Safety of SC Daratumumab in the Treatment of Plasma-Cell Disorders: A Single-Center Experience

JHOP - April 2023 Vol 13, No 2 - Original Article
Jung Kye, PharmD, BCOP; Samit Patel, PharmD, BCOP; Maggie Seyer, PharmD, BCPS; Eun-Jeong Kim, PharmD, MS, BCOP; Rhonda Hewitt, MSN, ANP, AOCNP; Michaela Liedtke, MD; David Iberri, MD
Dr Kye is Clinical Oncology Pharmacist, Dr Patel was Clinical Oncology Pharmacist during the study, Dr Seyer is Clinical Oncology Pharmacist, and Dr Kim was Clinical Oncology Pharmacist during the study, Stanford Health Care, Pharmacy Department, Stanford, CA; Ms Hewitt is Hematology Nurse Practitioner, Stanford Hospital and Clinics, Stanford, CA; Dr Liedtke is Hematologist, and Dr Iberri is Hematologist, Division of Hematology, Department of Medicine, Stanford University, Stanford, CA.
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BACKGROUND: Daratumumab is a CD38-directed monoclonal antibody that is approved by the US Food and Drug Administration for the treatment of multiple myeloma and light-chain amyloidosis. Infusion-related reactions (IRRs) have been reported in 28% to 56% of individuals receiving the intravenous (IV) formulation of daratumumab, necessitating slow infusions and the frequent use of rescue medications. In 2020, subcutaneous (SC) daratumumab was approved for the treatment of multiple myeloma, and randomized data suggest a lower rate of IRRs compared with IV daratumumab. Guidelines regarding postinjection monitoring with SC daratumumab are not well-established.

OBJECTIVES: To evaluate the safety of SC daratumumab and to suggest guidelines for monitoring patients after the administration of SC daratumumab.

METHODS: This single-center, retrospective study included patients with multiple myeloma and/or light-chain amyloidosis who were receiving SC daratumumab at Stanford Health Care between June 1, 2020, and December 31, 2020. The primary outcome of the study was the incidence of IRRs. The secondary outcomes include the timing and severity of IRRs based on the Common Terminology Criteria for Adverse Events version 5.0.

RESULTS: A total of 82 patients received SC daratumumab during the study period. Of these patients, 49 (60%) had previously received IV daratumumab (daratumumab-exposed), and 33 (40%) had never received IV daratumumab previously (daratumumab-naïve). Of the total cohort, 8 (9.8%) had an IRR. All IRRs were grade 1 (N = 5; 63%) or grade 2 (N = 3; 38%) in severity. A total of 7 (21%) patients in the daratumumab-naïve group had an IRR, and 1 (2%) patient in the daratumumab-exposed group had IRRs with the first SC dose. Among the daratumumab-naïve patients, 6 had IRRs after receiving the first SC dose and 1 had IRRs after receiving the second SC dose. Of all the patients who had IRRs, 3 patients had immediate reactions (onset <15 minutes) and 4 patients had delayed reactions (onset >4 hours) after the SC administration of daratumumab (median, 11.9 hours; range, 5-24 hours). One patient had IRRs right before the 4-hour observation was completed. Among the patients with delayed reactions, 3 had reactions after being discharged from the treatment area, but their symptoms resolved without any intervention.

CONCLUSIONS: In this single-center study of patients who were receiving SC daratumumab, IRRs occurred in approximately 10% of patients and were more likely after a patient received the first dose of SC daratumumab than with subsequent doses. All reactions were mild to moderate in severity and could be managed in the outpatient setting. We suggest that patients who are receiving their first dose of SC daratumumab be monitored for 1 hour after administration. Monitoring is not necessary for patients who are transitioning from IV to SC daratumumab or in patients who are receiving subsequent doses of SC daratumumab.

