SUMMARY

• There are no systematically collected data to define the postinjection observation time of DARZALEX FASPRO for subcutaneous (SC) use. Clinical judgment should be exercised when considering observation times after DARZALEX FASPRO injection.
• DARZALEX FASPRO can cause severe and/or serious infusion-related reactions (IRRs), including anaphylactic reactions. In clinical trials, approximately 8% (95/1249) of patients experienced an IRR. Most IRRs occurred following the first injection and were grade 1-2. IRRs occurring with subsequent injections were seen in 1% of patients. The median time to onset of IRRs following DARZALEX FASPRO was 3.2 (range, 0.15-83) hours. The majority of IRRs occurred on the day of treatment. Delayed IRRs have occurred in 1% of patients.¹
• In the DARZALEX FASPRO clinical trial protocols (COLUMBA [MMY3012], APOLLO [MMY3013], and PLEIADES [MMY2040]), all patients were observed for at least 6 hours after the end of the SC injection during cycle 1 day 1 (C1D1) and after subsequent injections if deemed necessary by the investigator.^2-4
• The protocol for part 2 of the phase 1b PAVO (MMY1004) study required inpatient hospitalization for 24 hours after the first dose of DARZALEX FASPRO.¹⁵
• Nahi et al (2023)⁵ presented the updated safety and efficacy results from part 3 of the PAVO study. This study, conducted in 42 patients with relapsed or refractory multiple myeloma (RRMM) receiving DARZALEX FASPRO, demonstrated that rapidly tapering off pre- and post-dose corticosteroids over a 1- to 3-week period was safe, without an increased risk of IRRs (reported in a total of 5 patients, all but 1 of which were grade 1 or 2 in severity). All IRRs occurred with the first DARZALEX FASPRO administration, with a median onset time of 79 (range, 31-555) minutes.
• Maples et al (2023)⁶ conducted a retrospective analysis to determine the optimal duration of observation after administration of DARZALEX FASPRO to balance safety and convenience. IRRs (all of grade 1/2 and reversible) were reported in 2 patients in the 2hour observation group and in 1 patient in the 0-hour observation group.
• Tam et al (2021)⁷ conducted a single-center, retrospective analysis of patients who received at least 2 doses of DARZALEX FASPRO in the ambulatory care setting to evaluate the incidence and time to onset of real-world systemic reactions and injectionsite reactions (ISRs) after administration of DARZALEX FASPRO. Patients without previous exposure to DARZALEX (dara-naïve) were monitored for 6 hours while patients with previous exposure (dara-exposed) were monitored for 5 minutes or 2 hours if history of reaction with DARZALEX. Incidence of systemic reactions and ISRs were similar between dara-naïve vs dara-exposed patients (22.4% vs 20.4%; P=1.00). Median time to systemic reaction was 3 hours in dara-naïve patients vs 12 hours in dara-exposed patients (P=0.18). Median time to ISR was 6 hours in dara-naïve patients vs 24 hours in dara-exposed patients (P=0.029).
• Hughes et al (2022)⁸ conducted a retrospective analysis of the monitoring time, infusion chair time/improvement in clinical efficiency, and safety of DARZALEX FASPRO in patients with multiple myeloma (MM) and/or light-chain (AL) amyloidosis who were either previously treated with DARZALEX (n=18) or DARZALEX-naïve (n=40). All patients had a 30-minute postinjection observation time. Incidence of administrationrelated reaction (ARR) in the overall population was 1.7% (DARZALEXnaïve, 2.5%). Nine (15.5%) patients reported grade 3/4 neutropenia. The average chair time saved with DARZALEX FASPRO per patient was 14.95 hours; the total chair time saved was 867 hours.
• Tadros et al (2024)⁹ conducted a single-center, retrospective chart review to evaluate the incidence of ARRs and to determine if the observation time on subsequent injections could be reduced or eliminated in patients with MM or plasmablastic lymphoma who received DARZALEX FASPRO over a duration of 6 months (N=33). All patients had a
  3-hour and 1-hour observation time after the initial and each subsequent injection, respectively. None of the patients reported ARRs after administration of the first 3 SC injections. A total of 24 (72.7%) patients had at least 1 specific documentation of tolerance with any of the 3 doses, and 2 (6.1%) patients had documentation of tolerance after all 3 doses.
• Hamadeh et al (2021)¹⁰ conducted a retrospective chart review to report patient tolerability after DARZALEX for intravenous (IV) use to DARZALEX FASPRO switch. DARZALEX-experienced patients were monitored for approximately 1 hour while DARZALEX-naïve patients were monitored for approximately 4 hours after the first DARZALEX FASPRO administration. No ARRs were reported. In addition, no emergency department visits were reported within 24 to 48 hours.
• Soefje et al (2023)¹¹ assessed clinical administration characteristics of DARZALEX and DARZALEX FASPRO in patients with MM, including time parameters of interest related to in-clinic patient time (clinic time and chair time) as well as the incidence of ARRs in patients who switched from DARZALEX to DARZALEX FASPRO and initiated treatment with DARZALEX FASPRO at the Mayo Clinic infusion centers. The treatment plan was revised to reduce the mandated post-administration observation time for DARZALEX FASPRO from 4 to 2 hours for dose 1 and from 1 hour to 30 minutes for doses 2 and 3 (defined as DARZALEX FASPRO shortened). There was no mandated observation time for doses 4+. The median total clinic time was 4.8 hours with DARZALEX and 2.7-3.0 hours shorter with DARZALEX FASPRO. The median total chair time was 4.0 hours with DARZALEX and 2.7-2.8 hours shorter with DARZALEX FASPRO.
• Davis et al (2022)¹² conducted a retrospective real-world study evaluating the incidence of IRRs within different observation times in patients who received DARZALEX FASPRO. IRRs (all of grade 1/2 and reversible) were reported in 6 patients in the 6-hour observation group and in 0 patients in both the 4-hour and 2-hour observation groups.
• Kim et al (2021)¹³ assessed the real-world data on the incidence and severity of systemic reactions after DARZALEX FASPRO initiation, optimal monitoring duration, DARZALEX to DARZALEX FASPRO switch, and patient-reported adverse events (AEs). Patients considered to have high risk for systemic reactions (daratumumab naïve, treatment breaks of ≥90 days between doses and any prior reactions) were monitored for 4 hours after DARZALEX FASPRO infusion. After the firstdose of DARZALEX FASPRO, systemic reactions were reported in 4.0% patients who were at high risk for reactions.
• The protocol for randomized part of the phase 3 ANDROMEDA (AMY3001) study required patients randomized to DARZALEX FASPRO + bortezomib, cyclophosphamide, and dexamethasone (VCd) treatment arm to be observed for at least 6 hours after the end of SC injection during C1D1 and after subsequent injections if deemed necessary by the investigator.¹⁴

