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

JHOP - June 2023 Vol 13, No 3 - Letters to the Editor, Editorial

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.

AUTHORS’ RESPONSE:

I also find it very interesting that our daratumumab-naïve patients had a higher infusion-related reaction (IRR) rate than the patients in the 2 real-world studies you reference (21% vs 4.7% and 13%, respectively), especially because our institution also uses the 4-drug premedication regimen (dexamethasone, acetaminophen, diphenhydramine, and montelukast) before the administration of (SC) subcutaneous daratumumab.1,2

To answer your question regarding montelukast administration, every dose of montelukast is administered at our infusion center approximately 30 minutes to 1 hour before a SC daratumumab injection. Our treatment plan does not include home-administered montelukast that would allow the patient to take it before their treatment appointment. Given that there is no difference in the premedication regimen, I am unsure why our daratumumab-naïve cohort had a higher IRR rate than the patients in the COLUMBA study and the 2 real-world studies you reference. This discrepancy could be related to patient-specific risk factors, which would warrant further studies to identify any patient risk factors that may be associated with IRRs related to the administration of daratumumab.

For the 1 patient who had IRRs after transitioning from intravenous (IV) to SC daratumumab, the treatment gap between IV and SC doses of daratumumab was 56 days (approximately 2 half-lives). Therefore, it is safe to consider that the drug was not totally cleared. One thing to note is that at the beginning of the COVID-19 pandemic, the patient and the provider agreed to temporarily increase the maintenance daratumumab dose frequency to every other month (56 days). This patient received a total of 10 doses of IV daratumumab with monthly frequency and 5 doses of IV daratumumab with every-other-month frequency before transitioning to maintenance treatment with SC daratumumab. Since August 2020, the patient has been stable and has been receiving every-other-month maintenance treatment with SC daratumumab to date without any IRRs other than itching and injection-site erythema, which were observed from the first SC dose.

Jung Kye, PharmD, BCOP

  1. 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.
  2. 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.
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