daratumumab

In May 2018, the US Food and Drug Administration (FDA) approved daratumumab for use in combination with bortezomib, melphalan and prednisone to include the treatment of people with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant.{{Cite web|url=https://www.healio.com/hematology-oncology/myeloma/news/online/%7Bf43b9c68-20f6-4da8-93a6-d1dadc79c0b7%7D/fda-approves-darzalex-for-newly-diagnosed-transplant-ineligible-multiple-myeloma|title=FDA approves Darzalex for newly diagnosed, transplant-ineligible multiple myeloma|website=www.healio.com|access-date=8 May 2018}}

In the European Union it is indicated as monotherapy for the treatment of adults with relapsed and refractory multiple myeloma,{{cite journal | vauthors = Vincent L, Gras L, Ceballos P, Finke J, Passweg J, Harel S, Rosinol L, Minnema M, Teipel R, van Doesum J, Hänel M, Lenain P, Botella-Garcia C, Koenecke C, Ducastelle S, Sanz J, Schroyens W, Zuckerman T, Monaco F, Koster L, de Wreede L, Hayden PJ, Schönland S, Yakoub-Agha I, Beksac M | title = Daratumumab after allogeneic hematopoietic cell transplantation for multiple myeloma is safe and synergies with pre-existing chronic graft versus host disease. A retrospective study from the CMWP EBMT | journal = Bone Marrow Transplantation | volume = 57 | issue = 3 | pages = 499–501 | date = March 2022 | pmid = 35013536 | doi = 10.1038/s41409-021-01560-y | s2cid = 245861546 | url = https://pure.rug.nl/ws/files/215521951/s41409_021_01560_y.pdf }} whose prior therapy included a proteasome inhibitor and an immunomodulatory agent and who have demonstrated disease progression on the last therapy.{{cite web |url=https://www.ema.europa.eu/en/documents/product-information/darzalex-epar-product-information_en.pdf |title=SUMMARY OF PRODUCT CHARACTERISTICS|website=www.ema.europa.eu |access-date=4 June 2019}}

Treatment of multiple myeloma with daratumumab potentially increases the patient's susceptibility to bacterial and viral infections, due to the killing of natural killer cells (which are the main innate immune system defense against virus).{{cite journal | vauthors = Nahi H, Chrobok M, Gran C, Lund J, Gruber A, Gahrton G, Ljungman P, Wagner AK, Alici E | title = Infectious complications and NK cell depletion following daratumumab treatment of Multiple Myeloma | journal = PLOS ONE | volume = 14 | issue = 2 | pages = e0211927 | date = 2019 | pmid = 30759167 | pmc = 6374018 | doi = 10.1371/journal.pone.0211927 | doi-access = free | bibcode = 2019PLoSO..1411927N }} Daratumumab frequently causes human cytomegalovirus (CMV) reactivation by an unknown mechanism.{{cite journal | vauthors = Nakagawa R, Onishi Y, Kawajiri A, Onodera K, Furukawa E, Sano S, Saito K, Ichikawa S, Fujiwara T, Fukuhara N, Harigae H | title = Preemptive therapy for cytomegalovirus reactivation after daratumumab-containing treatment in patients with relapsed and refractory multiple myeloma | journal = Annals of Hematology | volume = 98 | issue = 8 | pages = 1999–2001 | date = August 2019 | pmid = 30824957 | doi = 10.1007/s00277-019-03645-7 | s2cid = 71146150 }} Injection related reactions (inflammation-like) are also common.{{cite journal | vauthors = Jain A, Ramasamy K | title = Evolving Role of Daratumumab: From Backbencher to Frontline Agent | journal = Clinical Lymphoma, Myeloma & Leukemia | volume = 20 | issue = 9 | pages = 572–587 | date = September 2020 | pmid = 32331971 | doi = 10.1016/j.clml.2020.03.010 | s2cid = 216131042 }}