PRODUCT LABELING

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

CLINICAL DATA

Multiple Myeloma Studies

Non-inferiority Study Evaluating DARZALEX vs DARZALEX FASPRO

COLUMBA (MMY3012; clinicaltrials.gov identifier: NCT03277105) is an ongoing phase 3, randomized, open-label, multicenter, non-inferiority study evaluating the efficacy, pharmacokinetics (PK), and IRRs of DARZALEX vs DARZALEX FASPRO in patients with RRMM.^16,17

Study Design/Methods

• All patients were observed for at least 6 hours after the end of the SC injection during C1D1 and after subsequent injections if deemed necessary by the investigator.¹⁸
• Co-primary endpoints: overall response rate (ORR) and maximum C_trough (serum predose DARZALEX concentration on cycle 3 day 1).¹⁶
• Secondary endpoints: IRR rates, progression-free survival (PFS), rate of very good partial response or better (≥VGPR) and rate of complete response or better (≥CR), time to next therapy, overall survival (OS), patient-reported satisfaction with therapy, duration of response (DOR), and time to response.¹⁶

Results

• The median time to onset for IRRs in the DARZALEX FASPRO arm was 3.6 hours and 1.5 hours in the DARZALEX arm, with most of the IRRs occurring on the day of the first dose.¹⁹
• Time to onset of treatment-emergent IRRs is summarized in Table: Time to Onset of Treatment-Emergent Infusion-Related Reactions.
  • Two patients (5 events) in the DARZALEX FASPRO group and 3 patients (4 events) in the DARZALEX group reported IRRs on non-treatment days.¹⁹
• The incidence of IRRs reported in the DARZALEX FASPRO group and the DARZALEX group was 12.7% and 34.5%, respectively (odds ratio [OR], 0.28; 95% CI, 0.18-0.44; P<0.0001).¹⁹Treatment-emergent IRRs are summarized in Table: Summary of Treatment-Emergent Infusion-Related Reactions.
• Most IRRs reported in either treatment group were grade 1/2. Grade 3 IRRs were reported less frequently in the DARZALEX FASPRO group (1.5% vs 5.4% in the DARZALEX group).¹⁹
  • Seven of the IRRs reported in the DARZALEX FASPRO group were serious (chest pain, cough, pyrexia [n=2], oxygen saturation decreased, hypertension, and tachycardia), compared with 3 such IRRs in the DARZALEX group (vomiting, blood pressure increased, and bronchospasm).¹⁹
  • Four of the 7 serious IRRs in the DARZALEX FASPRO group were grade 1/2, while all serious IRRs in the DARZALEX group were grade 3.¹⁹
  • All serious IRRs occurred within 6 hours of the start of the first administration of study drug.¹⁹
• No IRRs in the DARZALEX FASPRO group led to treatment discontinuation, dose interruption, or injection being aborted; rate of administration was not assessed for DARZALEX FASPRO.¹⁹

APOLLO - DARZALEX FASPRO in Combination with Pomalidomide and Dexamethasone

APOLLO (MMY3013; clinicaltrials.gov identifier: NCT03180736) is an ongoing, phase 3 study evaluating the safety and efficacy of DARZALEX FASPRO + Pd vs Pd alone in patients with RRMM who received ≥1 prior treatment with both lenalidomide and a proteasome inhibitor (PI; N=304).²⁰ Dimopoulos et al (2021)²¹ reported the primary analysis of this ongoing study, which is summarized below.

