Clinical Administration Characteristics of Subcutaneous and Intravenous Administration of Daratumumab in Patients With Multiple Myeloma at Mayo Clinic Infusion Centers

PURPOSE:

Median duration of daratumumab (DARA) administration for treatment of multiple myeloma is 3-7 hours for the intravenous formulation (DARA IV) and 3-5 minutes for the subcutaneous formulation (DARA SC). Here, we describe clinical administration characteristics of DARA using a novel method for data extraction from electronic health records.

METHODS:

Time-based measurements were extracted using a scheduling/pharmacy software program that tracked patient movement through appointments for patients initiating DARA in Mayo Clinic infusion centers from April 5, 2017, to October 14, 2021. Cohorts included patients who received DARA IV or DARA SC, or converted from DARA IV to DARA SC. The DARA SC cohort was further analyzed before (DARA SC initial) and after (DARA SC shortened) a reduction in the postadministration observation time mandated by the treatment plan. Events associated with administration-related reactions (ARRs) were also identified.

RESULTS:

Median total clinic times were 2.7-3.0 hours shorter for DARA SC versus DARA IV. Median clinic times were highest at dose 1 and decreased with subsequent doses. Median total chair times were 2.7-2.8 hours shorter for DARA SC versus DARA IV. Incidences of ARR-related events with DARA SC were low across doses.

CONCLUSION:

Reduced clinic times were observed with DARA SC, indicating that use of DARA SC as a treatment option results in time savings that may free clinic resources. Furthermore, novel methods of electronic health record data extraction can provide insights that may help inform clinic resource optimization.

INTRODUCTION

Daratumumab (DARA) is a human IgG_κ monoclonal antibody targeting CD38 with a direct on-tumor^1-4 and immunomodulatory^5-7 mechanism of action. DARA is approved across lines of therapy for the treatment of multiple myeloma (MM) and may be administered either intravenously or subcutaneously.^8,9 In clinical studies using intravenous DARA (DARA IV), administration-related reactions (ARRs) mainly occurred at the first infusion dose.⁸ A longer infusion time is used for the first dose to mitigate against ARRs, with shorter times for subsequent doses when the incidence of ARRs lessens; the median duration of DARA IV is 7 hours, 4 hours, and 3 hours for the first, second, and subsequent infusions, respectively.⁸ Clinical studies have also resulted in the use of a split first dose of DARA IV as an alternative to a single first dose of DARA IV,⁸ thereby providing flexibility for both patients and health care providers. When the first dose of DARA IV is given by split dose, administration of the first full dose is divided over 2 consecutive days, with a median duration of around 4 hours on each day.^10,11

The subcutaneous formulation of DARA (DARA SC; DARA 1,800 mg coformulated with recombinant human hyaluronidase PH20 [rHuPH20; 2,000 U/mL; ENHANZE drug delivery technology, Halozyme Inc, San Diego, CA])⁹ was developed to reduce patient and provider burden by improving administration characteristics. DARA SC and DARA IV are comparable with regards to efficacy, overall safety, and pharmacokinetics.^12,13 Additionally, DARA SC is associated with fewer ARRs compared with DARA IV,^12,13 and has other notable benefits of administration, including reduced administration time (3-5 minutes for DARA SC v 3-7 hours for DARA IV) and improved patient satisfaction.^8,9,12,14

With the increased use of DARA SC, there is a need to better characterize and assess the potential advantages of this formulation's use in real-world clinical practice. Namely, measures such as duration of time spent by patients in clinic, use of preadministration and postadministration medications, and incidence of ARR-related events are valuable assessments to evaluate the potential benefits of DARA SC. These benefits may have implications for clinical practice, especially related to efficient resource utilization and maximization of the capacity of a clinic. Other analyses have offered web-based prospective survey data on clinic time parameters and general observations on time in clinic on the basis of treatment protocols.^15-17 However, an empirical method for uniformly assessing individual patient time in clinic has not been described. In this study, a novel empirical data extraction approach was applied to the electronic health records (EHRs) system at the Mayo Clinic to describe DARA administration characteristics, including time parameters of interest related to in-clinic patient management.

