Ninety-Minute Daratumumab Infusions for Relapsed and Refractory Multiple Myeloma: Two Years of Italian Single-Center Observational Study.

Daratumumab was the first fully human anti-CD38 monoclonal antibody (mAb) to be tested in clinical trials, 1 van de Donk NWCJ Janmaat ML Mutis T et al. Monoclonal antibodies targeting CD38 in hematological malignancies and beyond. Immunol Rev. 2016; 270: 95-112https://doi.org/10.1111/imr.12389 Crossref PubMed Scopus (211) Google Scholar demonstrating efficacy as a single agent in patients with relapsed/refractory multiple myeloma (RRMM). Daratumumab exerts direct antitumor and indirect immunomodulatory effects by targeting CD38, a cell surface receptor highly expressed on neoplastic plasma cells. 2 Overdijk MB Verploegen S Bögels M et al. Antibody-mediated phagocytosis contributes to the anti-tumor activity of the therapeutic antibody daratumumab in lymphoma and multiple myeloma. MAbs. 2015; 7: 311-321https://doi.org/10.1080/19420862.2015.1007813 Crossref PubMed Scopus (317) Google Scholar ,3 de Weers M Tai YT van der Veer MS et al. Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors. J Immunol. 2011; 186: 1840-1848https://doi.org/10.4049/jimmunol.1003032 Crossref PubMed Scopus (650) Google Scholar Daratumumab was first approved in patients with RRMM as monotherapy 4 Lonial S Weiss BM Usmani SZ et al. Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): An open-label, randomised, phase 2 trial. Lancet. 2016; 387: 1551-1560https://doi.org/10.1016/S0140-6736(15)01120-4 Abstract Full Text Full Text PDF PubMed Scopus (594) Google Scholar and subsequently in combination with proteasome inhibitors (PIs, Dara-VD) 5 Palumbo A Chanan-Khan A Weisel K et al. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med. 2016; 375: 754-766https://doi.org/10.1056/NEJMoa1606038 Crossref PubMed Scopus (953) Google Scholar ,6 Mateos M-V Dimopoulos MA Cavo M et al. Daratumumab plus bortezomib, melphalan, and prednisone for untreated myeloma. N Engl J Med. 2018; 378: 518-528https://doi.org/10.1056/NEJMoa1714678 Crossref PubMed Scopus (565) Google Scholar or immunomodulatory drugs (IMiDs, Dara-RD) 7 Dimopoulos MA Oriol A Nahi H et al. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016; 375: 1319-1331https://doi.org/10.1056/NEJMoa1607751 Crossref PubMed Scopus (958) Google Scholar ; currently, it is employed also for the treatment of newly diagnosed patients with MM who are not candidate for autologous stem cell transplantation. Daratumumab displays an excellent safety profile, with moderate-grade infusion-related reactions (IRRs) occurring mostly during the first infusion. IRRs generally consist of respiratory symptoms (nasal congestion, throat irritation, and cough) and only rarely lead to treatment discontinuation. IRRs were reported in approximately 40% of patients during the first infusion and 5% during the second infusion; from the third infusion, the risk becomes minimal with an estimated frequency of less than 4%. The average time to the occurrence of an IRR is 1.4 hours. Because of this, the recommended administration rates correspond to a timing of 6.5, 4.5, and 3.5 hours for the first, second, and following infusions, respectively. In a few retrospective single-center experiences, involving occasional patients, daratumumab was used with a rapid infusion (90 minutes) schedule, starting from the third infusion, suggesting that the procedure is safe even for patients undergoing fractional doses. 8 Barr H Dempsey J Waller A et al. Ninety-minute daratumumab infusion is safe in multiple myeloma. Leukemia. 2018; 32: 2495-2518https://doi.org/10.1038/s41375-018-0120-2 Crossref PubMed Scopus (41) Google Scholar , 9 Lombardi J Boulin M Devaux M et al. Safety of ninety-minute daratumumab infusion. J Oncol Pharm Pract. 2020; https://doi.org/10.1177/1078155220951231 Crossref PubMed Scopus (8) Google Scholar , 10 Gozzetti A Bacchiarri F Sammartano V et al. Long-term safety of rapid daratumumab infusions in multiple myeloma patients. Front Oncol. 2020; 10https://doi.org/10.3389/fonc.2020.570187 Crossref PubMed Scopus (6) Google Scholar , 11 Gordan L Chang M Lafeuille MH et al. Real-world utilization and safety of daratumumab iv rapid infusions administered in a community setting: a retrospective observational study. Drugs Real World Outcomes. 