Daratumumab

Last updated

Daratumumab
Daratumumab CD38 7DHA.png
Fab fragment of daratumumab (teal/green) binding CD38 (pale pink). From PDB entry 7DHA
Monoclonal antibody
Type Whole antibody
Source Human
Target CD38
Clinical data
Trade names Darzalex, Darzalex SC
AHFS/Drugs.com Monograph
MedlinePlus a616002
License data
Pregnancy
category
  • AU:C
Routes of
administration 		Intravenous, subcutaneous
ATC code
Legal status
Legal status
Identifiers
CAS Number
DrugBank
ChemSpider
  • none
UNII
KEGG
ChEMBL
Chemical and physical data
Formula C6466H9996N1724O2010S42
Molar mass 145391.67 g·mol−1
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Daratumumab, sold under the brand name Darzalex among others, is an anti-cancer monoclonal antibody medication. It binds to CD38, [7] which is overexpressed in multiple myeloma cells. [8] Daratumumab was originally developed by Genmab, but it is now being jointly developed by Genmab along with the Johnson & Johnson subsidiary Janssen Biotech, which acquired worldwide commercialization rights to the drug from Genmab. [9]

Contents

Daratumumab was granted breakthrough therapy drug status in 2013, for multiple myeloma. It was granted orphan drug status for multiple myeloma, diffuse large B cell lymphoma, follicular lymphoma, and mantle cell lymphoma. [10]

It is available in combination with hyaluronidase as daratumumab/hyaluronidase (brand name Darzalex Faspro). [11] [12]

Medical uses

In May 2018, the US Food and Drug Administration (FDA) approved daratumumab for use in combination with bortezomib (also termed Velcade), melphalan and prednisone to include the treatment of people with newly diagnosed multiple myeloma who were ineligible for autologous stem cell transplant. [13]

In the European Union it is indicated as monotherapy for the treatment of adults with relapsed and refractory multiple myeloma, [14] whose prior therapy included a proteasome inhibitor and an immunomodulatory agent and who have demonstrated disease progression on the last therapy. [15]

The recently completed ALCYONE 7-year study of 350 multiple myeloma patients treated with the standard Velcade, melphalan, and prednisone, i.e., VMP regimen versus 356 multiple myeloma patients treated with VMP plus daratumumab, i.e., D-VMP regimen. All patients were ineligible for autologous stem cell transplant. During the 9 cycles of treating patients with VMP, D-VMP patients received intravenous injections of daratumumab (16 mg/kilogram body once weekly during cycle 1, once every 3 weeks during cycles 2-9, and once every 4 weeks thereafter until a VMP or D-VMP patient developed unacceptable toxicity or disease progression or when the study was ended after an average of 86.7 months. The median overall survival time (i.e., time when 50% of the patients were still alive) was 83.0 months for D-MVP patients compared to 53.6 months for VMP patients (p<000.1). There were no significant differences in the adverse responses of the two groups with respect to the development of treatment-related neutropenia, thrombocytopenia, anemia, or other serious adverse drug-related responses. D-VMP-treated patients often had minimal residual disease whereas VMP-treated patients more often had more extensive disease, i.e., D-VMP patients had less disease as defined by having fewer malignant plasma cells in their bone marrow than VMP patients. [16] The MIAI study published in 2022 reported ed that the addition of daratumumab to treating autologous stem cell transplant-ineligible multiple myeloma patients treated with lenalidomide plus dexamethasone significantly improved their responses. [16] [17] .

Results of the recently completed ALCYONE 7-year study were published in 2025. This study compared 350 newly diagnosed multiple myeloma patients treated with the standard Velcade, melphalan, and prednisone, i.e., VMP, regimen versus 356 newly diagnosed multiple myeloma patients treated with VMP plus Darzalex, i.e., D-VMP, regimen. All patients were ineligible for autologous stem cell transplantation. During the 9 cycles of treating patients with VMP, D-VMP patients also received intravenous injections of Darzalex (16 mg/kilogram body weight) once weekly in cycle 1, once every 3 weeks in cycles 2-9, and once every 4 weeks thereafter until a patient developed unacceptable toxicity or disease progression or when the study was ended after an average of 86.7 months. The median overall survival time (i.e., time when 50% of the patients were still alive) was 83.0 months for D-MVP patients compared to 53.6 months for VMP patients (p<000.1). There were no significant differences in the adverse responses of the two groups with respect to their development of treatment-related neutropenia, thrombocytopenia, anemia, or other serious adverse drug-related responses. D-VMP-treated patients often had minimal residual disease whereas VMP-treated patients more often had more extensive disease, i.e., D-VMP patients had less disease as defined by having fewer malignant plasma cells in their bone marrow than VMP patients. [16] In another study, the MIAI study published in 2022 reported similar findings, e.g., the addition of Darzalex to treating autologous stem cell transplant-ineligible multiple myeloma patients with lenalidomide plus dexamethasone significantly improved their responses. [16] [17] .

