DARZALEX (daratumumab)

Darzalex^® (daratumumab) is the first FDA-approved monoclonal antibody that targets the CD38 protein on the surface of myeloma cells. 

What Is Darzalex?

Darzalex® (daratumumab) is a laboratory-made monoclonal antibody designed to function like a naturally occurring antibody. It targets a specific single protein on the surface of myeloma cells. It punches holes in the myeloma cells to kill them. This is called “targeted therapy.”  

Darzalex is administered intravenously (infused from the vein, or IV) at a doctor’s office or a hospital clinic. 

How Does Darzalex Work?

Darzalex induces myeloma cell death through direct or indirect mechanisms of action (MOA). MOA is a biochemical process through which a substance (e.g. a drug or molecule) induces its effect in the body. 

Darzalex targets CD38, or glycoprotein. “CD” in CD38 stands for “cluster of differentiation.” This is a system for identifying the various molecules that serve as binding sites, or antigens. The antibodies bind to these antigens on the surface of the cells.  

CD38 is found in very high amounts on the surface of myeloma cells in the bone marrow. CD38 is found in very low amounts on healthy cells, making it easier for the healthy cells to recover after treatment. 

In brief, Darzalex works in the following ways:
 Darzalex kills myeloma cells directly.

• Darzalex enlists the cells of the human immune system cells to attach to the Darzalex-CD38 complex and kill the myeloma cells.
• Darzalex recruits complement proteins that boost the killing power of antibodies.
• Darzalex prevents the cellular transfer of calcium ions, which is toxic to cancer cells but not to normal cells.

For more information about the human immune system, read the IMF’s publication, Understanding the Immune System in Myeloma.

What Are FDA-Approved Treatment Regimens That Use Darzalex? 

Darzalex® is a prescription medicine used to treat adults with multiple myeloma: 

• For patients with newly diagnosed multiple myeloma (NDMM):
  • Darzalex. Velcade® (bortezomib), thalidomide, and dexamethasone [DVTd] in patients with NDMM who are eligible for autologous stem cell transplant (ASCT).
  • Darzalex, Revlimid® (lenalidomide), and dexamethasone [DRd] in patients with NDMM who are ineligible for ASCT. 
  • Darzalex, Velcade, melphalan, and prednisone [DVMP] in patients with NDMM who are ineligible for ASCT. 
• For patients with relapsed or refractory multiple myeloma (RRMM):
  • Darzalex, Revlimid, and dexamethasone [DRd] in patients with RRMM who have received at least 1 prior therapy.
  • Darzalex, Velcade, and dexamethasone [DVd] in patients with RRMM  who have received at least 1 prior therapy
  • Darzalex, Kyprolis® (carfilzomib), and dexamethasone [DKd] in patients with RRMM who have received 1 to 3 prior lines of therapy.
  • Darzalex, Pomalyst® (pomalidomide), and dexamethasone [DPd] in patients with RRMM who have received at least 2 prior therapies including Revlimid with a proteasome inhibitor (Velcade, Kyprolis, or Ninlaro® [ixazomib]).
  • Darzalex monotherapy – In patients with RRMM who have received at least 3 prior lines of therapy, including a proteasome inhibitor (Velcade, Kyprolis, or Ninlaro) and an immunomodulatory agent (Pomalyst, Revlimid, or thalidomide), or who are double-refractory to a proteasome inhibitor and an immunomodulatory agent.

Darzalex Combinations in Clinical Trials

DVRd for autologous stem cell transplant-eligible patients

In December 2019, at the annual meeting of the American Society of Hematology (ASH), data were presented from the GRIFFIN phase 2 clinical trial. The trial compared VRd vs. DVRd in induction therapy for two cycles of consolidtation therapy after an autologous stem cell transplant (ASCT). This trial introduced adding Darzalex to the VRd combination.

After the GRIFFIN study ended, an analysis of sustained minimal residual disease (MRD) was presented at the annual meeting of the American Society of Clinical Oncology (ASCO) in June 2022. Data showed that DVRd induction therapy and consolidation therapy followed by Revlimid maintenance therapy may lead to durable MRD-negativity in ASCT-eligible patients with newly diagnosed multiple myeloma (NDMM), high-risk cytogenetics, ISS stage III myeloma, and those who achieve complete response (CR) or stringent complete response (sCR).