KEY WORDS: daratumumab, dosing, infusion-related reactions, light-chain amyloidosis, multiple myeloma, plasma-cell disorders, subcutaneous dosing

J Hematol Oncol Pharm.
2023;13(2):65-70
Disclosures at end of text

Daratumumab is a human immunoglobulin G, CD38-targeting monoclonal antibody that is a valuable treatment option for patients with plasma-cell disorders, including multiple myeloma or systemic immunoglobulin light-chain amyloidosis, as monotherapy and as part of combination regimens.1-6

Although studies have demonstrated its safety and efficacy, one of the main concerns for intravenous (IV) daratumumab is infusion-related reactions (IRRs), particularly during the initial infusions. IRRs have been reported in 28% to 50% of patients who received daratumumab in phase 2 and 3 studies, resulting in prolonged infusions, a higher level of infusion acuity, and more frequent use of rescue medications to mitigate complications.3,7-10

In the recent phase 3 COLUMBA study, subcutaneous (SC) daratumumab had comparable efficacy with IV daratumumab, and the SC formulation had a lower incidence of IRRs (13% vs 34%, respectively).11

In addition to a lower risk for IRRs, SC daratumumab offers advantages versus IV daratumumab, including a lower risk for compounding errors, a significantly shorter infusion duration, and a shorter stay in the infusion areas, which improve patients’ satisfaction and quality of life (QOL).6,8,9,12

According to the prescribing information for SC daratumumab, the incidence of IRRs in a pooled safety population of 898 patients was 9%.13 IRRs occurred in 8% of patients with the first injection, 0.3% with the second injection, and cumulatively in 1% of patients who received subsequent injections.13

The median time to the onset of IRRs was 3.7 hours.3 Although the onset of IRRs ranges from 9 minutes to 3.5 days, the majority of IRRs occurred on the day of treatment, with ≤1% of patients having a delayed reaction, which was defined in the package insert as a reaction occurring the day after the administration of daratumumab.3,13,14

Guidelines regarding postinjection monitoring with SC daratumumab are not well-established. Establishing guidelines for the administration of SC daratumumab in the clinic was explored by Sanchez and colleagues.3 They recommend monitoring for systemic reactions for 4 hours after the injection of daratumumab on cycle 1, day 1 for daratumumab-naïve patients and transitioning from IV to SC daratumumab.3 No observation period is recommended for subsequent doses of daratumumab if there are no IRRs after dose 1.3

Based on these available data, Stanford Health Care initially monitored patients for 4 hours after the administration of the first dose of SC daratumumab and for 15 minutes after the administration of subsequent doses. Any IRRs that occurred after discharge were reported by patients and were assessed by nurses during the subsequent visit.

The purpose of this study was to evaluate the safety of SC daratumumab in patients with multiple myeloma and/or light-chain amyloidosis, and to suggest guidelines for patient monitoring after the SC administration of daratumumab.

Methods

In this single-center, retrospective study conducted at Stanford Health Care in Stanford, CA, adults aged >18 years with multiple myeloma and/or light-chain amyloidosis who received SC daratumumab between June 1, 2020, and December 31, 2020, were evaluated for IRR. The study protocol was approved by the Institutional Review Board.

The institution’s electronic health record system was used for chart review and data collection. The patients’ demographic information, including age, sex, weight, body mass index, and preselected medical history, was collected.

Information regarding treatment, including the indication for daratumumab, previous exposure to daratumumab, and the number of doses of daratumumab that were previously received, was collected.

Other data that were collected include premedication before daratumumab, the incidence and onset of IRRs, the severity of the reactions, and the symptoms of the IRRs. The physician and nursing progress notes after each dose of daratumumab were reviewed for the documentation of daratumumab-associated IRRs.

The primary end point of the study was the incidence of IRRs. The secondary end points include the timing and severity of the IRRs. The severity of the adverse drug reactions was based on the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.15

For statistical analysis, Fisher’s exact test with a P value of .05 was used to evaluate the categorical variables and Student’s t-test with a P value of .05 was used to compare the numerical data points between patients with and without IRRs.

Results

A total of 484 doses of daratumumab were evaluated for 82 patients during the study period. The patients’ baseline characteristics are shown in Table 1. Of these patients, 49 (60%) had previously received IV daratumumab (daratumumab-exposed), and 33 (40%) had not received IV daratumumab previously (daratumumab-naïve). A total of 8 (9.8%) patients had IRRs, all of which were grade 1 (N = 5; 63%) or grade 2 (N = 3; 38%). No grade ≥3 infusion reactions occurred (Table 2).

Table 1


Table 2

For premedication before the first dose of SC daratumumab, 99% of patients received acetaminophen, 96% received an H1-receptor antagonist, 88% received a corticosteroid, and 82% received montelukast (Table 1). Overall, patients who had an IRR were younger than patients without an IRR (61.5 years vs 71 years, respectively; P = .0017) and more often had not received previous treatment with daratumumab (88% vs 35%, respectively; P = .0063). Patients who had IRRs, versus those who did not, were more often female (62% vs 32%, respectively) and had higher median weight (79.5 kg vs 71.7 kg, respectively).