Side effects

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). [18] Daratumumab frequently causes human cytomegalovirus (CMV) reactivation by an unknown mechanism. [19] Injection related reactions (inflammation-like) are also common. [20]

Interactions

With blood compatibility testing

Daratumumab can also bind to CD38 present on red blood cells and interfere with routine testing for clinically significant antibodies. People will show a panel-reactive antibody response, 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. [21] 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.

With flow cytometry testing

Daratumumab can also interfere with flow cytometric evaluation of multiple myeloma, causing an apparent lack of plasma cells. [22]

Pharmacology

Mechanism of action

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. [23] 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. [24] [25] [26] [27]

These effects are dependent upon fragment crystallizable region immune effector mechanisms. [28] Antibody-dependent cellular cytotoxicity is by means of natural killer cells. [29]

Unlike isatuximab which causes apoptosis directly, daratumumab only induces apoptosis indirectly. [28]

Multiple myeloma cells with higher levels of CD38 show greater daratumumab-mediated cell lysis than cells with low CD38 expression. [30] 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. [24]

Economics

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. [31]

History

Encouraging preliminary results were reported in June 2012, from a Phase I/II clinical trial in relapsed multiple myeloma participants. [32] Updated trial results presented in December 2012, indicate daratumumab is continuing to show promising single-agent anti-myeloma activity. [33] A 2015 study compared monotherapy 8 and 16 mg/kg at monthly to weekly intervals. [8]

Daratumumab was given priority review status by the US Food and Drug Administration (FDA) for multiple myeloma as a combination therapy (second line). [26]

Daratumumab phase III trials for multiple myeloma show great promise in combination therapy with lenalidomide and dexamethasone, [34] as well as with bortezomib and dexamethasone. [35] [ needs update ]

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. [36] [37] In May 2016 daratumumab was also conditionally approved by the European Medicines Agency for treatment of multiple myeloma. [38]

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. [39]

The European Commission granted a marketing authorization in May 2016. [40]