Study Design/Methods

• All patients were observed for at least 6 hours after the end of the SC injection during C1D1 and after subsequent injections if deemed necessary by the investigator.³
• Primary endpoint: PFS.²¹
• Secondary endpoints: ORR, VGPR or better rate, CR or better rate, minimal residual disease (MRD)-negativity rate, OS, time to response, DOR, time to next therapy, safety, health-related quality of life, immunomodulatory effects of DARZALEX FASPRO on T cells, pharmacokinetic analyses and immunogenicity of DARZALEX FASPRO.²¹

Results

• The median time to onset for any IRR after first DARZALEX FASPRO administration occurred within 3.2 (range, 2.5-4.2) hours.²²
• Six out of 8 subjects reported IRRs with the first administration of DARZALEX FASPRO.²²
• There were no IRRs associated with the secondadministration. Two subjects reported having an IRR at the 3^rd or later administrations of DARZALEX FASPRO.²²
• Time to onset of treatment-emergent IRRs is summarized in Table: Time to Onset of Treatment-Emergent Infusion-Related Reactions.
• No IRRs led to discontinuation or interruption of treatment.²²
• The IRR most frequently reported was pyrexia (3 subjects [2.0%]), with the majority being grade 1/2.²² See Table: Summary of Treatment-Emergent Infusion Reactions.

PLEIADES - Phase 2 Study

PLEIADES (MMY2040; clinicaltrials.gov identifier: NCT03412565) is a phase 2, non-randomized, open-label, multicenter study evaluating the clinical benefit of DARZALEX FASPRO administered in combination with various treatment regimens in patients with MM (N=265).²³ Chari et al (2020)²⁴ presented the results of the safety and efficacy analysis of DARZALEX FASPRO in combination with bortezomib, lenalidomide, and dexamethasone (DVRd), DARZALEX FASPRO in combination with bortezomib, melphalan, and prednisone (D-VMP), and DARZALEX FASPRO in combination with lenalidomide and dexamethasone (DRd) in the PLEIADES study.^24-27 Moreau et al (2020)²⁸ presented updated safety and efficacy results of DARZALEX FASPRO in combination with carfilzomib and dexamethasone (D-Kd), D-Rd, and D-VMP arms in the PLEIADES study.

Study Design/Methods

• All patients were observed for at least 6 hours after the end of the SC injection during C1D1 and after subsequent injections if deemed necessary by the investigator.²
• Primary endpoints: ORR (≥PR) for the D-VMP and D-Rd cohorts, and ≥VGPR after 4 induction cycles for the D-VRd cohort.²⁴
• Key secondary endpoints: maximum observed serum concentrations (C_max) and minimum observed serum concentrations (C_min) of DARZALEX FASPRO, percentage of participants with IRR, ≥CR, DOR, MRD-negativity rate.²⁴

Results

D-VRd, D-VMP, and D-Rd

• The median time to onset of IRR after the start of the first DARZALEX FASPRO administration occurred within approximately 5 hours in the D-VMP and D-Rd cohort, and 3.25 hours in the D-VRd cohort.²⁹
• There were no IRRs associated with the second DARZALEX FASPRO administration. One patient each in the D-VMP and D-VRd cohorts reported having an IRR at the 3^rd or later administrations of DARZALEX FASPRO.²⁹
• One patient in the D-VRd cohort reported having a delayed IRR, which was a grade 3 event of decreased oxygen saturation that resulted in permanent discontinuation of DARZALEX FASPRO.²⁹
• Time to onset of treatment-emergent IRRs is summarized in Table: Time to Onset of Treatment-Emergent Infusion-Related Reactions.
• Overall, the incidence of IRRs across all subjects in the study was low (7.5% [15/199]), and similar across treatment cohorts (6 subjects each [9.0%] in the D-VMP and D-VRd cohorts; 3 subjects [4.6%] in the D-Rd cohort).²⁹
• All IRRs, except in 1 subject, were most frequently reported as associated with the first administration of study drug (D-VMP, 5/6 subjects; D-Rd, 3/3 subjects; D-VRd, 6/6 subjects), which is consistent with previous DARZALEX FASPRO studies.²⁹ Treatmentemergent IRRs are summarized in Table: Summary of Treatment-Emergent Infusion Reactions.
• No IRRs led to dose interruption or incomplete administration of DARZALEX FASPRO.²⁹
• The IRRs most frequently reported (≥2%) were pyrexia (10 subjects [5.0%]) and chills (4 subjects [2.0%]), with the majority being grade 1/2.²⁹
• No grade 4 IRRs were reported in any treatment cohort.²⁹

D-Kd, D-Rd, and D-VMP

• Median (range) time to onset of IRRs was 65 (4-75) minutes, 330 (254-330) minutes, and 411 (121-534) minutes in the D-Kd, DRd, and D-VMP cohorts, respectively.²⁸
• Most patients with IRRs experienced them on the first administration (D-Kd, 100%; DRd, 100%; D-VMP, 83%).²⁸
• IRRs were mild (grade 1/2); 2 patients in the D-Kd cohort had a grade 3 IRR, and no patients reported grade 4 IRR.²⁸

PAVO - Phase 1b Study

PAVO (MMY1004; clinicaltrials.gov identifier: NCT02519452) is an ongoing, phase 1b, open-label, multicenter, dose-finding, proof-of-concept study evaluating the safety, PK, and efficacy of DARZALEX FASPRO 1200 mg or 1800 mg (daratumumab with the addition of fully human recombinant DNA-derived hyaluronidase enzyme [rHuPH20]) in patients with RRMM who have received ≥2 prior therapies.³⁰ San-Miguel et al (2021)³¹ published part 2 results of the PAVO study. Nahi et al (2020)³² presented initial results from part 3 of the PAVO study. Nahi et al (2023)⁵ published the updated results from part 3 of the PAVO study.