MRD is the presence of residual cancer cells after treatment has been completed. MRD-negativity means that not even 1 myeloma cell was found in 100,000 or 1,000,000 sampled bone marrow plasma cells (depending on the test being used).

At the annual meeting of ASH in December 2023, the primary results of the PERSEUS phase 3 clinical trial showed that DVRd significantly improved progression-free survival (PFS) in ASCT-eligible patients with NDMM and increased depth of response (DpR). PFS is the length of time during and after treatment that patients live with myeloma, but their disease does not relapse.

DVRd for autologous stem cell transplant-ineligible patients

In 2026, the FDA expanded its approval of DVRd to include patients with NDMM who were ineligible for ASCT or who declined ASCT as frontline therapy. The expanded approval is based on data from the CEPHEUS clinical trial of 395 patients, 197 in the DVRd arm of the study and 198 in the VRd arm (without Darzalex Faspro).

The CEPHEUS study demonstrated significant benefit as measured by MRD-negativity and PFS. MRD-negativity was 52.3% in the DVRd arm vs. 34.8% in the VRd arm. At a follow-up of 54 months, approximately 68% of patients in the DVRd arm remained progression-free vs. approximately 48% in the VRd arm. DVRd demonstrated a 43% lower risk of progression or death vs. VRd. Median PFS was not reached in the DVRd arm of the study, indicating superior, long-lasting, durable responses compared to the VRd arm.

The CEPHEUS study confirmed that for patients who are not proceeding to transplant as frontline therapy, DVRd is a new standard of care (SOC). Standard of care is a benchmark treatment that is widely accepted by medical experts as the most appropriate.

DVRd has become the SOC regimen for the majority of ASCT-eligible patients, as well as for fit or intermediate-fit ASCT-ineligible patients.

How Is Darzalex Given?

Very few patients are receiving Darzalex IV after the FDA approved Darzalex Faspro SQ. For patients who are still prescribed Darzalex IV, the first dose of is given over a period of up to 8 hours. As with Darzalex SQ, medications can be given before and after each Darzalex infusion to help prevent IRR.

Splitting the first dose of Darzalex IV over 2 consecutive days is called “split-dosing.” This is approved in the United States and in Europe. Split-dosing is not done with Darzalex Faspro SQ.

Special Precautions with Darzalex 

All treatments for myeloma require close monitoring. As documented in clinical trials with Darzalex or Darzalex Faspro, both drugs have the potential to cause Grade 3 or 4 side effects. A side effect is an unwanted or unexpected effect caused by a drug. In the U.S., the National Cancer Institute (NCI) toxicity is categorized as follows:

• Grade 0 – no symptoms,
• Grade 1 – mild symptoms,
• Grade 2 – moderate symptoms,
• Grade 3 – symptoms requiring treatment,
• Grade 4 – symptoms requiring urgent intervention,
• Grade 5 – symptoms resulting in death.

What Are Some Common Side Effects of Darzalex?

Hypersensitivity, infusion-related reaction (IRR), and administration-related reaction (ARR) with Darzalex IV

Hypersensitivity is an undesirable reaction that may occur if a drug overactivates the immune system or the patient has a non-immune activation. Some drug classes, including monoclonal antibodies, are known to cause hypersensitivity reactions. A mild hypersensitivity reaction may be uncomfortable. Yet a severe reaction may be life-threatening. If you experience a hypersensitivity reaction to Darzalex, your doctor will decide if you should stop receiving it.

An infusion-related reaction (IRR) may occur due to the release of cytokines, proteins that circulate in the bloodstream. This is sometimes called cytokine release syndrome (CRS). Reactions may be flu-like and include the following:

• nasal congestion
• fever
• chills
• cough
• throat irritation
• difficulty breathing
• low blood pressure
• nausea
• rash

In the Darzalex IV registration trials, IRR occurred in 46% of patients. IRR was mostly mild to moderate and decreased with subsequent infusions, but 3% of patients had IRR severe enough to require hospitalization. There were no life-threatening reactions.

To minimize the risk of IRR, patients receive medication before every infusion of Darzalex IV. If dexamethasone is part of the treatment regimen, it may serve as pre-medication on days when Darzalex IV is given.

A clinical trial published in 2020 evaluated the use of montelukast 10 mg as a premedication for Darzalex IV. Patients who received montelukast had lower rates of IRR during their first infusion, and the median duration of the first infusion was shorter.