In all, 7 (21%) patients in the daratumumab-naïve group had an IRR, and 1 (2%) patient in the daratumumab-exposed group had an IRR with the first SC dose after previously receiving 41 doses of IV daratumumab without any issues (Table 3). Among the 7 patients who had an IRR in the daratumumab-naïve group, 6 had an IRR with the first SC dose and 1 patient had an IRR with the second SC dose.

Table 3

The median onset of IRRs was 6.4 hours (range, 0.25-24 hours). Of the 8 patients who had a reaction after receiving SC daratumumab, 3 patients had immediate reactions, which was defined as an onset of <15 minutes after the administration of SC daratumumab. A total of 4 patients had delayed reactions, which we defined as any reaction that occurred more than 4 hours after the administration of SC daratumumab (median, 11.9 hours; range, 5-24 hours). One patient had IRRs right before his 4-hour observation period was completed.

Among the patients with delayed reactions, 3 patients had symptoms after being discharged from the infusion treatment area, but they resolved without any intervention. It is interesting to note that 1 patient with a delayed reaction requested to stay longer than the 4-hour observation period and had IRRs 6 hours after receiving daratumumab. The common daratumumab-associated IRRs and descriptions are shown in Table 2 and Table 3.

Our cohort comprised 2 indications: multiple myeloma and light-chain amyloidosis. The rates of IRRs were 6.7% among the multiple myeloma group and 18.2% among the light-chain amyloidosis group, but the differences were not statistically significant (P = .2).

Discussion

In this retrospective analysis of patients with multiple myeloma and/or light-chain amyloidosis who were receiving SC daratumumab, approximately 10% of all patients had an IRR, but the majority were grade 1 and required no pharmacologic intervention. Most IRRs occurred after the first SC daratumumab dose, with only 1 patient having an IRR after the second SC dose. This patient had never received IV daratumumab before. Nearly 90% of all of the patients received appropriate institutional standard premedication, including acetaminophen, corticosteroid, antihistamine, and montelukast, before receiving the first dose of daratumumab. No significant difference was seen in the premedication received between the patients with and without IRRs. The findings that 10% of patients had an IRR, all of which were grades 1 and 2, and that the majority of the IRRs occurred after the first SC daratumumab dose were consistent with other studies of SC daratumumab.2,3,9-11

The median onset of IRRs was 6.4 hours in our study compared with 3.2 hours reported in a pooled safety analysis by Janssen Pharmaceuticals.14 The characteristics of IRRs with SC daratumumab have been reported in other studies.2,9

In the PAVO trial, SC daratumumab was administered in patients with relapsed or refractory multiple myeloma.9 The incidence and severity of IRRs in this study were low with SC daratumumab. Among 25 patients who received SC daratumumab, 4 (16%) had an IRR, of which most occurred on day 1, cycle 1 of treatment. The median time to the onset of IRRs was 70 minutes (range, 9-80 minutes). Most of the IRRs were grade 1 or 2 and were reversible, and hypertension was the most common grade 3 IRR. No grade 4 IRRs were reported.9

The ANDROMEDA study evaluated the outcomes of SC treatment with daratumumab in 388 patients with light-chain amyloidosis.2 Systemic IRRs occurred in 14 (7.3%) patients, all of which were grade 1 or 2. The median time to the onset of IRRs was 1.3 hours (range, 0.2-7.3 hours).2

In our study, 50% of patients had delayed IRRs, with a median onset of 11.9 hours. Only 1 patient required evaluation in the emergency department and ultimately received antibiotics for a suspected infection, but it is unclear if this was a true IRR.

Overall, the incidence of delayed reactions was higher in our retrospective study than in a pooled safety analysis of daratumumab (50% vs 1%, respectively).13,14 This may be because medications given after daratumumab treatment (post medication) are not routinely ordered at our institution. Further studies are warranted on the utility and impact of post medication on delayed reactions.