Daratumumab can also bind to CD38 present on red blood cells and interfere with routine testing for clinically significant antibodies. People will show a panreactive antibody panel, including a positive auto-control, which tends to mask the presence of any clinically significant antibodies. Treatment of the antibody panel cells with dithiothreitol (DTT) and repeating testing will effectively negate the binding of daratumumab to CD38 on the red blood cell surface; however, DTT also inactivates/destroys many antigens on the red blood cell surface by disrupting disulfide bonds. The only antigen system affected that is associated with common, clinically significant antibodies is Kell, making crossmatch testing with K-negative RBCs a reasonable alternative when urgent transfusion is indicated.{{cite journal | vauthors = Chapuy CI, Nicholson RT, Aguad MD, Chapuy B, Laubach JP, Richardson PG, Doshi P, Kaufman RM | title = Resolving the daratumumab interference with blood compatibility testing | journal = Transfusion | volume = 55 | issue = 6 Pt 2 | pages = 1545–1554 | date = June 2015 | pmid = 25764134 | doi = 10.1111/trf.13069 | doi-access = free }}

It is therefore advisable to do a baseline antibody screen and Rh & Kell phenotyping (type and screen) before starting the therapy. If antibody screen is negative, proceed with phenotype matched transfusions during therapy. If antibody screen is positive, give specific antigen negative blood. The incompatibility may persist for up to 6 months after stopping the medicine. Furthermore, blood transfusion centers should be routinely notified when sending such a sample.

Daratumumab can also interfere with flow cytometric evaluation of multiple myeloma, causing an apparent lack of plasma cells.{{cite journal| vauthors = Perincheri S, Torres R, Tormey CA, Smith BR, Rinder HM, Siddon AJ |date=2 December 2016|title=Daratumumab Interferes with Flow Cytometric Evaluation of Multiple Myeloma |journal=Blood |volume=128 |issue=22 |pages=5630 |issn=0006-4971 |doi=10.1182/blood.V128.22.5630.5630 |doi-access=}}

Daratumumab is an IgG1k monoclonal antibody directed against CD38. CD38 is overexpressed in multiple myeloma cells. Daratumumab binds to a different CD38 epitope amino-acid sequence than does the anti-CD38 monoclonal antibody isatuximab.{{cite journal | vauthors = Dhillon S | title = Isatuximab: First Approval | journal = Drugs | volume = 80 | issue = 9 | pages = 905–912 | date = June 2020 | pmid = 32347476 | doi = 10.1007/s40265-020-01311-1 | s2cid = 216597315 }} Daratumumab binds to CD38, causing cells to apoptose via antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, inhibition of mitochondrial transfer or antibody-dependent cellular phagocytosis.{{cite journal | vauthors = Roccatello D, Fenoglio R, Sciascia S, Naretto C, Rossi D, Ferro M, Barreca A, Malavasi F, Baldovino S | title = CD38 and Anti-CD38 Monoclonal Antibodies in AL Amyloidosis: Targeting Plasma Cells and beyond | journal = International Journal of Molecular Sciences | volume = 21 | issue = 11 | pages = 4129 | date = June 2020 | pmid = 32531894 | pmc = 7312896 | doi = 10.3390/ijms21114129 | doi-access = free }}{{cite web|url=https://adisinsight.springer.com/drugs/800022454|title=Daratumumab - Janssen Biotech - AdisInsight|website=adisinsight.springer.com}}{{cite journal | vauthors = Mistry JJ, Moore JA, Kumar P, Marlein CR, Hellmich C, Pillinger G, Jibril A, Di Palma F, Collins A, Bowles KM, Rushworth SA | title = Daratumumab inhibits acute myeloid leukaemia metabolic capacity by blocking mitochondrial transfer from mesenchymal stromal cells | journal = Haematologica | volume = 106 | issue = 2 | pages = 589–592 | date = February 2021 | pmid = 32193250 | pmc = 7849566 | doi = 10.3324/haematol.2019.242974 | doi-access = free }}