METHODS

Study Sample and Design

Data were extracted from the Mayo Clinic's EHR database, which holds the records of 6.5 million patient lives from 1990 through the current date. nference (Cambridge, MA), a biotechnology company specializing in EHR data extraction and natural language processing, accessed this database and curated it to analyze aspects of clinical practice with DARA IV and DARA SC administrations. This research was conducted under the internal review board–approved project: Characterization of Outcomes and Quality of Life in Multiple Myeloma Patients Receiving Daratumumab-Intravenous Therapy (retrospective). All analyses of EHRs were performed in the privacy-preserving environment secured and controlled by the Mayo Clinic. nference and the Mayo Clinic subscribe to the basic ethical principles underlying the conduct of research involving human subjects as set forth in the Belmont Report and strictly ensure compliance with the Common Rule in the Code of Federal Regulations (45 CFR 46) on Protection of Human Subjects.

Patients were identified from 13 Mayo Clinic sites (complete listing in the Data Supplement, online only) in the database for inclusion if they met the following criteria: age ≥ 18 years with first DARA treatment outside of an interventional clinical trial and occurring between April 5, 2017, and October 14, 2021; had an International Classification of Diseases (ICD), Ninth Revision, or ICD, Tenth Revision diagnosis code of MM; and had record availability of medications administered. Other data types (prescription orders, appointment times, and total DARA administration time) were complete within the EHR and were noted along with attrition (ie, not all patients had available information for clinic time data for each dose). Both DARA IV and DARA SC administrations were captured. Patients were assigned to three main cohorts for analysis by the formulation(s) received: DARA IV (IV treatment for DARA-naive patients), DARA SC (patients receiving only DARA SC over their course of treatment), and DARA IV to SC (patients initially receiving DARA IV who subsequently converted to DARA SC over the course of their treatment; Data Supplement).

The Mayo Clinic treatment plan included guidance on observation time following DARA administration. Because of the median time to onset of 3.4 hours for ARRs with the first dose of DARA SC in the COLUMBA clinical trial,¹² a 4-hour observation period was incorporated into the initial Mayo Clinic treatment plan following the first DARA SC administration and for 1 hour following subsequent doses, to monitor for ARRs. On May 3, 2021, on the basis of clinical experience with DARA SC administration, the treatment plan for DARA SC was amended to shorten the mandated postadministration observation time from 4 to 2 hours for dose 1 and from 1 hour to 30 minutes for doses 2 and 3, with no mandated observation time for doses 4+. However, if an ARR occurred, the observation time of the next dose returned to 4 hours. Accordingly, the DARA SC cohort was analyzed as two subcohorts: those treated under the initial Mayo Clinic treatment plan for DARA SC (DARA SC initial) and those treated after the treatment plan amendment with shortened observation times (DARA SC shortened; Data Supplement).

Time-Based Measurements

Time-based measurements were defined as follows (and as shown in the Data Supplement). Total clinic time was calculated as the difference between the time at patient check-in and check-out. Total chair time included the time from infusion room entry to infusion room exit or check-out (whichever occurred earlier), and included order review, pharmacy preparation, and postadministration observation. Postadministration observation time included the time from the end of medication administration to infusion room exit or patient check-out. Of note, the time documented for DARA SC administration was 0 minutes, as defined by the default duration for SC injections in the EHR.

Preadministration and Postadministration Medication Capture

Preadministration medications were recorded from the beginning of the calendar date of the visit until the start time of DARA administration. Postadministration medications were recorded from the start time of DARA administration until 72 hours after that time. The preadministration and postadministration medication repertoire for ARR management, including medication type, class, and route of administration, were captured from the EHR and included acetaminophen, dexamethasone, prednisolone, prednisone, diphenhydramine, hydroxyzine, famotidine, and epinephrine. The full list of any preadministration and postadministration medications captured, including those not necessarily for ARR management, consisted of albuterol, salbutamol, salmeterol, budesonide, formoterol, vilanterol, ipratropium, diphenhydramine, methylprednisolone, fluticasone, dexamethasone, prednisone, and acetaminophen.

ARR-Related Event Capture

ARR-related events in clinical studies have been previously reported for patients receiving either DARA IV or DARA SC^8,12; this study focused on ARR-related events for patients at Mayo Clinic transitioning to DARA SC from DARA IV and for patients who initiated therapy on DARA SC. Data for three categories of ARR-related events that occurred within 72 hours after administration were captured: administration of known medications for ARR management after initiation of a DARA SC administration (namely diphenhydramine, given as IV or intramuscular therapy; hydroxyzine; famotidine; corticosteroids; and/or epinephrine for severe reactions), entry of ICD codes associated with ARR-related symptoms not reported before DARA therapy began, and admission to an emergency department (ED) or hospitalization within the Mayo Clinic system.

