Introduction:
Aggressive neoplastic conditions are a common cause of mortality in individuals suffering from cancer. One such aggressive malignancy with hematological origin is multiple myeloma. New drugs emerge every day to combat the discomfort caused by such cancerous conditions and cause complete death of the neoplastic cells. Among the various medicines, Daratumumab is developing as adjunctive therapy for individuals with multiple myeloma.
What Is Multiple Myeloma?
Multiple myeloma is a cancerous condition of hematologic origin with abnormal formation and proliferation of plasma cells. As a result of excessive accumulation of plasma cells in the bone marrow, normal blood cell production gets disrupted. This can present clinically as anemia (due to reduced erythrocytes), intense bone pain, particularly in the spine and chest, hypercalcemia (excessive circulating calcium levels in the blood), and kidney disorder. To treat this condition, several medications and therapies are prescribed, as multiple myeloma is a heterogeneous condition with varied clinical presentations.
What Is Daratumumab?
Daratumumab is a monoclonal antibody that is specifically given to target the CD38 protein that is present on the cell surface of cancerous plasma cells. This is a targeted action of Daratumumab that helps destroy malignant plasma cells and leaves behind normal cells. By binding to malignant plasma cells and inhibiting the action of CD38 protein, there is apoptosis (cell death) directly or indirectly through antibody and complement-mediated cytotoxicity. As a result of such comprehensive actions, all the malignant neoplastic cells undergo destruction. The Food and Drug Administration (FDA) approved Daratumumab usage in 2015.
Daratumumab is given either as a combined drug with Lenalidomide, Bortezomib, and Dexamethasone or as a monotherapy when individuals do not show sufficient response to proteasome inhibitors and other immunomodulators.
Dosage and Route of Administration:
Daratumumab is given through a parenteral (intravenous) route. The dosage of Daratumumab is 16 milligrams (mg) per kilogram of the patient's body weight. This will be administered as follows:
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For the first eight weeks, a weekly once dosage will be administered.
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For the weeks nine to 24, one dose will be given in two weeks.
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In the subsequent weeks, one dose will be given in four weeks until there is disease progression.
Before administering Daratumumab, corticosteroids (Methylprednisolone), antipyretics (Acetaminophen 600 mg), and antihistamines (Diphenhydramine 50 mg) will be given.
Daratumumab is available in a single vial of 100 mg/5 mL and 400 mg/20 mL doses. This should be diluted with 0.9 percent sodium chloride before administration. Also, Daratumumab is administered intravenously over a specified period, typically ranging from several hours for the first infusion to shorter durations for subsequent infusions.
Pharmacokinetics:
Following intravenous administration, Daratumumab undergoes distribution into the extracellular fluid compartments, including the blood and interstitial fluid. Its clearance primarily occurs via catabolism and elimination mediated by the reticuloendothelial system, with a long half-life of approximately 14 to 21 days. The pharmacokinetics of Daratumumab are linear and dose-proportional within the therapeutic dose range, showing time-independent clearance and volume of distribution. Additionally, Daratumumab demonstrates target-mediated drug disposition, with CD38 expression levels influencing its distribution and elimination.
Pharmacodynamics:
Daratumumab exerts its pharmacodynamic effects primarily through several mechanisms, including direct induction of apoptosis in CD38-expressing multiple myeloma cells, antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and antibody-dependent cellular phagocytosis (ADCP). By binding to CD38, Daratumumab triggers signaling cascades leading to programmed cell death, inhibiting the proliferation and survival of malignant plasma cells. Furthermore, Daratumumab-mediated ADCC and ADCP involve attracting and activating immune cells, such as natural killer cells, macrophages, and neutrophils, to engage and eliminate CD38-expressing target cells. These pharmacodynamic mechanisms collectively contribute to the potent anti-myeloma activity of Daratumumab, leading to tumor cell lysis, clearance, and, ultimately, therapeutic efficacy in patients with multiple myeloma.
What Are the Adverse Effects of Daratumumab?
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Daratumumab is known to cause infusion-site reactions, and the administration of this drug is stopped immediately if the severity increases. Such reactions are categorized into four grades. Depending on the grade of the infusion-site reaction, the administration rate will be lowered or completely discontinued in advanced cases. To prevent these reactions, post-administration medicines like corticosteroids will be given through oral or parenteral routes.
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All the blood cell count will be reduced after administering Daratumumab. This occurs especially with white blood cells (neutrophils) and platelets, thus resulting in neutropenia and thrombocytopenia.
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Patients are highly susceptible to developing infectious diseases after administration of Daratumumab. So, post-administration antibiotics are given. To prevent the recurrence of Herpes infection, vaccines will be administered after the first dose of Daratumumab.
Other Minor Side Effects Noted Are:
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Diarrhea.
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Nausea.
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Vomiting.
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Fatigue.
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Upper respiratory tract infection.
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Pneumonia.
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Breathing difficulty.
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Chest pain.
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Fever.
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Chills.
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Rigor.
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Night sweats.
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Muscular spasms.
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Neuropathy.
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Dizziness.
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Confusion.
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Cough.
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Rashes.
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Pruritus.
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Arthralgia.
Precautions and Warnings:
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As Daratumumab can cause a significant reduction in blood count, a complete blood count and other hematological investigations should be done to examine the cytopenias and their extent.
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Infusion site reactions should be assessed immediately as they can be life-threatening in advanced cases.
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Daratumumab may cause fetal harm. So, this drug is not given to pregnant ladies.
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Daratumumab binds to CD38, which can interfere with certain laboratory tests that rely on CD38 expression. This could result in inaccurate positive or negative outcomes, particularly in tests assessing blood compatibility and immunophenotyping. Alternative testing methods should be considered when Daratumumab interference is suspected.
Is Daratumumab Clinically Effective?
Clinical trials evaluating Daratumumab in both newly diagnosed and relapsed/refractory multiple myeloma have demonstrated remarkable efficacy. In newly diagnosed patients, Daratumumab-based regimens have significantly improved overall response rates, progression-free survival, and minimal residual disease negativity, paving the way for deeper and more durable responses. In the relapsed/refractory setting, Daratumumab has proven to be particularly effective, both as a single agent and in combination with other anti-myeloma therapies. Studies have shown impressive response rates and prolonged survival outcomes in heavily pretreated patients for multiple myeloma. Furthermore, Daratumumab has been successfully integrated into combination regimens with other anti-myeloma agents, such as proteasome inhibitors and immunomodulatory drugs, resulting in synergistic effects and enhanced therapeutic efficacy.
Conclusion:
Daratumumab has undoubtedly revolutionized the management of multiple myeloma, offering unprecedented efficacy and tolerability across a spectrum of disease states. Its approval marked a significant milestone in the field of oncology, providing new hope for patients and clinicians alike.
