DRd, 19.7%; Rd, 12.6%).
• TEAEs led to treatment discontinuation in 15.3% vs 27.7% of patients in the DRd vs Rd arm.
• TEAEs resulting in death were reported in 11.5% vs 13.2% of patients in the DRd vs Rd arm.
  

Subgroup Analysis in Patients with Renal Impairment and/or High Cytogenetic Risk in the MAIA Study

Facon et al (2022)¹² conducted a subgroup analysis of the phase 3 MAIA study that evaluated the efficacy and PROs of DRd vs Rd in subgroups of patients with NDMM who had renal impairment (CrCl ≤60 mL/min) and/or high-risk cytogenetics (del17p, t[4;14], or t[14;16] abnormality). Results of a subgroup of patients based on renal function are summarized below.

Study Design/Methods

• Renal impairment was defined as CrCl ≤60 mL/min.
• Patients with high cytogenetic risk had a del17p, t(4;14), or t(14;16) abnormality.

Results

Patient Characteristics

• Overall, 368 and 369 patients were randomized to the DRd and Rd arms, respectively. Baseline renal function status in the ITT population is summarized in Table: Baseline Renal Function.

Efficacy

• The median duration of follow-up was 56.2 months.
• In the overall study population and in patient subgroup based on renal function status, median times to very good partial response (VGPR) or better and complete response (CR) or better were shorter and durations of ≥CR and partial response (PR) or better were longer in the DRd vs Rd arm. Efficacy outcomes are summarized in Table: Efficacy Outcomes in the Overall Study Population and in Renal Function Subgroup.

• Among patients with renal impairment, greater improvements from baseline in patientreported pain scores, patient-reported fatigue, and nausea and vomiting symptom scores were observed in the DRd vs Rd arm across most time points.
  • A greater meaningful reduction in pain score was reported in the DRd vs Rd arm, respectively, at cycle 6 day 1 (least squares [LS] mean change from baseline, 14.9 vs 7.0; P=0.0241) in patients with renal impairment.
  • A greater reduction in fatigue symptom score was reported in the DRd vs Rd arm, respectively, at cycle 24 day 1 (LS mean change from baseline, -2.9 vs 8.1; P=0.0018), cycle 30 day 1 (LS mean change from baseline, -3.7 vs 4.4; P=0.0258), and cycle 36 day 1 (LS mean change from baseline, -2.6 vs 6.5; P=0.0183) in patients with renal impairment.
  • A greater reduction in nausea and vomiting symptom score was observed in the DRd vs Rd arm, respectively, at cycle 36 day 1 (LS mean change from baseline, 3.7 vs 3.3; P=0.0035) in patients with renal impairment.
• Greater improvements from baseline in patient-reported symptoms were observed in the DRd vs Rd arm in patients without renal impairment (CrCl >60 mL/min).

Post Hoc Analysis of CASTOR and POLLUX in Clinically Relevant Subgroups

Mateos et al (2022)¹³ presented a post hoc analysis of the phase 3 CASTOR and POLLUX studies to evaluate the efficacy of DVd vs Vd and DRd vs Rd in subgroups of patients with RRMM. Results of a subgroup of patients with renal impairment (CrCl ≤60 mL/min) are summarized below.

Study Design/Methods

• Patients with RRMM who had received ≥1 prior line of therapy (PL) were included.
• Patients refractory or intolerant to bortezomib or refractory to another proteasome inhibitor (PI) were excluded from CASTOR, and patients refractory or intolerant to lenalidomide were excluded from POLLUX.
• Patients were randomly allocated to receive DVd or Vd in CASTOR and DRd or Rd in POLLUX.
• Primary endpoint: PFS
• The efficacy outcomes were compared between treatment arms according to subgroups based on the following criteria:
  • Age ≥75 years
  • International staging system (ISS) stage III disease
  • High-risk cytogenetic risk abnormalities such as t(4;14), t(14;16), and/or del17p
  • 1PL
  • Renal impairment (CrCl ≤60 mL/min)
  • Prior autologous stem cell transplant (ASCT)
  • Prior bortezomib or lenalidomide exposure
  • Refractory to lenalidomide or bortezomib