In 2022, a retrospective study of montelukast as a pre-medication for Darzalex IV confirmed that the rate of IRR was lower with montelukast than without it. If a reaction of any kind occurs during the administration of Darzalex IV, the infusion will be stopped.

Systemic administration-related reaction (ARR), a broader term that includes IRR, was documented in approximately 7%–11% of patients receiving Darzalex Faspro SQ in a clinical trial.

Risk of herpes zoster infection

Herpes zoster (“shingles”) is caused by the reactivation of the varicellazoster virus (VZV), the same virus that causes varicella (“chickenpox”). Herpes zoster frequently affects nerves. A small percentage of patients in clinical trials developed shingles.

All patients should receive preventive treatment with antiviral medication within 1 week after starting Darzalex. Patients should continue taking anantiviral medication for 3 months following the last dose of treatment with Darzalex.

Risk of hepatitis B virus reactivation

At any treatment phase, Darzalex IV can cause the reactivation of the hepatitis B virus (HBV). This has been reported in fewer than 1% of clinical trial patients, but there were fatal cases. Regular monitoring is required on a long-term basis. Ask your doctor if prevention strategies are recommended in your particular case.

Neutropenia, lymphopenia, and thrombocytopenia

Neutropenia is a reduced level of neutrophils, a type of white blood cell necessary to combat bacterial infection. Lymphopenia (also called lymphocytopenia) is low levels of B cells, T cells, and natural killer (NK) cells.

Thrombocytopenia is a low number of platelets (thrombocytes) in the blood. The “normal” level varies from laboratory to laboratory. For example, at Mayo Clinic the “normal” level is ≥150,000 platelets per microliter of circulating blood. If the platelet count is less than 50,000, bleeding problems may occur. Major bleeding is usually associated with a reduction in count to less than 10,000 platelets. 

In studies with Darzalex Faspro SQ, blood tests in 40% or more patients identified decreased leukocytes, decreased platelets, and decreased hemoglobin. Your doctor will use the complete blood count (CBC) test to monitor you during treatment.

If your blood cell counts are low, your doctor will either hold your dose of Darzalex until your counts improve or will provide you with supportive care in the form of transfusions or medications that stimulate the formation of new blood cells.

Embryo-fetal toxicity

Women of reproductive potential and males with female partners of reproductive potential must ask the doctor which effective contraception method to use, and how long to continue using contraception after the last dose of treatment is received. Due to the potential for harm in the breastfed child, lactating women should not breastfeed during treatment and for a period of time after treatment ends.

Interference with blood tests

Darzalex IV can interfere with red blood cell (RBC) antibody screening. Darzalex IV may also interfere with blood compatibility testing, including the matching done before blood  transfusions. 

Before starting Darzalex IV, your doctor should screen your blood and establish your blood type in case you might need a blood transfusion later. Blood banks must be informed that you have received Darzalex or Darzalex Faspro.

Darzalex is known to interfere with the results of serum protein electrophoresis (SPEP) and immunofixation electrophoresis (IFE) tests used to monitor myeloma. This can lead to inaccurate results when testing for complete response or disease progression. In 2018, the FDA approved a new blood test for evaluating M-protein in patients treated with Darzalex.

Other Possible Side Effects of Darzalex

Side effects that were reported in 20% or more patients in clinical trials include the following:

Fatigue

In the registration trials for Darzalex, 39% of the patients experienced fatigue, all but 2% of which was mild to moderate and did not limit the patients’ ability to care for themselves. Exercise caution when operating machinery, including automobiles. The effects of fatigue may be minimized by maintaining:

• A moderate level of activity.
• A healthy diet and sufficient fluid intake.
• A consistent sleeping schedule with enough rest.
• Regularly scheduled visits with your healthcare team to discuss issues that may contribute to your fatigue.
• A careful review of the side effects of any other products you are taking to ensure that they are not contributing to your fatigue.

For more information, please see the IMF publication Understanding Fatigue in Myeloma.

Nausea

Approximately 25% of the patients in the registration trials for Darzalex IV had mild to moderate nausea. There were no cases of severe nausea. Medications given before and after helped reduce the occurrence and severity of nausea. Ask your doctor prior to your Darzalex IV infusion if you need to fill a prescription of anti-nausea in advance.