2021; https://doi.org/10.1007/s40801-020-00226-3 Crossref PubMed Scopus (4) Google Scholar , 12 Geirnaert M Howarth J Martin K et al. A multicenter review of infusion-related reactions to daratumumab for relapsed multiple myeloma in the real world setting. J Oncol Pharm Pract. 2020; 107815522096773https://doi.org/10.1177/1078155220967738 Crossref Scopus (2) Google Scholar Recently, some clinical studies have shown that subcutaneous administration of daratumumab is noninferior to conventional intravenous daratumumab with a lower risk of infusion-related reactions and shorter administration times. 13 Paul B Atrash S Bhutani M et al. An evaluation of subcutaneous daratumumab for the treatment of multiple myeloma. Exp Rev Hematol. 2020; 13https://doi.org/10.1080/17474086.2020.1795829 Crossref PubMed Scopus (1) Google Scholar However, this practice is not yet allowed in Italy. Therefore, based on the low rate of adverse reactions even in patients with advanced disease observed in our clinical practice, we have adopted a similar rapid (90 minutes) infusion protocol and report here the results of a single-center study of 900 rapid infusions of daratumumab, performed since February 2019 in December 2020. This study was approved by our Institutional board and by our Ethical committee and was performed in accordance with the ethical standards of the Declaration of Helsinki; informed consent was obtained from all patients. The only inclusion criterion for the study was to have received previous four doses of daratumumab according to standard practice. Occurrence of a previous IRR was not an exclusion criterion. All patients were treated at our institution (Haematology Department, Careggi Hospital of Florence, Italy). Adverse events were described according to the National Cancer Institute Common Terminology Criteria version 5.0. We evaluated 72 consecutive patients affected by RRMM. Median age was 65 years (42-81 years). Patient's characteristics are summarized in Table 1. ECOG performance status was ≥2 for 17 (23.6%) patients, including 2 patients with an ECOG score of 3 and 4, respectively. Ten (14%) patients were on treatment with daratumumab single agent, 15 patients (21%) with Dara-VD and 47 (65%) with Dara-RD. Median previous lines of treatment were 2 (2-5). Median number of daratumumab infusions prior to be enrolled in the protocol was 8 (4-30), as reported in Table 2. Standard vital signs (body temperature, oxygen saturation, pulse and blood pressure) were collected before the start of the daratumumab infusion and every 15 minutes. Premedication regimens with rapid infusion procedure did not differ from standard of care. Sixty minutes before daratumumab infusion, patients received chlorphenamine 10 mg, paracetamol 1000 mg and intravenous dexamethasone 20 mg or 40 mg, according to Dara-VD or Dara-RD regimen, respectively. None of our patients received additional premedications such as inhaled corticosteroids or bronchodilators before daratumumab infusion. Short time infusion was carried out by administering daratumumab at 200 mL/h rate for the first 30 minutes, progressively increasing up to 400 mL/h for the next 60 minutes. Beyond infusion lapse, patients remained under surveillance for at least 30 minutes after the end of the infusion to assess for delayed IRRs. Fifty-seven patients (79%) had experienced IRRs at time of their first dose. These reactions were mainly conjunctivitis, rhinorrhea, cough, wheezing, or arterial hypertension, mostly grade 2 (72%) and promptly reverted with hydrocortisone 500 mg/1000 mg. The median number of fast infusions for patient was 12. No adverse events were observed during the rapid infusion, or within 30 minutes following completion, in a total of 900 procedures. We also evaluated the impact of rapid infusion on 38 (53%) patients defined as “at risk” by the presence of cardiovascular disease (arterial hypertension, arrhythmia or valvulopathy) or pulmonary comorbidities (COPD, asthma and allergic rhinitis). Daratumumab administration over ninety minutes was well tolerated in 8 patients with cardiac or renal amyloidotic involvement. Rapid infusion turned out to be safe even in patients who suffered from grade I (65.3%) and II (8.3%) anemia, in those with concomitant COPD (23,6%) and in patients with history of aeroallergens or asthma (18%). All patients maintained accelerated infusion regimen for subsequent administrations. Based on these