Study Design/Methods

• Per protocol, patients in part 2 of PAVO remained in hospital for observation for at least 24 hours after the end of C1D1 injection. Inpatient observation after subsequent doses was implemented if deemed necessary by the investigator based on safety findings.¹⁵
• Key inclusion criteria: RRMM with measurable disease; ≥2 previous lines of treatment; no previous anti-CD38 therapy.³¹
• Key exclusion criteria: received anti-myeloma treatment within 2 weeks; received an allogeneic stem cell transplant or received autologous stem cell transplantation within 12 weeks; history of malignancy (other than MM within 5 years); meningeal involvement of MM).³³
• Primary endpoints: C_trough of DARZALEX FASPRO at C3D1, and safety.³¹
• Select secondary endpoints: percentage of patients with CR, percentage of patients with ORR, DOR, and time to response.^31,33

Results

• In part 2, IRRs with DARZALEX FASPRO occurred in 4 of 25 (16%) patients, the majority of which occurred on day 1.³¹
  • Symptoms included grade 3 hypertension, grade 2 chills, and grade 2 dyspnea in 1 patient; grade 1 allergic rhinitis in 1 patient; grade 1 sneezing in 1 patient; and grade 3 hypertension in 1 patient.
• The IRRs of grade 3 hypertension were reversible and occurred in patients with a medical history of hypertension.³¹
• There were no grade 4 IRRs or treatment discontinuations due to IRRs.
• Median (range) time to onset of IRRs was 70 (9-80) minutes.³¹

Evaluation of Pre- and Post-dose Corticosteroid Tapering in Part 3 of the PAVO Study

Nahi et al (2020)³² presented the initial results from part 3 of the phase 1b PAVO study evaluating the safety of pre- and post-dose corticosteroid tapering during administration of DARZALEX FASPRO in patients with RRMM. Nahi et al (2023)⁵ published the updated results from part 3 of the PAVO study.

Study Design/Methods

• Key eligibility criteria: measurable RRMM, ≥2 prior lines of therapy (including a PI and an immunomodulatory drug), and an Eastern Cooperative Oncology Group performance status score of ≤2.³²
• Patients received 28-day cycles of DARZALEX FASPRO and either a 1-, 2- or 3-week corticosteroid taper schedule as follows^5,34:
  • 3-week taper: methylprednisolone (MP) given orally (PO)/IV pre-dose (C1D1, 100 mg; cycle 1 day 8 [C1D8], 60 mg; cycle 1 day 15 [C1D15], 30 mg) and PO postdose (C1D1, 20 mg for 2 days; C1D8, 20 mg for 1 day; C1D15, 20 mg for 1 day).
  • 2-week taper: MP given PO/IV pre-dose (C1D1, 100 mg; C1D8, 60 mg) and PO postdose (C1D1, 20 mg for 2 days; C1D8, 20 mg for 1 day).
  • 1-week taper: dexamethasone given IV pre-dose (C1D1, 20 mg).
  • Dose-limiting toxicities (DLTs) were assessed from C1D1 to cycle 2 day 4 for the 3week taper schedule, from C1D1 to cycle 1 day 25 for the 2-week taper schedule, and from C1D1 to cycle 1 day 11 for the 1-week taper schedule.
• Primary endpoint: safety of pre- and post-dose steroid tapering.³²
• Key secondary endpoints: ORR and CR per International Myeloma Working Group criteria⁵

Results

Patient Characteristics⁵

• A total of 42 patients were enrolled in part 3 of the PAVO study (3-week corticosteroid taper group, n=15; 2-week corticosteroid taper group, n=15; and 1-week corticosteroid taper group, n=12).
• Patients received a median of 3 (range, 2-7) prior lines of therapy and 45.2% of patients were refractory to both a PI and an immunomodulatory drug.
• The median duration of follow-up was 8.3 months overall, 9.2 months (range, 1.9-25.5) for the 3-week corticosteroid taper group, 11.1 months (range, 1.7-24.0) for the 2-week corticosteroid taper group, and 8.3 months (range, 0.4-13.1) for the 1-week corticosteroid taper group.
• The median number of DARZALEX FASPRO doses was 18 (range, 2-38).
• Treatment discontinuation was reported in 13 (86.7%) patients in the 3-week corticosteroid taper group, in 13 (86.7%) patients in the 2-week corticosteroid taper group, and in 7 (58.3%) patients in the 1-week corticosteroid taper group. Most discontinuations were due to progressive disease (3-week corticosteroid taper group, 10 [66.7%] patients; 2-week corticosteroid taper group, 12 [80.0%] patients; and 1week corticosteroid taper group, 5 [41.7%] patients).

