DARZALEX (Daratumumab)

What Is DARZALEX and What Is It Used For?

Quick Answer: DARZALEX (daratumumab) is a monoclonal antibody medicine used to treat multiple myeloma, smoldering multiple myeloma, and AL amyloidosis in adults. It works by targeting CD38 on cancer cells so the immune system can destroy them.

DARZALEX contains the active substance daratumumab, which belongs to a class of medicines known as monoclonal antibodies. Monoclonal antibodies are laboratory-engineered proteins designed to recognize and bind to specific targets on cells in the body. Daratumumab has been designed to bind to a protein called CD38, which is found at high levels on the surface of multiple myeloma cells and certain other abnormal blood cells. By attaching to CD38, daratumumab triggers the body's immune system to attack and destroy these cancer cells through several complementary mechanisms.

The primary indication for DARZALEX is the treatment of multiple myeloma, a cancer that develops in the bone marrow when a type of white blood cell called a plasma cell becomes malignant. These abnormal plasma cells multiply uncontrollably, crowding out normal blood-forming cells and producing excessive amounts of a single type of antibody protein (M-protein). This leads to bone destruction, kidney damage, impaired immunity, and anemia. Multiple myeloma accounts for approximately 10% of all hematologic malignancies, with an estimated 176,000 new cases diagnosed globally each year according to the World Health Organization.

DARZALEX has fundamentally transformed the treatment landscape for multiple myeloma since its initial approval. It can be used as monotherapy in patients who have received at least three prior lines of therapy, or more commonly in combination with other anti-myeloma agents such as lenalidomide, pomalidomide, bortezomib, carfilzomib, thalidomide, or dexamethasone. The specific combination regimen depends on whether the patient is newly diagnosed or has relapsed/refractory disease, their fitness for transplantation, and prior treatment history. The National Comprehensive Cancer Network (NCCN) and European Society for Medical Oncology (ESMO) guidelines now include daratumumab-containing regimens as preferred first-line and subsequent-line treatment options.

Beyond multiple myeloma, DARZALEX is approved for the treatment of adults with smoldering (asymptomatic) multiple myeloma, a precursor condition that carries a risk of progression to active myeloma. Clinical trials have demonstrated that early intervention with daratumumab in high-risk smoldering myeloma can significantly delay or prevent progression to symptomatic disease. Additionally, DARZALEX has received approval for the treatment of AL amyloidosis (light-chain amyloidosis), a rare and serious condition in which abnormal plasma cells produce misfolded light-chain proteins that deposit as amyloid fibrils in vital organs including the heart, kidneys, liver, and nervous system, progressively impairing their function.

Mechanism of Action

Daratumumab exerts its anti-tumor activity through multiple immune-mediated mechanisms, which collectively contribute to its efficacy. CD38, the target of daratumumab, is a transmembrane glycoprotein that functions as both a receptor and an ectoenzyme involved in calcium signaling and cell adhesion. It is expressed at particularly high levels on multiple myeloma cells, making it an ideal therapeutic target.

The key mechanisms of action include: complement-dependent cytotoxicity (CDC), where binding of daratumumab to CD38 activates the complement cascade, forming a membrane attack complex that directly lyses tumor cells; antibody-dependent cell-mediated cytotoxicity (ADCC), which recruits natural killer (NK) cells and other immune effector cells to kill the antibody-coated tumor cells; antibody-dependent cellular phagocytosis (ADCP), where macrophages engulf and destroy daratumumab-bound myeloma cells; and direct apoptosis triggered through Fc-mediated crosslinking of CD38 molecules. Beyond these direct anti-tumor effects, daratumumab has important immunomodulatory properties — it depletes CD38-positive immunosuppressive cells including regulatory T cells (Tregs), regulatory B cells (Bregs), and myeloid-derived suppressor cells (MDSCs), thereby enhancing the overall anti-tumor immune response.

What Should You Know Before Receiving DARZALEX?