Results

Patient Characteristics

• The median duration of follow-up was 72.6 months for CASTOR and 79.7 months for POLLUX.
• In a pooled analysis of CASTOR and POLLUX, PFS and OS benefits of the DARZALEX vs control arm was observed in patients with renal impairment. See Table: PFS and OS in the Pooled ITT Population from CASTOR and POLLUX.
• In the ITT population, PFS benefit of DARZALEX vs control arm was observed in patients with renal impairment both in CASTOR and POLLUX studies. See Tables: PFS in the ITT Populations of CASTOR and PFS in the ITT Populations of POLLUX.
• In CASTOR, improved ORRs and MRD-negativity rates were reported in the DVd vs Vd arm in patients with renal impairment. See Table: ORR and MRD-negativity (10^-5) Rates in CASTOR.
• In POLLUX, improved ORRs and MRD-negativity rates were reported in the DRd vs Rd arm in patients with renal impairment. See Table: ORR and MRD-Negativity (10^-5) Rates in POLLUX.

Phase 2 Study in Patients with NDMM

Harvey et al (2023)¹³ presented the phase 2 efficacy and safety results of patients with NDMM and AKI (CrCl <30 mL/min) treated with DARZALEX-based induction regimen.

Study Design/Methods

• A real-world phase 2 study assessed NDMM patients with CrCl <30 mL/min via the Crockcroft-Gault (C-G), modification of diet in renal disease (MDRD), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and/or 24-hour urine collection.
• Key eligibility: an Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0-2, MM as per the International Myeloma Working Group (IMWG) 2014 criteria, 2 doses of bortezomib and/or dexamethasone 160 mg total, red blood cell and platelet transfusion for hemoglobin ≥7 g/dL and platelet ≥75,000/mm³, absolute neutrophil count ≥1000/mm³, negative for hepatitis B/C.
• Patients received 4 x 21-day cycles of:
  • DARZALEX 16 mg/kg IV weekly (cycles 1-3 and cycle 4 day 1 only)
  • Bortezomib 1.3 mg/m³ SC on days 1, 4, 8, and 11 all cycles
  • Dexamethasone 40 mg (reduction to 20 mg permitted at cycle 2 in patients with >75 years of age or AEs) PO or IV on days 1-4 (cycle 1 only, day 1 only during cycles 2-4), 8, and 15
  • Add thalidomide 100 mg PO at bedtime daily or lenalidomide 25 mg PO daily on days 1-14 (for CrCl ≥30 mL/min) during cycle 2-4
• Following outcomes were evaluated:
  • Renal function at cycle 3 day 1 and end of study
  • Disease response at cycle 3 day 1 and end of study per IMWG criteria
  • AEs
  • Daratumumab PK: cycle 1 day 1, cycle 1 day 4, cycle 1 day 8, cycle 1 day 15, cycle 2 day 1, cycle 2 day 8, cycle 2 day 15 pre-dose, end of infusion (2 hour and 24 hour)
• Goal: Renal recovery to CrCl ≥50 mL/min after 2 cycles, Simon’s two-stage (Optimal), if ≥7 responses in first 11 enrolled, proceed to total of 25 patients

Results

Baseline Characteristics

• A total of 13 patients were enrolled in this study. The baseline patient characteristics are included in Table: Baseline Patient Characteristics.

Patient Disposition and Treatment Exposure

• Out of 13 patients, 11 patients were evaluable (withdrew consent, n=1; rapid PD and death, n=1).
• Median dose density (% delivered /planned per protocol) for DARZALEX was 100% (range, 40-100), bortezomib was 100% (range, 25-100), dexamethasone was 80% (67100), and lenalidomide 100% (0-100).

Efficacy

• Disease outcomes are presented in Table: Efficacy Outcomes in Evaluable Patients.