References

  1. ↑ "Prescription medicines: registration of new chemical entities in Australia, 2017". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 9 April 2023.
  2. ↑ "Prescription medicines and biologicals: TGA annual summary 2017". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 31 March 2024.
  3. ↑ "Health Canada New Drug Authorizations: 2016 Highlights". Health Canada . 14 March 2017. Retrieved 7 April 2024.
  4. ↑ "Darzalex SC Product information". Health Canada . 12 August 2020. Retrieved 24 June 2024.
  5. ↑ "Darzalex- daratumumab injection, solution, concentrate Darzalex IV- daratumumab injection, solution, concentrate". DailyMed. Retrieved 18 December 2021.
  6. ↑ "Darzalex EPAR". European Medicines Agency (EMA). 17 July 2013. Retrieved 21 September 2024.
  7. ↑ World Health Organization (2009). "International Nonproprietary Names for Pharmaceutical Substances (INN). Proposed INN: List 101" (PDF). WHO Drug Information. 23 (2). Archived from the original (PDF) on 17 December 2010.
  8. 1 2 Lokhorst HM, Plesner T, Laubach JP, Nahi H, Gimsing P, Hansson M, et al. (September 2015). "Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma". The New England Journal of Medicine. 373 (13): 1207–1219. doi: 10.1056/NEJMoa1506348 . hdl: 1874/331934 . PMID   26308596.
  9. ↑ "Janssen Biotech Announces Global License and Development Agreement for Investigational Anti-Cancer Agent Daratumumab". Janssen Biotech. Retrieved 31 January 2013.
  10. ↑ "Daratumumab Receives Breakthrough Therapy Designation from US Food and Drug Administration". Genmab A/S. 1 May 2013. Archived from the original on 13 January 2017. Retrieved 10 January 2017.
  11. ↑ "FDA approves daratumumab and hyaluronidase-fihj for multiple myeloma". U.S. Food and Drug Administration (FDA) (Press release). 1 May 2020. Archived from the original on 1 September 2020. Retrieved 1 May 2020.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  12. ↑ "Genmab Announces U.S. FDA Approval of Subcutaneous Formulation of Daratumumab, Darzalex Faspro (daratumumab and hyaluronidase-fihj), for the Treatment of Patients with Multiple Myeloma" (Press release). Genmab. 1 May 2020. Retrieved 1 May 2020– via GlobeNewswire.
  13. ↑ "FDA approves Darzalex for newly diagnosed, transplant-ineligible multiple myeloma". Healio. Retrieved 8 May 2018.
  14. ↑ Vincent L, Gras L, Ceballos P, Finke J, Passweg J, Harel S, et al. (March 2022). "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" (PDF). Bone Marrow Transplantation. 57 (3): 499–501. doi:10.1038/s41409-021-01560-y. PMID   35013536. S2CID   245861546.
  15. ↑ "SUMMARY OF PRODUCT CHARACTERISTICS" (PDF). European Medicines Agency (EMA). Retrieved 4 June 2019.
  16. 1 2 3 4 Mateos MV, San-Miguel J, Cavo M, Suzuki K, Jakubowiak A, Knop S, et al. (May 2025). "Bortezomib, melphalan, and prednisone with or without daratumumab in transplant-ineligible patients with newly diagnosed multiple myeloma (ALCYONE): final analysis of an open-label, randomised, multicentre, phase 3 trial". The Lancet. Oncology. 26 (5): 596–608. doi:10.1016/S1470-2045(25)00018-X. PMID   40220771.
  17. 1 2 San-Miguel J, Avet-Loiseau H, Paiva B, Kumar S, Dimopoulos MA, Facon T, et al. (January 2022). "Sustained minimal residual disease negativity in newly diagnosed multiple myeloma and the impact of daratumumab in MAIA and ALCYONE". Blood. 139 (4): 492–501. doi:10.1182/blood.2020010439. PMC   8796656 . PMID   34269818.
  18. ↑ Nahi H, Chrobok M, Gran C, Lund J, Gruber A, Gahrton G, et al. (2019). "Infectious complications and NK cell depletion following daratumumab treatment of Multiple Myeloma". PLOS ONE. 14 (2) e0211927. Bibcode:2019PLoSO..1411927N. doi: 10.1371/journal.pone.0211927 . PMC   6374018 . PMID   30759167.
  19. ↑ Nakagawa R, Onishi Y, Kawajiri A, Onodera K, Furukawa E, Sano S, et al. (August 2019). "Preemptive therapy for cytomegalovirus reactivation after daratumumab-containing treatment in patients with relapsed and refractory multiple myeloma". Annals of Hematology. 98 (8): 1999–2001. doi:10.1007/s00277-019-03645-7. PMID   30824957. S2CID   71146150.