Quick Answer: Do not receive DARZALEX if you are allergic to daratumumab or any of its ingredients. Inform your doctor about any history of hepatitis B, respiratory conditions, or pregnancy. Pre-medications are given before each injection to reduce the risk of reactions.

Contraindications

The primary contraindication for DARZALEX is known hypersensitivity (allergy) to daratumumab or to any of the excipients contained in the formulation. If you have experienced a severe allergic reaction to daratumumab in the past, you must not receive this medicine again. Signs of a severe allergic reaction can include swelling of the face, lips, mouth, tongue, or throat, difficulty swallowing or breathing, and widespread itchy rash (urticaria). If you are uncertain about any previous allergic reactions, discuss this with your treating physician before starting therapy.

The subcutaneous formulation of DARZALEX contains several excipients including recombinant human hyaluronidase (rHuPH20), L-histidine, L-histidine hydrochloride monohydrate, L-methionine, polysorbat 20, sorbitol, and water for injections. Patients with known allergies to any of these components should inform their healthcare team. In particular, patients with hereditary fructose intolerance should be aware that sorbitol is a source of fructose and should consult their doctor before receiving this medicine.

Warnings and Precautions

Several important precautions and monitoring requirements apply to patients receiving DARZALEX. Understanding these helps ensure the safest possible treatment experience. Discuss all of the following with your doctor or nurse before and during treatment:

• Infusion-related reactions: Although DARZALEX subcutaneous is given as an injection rather than an intravenous infusion, injection-related reactions can still occur, typically within 3–4 days after the injection. These are most common after the first dose and become less frequent with subsequent treatments. Symptoms can include chills, sore throat, cough, nausea, shortness of breath, chest discomfort, dizziness, and wheezing. To minimize these reactions, you will receive pre-medications (antihistamines, corticosteroids, and paracetamol/acetaminophen) before each injection and post-medications (corticosteroids) afterwards. In rare cases, a severe allergic reaction (anaphylaxis) can occur, presenting with facial swelling, difficulty breathing, or widespread urticaria — seek immediate medical attention if this occurs.
• Reduced blood cell counts: DARZALEX can decrease the number of white blood cells (which fight infection), red blood cells (which carry oxygen), and platelets (which help blood to clot). Your doctor will monitor your blood counts regularly with blood tests throughout treatment. Report any signs of infection (such as fever, chills, or sore throat), unusual bleeding or bruising, or persistent fatigue to your healthcare team promptly.
• Blood transfusion interference: Daratumumab binds to CD38 on red blood cells, which can cause a false positive indirect antiglobulin test (Coombs test). This may interfere with blood compatibility testing (cross-matching) required before a blood transfusion. Before you start DARZALEX, your blood bank will perform blood typing. Inform anyone performing blood tests that you are being treated with DARZALEX. This interference can persist for up to 6 months after the last dose.
• Hepatitis B virus (HBV) reactivation: DARZALEX can cause reactivation of hepatitis B virus in patients who are chronic carriers or have had prior HBV infection. Your doctor will screen you for HBV before starting treatment and will monitor you for signs of reactivation during and for some time after treatment. If you develop increasing fatigue or yellowing of the skin or eyes (jaundice), contact your doctor immediately.
• Respiratory conditions: If you have breathing problems such as asthma or chronic obstructive pulmonary disease (COPD), you will receive additional medications including inhaled bronchodilators and corticosteroids to help keep your airways open and reduce inflammation during treatment.

Pregnancy and Breastfeeding

If you are pregnant, think you may be pregnant, or are planning to become pregnant, consult your doctor before receiving DARZALEX. As a human IgG1 monoclonal antibody, daratumumab has the potential to cross the placental barrier and could affect the developing fetus. There are no adequate and well-controlled studies of daratumumab in pregnant women. Based on its mechanism of action (depleting CD38-positive cells), daratumumab could potentially cause harm to the unborn child, including depletion of fetal immune cells. Your doctor will weigh the potential benefits of treatment against the risks to your baby.