Back pain

If you have myeloma-related back pain, read the IMF’s publication Understanding Treatment of Myeloma Bone Disease. 

If you have treatment-related back pain and body aches, this could be due to the release of cytokines in the bloodstream in reaction to Darzalex. Back pain and body aches may also occur if you develop an infection due to low levels of white blood cells (WBC). In the Darzalex registration trials, 25% of patients experienced back pain, with 2% experiencing back pain that limited their ability to care for themselves. Medications given before and after your dose of Darzalex IV may reduce or prevent infusion-related back pain.

Fever

Fever can be a sign of the interaction of Darzalex with the immune system.

To protect yourself, be proactive in the following ways:

• Check your temperature twice a day if you feel warm.
• If you have an oral temperature greater than 100.4°F (38°C), you must get medical care immediately.
• If you are not able to reach your healthcare team, go to an emergency room (ER) or urgent care facility.
• To avoid dehydration, drink a lot of non-alcoholic and non-caffeinated liquids.
• To control the fever, do not take any medication on your own.
• Take medication only as directed by a medical professional familiar with your medical history.

If your fever is a result of an infection, you may be prescribed antibiotics. You may also be given a colony-stimulating factor (CSF) to stimulate the development and growth of white blood cells.

Cough can be managed with medication taken before and after your infusion of Darzalex IV. If you develop a cough as a result of an upper respiratory infection, your doctor will give you medication, if needed.

Typically, you can help relieve your cough by:

• maintaining good hydration
• drinking hot or warm liquids
• taking throat lozenges
• avoiding irritants
• breathing warm steam from a shower or humidifier

Respiratory problems

In the registration trials for Darzalex, 20% of the patients experienced an upper respiratory tract infection. All but 1% were mild to moderate. Upper respiratory tract infections can be a bacterial or viral infection of the nose, throat, sinuses, or larynx. Possible respiratory infections include lung problems such as pneumonia (an infection in one or both lungs). Shortness of breath is also a common side effect. Immediately report your symptoms to your doctor.

If your infection is serious and your white blood cell count is low, the doctor may pause your Darzalex IV until you recover or support you with medications to help with the production of new white blood cells.

Peripheral neuropathy

Peripheral neuropathy (PN) is a serious condition that affects nerves in the hands, feet, lower legs, and/or arms. Myeloma patients may experience PN from the effects of the disease itself or from treatments for myeloma.

Symptoms of PN may include a feeling of:

• numbness 
• tingling
• burning
• pain

Velcade, a drug that is part of many myeloma combination therapies, including regimens with Darzalex or Darzalex Faspro, is known to cause PN. Velcade causes significantly less PN when it is given as an SQ injection under the skin rather than as an IV infusion. In a clinical trial, 6% of patients who received Velcade SQ experienced PN of Grade 3 or 4 vs. 16% of patients who received Velcade IV. If Velcade IV is part of your regimen, be sure to ask your doctor about Velcade SQ.

Diarrhea

Diarrhea is defined as 3 or more loose stools per day. Severe diarrhea is defined as 7 or more loose stools per day. Dizziness, lightheadedness, or fainting may occur due to dehydration caused by either excessive or persistent diarrhea.

Precautions should be taken to prevent dehydration. Ask your doctor how you can maintain an adequate level of hydration. Contact your doctor if you experience dizziness, lightheadedness, or fainting. Your doctor may administer antidiarrheal medication or intravenous fluids on an outpatient basis or may recommend hospitalization if needed.

Constipation

The medical definition of constipation is 3 or fewer bowel movements in 1 week. The stool may become hard, dry, and difficult to pass. You may experience stomach cramps and bloating. Not eating, not drinking enough water, and being less active can make constipation worse.

Ask your doctor for instructions on drinking sufficient fluids and eating high-fiber foods. Try to be active every day, even if you exercise in a chair. Moving your body increases the rhythmic contractions that move food through your intestines.

Darzalex Assistance Program

If you are prescribed Darzalex or Darzalex Faspro, you can sign up for the “DARZALEX withMe” program. Visit darzalex.com or call 1.833.565.9631 Monday–Friday, 8 a.m.–8 p.m. (ET) for help with personalized appointment reminders, access to nurse educators, and referrals to organizations that may provide assistance relevant to the patient’s needs.

For information about the new formulation of Darzalex for subcutaneous (under the skin) administration, visit DARZALEX FASPRO™ .