RESULTS

Patients and Treatment

Between April 5, 2017, and October 14, 2021, patients were identified for analysis in the Mayo Clinic's EHR database and assigned to cohorts as follows (and as shown in the Data Supplement): DARA IV (n = 587), DARA SC (n = 215), and DARA IV to SC (n = 80). The DARA IV cohort (n = 587) included 80 patients who switched from DARA IV to SC. The DARA SC cohort (n = 215) was further divided into DARA SC initial (n = 144) and DARA SC shortened (n = 71). In total, data for 802 patients receiving DARA treatment for MM were captured in this analysis, and patient demographics are summarized in Table 1. The median numbers of doses of DARA IV or DARA SC administered in each cohort are summarized in the Data Supplement.

TABLE 1.

Patient Demographics

Administration Characteristics: Clinic Times

For all doses combined, the median total clinic time for patients receiving DARA IV was 4.8 hours. Patients receiving DARA SC, whether administered initially or switched over from IV administration, experienced 2.7-3.0 hours shorter median total clinic times for all doses combined (reduction in times: DARA SC, 2.9 hours; DARA IV to SC, 3.0 hours; DARA SC initial, 2.9 hours; DARA SC shortened, 2.7 hours). For all methods of administration, the median clinic time was highest at dose 1 and decreased with subsequent doses, consistent with the extended day 1 administration time for DARA IV and longer mandated observation time for DARA SC at dose 1 (Fig 1). The median total chair time was 2.7-2.8 hours shorter for DARA SC compared with the DARA IV for all doses combined (median total chair time: DARA IV, 4.0 hours; DARA SC, 1.3 hours; DARA IV to SC, 1.2 hours; DARA SC initial, 1.3 hours; DARA SC shortened, 1.3 hours). As expected, longer times at earlier doses, with subsequently shorter times for later doses, were seen for both median total clinic time and median total chair time (Table 2).

FIG 1.

Total clinic times by dose administered for patients receiving DARA IV or DARA SC. Total clinic time was defined as the duration from patient check-in through check-out, including total chair time (time from infusion room entry to infusion room exit or check-out, including order review, pharmacy preparation, and postadministration observation time). Data shown include evaluable patients and clinic visits per dose. Data for DARA SC patients were captured before (DARA SC initial) and after (DARA SC shortened) adoption of an updated Mayo Clinic treatment plan on May 3, 2021, which reduced the mandated postadministration observation time for DARA SC. Data shown for the DARA IV to SC cohort reflect data collected after patients switched to DARA SC, and the dose numbers reflect those once the patient switched to DARA SC. DARA, daratumumab; IV, intravenous; SC, subcutaneous.

TABLE 2.

Summary of Administration Characteristics by Dose for Patients Receiving DARA IV or DARA SC

Preadministration and Postadministration Medications

Data for the DARA IV cohort represent medication usage since April 2017, compared with May 2020 for the DARA SC cohort. Preadministration medication use was generally higher than postadministration medication use across cohorts and doses (Data Supplement), in concordance with preadministration medications being mandated per treatment plan. In general, fewer patients in the DARA SC cohorts received postadministration medications across doses compared with those in the DARA IV cohort (Data Supplement).

ARR-Related Events

Occurrences of ARR-related events following DARA SC administrations, as indicated by a record of receipt of an ARR-related medication (on the basis of drug type and route of administration, and as directed per Mayo Clinic protocol for management of ARRs), ICD coding, and/or an ED visit or hospitalization, are summarized by category in the Data Supplement. Among patients who received DARA SC and had a record of an ARR-related event, most of these events were captured because of use of a medication prespecified for and potentially related to the treatment of an ARR. For dose 1, ARR-related events, as identified by use of relevant medications, occurred in four (5.0%) patients who switched from DARA IV to SC and in 18 (8.4%) patients who initiated therapy with DARA SC. In the DARA IV to SC group, ARR-related events as identified by any source except medications occurred in one (1.3%) patient on their first DARA SC dose and in one other patient on dose 4+ (1.4%). Few ARR-related events (excluding those identified by medication use) occurred among patients who initiated treatment with DARA SC; the incidence was < 2% for doses 1-3 and < 3% cumulatively for dose 4 and onward.

DISCUSSION

This study demonstrates that treatment of MM with DARA SC helps reduce total clinic times in a clinical practice setting compared with DARA IV. Both median total clinic time and median total chair time of the initial DARA administration were reduced by approximately 3 hours for patients treated with DARA SC compared with patients receiving DARA IV. Furthermore, reduction in median times of a generally similar magnitude (> 2 hours) was observed with DARA SC compared with DARA IV across all doses.