Safety

• TEAEs are presented in Table: Grade 1/2 and 3/4 TEAEs.
• Infusion-related reactions (IRRs) were reported in 3 patients.

DARE - Phase 2 Study in Patients with RRMM

Kastritis et al (2023)^15,16 reported the updated efficacy and safety results of treatment with DARZALEX in patients with RRMM and severe renal impairment or in need of hemodialysis using data from the phase 2 DARE study.

Study Design/Methods

• Prospective, phase 2, multicenter, single-arm, open-label study
• Inclusion criteria: Patients with RRMM and severe renal impairment (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m² or in need of hemodialysis) who had ≥2PL with both bortezomib- and lenalidomidebased regimens, PD as per the IMWG criteria, an ECOG PS score of ≤2, and no prior exposure to anticluster of differentiation 38 (CD38) antibody treatment (including DARZALEX) were included.¹⁸
• Patients received DARZALEX 16 mg/kg IV weekly for cycles 1-2, every 2 weeks for cycles 3-6, and every 4 weeks for subsequent cycles. In addition, patients received dexamethasone PO 40 mg weekly, every cycle.
• Outcomes evaluated in the study included PFS, ORR, renal response rate (RRR), duration of response (DoR), time to next therapy (TNT), OS, and safety.

Results

Patient Characteristics

• A total of 38 patients were included. Baseline patient characteristics are summarized in Table: Baseline Patient Characteristics in the DARE Study.

Efficacy

• The median duration of follow-up was 11.3 (interquartile range, 3.3-22.5) months
• The median PFS for all patients (N=38) was 11.8 (95% CI, 2.8-20.8) months.
  • The 6- and 12-month PFS rates were 54.0% and 48.1%, respectively.
• The median PFS for patients on vs not on dialysis was 2.8 (95% CI, 1.216.1) months vs 13.3 (95% CI, 3.9-NR) months, respectively (HR, 1.453; 95% CI, 0.649-3.249; P=0.358).
• The median OS for patients on vs not on dialysis was 12.5 (95% CI, 2.2-NR) months vs 24.5 (95% CI, 10.1-NR) months, respectively (HR, 1.798; 95% CI, 0.6904.682; P=0.223).
• The 12- and 24month OS rates for all patients (N=38) were 62.7% and 51.7%, respectively.
• The ORR for all patients was 47.4% (95% CI, 31.5-63.2).
• The RRR for all patients (partial renal response or better) was 18.4% (95% CI, 7.734.3), and 31 (81.6%) patients had either minor renal response (n=2) or no response (n=29). See Table: Efficacy Outcomes.
• Eight (21.1%) patients died without prior documented disease progression and 16 (42.1%) patients experienced disease progression on DARZALEX.
• In total, 16 (42.1%) patients died without receiving next-line therapy and 3 (7.9%) received subsequent systemic treatment.
  • The median TNT was 18.0 (95% CI, 5.5-NR) months.
  • A total of 17 (44.7%) patients died during the observation period of the study.

Safety

• The most frequently reported grade 3/4 AEs were anemia (n=6; 15.8%), hyperglycemia (n=5; 13.2%), and hypercalcemia (n=3; 7.9%); see Table: Most Common AEs (Overall >5%).
• Overall, 12 SAEs were reported in 11 (28.9%) patients, with the most common being septic shock (n=4; 10.5%).
  • An SAE of AKI was reported in 1 patient (not treatment related).
  • Among all the SAEs, 1 patient experienced grade 3 pneumonia requiring hospitalization; 1 patient on peritoneal dialysis experienced fatal peritonitis; and 2 patients experienced a fatal lower respiratory tract infection.
• In 33 (86.8%) and 26 (68.4%) patients, antivirals (acyclovir or valacyclovir) and antibiotics were administered as prophylaxis against viral and bacterial infections, respectively.
• Three patients required dialysis due to disease progression.

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
31 March 2025. For streamlining purposes, retrospective analysis, systematic reviews, review articles, and case reports have been excluded.

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