Our study included a significant proportion of patients who switched from IV to SC daratumumab, which is not clearly evaluated in clinical trials in terms of IRRs. Among all of the patients who switched from IV to SC daratumumab, only 1 patient had an IRR after her first SC dose, but the patient had only minor localized reactions (ie, injection-site pruritus and erythema) that resolved without any intervention. This patient had received 41 doses of IV daratumumab previously without having any IRRs.

In our study, younger patients and daratumumab treatment–naïve patients were more likely to have IRRs than older patients and those who had previously received daratumumab. These findings potentially can be explained by immunosenescence. Elderly patients have reduced neutrophil and macrophage phagocytic capacities that lead to the diminished activation and stimulation of adaptive immune cells.16,17 Also, elderly patients have numerical and functional impairment of naïve T-cells, which hampers the induction of adaptive immune response to neoantigens.16,17

Although not statistically significant, a trend was seen in our study that female patients and heavier patients were more likely to have IRRs than male patients and lower-weight patients. Further studies are warranted to distinguish the factors that are associated with IRRs.

Higher rates of satisfaction have been reported with the SC method of drug administration than with the IV route among healthcare professionals and patients.8,18-20 Because our study was retrospective in nature, we did not assess the patients’ QOL. The reduced treatment burden with SC daratumumab has been shown to increase patients’ satisfaction versus IV dosing of daratumumab.8

The phase 3 COLUMBA trial assessed patient satisfaction with therapy as a secondary end point using a modified version of the Cancer Therapy Satisfaction Questionnaire.8 This study’s results show that patients who received SC daratumumab were more satisfied with their treatment and had a more positive outlook regarding their cancer therapy than patients who received IV daratumumab.8

According to the results of a web-based prospective survey that examined healthcare professionals’ involvement with patients who were receiving IV or SC daratumumab, the median active time spent by healthcare professionals, including for drug preparation activities and activities in the patient care or infusion center areas, was significantly shorter with SC daratumumab than with IV daratumumab (98.7 minutes vs 294.2 minutes, respectively, for the first injection; 82.2 minutes vs 194.9 minutes, respectively, for subsequent injections).12

The estimated chair times for the first and subsequent administrations of IV versus SC daratumumab were 445.6 minutes and 243.1 minutes versus 8.6 minutes and 6.9 minutes, respectively.12 In addition to having a better safety profile without altering the efficacy outcomes, SC daratumumab is associated with less active time spent by healthcare professionals on drug preparation and administration, and thus a reduction in the patients’ overall chair time at the infusion centers, versus IV dosing of daratumumab.

Based on the results of our retrospective analysis, our institution changed the duration of daratumumab monitoring to 1 hour after the initial SC dose and no monitoring for all subsequent doses. The 1-hour monitoring for the initial dose of daratumumab was chosen because all of our patients had either immediate (onset <15 minutes) or delayed IRRs (onset >4 hours), except for 1 patient who had a reaction right before the 4-hour observation period was over.

Also, patients with delayed IRRs had grade 1 or 2 reactions only, and most of the reactions did not require any pharmacologic interventions. The delayed IRRs in our study could be easily managed in the outpatient setting, so our providers were confident with 1-hour postdose monitoring to capture any immediate reactions. Because the median onset of delayed IRRs in our study was 11.9 hours, it is unrealistic to monitor patients for such a long period of time.

Our retrospective data demonstrated that only 1 patient had an infusion reaction after receiving the subsequent dose of daratumumab, which was grade 1 injection-site erythema only. It was therefore reasonable to remove monitoring for the subsequent doses of daratumumab.

Limitations

Our study has several limitations. This study was a single-center, retrospective study that relied solely on provider and nursing documentation for the data collection and evaluation of IRRs, including symptoms, onset, and grading.

In addition, the data may not be available for some patients who had delayed IRRs after they left the infusion treatment areas and were lost to follow-up. Furthermore, 1 patient in our study received rescue medications for potentially non-IRR symptoms, which subsequently was categorized as a CTCAE grade 2 IRR.

Another limitation is that our institution does not use posttreatment long-acting corticosteroids, whereas previous daratumumab clinical trials used pre- and postinfusion medications. Therefore, it is unclear whether the delayed reactions observed in this study are potentially related to the omission of posttreatment medications.