Safety⁵

• IRRs were reported in 5 (11.9%) patients during the first administration only (3-week corticosteroid taper group, n=0; 2-week corticosteroid taper group, n=3 [20.0%]; 1week corticosteroid taper group, n=2 [16.7%]).
• The median time to onset of IRRs was 79.0 minutes (range, 31-555). All IRRs resolved on the same day.
• The most common (≥5%) IRRs were chills and pyrexia (n=3 [7.1%] each). Additional IRRs included tachycardia, increased blood pressure, and oropharyngeal pain (n=1 [2.4%] each).
• All IRRs were generally mild, except for one grade 3 IRR (increased blood pressure) reported in the 2-week corticosteroid taper group.
• IRRs of grade 4, IRRs meeting the DLT definition, or IRRs leading to treatment discontinuation were not reported.
• All patients experienced ≥1 treatment-emergent adverse event (TEAE), 16 (38.1%) patients experienced serious TEAEs, and 21 (50.0%) patients experienced grade ≥3 TEAEs.
• The most common TEAEs are presented in Table: Most Common TEAEs.
• TEAEs led to death in 6 patients (3-week corticosteroid taper group, n=2 [complications from diffuse large B-cell lymphoma and progressive disease]; 2-week corticosteroid taper group, n=1 [progressive disease]; 1-week corticosteroid taper group, n=3 [staphylococcal pneumonia (grade 5), pulmonary embolism (grade 5), and progressive disease]).

Retrospective, Single-Center Analysis of Patients with MM, AL Amyloidosis, Lymphoma, or POEMS who Received DARZALEX FASPRO

Maples et al (2023)⁶ conducted a retrospective analysis to determine the optimal duration of observation after DARZALEX FASPRO administration to balance the safety and convenience.

Study Design/Methods

• The 16-week study was conducted in the following steps:
  • At C1D1, patients were observed for 3.5 hours after administering DARZALEX FASPRO.
  • After C1D1, the observation time was reduced to 2 hours for subsequent administrations up to week 8.
  • After 8 weeks from the last reduction, due to the incidence of IRRs being <10%, observation was discontinued, and the incidence of IRRs were recorded as per reports received from patients over telephone for the next 8 weeks.
• The premedication protocol included acetaminophen, diphenhydramine, montelukast, and dexamethasone. No postmedications were given.
• For patients on a combination regimen, DARZALEX FASPRO was the last medication to be administered on the day of treatment.

Results

Patient Characteristics

• Overall, 64 dara-naïve patients were included (2-hour observation, n=29 [45%]; 0-hour observation, n=35 [55%]).
• The baseline patient and disease characteristics are summarized in Table: Key Baseline Patient and Disease Characteristics.

Safety

• IRRs were reported in 3 (4.7%) patients. See Table: Infusion-Related Reactions.
  • The patients who experienced IRRs in the 2-hour observation group (n=2) had a body weight of 65-85 kg. One patient in this group experienced an IRR at home after being discharged from the hospital. The IRR was managed with instructions over phone.
  • The patient who experienced an IRR (injection site pain) in the 0-hour observation group (n=1) had a body weight of <65 kg.
• All IRRs were reversible, and no serious (grade ≥3) treatment-related IRRs or IRRs leading to treatment discontinuation were reported.

Retrospective Analysis of Patients who Received DARZALEX FASPRO in the Ambulatory Care Setting

Tam et al (2021)⁷ conducted a single-center, retrospective analysis of patients who received at least 2 doses of DARZALEX FASPRO in the ambulatory care setting to evaluate the incidence and time to onset of real-world systemic reactions and ISRs after administration of DARZALEX FASPRO.

Study Design/Methods

• Electronic health record (EHR) data were utilized to identify patients diagnosed with MM, amyloidosis, or plasmablastic lymphoma who received at least 2 doses of DARZALEX FASPRO in the ambulatory care setting at University of California, San Francisco Medical Center between May 1, 2020, and December 31, 2020.
• Patients were divided into 2 cohorts:
  • Dara-naïve patients were monitored for 6 hours.
  • Dara-exposed patients were monitored for 5 minutes or 2 hours if history of reaction with DARZALEX.
• Incidence of adverse drug reactions following the administration of the first dose of DARZALEX FASPRO was assessed through patient telephone interviews.
• Primary endpoint: incidence of systemic reactions and ISRs after the first dose of DARZALEX FASPRO.
• Secondary endpoints: time to systemic reactions and ISRs, severity of systemic reactions and ISRs, incidence of reaction after the second dose of DARZALEX FASPRO.

Results

• A total of 80 patients were included in the analysis (dara-naïve, n=31; dara-exposed, n=49). Background demographics were similar between cohorts.
• Incidence of systemic reactions and ISRs were similar between cohorts. See Table: Incidence of Systemic and Injection-Site Reactions Following First Dose of DARZALEX FASPRO.
• Median time to systemic reaction was 3 hours in dara-naïve patients vs 12 hours in dara-exposed patients (P=0.18).
• Median time to ISR was 6 hours in dara-naïve patients vs 24 hours in dara-exposed patients (P=0.029).
• All systemic reactions were grade 1 and did not require medical intervention by infusion center staff.
• All ISRs were grade 1 or 2, consisted of redness, rash, itching, or pain, and were managed with supportive care.

Retrospective, Single-Center Analysis of Patients With MM and/or AL Amyloidosis who Received DARZALEX FASPRO

Hughes et al (2022)⁸ conducted a retrospective analysis of the monitoring time, infusion chair time/improvement in clinical efficiency, and safety of DARZALEX FASPRO in patients with MM and/or AL amyloidosis who were either previously treated with DARZALEX or DARZALEX-naïve.

