Safety of Split First Dosing Vs Standard Dosing Administration of Daratumumab Among Multiple Myeloma Patients Treated in a US Community Oncology Setting: A Real-World Observational Study

INTRODUCTION:

Daratumumab (DARA) is a human IgGκ monoclonal anti-CD38 antibody for treatment of multiple myeloma (MM). In clinical trials, median durations for the 1^st, 2^nd and subsequent infusions were 7.0, 4.3 and 3.5 hours, respectively. To optimize the first infusion duration of DARA, the US Oncology Network (USON), a community oncology practice network, implemented a split first dose protocol. The USON split first dose protocol requires 2 IV bags, one for Day 1 and one for Day 2 of consecutive days. On each day, DARA is diluted with normal saline to a total volume of 500 mL. On each day, DARA is administered at 50 mL/hour for one hour. If no infusion events occur, the infusion rate can be increased in 50 mL/hour increments every hour to a maximum of 200 mL/hour. While the split first dose may increase convenience, limited information is available on the safety of split first dose DARA.

METHODS:

This was a retrospective, observational study of adult MM patients who initiated DARA in routine care within USON between 11/01/2015 - 06/30/2017 to compare infusion times and safety of DARA split first dose vs DARA standard dose schedule (i.e., 1 infusion of 16 mg/kg per FDA-approved prescribing information). In this study, patients were grouped into either the split first dose cohort or the standard dose schedule cohort according to the dosing schedule that they had experienced. Data were sourced from USON's electronic healthcare record system. Information on infusion reactions was available only through chart review, which was conducted among a random sample of patients in each study cohort. Descriptive analyses were conducted to compare demographic, clinical and treatment characteristics of MM patients who received split first dose schedule vs standard dosing schedule. Chi-square tests or Fisher's exact tests were used to assess associations between categorical variables. ANOVA/t-tests or Kruskal-Wallis tests were used to assess associations for continuous variables. A p-value of <0.05 was considered as statistically significant.

RESULTS:

Of the 622 patients included in the landscape analysis, 365 (58.5%) had received the split first dose schedule and 258 (41.5%) had received the standard dosing schedule. Overall, the median age was 63.6 years, 54.2% male and 78.3% Caucasian. The utilization of the split first dose schedule increased significantly over time with more patients in 2017 Q2 having received split dose vs standard dose (p< 0.0001). Karnofsky performance status (KPS) scores differed significantly between patients treated with split first dose vs standard dose (p=0.02). No other baseline differences between groups were found. The median infusion duration was 4.5 hours for Day 1 of split first dose and 6.5 hours for standard dose (p<0.0001). Among patients selected for chart review (n = 302), 47.8% (88/184) of split first dose patients and 48.3% (57/118) of standard dose patients experienced at least one infusion reaction. The most common infusion reactions included lower-respiratory (26.1%), upper-respiratory (17.2%) and gastrointestinal reactions (12.5%), chills (8.9%), flushing (6.6%), with no statistically significant differences between study groups for any infusion reaction. Among patients treated with split first dose DARA, 3.8% experienced an infusion reaction during Day 2 of the split dose schedule.

CONCLUSIONS:

As a retrospective observational study at community-based oncology clinics, these findings provide real-world evidence on the infusion time and safety of the first infusion of DARA. This study found that the utilization of split first dose has increased over time. Interestingly, more patients in the split dose group had higher KPS scores than patients in the standard dose group, which may be due to selection of patients, at least initially, for the split first dose. This study found also that the length of the first day of the split first dose schedule is shorter than the length of the standard dosing schedule. Additionally, although determination of severity or grade was not feasible in this study, the proportion of patients in split first and standard dosing schedule groups who experienced infusion reactions was equal. This study suggests that the split first dose is comparable to the standard dose schedule and may be a practical option for patients and institutions seeking options to manage the operational considerations of DARA administrations.

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