Women of childbearing potential should use effective contraception during treatment with DARZALEX and for at least 3 months after the last dose. If you become pregnant during treatment, inform your doctor immediately. The decision to breastfeed during DARZALEX treatment should be made in consultation with your doctor. It is not known whether daratumumab passes into breast milk, but human IgG antibodies are known to be excreted in breast milk. A risk to the breastfed infant cannot be excluded.

Driving and Operating Machinery

DARZALEX may cause fatigue (tiredness) that could affect your ability to drive or operate machinery. If you feel tired after receiving DARZALEX, you should not drive or use machines until you feel well enough to do so safely. This is particularly important in the days immediately following injection, when fatigue and other infusion-related symptoms are most likely to occur.

Children and Adolescents

DARZALEX should not be given to children or adolescents under 18 years of age. The safety and efficacy of daratumumab have not been established in the pediatric population, and there is currently no approved indication for use in this age group. Multiple myeloma is extremely rare in children and adolescents.

How Does DARZALEX Interact with Other Drugs?

Quick Answer: DARZALEX is commonly used in combination with other anti-myeloma drugs. Its most clinically significant interaction is with blood typing tests, where it can cause false positive results. Always inform your healthcare team about all medications you are taking.

As a monoclonal antibody, daratumumab has a different pharmacological profile from small-molecule drugs, and traditional drug-drug interactions mediated by cytochrome P450 enzymes are generally not a concern. However, several important interactions and considerations apply to patients receiving DARZALEX, particularly given that it is almost always used in combination with other medications.

Clinically Significant Interactions

Combination Therapy Considerations

DARZALEX is most frequently used in combination with other anti-myeloma drugs. Common combination partners include lenalidomide and dexamethasone (DRd), bortezomib and dexamethasone (DVd), pomalidomide and dexamethasone (DPd), carfilzomib and dexamethasone (DKd), and bortezomib, thalidomide, and dexamethasone (DVTd). When DARZALEX is used in combination, the side-effect profile reflects contributions from all agents in the regimen. For example, when combined with lenalidomide, the risk of neutropenia and infection may be higher than with either drug alone.

The interaction with blood typing is particularly important to understand. Daratumumab binds to CD38 molecules on the surface of red blood cells, causing a positive result on the indirect antiglobulin (Coombs) test. This does not indicate an actual transfusion incompatibility but can mask the detection of clinically significant alloantibodies. Blood banks should be informed of DARZALEX treatment so they can use methods such as dithiothreitol (DTT)-treated red blood cells or other techniques to mitigate this interference. This effect can persist for up to 6 months after the last dose of daratumumab.

Additionally, daratumumab can be detected as a monoclonal band on serum protein electrophoresis (SPEP) and immunofixation electrophoresis (IFE), as it is itself an IgG1 kappa monoclonal antibody. This can complicate the assessment of complete response in patients being monitored for disease status. Daratumumab-specific immunofixation reflex assay (DIRA) or mass spectrometry-based assays can help differentiate the therapeutic antibody from disease-related M-protein.

What Is the Correct Dosage of DARZALEX?

Quick Answer: The DARZALEX subcutaneous dose is a fixed 1,800 mg injection given under the skin of the abdomen over 3–5 minutes. It is given weekly for the first 8 weeks, then every 2 weeks for 16 weeks, then every 4 weeks thereafter. Your doctor may adjust the schedule based on the combination regimen used.

DARZALEX subcutaneous injection is administered exclusively by healthcare professionals in a hospital or clinic setting. The dosing is standardized as a flat dose — meaning all adult patients receive the same amount regardless of body weight — which simplifies preparation and administration compared to weight-based intravenous dosing.

Adults

Treatment with DARZALEX continues for as long as the disease does not worsen and the treatment remains tolerable. When DARZALEX is used in combination with other anti-myeloma medicines, your doctor may adjust the treatment intervals based on the specific combination regimen and treatment protocol being followed.