Study Design/Methods

• Retrospective analysis of patients at the Boston Medical Center who received ≥1 dose of DARZALEX FASPRO from June 1, 2020, through October 31, 2021.
• Patients who received DARZALEX were transitioned to DARZALEX FASPRO for the next scheduled dose; DARZALEX-naïve patients received DARZALEX FASPRO (daratumumab 1800 mg with rHuPH20 30,000 units) SC injection over 57 minutes (15 mL) once weekly for 8 doses, every 2 weeks for 8 doses, and monthly thereafter.
• Patients were monitored for 30 minutes after the first dose; no monitoring was performed for subsequent doses.
• Pre-administration medications: acetaminophen 650 mg, dexamethasone 20-40 mg, and diphenhydramine 25-50 mg.
  • Additional pre-administration medications included montelukast 10 mg and famotidine 20-40 mg administered at the physician’s discretion.

Results

• A total of 58 patients who received ≥1 dose of DARZALEX FASPRO were included in this analysis (DARZALEX-exposed, n=18 [31%]; DARZALEX-naïve, n=40 [69%]).
• A total of 867 DARZALEX FASPRO doses were administered to patients.
  • Prior to the first dose of DARZALEX FASPRO, all patients received acetaminophen, dexamethasone, and diphenhydramine; 24 (41.3%) and 20 (34.4%) patients, respectively, received montelukast and famotidine in addition to the standard premedications.
• All patients had a 30-minute postinjection observation time.
• Incidence of ARR in the overall population was 1.7% (n=1; DARZALEX-naïve, 1 of 40 [2.5%] patients).
  • One patient experienced grade 1 nausea, grade 1 rigors, and chills 30 minutes after DARZALEX FASPRO administration; the ARRs were treated with supportive medications and were not reported during subsequent cycles.
• Nine (15.5%) patients reported grade 3/4 neutropenia.
• The average chair time saved with DARZALEX FASPRO per patient was 14.95 hours; the total chair time saved was 867 hours. See Table: Summary of Chair Time Analysis.

Retrospective Single-Center Chart Review of Patients With MM or Plasmablastic Lymphoma Who Received DARZALEX FASPRO

Tadros et al (2024)⁹ conducted a single-center, retrospective chart review to evaluate the incidence of ARRs and to determine if the observation time on subsequent injections could be reduced or eliminated in patients with MM or plasmablastic lymphoma who received DARZALEX FASPRO over a duration of 6 months (N=33).

Study Design/Methods

• All patients received DARZALEX FASPRO over a duration of 6 months (July 1, 2020, to December 31, 2020).
• Proper premedications prior to DARZALEX FASPRO were defined as acetaminophen
  (650-1000 mg), dexamethasone (20 mg), and diphenhydramine (25 or 50 mg) given intravenously or orally 30 to 60 minutes prior to injection in accordance with prescribing criteria. In addition, patients received montelukast sodium (10 mg) as a safety precaution.
• Patients had a 3-hour and 1-hour observation time after the initial and each subsequent DARZALEX FASPRO injection, respectively.
• Primary endpoint: incidence of ARRs after DARZALEX FASPRO administration
• Secondary endpoint: assessment of the institution’s compliance regarding documentation of injection tolerance and use of premedication prior to DARZALEX FASPRO administration

Results

A total of 33 patients were included in this study. See Table: Baseline Patient Characteristics.

• Of the 18 (54.5%) patients who previously received DARZALEX IV, 1 patient stopped the dose owing to the occurrence of a severe hypersensitivity reaction but was able to tolerate DARZALEX FASPRO without any reported reactions.
• Appropriate premedication was administered in 30 (90.9%) patients. None of the patients who received premedication experienced any hypersensitivity reaction.
  • Protocol deviation was reported in 3 (9.1%) patients due to dexamethasone dose omission (n=1), decrease in dexamethasone dose (n=1), and ibuprofen substituted for acetaminophen along with decrease in dexamethasone dose (n=1).
• None of the patients experienced ARRs after administration of the first 3 doses of DARZALEX FASPRO. However, 4 patients encountered reactions that were not related to DARZALEX FASPRO and were resolved either spontaneously or with medical intervention.
• A total of 24 (72.7%) patients had at least 1 specific documentation of tolerance with any of the 3 DARZALEX FASPRO doses, and 2 (6.1%) patients had documentation of tolerance after all 3 DARZALEX FASPRO doses. A lack of documentation of both tolerance and/or reactivity was assumed to indicate that the patient did not have an ARR.

Retrospective Chart Review of Patients Transitioning from DARZALEX to DARZALEX FASPRO

Hamadeh et al (2021)¹⁰ presented a retrospective chart review and tolerability of patients who were either switched from DARZALEX to DARZALEX FASPRO or were started on a DARZALEX FASPRO-containing regimen.

Study Design/Methods

• Patients who were switched from a DARZALEX-containing regimen to DARZALEX FASPRO were defined as experienced.
• Patients who were started on a DARZALEX FASPRO-containing regimen were defined as naïve.
• In the DARZALEX-experienced cohort, patients were to be monitored for approximately 1 hour after the first DARZALEX FASPRO administration.
• In the DARZALEX-naïve cohort, patients were to be monitored for approximately 4 hours after the first DARZALEX FASPRO administration.
• Primary endpoint: rate of ARRs after the first dose of DARZALEX FASPRO (at the infusion center and/or after discharge).
• Secondary endpoint: use of home medications for ARR treatment, emergency visits due to ARRs.