These effects are dependent upon fragment crystallizable region immune effector mechanisms. Antibody-dependent cellular cytotoxicity is by means of natural killer cells.{{cite journal | vauthors = Nooka AK, Kaufman JL, Hofmeister CC, Joseph NS, Heffner TL, Gupta VA, Sullivan HC, Neish AS, Dhodapkar MV, Lonial S | title = Daratumumab in multiple myeloma | journal = Cancer | volume = 125 | issue = 14 | pages = 2364–2382 | date = July 2019 | pmid = 30951198 | doi = 10.1002/cncr.32065 | doi-access = free }}

Unlike isatuximab which causes apoptosis directly, daratumumab only induces apoptosis indirectly.{{cite journal | vauthors = Martin TG, Corzo K, Chiron M, Velde HV, Abbadessa G, Campana F, Solanki M, Meng R, Lee H, Wiederschain D, Zhu C, Rak A, Anderson KC | title = Therapeutic Opportunities with Pharmacological Inhibition of CD38 with Isatuximab | journal = Cells | volume = 8 | issue = 12 | pages = 1522 | date = November 2019 | pmid = 31779273 | pmc = 6953105 | doi = 10.3390/cells8121522 | doi-access = free }}

Multiple myeloma cells with higher levels of CD38 show greater daratumumab-mediated cell lysis than cells with low CD38 expression.{{cite journal | vauthors = Franssen LE, Stege CA, Zweegman S, van de Donk NW, Nijhof IS | title = Resistance Mechanisms Towards CD38-Directed Antibody Therapy in Multiple Myeloma | journal = Journal of Clinical Medicine | volume = 9 | issue = 4 | pages = 1195 | date = April 2020 | pmid = 32331242 | pmc = 7230744 | doi = 10.3390/jcm9041195 | doi-access = free }} CD38 enzyme results in the formation of the immunosuppressive substance adenosine, so eliminating CD38-containing cells increases the ability of the immune system to eliminate cancer.{{cite journal | vauthors = Konen JM, Fradette JJ, Gibbons DL | title = The Good, the Bad and the Unknown of CD38 in the Metabolic Microenvironment and Immune Cell Functionality of Solid Tumors | journal = Cells | volume = 9 | issue = 1 | pages = 52 | date = December 2019 | pmid = 31878283 | pmc = 7016859 | doi = 10.3390/cells9010052 | doi-access = free }}

In 2023, the Institute for Clinical and Economic Review (ICER) identified Darzalex (daratumumab) as one of five high-expenditure drugs that experienced significant net price increases without new clinical evidence to justify the hikes. Specifically, Darzalex's wholesale acquisition cost rose by approximately 7.6%, leading to an additional $190 million in costs to U.S. payers.{{Cite web |title=Institute for Clinical and Economic Review Announces Most Significant Drug-Price Hikes Unsupported by New Clinical Evidence in US |url=https://icer.org/news-insights/press-releases/icer-announces-most-significant-drug-price-hikes-unsupported-by-new-clinical-evidence-in-us/?mkt_tok=NjM4LVBYUi0zMTgAAAGYMxe5Fv3mzhJbiVnr0V4g2FUAcS3PgZOZSYRvQcW3_VFPXIet0TCD7bWAyVVeW2Q62e3AynO8rDpP8sIoIbs_qux8kQcMBBD4cDSe3Q |access-date=2025-02-06 |website=ICER |language=en-US}}

Encouraging preliminary results were reported in June 2012, from a Phase I/II clinical trial in relapsed multiple myeloma participants.{{cite news |url=http://www.medpagetoday.com/HematologyOncology/Myeloma/33115 |title=ASCO: Drug Shows Promise in Myeloma | publisher=MedPage Today}} Updated trial results presented in December 2012, indicate daratumumab is continuing to show promising single-agent anti-myeloma activity.{{cite news|title=Daratumumab Continues To Show Promise For Relapsed/Refractory Myeloma Patients (ASH 2012) | url=http://www.myelomabeacon.com/news/2013/01/09/daratumumab-for-relapsed-refractory-myeloma-patients-ash-2012/ | publisher=The Myeloma Beacon | access-date=31 January 2013}} A 2015 study compared monotherapy 8 and 16 mg/kg at monthly to weekly intervals.