Total clinic times and median administration times observed in this clinical setting are generally consistent with expected DARA administration times on the basis of US prescribing information. DARA IV administration is expected to take a median of 7 hours for the first dose and decrease for subsequent doses⁸; our findings confirmed that initial dose administrations required the longest durations of time in clinic. Usage of postadministration medications was lower with DARA SC compared with DARA IV. However, as previously noted, some observed differences in medication use may be due to the fact that relevant data for the DARA IV cohort represent medication usage since April 2017, whereas data for the DARA SC cohort represent usage since May 2020. Over time, it is likely that DARA treatment patterns may have changed for reasons such as patient preference, physician comfort with the DARA SC versus IV administration, or other changes in clinical practice.

This study also explores the feasibility of assessing ARR-related events with DARA SC administration using this novel data extraction approach. Particularly, as assessed by ICD codes, ED visits, or hospitalizations, ARR-related events observed for DARA SC in this study were low across all doses; this finding is consistent with prior observations of the safety of this formulation in the clinical trial setting.¹² However, our real-world assessment of ARRs has potential limitations and challenges, particularly when these events were identified in the EHR database via the timing and route of administration of specific medications. For instance, although expected to be relatively rare, medications of interest may have been administered within the defined postadministration window for reasons other than an ARR. In addition, it is possible that some medications could have been captured as artifacts of logistical difficulties. For example, a medication given preadministration might have been recorded in the EHR after the DARA dose was administered. For these reasons, the ARR incidence rates reported in this EHR-based study may be overestimates, particularly those identified by medication use.

In addition to patient safety, improvements in DARA administration characteristics may have positive impacts on utilization of clinic resources. Time savings, such as those reported here, may help to reduce the burden on the resources of patients, caregivers, and health care providers. A reduced total clinic time per individual patient may allow for more patients to have access to care at the clinic or infusion center, potentially resulting in effective increases in facilities' capacity to administer treatments and improve scheduling flexibility. For example, it may be possible to treat two to three patients receiving subsequent DARA SC doses, compared with a single patient receiving DARA IV, in the same 4- or 5-hour period. Furthermore, the shorter DARA SC total clinic time may allow patients receiving other treatments for other cancers to be scheduled in the time freed by use of DARA SC. Notably, a shortened total clinic time, as demonstrated here, may also improve patient and caregiver satisfaction. Such efficiencies could be explored by other clinical practices by developing and applying analytical methods that leverage their own EHR databases, providing a potential for standardized and empirical methods to address operational efficiency across both networks and nonintegrated practices.

In summary, our findings add to the growing body of real-world evidence investigating DARA SC as an efficient and convenient administration option for the treatment of patients with MM. The added time savings gained by use of DARA SC may free up clinic resources, such as chairs, nurses, and other staff; provide more flexibility in patient scheduling; and allow clinics to deliver treatment to more patients, not only those receiving DARA for MM, but also those receiving other therapies for other cancers. More broadly, this study is a proof of principle that analyses of EHRs using novel empirical data extraction methods can enable the identification and quantification of potential time advantages of different clinical workflows, treatments, or change to treatment plans. This method also enables assessment of medication usages and safety-associated parameters in this setting. Such analytical methods may be applicable to other clinical scenarios to help optimize use of clinical resources and improve patient care.

DATA SHARING STATEMENT

The data sharing policy of Janssen Pharmaceutical Companies of Johnson & Johnson is available at https://www.janssen.com/clinical-trials/transparency. These data were made available by Mayo Clinic for the current study and are not publicly available due to inclusion of protected health information (PHI). To request data from this study, researchers should contact the Corresponding Author and follow Mayo Clinic’s standard IRB process for such requests.

AUTHOR CONTRIBUTIONS

Conception and design: Scott A. Soefje, Corinne Carpenter, Samir Awasthi, Thomas S. Lin, Shuchita Kaila, Daniel Tarjan, Nikhil Kayal, Tyler E. Wagner, Kathleen Gray, Shaji Kumar

Administrative support: Tyler E. Wagner

Collection and assembly of data: Scott A. Soefje, Corinne Carpenter, Katherine Carlson, Christian Kirkup, Kathleen Gray, Shaji Kumar

Data analysis and interpretation: Scott A. Soefje, Corinne Carpenter, Katherine Carlson, Samir Awasthi, Thomas S. Lin, Shuchita Kaila, Daniel Tarjan, Tyler E. Wagner, Kathleen Gray, Shaji Kumar

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Clinical Administration Characteristics of Subcutaneous and Intravenous Administration of Daratumumab in Patients With Multiple Myeloma at Mayo Clinic Infusion Centers

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