Results

• A total of 58 patients were included in this study (DARZALEX-experienced, n=36; DARZALEX-naïve, n=22).
• The median monitoring time was 2.5 (range, 1-4) hours for 16 of 22 DARZALEX-naïve patients.
• The median monitoring time was 1.0 (range, 1-4) hours for 17 of 36 DARZALEXexperienced patients.
• No ARRs were reported. In addition, no emergency department visits were reported within 24 to 48 hours.

Real-World Evidence Study Assessing Clinical Administration Characteristics of SC DARZALEX FASPRO vs DARZALEX IV in Patients with MM

Soefje et al (2023)¹¹ assessed clinical administration characteristics of DARZALEX and DARZALEX FASPRO in patients with MM, including time parameters of interest related to inclinic patient time (clinic time and chair time) as well as the incidence of ARRs in patients who switched from DARZALEX to DARZALEX FASPRO and initiated treatment with DARZALEX FASPRO at the Mayo Clinic infusion centers.

Study Design/Methods

• Mayo Clinic’s EHR database, which included data from 13 Mayo Clinic sites, was used to identify patients with the following eligibility criteria: ≥18 years of age; International Classification of Diseases, Ninth Revision (ICD9) or ICD, Tenth Revision (ICD-10) diagnosis code of MM; and first DARZALEX treatment administered between April 5, 2017, and October 14, 2021.
• After the first DARZALEX FASPRO administration, a 4-hour observation period was incorporated into the initial Mayo Clinic treatment plan and after subsequent doses, a 1hour observation period was incorporated, to monitor ARRs.
• On May 3, 2021, the treatment plan was revised to reduce the mandated postadministration observation time for DARZALEX FASPRO from 4 to 2 hours for dose 1 and from 1 hour to 30 minutes for doses 2 and 3 (defined as DARZALEX FASPRO shortened). There was no mandated observation time for doses 4+.
  • In case of the occurrence of ARRs, the observation time for the next dose was returned to 4 hours.
• For DARZALEX FASPRO, data were captured for patients starting therapy on the initial treatment plan (DARZALEX FASPRO initial) and after the amendment to treatment plan with shortened post-administration observation time (DARZALEX FASPRO shortened).
• For DARZALEX, data were captured for patients starting therapy throughout the defined treatment window.
• Study outcomes and assessments included:
  • Total clinic time was defined as patient check-in time through checkout time.
  • Total chair time was defined as time from infusion room entry to infusion room exit or checkout time, whichever occurred earlier, and includes order review, pharmacy preparation time, and post-administration observation time (time from end of medication administration to infusion room exit or patient checkout).
• The medication administration time for DARZALEX FASPRO was 0 minutes due to the default duration for SC injections in the EHRs.
• Data on pre-administration medications were collected from the first visit until the start time of DARZALEX administration. Data on post-administration medications were collected from the start time of DARZALEX administration until 72 hours after that time.

Results

Patient Characteristics

• A total of 802 patients were included (DARZALEX, n=587; DARZALEX to DARZALEX FASPRO, n=80; DARZALEX FASPRO, n=215 [DARZALEX FASPRO initial, n=144; DARZALEX FASPRO shortened, n=71]). See Table: Baseline Patient Demographics.

Clinical Administration Characteristics

• The median total clinic time for all doses combined was 2.7-3.0 hours shorter with DARZALEX FASPRO (DARZALEX to DARZALEX FASPRO, 3.0 hours; DARZALEX FASPRO initial, 2.9 hours; DARZALEX FASPRO shortened, 2.7 hours) vs DARZALEX (4.8 hours). See Table: Summary of Administration Characteristics by Dose for Patients Receiving DARZALEX or DARZALEX FASPRO.
• Dose 1 was associated with the highest median total clinic time for both SC DARZALEX FASPRO and DARZALEX IV. Subsequent doses were associated with a lower median total clinic time.
• The median total chair time for all doses combined was 2.7-2.8 hours shorter with DARZALEX FASPRO (DARZALEX to DARZALEX FASPRO, 1.2 hours; DARZALEX FASPRO initial, 1.3 hours; DARZALEX FASPRO shortened, 1.3 hours) vs DARZALEX (4.0 hours).
• The median total chair time for DARZALEX FASPRO was highest for dose 1 and lower for subsequent doses.
• Fewer patients in the DARZALEX FASPRO vs DARZALEX cohort received post administration medications across doses.

ARR-Related Events

• For dose 1, ARR-related events (as identified by the use of relevant medications) were reported in 5.0% (n=4) and 8.4% (n=18) of patients who switched from DARZALEX to DARZALEX FASPRO and those who initiated therapy with DARZALEX FASPRO, respectively.
• Among patients who switched from DARZALEX to DARZALEX FASPRO, ARR-related events (as identified by any source except medications) were reported in 1 (1.3%) patient each for dose 1 (1.3%) and dose 4+ (1.4%) of DARZALEX FASPRO.
• Among patients who initiated treatment with DARZALEX FASPRO, the incidence of ARRrelated events (excluding medicationrelated events) was low (doses 1-3, <2%; dose 4+, <3% cumulatively).

Real-World Data/Observation of DARZALEX FASPRO Administration

Davis et al (2022)¹² conducted a retrospective real-world study evaluating the incidence of IRRs within different observation times in patients who received DARZALEX FASPRO.