  20. ↑ Jain A, Ramasamy K (September 2020). "Evolving Role of Daratumumab: From Backbencher to Frontline Agent". Clinical Lymphoma, Myeloma & Leukemia. 20 (9): 572–587. doi:10.1016/j.clml.2020.03.010. PMID   32331971. S2CID   216131042.
  21. ↑ Chapuy CI, Nicholson RT, Aguad MD, Chapuy B, Laubach JP, Richardson PG, et al. (June 2015). "Resolving the daratumumab interference with blood compatibility testing". Transfusion. 55 (6 Pt 2): 1545–1554. doi: 10.1111/trf.13069 . PMID   25764134.
  22. ↑ Perincheri S, Torres R, Tormey CA, Smith BR, Rinder HM, Siddon AJ (2 December 2016). "Daratumumab Interferes with Flow Cytometric Evaluation of Multiple Myeloma". Blood. 128 (22): 5630. doi:10.1182/blood.V128.22.5630.5630. ISSN   0006-4971.
  23. ↑ Dhillon S (June 2020). "Isatuximab: First Approval". Drugs. 80 (9): 905–912. doi:10.1007/s40265-020-01311-1. PMID   32347476. S2CID   216597315.
  24. 1 2 Konen JM, Fradette JJ, Gibbons DL (December 2019). "The Good, the Bad and the Unknown of CD38 in the Metabolic Microenvironment and Immune Cell Functionality of Solid Tumors". Cells. 9 (1): 52. doi: 10.3390/cells9010052 . PMC   7016859 . PMID   31878283.
  25. ↑ Roccatello D, Fenoglio R, Sciascia S, Naretto C, Rossi D, Ferro M, et al. (June 2020). "CD38 and Anti-CD38 Monoclonal Antibodies in AL Amyloidosis: Targeting Plasma Cells and beyond". International Journal of Molecular Sciences. 21 (11): 4129. doi: 10.3390/ijms21114129 . PMC   7312896 . PMID   32531894.
  26. 1 2 "Daratumumab - Janssen Biotech - AdisInsight". adisinsight.springer.com.
  27. ↑ Mistry JJ, Moore JA, Kumar P, Marlein CR, Hellmich C, Pillinger G, et al. (February 2021). "Daratumumab inhibits acute myeloid leukaemia metabolic capacity by blocking mitochondrial transfer from mesenchymal stromal cells". Haematologica. 106 (2): 589–592. doi: 10.3324/haematol.2019.242974 . PMC   7849566 . PMID   32193250.
  28. 1 2 Martin TG, Corzo K, Chiron M, Velde HV, Abbadessa G, Campana F, et al. (November 2019). "Therapeutic Opportunities with Pharmacological Inhibition of CD38 with Isatuximab". Cells. 8 (12): 1522. doi: 10.3390/cells8121522 . PMC   6953105 . PMID   31779273.
  29. ↑ Nooka AK, Kaufman JL, Hofmeister CC, Joseph NS, Heffner TL, Gupta VA, et al. (July 2019). "Daratumumab in multiple myeloma". Cancer. 125 (14): 2364–2382. doi: 10.1002/cncr.32065 . PMID   30951198.
  30. ↑ Franssen LE, Stege CA, Zweegman S, van de Donk NW, Nijhof IS (April 2020). "Resistance Mechanisms Towards CD38-Directed Antibody Therapy in Multiple Myeloma". Journal of Clinical Medicine. 9 (4): 1195. doi: 10.3390/jcm9041195 . PMC   7230744 . PMID   32331242.
  31. ↑ "Institute for Clinical and Economic Review Announces Most Significant Drug-Price Hikes Unsupported by New Clinical Evidence in US". ICER. Retrieved 6 February 2025.
  32. ↑ "ASCO: Drug Shows Promise in Myeloma". MedPage Today.
  33. ↑ "Daratumumab Continues To Show Promise For Relapsed/Refractory Myeloma Patients (ASH 2012)". The Myeloma Beacon. Retrieved 31 January 2013.
  34. ↑ Dimopoulos MA, Oriol A, Nahi H, San-Miguel J, Bahlis NJ, Usmani SZ, et al. (October 2016). "Daratumumab, Lenalidomide, and Dexamethasone for Multiple Myeloma". The New England Journal of Medicine. 375 (14): 1319–1331. doi: 10.1056/NEJMoa1607751 . PMID   27705267.
  35. ↑ Palumbo A, Chanan-Khan A, Weisel K, Nooka AK, Masszi T, Beksac M, et al. (August 2016). "Daratumumab, Bortezomib, and Dexamethasone for Multiple Myeloma". The New England Journal of Medicine. 375 (8): 754–766. doi: 10.1056/NEJMoa1606038 . hdl: 11343/240283 . PMID   27557302.
  36. ↑ "Daratumumab Approved for Multiple Myeloma in US". Medscape.
  37. ↑ "Darzalex New FDA Drug Approval". CenterWatch. Archived from the original on 5 August 2019. Retrieved 4 June 2019.
  38. ↑ "Janssen's Single-Agent Darzalex (daratumumab) Approved by European Commission for Treatment of Multiple Myeloma (MM)" (Press release). 23 May 2016. Retrieved 23 May 2016– via Business Wire.
  39. ↑ "Daratumumab (Darzalex)". U.S. Food and Drug Administration (FDA). 9 February 2019.
  40. ↑ "An overview of Darzalex and why it is authorised in the EU" (PDF). European Medicines Agency (EMA). 2018. Retrieved 4 June 2019.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.