How the Injection Is Given

DARZALEX subcutaneous is a ready-to-use solution that does not require dilution. The healthcare professional will inject the full 15 mL volume under the skin of the abdomen using a thin needle. The injection is given over approximately 3 to 5 minutes. The medicine must not be injected into other body sites, and the injection site must be free of redness, bruising, tenderness, hardness, or scarring. If you experience pain during the injection, the healthcare professional may pause the injection or move to a different site on the opposite side of the abdomen.

Pre- and Post-Medications

Before each DARZALEX injection, you will receive pre-medications to reduce the risk of infusion-related reactions. These typically include an antihistamine, a corticosteroid (such as methylprednisolone or dexamethasone), and an antipyretic (such as paracetamol/acetaminophen). After each injection, you will receive a corticosteroid to further reduce the risk of delayed reactions. If you have breathing problems such as asthma or COPD, you will also receive inhaled bronchodilators and inhaled corticosteroids. You may also receive prophylactic antiviral medication to prevent herpes zoster (shingles) reactivation.

Children and Adolescents

DARZALEX is not indicated for use in children and adolescents under 18 years of age. Safety and efficacy have not been established in the pediatric population. Do not administer DARZALEX to individuals under 18 years.

Missed Dose

It is very important that you attend all scheduled treatment appointments to ensure that your treatment is effective. If you miss a scheduled dose of DARZALEX, contact your healthcare team to reschedule as soon as possible. Your doctor will advise you on the best timing for the rescheduled dose and any necessary adjustments to the subsequent dosing schedule.

Overdose

What Are the Side Effects of DARZALEX?

Quick Answer: The most common side effects include injection-site reactions, infusion-related reactions (chills, cough, nausea, shortness of breath), fatigue, fever, diarrhea, upper respiratory infections, pneumonia, and decreases in blood cell counts. Most infusion-related reactions occur during or after the first dose.

Like all medicines, DARZALEX can cause side effects, although not everybody gets them. Many of the side effects listed below may also be related to the underlying disease (multiple myeloma) or to other medicines used in combination with DARZALEX. Your healthcare team will monitor you carefully during and after each treatment to manage any side effects that arise.

Infusion-Related Reactions

Infusion-related reactions are among the most notable side effects of DARZALEX. These reactions are most likely to occur during or after the first injection and become less common with subsequent doses. If you have experienced an infusion-related reaction once, the likelihood of it recurring is reduced. However, delayed reactions may occur 3–4 days after the injection. Your doctor may decide to discontinue DARZALEX if you experience a severe reaction.

Injection-Site Reactions

Local skin reactions at or near the injection site are very common with subcutaneous DARZALEX. These may include redness, itching, swelling, pain, bruising, rash, or bleeding at the injection site. These reactions are typically mild to moderate and resolve on their own.

The decrease in blood cell counts (neutropenia, anemia, thrombocytopenia, lymphopenia) is a very common effect of DARZALEX treatment, particularly when used in combination with other anti-myeloma agents. Your doctor will perform regular blood tests to monitor your blood counts and may adjust your treatment schedule or provide supportive care (such as growth factor support or blood transfusions) if your counts fall too low. It is important to report any signs of infection, unusual bleeding or bruising, or persistent tiredness to your healthcare team.

Infections, including pneumonia and upper respiratory tract infections, are common with DARZALEX treatment because the medicine affects the immune system. Your doctor may prescribe prophylactic medications, such as antiviral agents to prevent herpes zoster reactivation or antibiotics in certain situations. Practicing good hygiene and avoiding close contact with people who have active infections can help reduce your risk.

Reporting Side Effects

If you experience any side effects, including any not listed above, talk to your doctor or nurse. You can also report suspected adverse reactions directly to your national pharmacovigilance authority. By reporting side effects, you help provide more information on the safety of this medicine.

How Should You Store DARZALEX?