Study Design/Methods

• Key inclusion criteria: patients with newly diagnosed multiple myeloma (NDMM), RRMM, or AL amyloidosis who received DARZALEX FASPRO.
• Key exclusion criteria: patients who had received prior DARZALEX IV
• Observation times for the first dose were:
  • Six hours for the first 12 months, as per institutional policy.
  • Four hours for the following 4 months, as per amended institutional policy due to lack of observed IRRs.
  • Two hours for the subsequent 2 months, due to COVID-associated staffing shortages and chair time constraints.
• The observation time for the second dose was 2 hours throughout the entire study period (18 months).
• If no IRR was reported after the first 2 DARZALEX FASPRO doses, no observation was done for the subsequent doses.
• Patients who reported an IRR at the first administration were observed for 6 hours after the subsequent administration.
• The premedication protocol included acetaminophen, diphenhydramine, fexofenadine, montelukast, and dexamethasone.

Results

Patient Characteristics

• Overall, 66 patients were included (observation time after the first DARZALEX FASPRO dose: 6 hours, n=31 [47%]; 4 hours, n=23 [35%]; 2 hours, n=12 [18%]).
• A total of 904 administrations were performed during the study period.
• The baseline patient and disease characteristics are summarized in Table: Key Baseline Patient and Disease Characteristics.

Safety

• All IRRs were of grade 1/2 and were reversible with supportive care. See Table: Infusion-Related Reactions.
• No serious (grade ≥3) treatment-related IRRs or IRRs leading to treatment discontinuation were reported.

Real-World Data After DARZALEX FASPRO Initiation or Transition from DARZALEX

Kim et al (2021)¹³ presented real-world data on incidence and severity of systemic reactions after DARZALEX FASPRO initiation, optimal monitoring duration, DARZALEX to DARZALEX FASPRO transition, and patient-reported AEs.

Study Design/Methods

• Retrospective review of electronic health records of patients at Massachusetts General Hospital Cancer Center (n=208) who received ≥1 dose of DARZALEX FASPRO from June 2020 to June 2021.
• Post-dose observation time was set to 4 hours for patients (n=124) considered to have high risk for systemic reactions (daratumumab naïve, treatment breaks of ≥90 days between doses and any prior reactions).
• Pre-administration medications: dexamethasone 20 mg, diphenhydramine 25-50 mg, and acetaminophen 975 mg.
  • Additional pre-administration medications included montelukast 10 mg and fexofenadine 60 mg for the first 2 doses and was optional thereafter.

Results

• A total of 208 patients were included in this study (daratumumab naïve, 47.6% [n=99]; daratumumab exposed, 52.4% [n=109]).
• A total of 2195 DARZALEX FASPRO doses were administered to patients.
  • Systemic reactions occurred in 0.2% (5/2195) of all DARZALEX FASPRO doses administered and in 4.0% (5/124) of patients at high risk for reactions; all systemic reactions occurred after the firstdose.
    • Time to onset of systemic reactions: hypotension (2 hours), nausea/vomiting (2.5 hours), sinus tachycardia (4 hours), mild intermittent chest pressure (within 24 hours), and mild intermittent chest tightness (24 hours to 7 days).
• Other (n=38) patient-reported AEs included dyspnea/abdominal cramps/pain (1.4%), discomfort (1.9%), constipation (1.9%), fatigue (3.8%), ISRs (3.8%), and diarrhea (5.3%).

ANDROMEDA Study - Newly Diagnosed Systemic AL Amyloidosis

ANDROMEDA is an ongoing prospective, randomized, active-controlled, multicenter phase 3 study (AMY3001; clinicaltrials.gov identifier: NCT03201965) evaluating the efficacy and safety of DARZALEX FASPRO + VCd compared with VCd alone in newly diagnosed patients with AL amyloidosis. Kastritis et al (2021)³⁵ reported primary results of this study. Comenzo et al (2021)³⁶ presented updated efficacy and safety results of the ANDROMEDA study, with a median duration of follow-up of 25.8 months.

Study Design/Methods

• All patients were observed for at least 6 hours after the end of SC injection during C1D1 and after subsequent injections if deemed necessary by the investigator.¹⁴
• Primary endpoint: overall hematologic CR.³⁶
• Secondary endpoints: major organ deterioration PFS, organ response rate, time to hematologic response, OS, and safety.³⁶

Results

• A total of 14 (7.3%) patients experienced IRRs, and the majority of IRRs occurred during the first dose of administration (86%). All reactions were grade 1/2 and the median time to onset was 1.3 (range, 0.2-7.3) hours.³⁷
• Two (1%) patients had IRRs during the second dose administration and 3 patients (1.6%) during subsequent dose administrations.³⁷
• The median time to onset of IRRs was 80 minutes: 80 minutes for first dose administration (n=9), 200 minutes for second dose administration (n=1), and 75 minutes for subsequent dose administrations (n=2).³⁷
• Time to onset of treatment-emergent IRRs is summarized in Table: Time to Onset of Treatment-Emergent Infusion-Related Reactions.

• Treatment-emergent IRRs are summarized in Table: Summary of Treatment-Emergent Infusion-Related Reactions.

• No additional systemic ARRs were reported in the updated analysis at a median duration of followup of 25.8 months.³⁶

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 12 August 2024.