findings, we conclude that fast (90 minutes) daratumumab infusion is safe in patients with MM even in the presence of different comorbidities. Reducing the duration of the daratumumab infusion may not only improve the patient's quality of life by shortening hospitalization times, but also have an impact on cost savings for the healthcare system. Hamadeh et al. 14 Hamadeh IS Reese ES Arnall JR et al. Safety and cost benefits of the rapid daratumumab infusion protocol. Clin Lymphoma Myeloma Leuk. 2020; 20: 526-532.e1https://doi.org/10.1016/j.clml.2020.02.014 Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar reported an extensive cost analysis, highlighting significant savings in terms of either hospital productivity and patient productivity costs of about $25.000 with rapid infusion. Owing to differences between the American and Italian healthcare system, we tried to estimate the savings in two years of daratumumab short infusion experience in our unit, considering the nursing cost and the services offered to patients. The average gross annual salary of nurses is around 30.800 euros. Considering that nursing care in our Day Hospital allows the management of up to 4 infusion chairs or beds at one time, we estimated that the cost of personnel for each infusion of daratumumab decreases from € 14,40 to € 6,17. Drugs and administration costs were similar for standard and short infusion. To these savings the costs of patient management, including the cost of the meal (€7 per meal) provided by the Hospital for patients undergoing conventional prolonged infusions, must be added. Therefore, in our 2-year experience of 90 minutes infusion of daratumumab, we performed a total of 900 rapid infusions, realizing a potential cost saving of € 13.707 euros. Furthermore, the reduction of the times needed for each infusion brings not only an advantage in terms of staff management but also hospital resources more in general, first the possibility of using the chair several more times over the day, contributing to shorten waiting lists. Furthermore, patients with RRMM perform daratumumab chronically for long periods of time, so it is reasonable to anticipate that short infusions may foster their adherence to treatment, having less impact on personal daily activities, particularly for patients who are actively working. At this regard, in younger patients, we subsequently shifted the antihistamine treatment from i.v. infusion to oral administration, with no adverse events registered, aimed at reducing the common side effects of i.v. drug which might interfere with working capabilities. In conclusion, short daratumumab infusion over 90 minutes is safe and well tolerated, thus allowing a considerable saving of money for the health system and time for RRMM patients, potentially ameliorating their adherence to treatment. Table 1Patients’ Characteristics at Study Entry Characteristics Patients (no. = 72) Sex - no. of pts (%) Female 39 (54.2) Median age (range) 65 (42-81) ECOG ≥2 17 (23.6) Comorbidities - no. of pts (%) 38 (52.7) Pulmonary 30 (79) Cardiological 8 (21) Cytogenetic risk - no. of pts (%) Standard risk 26 (36) High risk 24 (34) - del(17p) 6 (8) - t(4;14) 5 (7) - amp1q 13 (18) NA 22 (30) Type of myeloma - no. of pts (%) IgG 44 (61) IgA 16 (22.2) Micromolecular 12 (17) Type of light chains - no. of pts (%) kappa 49 (68) lambda 23 (32) Amyloidosis AL - no. of pts (%) 8 (11) Previous lines of treatment - no. of patient (%) 1 previous line 18 (25) 2 previous lines 29 (40) ≥3 previous lines 25 (35) Open table in a new tab Table 2Treatment's Characteristics Type of treatment - no. of pts (%) Daratumumab + lenalidomide (Dara-RD) 47 (65) Daratumumab + bortezomib (Dara-VD) 15 (21) Daratumumab single agent 10 (14) Median no. of Infusions before Daratumumab in 90’ minutes (range) 8 (4-30) Total rapid infusions 900 Premedication - no. of pts (%) Paracetamol 1gr + chlorphenamine 10 mg + methylprednisolone 1 gr 7 (9.7) Paracetamol 1gr + chlorphenamine 10 mg + methylprednisolone 60 mg 7 (9.7) Paracetamol 1gr + chlorphenamine 10 mg + dexamethasone 40 mg 46 (64) Paracetamol 1gr + chlorphenamine 10 mg + dexamethasone 20 mg 12 (16,6) IRRs at first infusion - no. of pts (%) 57 (79) Respiratory symptoms 49 (78) Fever 4 (6) Hypertension 3 (4) Abdominal discomfort 5 (7) Conjunctivitis 5 (7) IRRs at fast infusion - no. of pts (%) 0 Open table in a new tab