Conclusion

In this single-center study of patients receiving SC daratumumab, IRRs occurred in approximately 10% of patients and were more likely with a patient’s first dose of SC daratumumab than with subsequent doses. All reactions were mild to moderate in severity and could be managed in the outpatient setting. Based on the results of this study, our institution incorporated new monitoring parameters: patients who are receiving their first SC daratumumab dose are monitored for 1 hour after SC daratumumab administration, and no monitoring is needed for patients who are transitioning from IV to SC daratumumab or who are receiving subsequent doses of SC daratumumab.

Author Disclosure Statement
Dr Kim was previously on the Speaker’s Bureaus of Bristol Myers Squibb and Takeda Oncology and is now a Medical Science Liaison for Bristol Myers Squibb; Ms Hewitt is on the Speaker’s Bureaus of Janssen and Sanofi; Dr Liedtke is a Consultant to GSK, Takeda, Kite, Janssen, and Natera; Dr Kye, Dr Patel, Dr Seyer, and Dr Iberri have no conflicts of interest to report.

References

  1. Phipps C, Chen Y, Gopalakrishnan S, Tan D. Daratumumab and its potential in the treatment of multiple myeloma: overview of the preclinical and clinical development. Ther Adv Hematol. 2015;6:120-127.
  2. Kastritis E, Palladini G, Minnema MC, et al; for the ANDROMEDA trial investigators. Daratumumab-based treatment for immunoglobulin light-chain amyloidosis. N Engl J Med. 2021;385:46-58.
  3. Sanchez L, Richter J, Cho HJ, et al. Subcutaneous daratumumab and hyaluronidase-fihj in newly diagnosed or relapsed/refractory multiple myeloma. Ther Adv Hematol. 2021;12:2040620720987075. doi: 10.1177/2040620720987075.
  4. Chong LL, Soon YY, Soekojo CY, et al. Daratumumab-based induction therapy for multiple myeloma: a systematic review and meta-analysis. Crit Rev Oncol Hematol. 2021;159:103211. doi: 10.1016/j.critrevonc.2020.103211.
  5. Palladini G, Milani P, Malavasi F, Merlini G. Daratumumab in the treatment of light-chain (AL) amyloidosis. Cells. 2021;10:545. doi: 10.3390/cells10030545.
  6. Iida S, Ishikawa T, Min CK, et al. Subcutaneous daratumumab in Asian patients with heavily pretreated multiple myeloma: subgroup analyses of the noninferiority, phase 3 COLUMBA study. Ann Hematol. 2021;100:1065-1077.
  7. Nooka AK, Gleason C, Sargeant MO, et al. Managing infusion reactions to new monoclonal antibodies in multiple myeloma: daratumumab and elotuzumab. J Oncol Pract. 2018;14:414-422.
  8. Usmani SZ, Mateos MV, Hungria V, et al. Greater treatment satisfaction in patients receiving daratumumab subcutaneous vs. intravenous for relapsed or refractory multiple myeloma: COLUMBA clinical trial results. J Cancer Res Clin Oncol. 2021;147:619-631.
  9. San-Miguel J, Usmani SZ, Mateos MV, et al. Subcutaneous daratumumab in patients with relapsed or refractory multiple myeloma: part 2 of the open-label, multicenter, dose-escalation phase Ib study (PAVO). Haematologica. 2021;106:1725-1732.
  10. Shibayama H, Matsumoto M, Kosugi H, et al. Subcutaneous delivery of daratumumab in Japanese patients with relapsed/refractory multiple myeloma. Int J Hematol. 2021;113:112-121.
  11. Mateos MV, Nahi H, Legiec W, et al. Subcutaneous versus intravenous daratumumab in patients with relapsed or refractory multiple myeloma (COLUMBA): a multicentre, open-label, non-inferiority, randomised, phase 3 trial. Lancet Haematol. 2020;7:e370-e380. Erratum in: Lancet Haematol. 2020;7:e710.
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  13. Darzalex Faspro (daratumumab and hyaluronidase-fihj) injection, for subcutaneous use [prescribing information]. Janssen Biotech; November 2022. www.janssenlabels.com/package-insert/product-monograph/prescribing-information/DARZALEX+Faspro-pi.pdf. Accessed February 16, 2023.
  14. Janssen Scientific Affairs. Darzalex Faspro-postinjection observation time. JanssenMD. Updated May 11, 2022. www.janssenmd.com/darzalex-faspro/dosage-administration/darzalex-faspro-postinjection-observation-time. Accessed February 16, 2023.
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