JHOP Editorial Board Member, Readers, and Author Interact - Comment on Kye et al (April 2023), Authors’ Response

We read with great interest the article by Kye and colleagues (April 2023 issue),¹ which discussed the safety of subcutaneous daratumumab for the treatment of plasma-cell disorders. After its approval in November 2015, daratumumab became the backbone of multiple myeloma treatment in the frontline and relapsed or refractory settings.^2-5

Daratumumab has a favorable side-effect profile; nonetheless, one of the main challenges associated with the administration of daratumumab is infusion-related reactions (IRRs), which tend to occur primarily with the first dose. With the introduction of the subcutaneous (SC) formulation of daratumumab in May 2020, IRRs became less of a problem, as was demonstrated in the pivotal COLUMBA study (34% with intravenous [IV] daratumumab vs 13% with SC daratumumab; P<.0001).⁶ Kye and colleagues note a rate for IRRs of approximately 10% (n=8) in the overall cohort (ie, patients who previously received daratumumab and daratumumab-naïve patients), which is comparable with the results of the COLUMBA study. However, there are some concerns that we would like to raise.

Of the 82 patients in the study by Kye and colleagues, 33 (40%) were naïve to the drug when they received their first SC dose of daratumumab; 7 (approximately 21%) of the 33 patients had an IRR. It is worth stating that these IRRs were mild to moderate in severity and intervention was warranted in 2 patients. Conversely, the COLUMBA study, which enrolled 263 patients with multiple myeloma who were daratumumab-naïve and received SC daratumumab in the study, reported a much lower rate of IRRs (13% in the SC arm vs 34% in the IV arm), as stated above.

Data from real-world studies also suggested that IRRs could be minimized or even abrogated with the optimization of a premedication regimen (ie, the addition of montelukast 10 mg to acetaminophen, diphenhydramine, and dexamethasone).^7,8 In the COLUMBA study, premedication with montelukast was not mandatory, whereas in the study by Kye and colleagues, 82% of the patients received premedication with montelukast.¹ This brings to question the high IRR rates in the daratumumab-naïve cohort noted by Kye and colleagues.¹ In addition, the investigators did not specify whether montelukast was given at an infusion center or if instructions were provided to patients to take the drug before their treatment appointment.¹

In the cohort that previously received daratumumab, only 1 patient had an IRR.¹ In a study similar to that of Kye and colleagues, transitioning from IV to SC daratumumab did not result in IRRs.⁷ Daratumumab has a long plasma half-life of 28 days. After 3 to 5 half-lives, the drug is expected to be totally cleared. Hence, it is important to ascertain whether there was a treatment gap that was long enough before this patient resumed treatment with SC daratumumab.

• Issam S. Hamadeh, PharmD
• Clinical Pharmacy Specialist
• Shebli Atrash, MD
• Hematologist/Oncologist
• Plasma Cell Disorders Division
• Department of Hematologic Oncology & Blood Disorders
• Levine Cancer Institute, Atrium Health
• Charlotte, NC

References

1. Kye J, Patel S, Seyer M, et al. Safety of SC daratumumab in the treatment of plasma-cell disorders: a single-center experience. J Hematol Oncol Pharm. 2023;13(2):65-70.
2. Lokhorst HM, Plesner T, Laubach JP, et al. Targeting CD38 with daratumumab monotherapy in multiple myeloma. N Engl J Med. 2015;373:1207-1219.
3. Palumbo A, Chanan-Khan A, Weisel K, et al. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375:754-766.
4. Facon T, Kumar S, Torben Plesner T, et al. Daratumumab plus lenalidomide and dexamethasone for untreated myeloma. N Engl J Med. 2019;380:2104-2115.
5. Dimopoulos MA, Oriol A, Nahi H, et al. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375:1319-1331.
6. 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.
7. Hamadeh IS, Moore DC, Martin A, et al. Transition from intravenous to subcutaneous daratumumab formulation in clinical practice. Clin Lymphoma Myeloma Leuk. 2021;21:470-475.
8. Maples KT, Hall KH, Joseph NS, et al. Eliminating the monitoring period with subcutaneous daratumumab: a single-center experience. Blood Cancer J. 2023;13:29.