Quick Answer: DARZALEX is stored and administered at the hospital or clinic. It must be kept refrigerated at 2–8°C, must not be frozen, and should be protected from light. Keep out of reach of children.

DARZALEX subcutaneous injection is stored and handled by healthcare professionals at the hospital or clinic where you receive treatment. You will not normally need to store this medicine at home. However, understanding the proper storage conditions can help ensure the medicine is always used safely and effectively.

• Temperature: Store in a refrigerator at 2°C to 8°C (36°F to 46°F). Do not freeze. If the medicine has been frozen, it must not be used.
• Light protection: Store in the original carton to protect from light. Do not expose to direct sunlight.
• Room temperature: The unopened vial may be stored at room temperature (15°C to 30°C) for up to 24 hours in the original carton.
• Prepared syringe: If not used immediately, the prepared syringe may be stored refrigerated for up to 24 hours, followed by up to 12 hours at 15°C to 25°C.
• Shelf life: Do not use after the expiry date stated on the carton and vial label after “EXP.” The expiry date refers to the last day of that month.

Keep this medicine out of the sight and reach of children. Do not shake the vial. The solution should be a clear to opalescent, colorless to yellow liquid. Do not use if the solution contains opaque particles, discoloration, or foreign matter. Unused medicine and waste should be disposed of in accordance with local requirements by healthcare personnel.

What Does DARZALEX Contain?

Quick Answer: Each 15 mL vial of DARZALEX subcutaneous injection contains 1,800 mg of the active ingredient daratumumab (120 mg/mL). Inactive ingredients include recombinant human hyaluronidase (rHuPH20), L-histidine, L-methionine, polysorbat 20, sorbitol, and water for injections.

Understanding the complete composition of your medication is important, particularly if you have known allergies or intolerances. Each vial of DARZALEX subcutaneous injection contains the following components:

Active Substance

The active pharmaceutical ingredient is daratumumab, a human IgG1 kappa monoclonal antibody produced in Chinese hamster ovary (CHO) cells by recombinant DNA technology. Each 15 mL vial contains 1,800 mg of daratumumab, at a concentration of 120 mg per mL. Daratumumab specifically targets the CD38 antigen on the surface of myeloma cells and other CD38-expressing cells.

Inactive Ingredients (Excipients)

The excipients in the subcutaneous formulation serve specific pharmaceutical functions:

• Recombinant human hyaluronidase (rHuPH20) — an enzyme that temporarily increases tissue permeability, allowing the large volume of the subcutaneous injection to be absorbed more rapidly
• L-histidine and L-histidine hydrochloride monohydrate — buffering agents that maintain the pH stability of the solution
• L-methionine — an antioxidant that protects the antibody from oxidative degradation
• Polysorbat 20 (E432) — a surfactant that prevents protein aggregation (0.4 mg per mL; 6.0 mg per 15 mL vial). Polysorbates can cause allergic reactions; inform your doctor if you have known allergies to polysorbates
• Sorbitol (E420) — a stabilizer. Sorbitol is a source of fructose; patients with hereditary fructose intolerance should consult their doctor
• Water for injections — the solvent vehicle

Solution Appearance

DARZALEX subcutaneous injection is supplied as a clear to opalescent, colorless to yellow, ready-to-use solution in a single-dose glass vial. Each carton contains one 15 mL vial. The solution should not contain visible particles, discoloration, or foreign matter. The subcutaneous formulation is compatible with polypropylene or polyethylene syringe materials, polypropylene, polyethylene, or PVC subcutaneous infusion sets, and stainless steel transfer and injection needles.

Marketing Authorization

DARZALEX is manufactured by Janssen Biologics B.V. (Leiden, Netherlands) and Janssen Pharmaceutica NV (Beerse, Belgium). The marketing authorization holder is Janssen-Cilag International NV, Beerse, Belgium. DARZALEX was first approved by the United States FDA in November 2015 for the intravenous formulation, and the subcutaneous formulation received EMA approval in 2020, offering patients a more convenient and faster administration option.