Daratumumab was given priority review status by the US Food and Drug Administration (FDA) for multiple myeloma as a combination therapy (second line).

Daratumumab phase III trials for multiple myeloma show great promise in combination therapy with lenalidomide and dexamethasone,{{cite journal | vauthors = Dimopoulos MA, Oriol A, Nahi H, San-Miguel J, Bahlis NJ, Usmani SZ, Rabin N, Orlowski RZ, Komarnicki M, Suzuki K, Plesner T, Yoon SS, Ben Yehuda D, Richardson PG, Goldschmidt H, Reece D, Lisby S, Khokhar NZ, O'Rourke L, Chiu C, Qin X, Guckert M, Ahmadi T, Moreau P | title = Daratumumab, Lenalidomide, and Dexamethasone for Multiple Myeloma | journal = The New England Journal of Medicine | volume = 375 | issue = 14 | pages = 1319–1331 | date = October 2016 | pmid = 27705267 | doi = 10.1056/NEJMoa1607751 | doi-access = free }} as well as with bortezomib and dexamethasone.{{cite journal | vauthors = Palumbo A, Chanan-Khan A, Weisel K, Nooka AK, Masszi T, Beksac M, Spicka I, Hungria V, Munder M, Mateos MV, Mark TM, Qi M, Schecter J, Amin H, Qin X, Deraedt W, Ahmadi T, Spencer A, Sonneveld P | title = Daratumumab, Bortezomib, and Dexamethasone for Multiple Myeloma | journal = The New England Journal of Medicine | volume = 375 | issue = 8 | pages = 754–766 | date = August 2016 | pmid = 27557302 | doi = 10.1056/NEJMoa1606038 | doi-access = free | hdl = 11343/240283 | hdl-access = free }}{{update inline|date=August 2020}}

In November 2015, the US Food and Drug Administration (FDA) approved daratumumab for treatment of multiple myeloma in people who had received at least three prior therapies.{{cite web|url=http://www.medscape.com/viewarticle/854548|title=Daratumumab Approved for Multiple Myeloma in US|website=Medscape}}{{cite web |url=https://www.centerwatch.com/drug-information/fda-approved-drugs/drug/100115/darzalex-daratumumab |title=Darzalex New FDA Drug Approval |website=CenterWatch |access-date=4 June 2019 |archive-date=5 August 2019 |archive-url=https://web.archive.org/web/20190805014559/https://www.centerwatch.com/drug-information/fda-approved-drugs/drug/100115/darzalex-daratumumab |url-status=dead }} In May 2016 daratumumab was also conditionally approved by the European Medicines Agency for treatment of multiple myeloma.{{Cite press release|url=http://www.businesswire.com/news/home/20160523005679/en/Janssen%25E2%2580%2599s-Single-Agent-DARZALEX%25C2%25AE-daratumumab-Approved-European-Commission|title=Janssen's Single-Agent Darzalex (daratumumab) Approved by European Commission for Treatment of Multiple Myeloma (MM) |date=23 May 2016 |via=Business Wire|access-date=23 May 2016}}

In November 2016, the FDA approved daratumumab in combination with lenalidomide or bortezomib and dexamethasone for the treatment of people with multiple myeloma who have received at least one prior therapy.{{cite web|url=https://www.fda.gov/drugs/resources-information-approved-drugs/daratumumab-darzalex|title=Daratumumab (Darzalex)|date=9 February 2019|website=U.S. Food and Drug Administration (FDA)}}

The European Commission granted a marketing authorisation in May 2016.{{cite web |url=https://www.ema.europa.eu/en/documents/overview/darzalex-epar-medicine-overview_en.pdf |title=An overview of Darzalex and why it is authorised in the EU |date= 2018|website=www.ema.europa.eu |access-date=4 June 2019}}

{{Reflist}}

{{Targeted cancer therapeutic agents}}

{{Monoclonals for tumors}}

{{Portal bar | Medicine}}

{{Authority control}}

Category:Antineoplastic and immunomodulating drugs

Category:Drugs developed by Johnson & Johnson

Category:Orphan drugs

Category:Monoclonal antibodies for tumors