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. This is called “targeted therapy.”  

Darzalex enlists immune system cells to help attack and kill myeloma cells. It 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 widely expressed on myeloma cells. It is only expressed at low levels on other cells in the bone marrow, making it easier for them to recover after therapy. 

When Darzalex binds to CD38, it causes myeloma cell death in multiple ways: 

• It kills myeloma cells directly. 
• It recruits immune system cells called macrophages. Macrophages bind to the Darzalex-CD38 complex. Then, these macrophages engulf and destroy myleoma cells. 
• It recruits natural killer (NK) cells, which target and kill myeloma cells. 
• It recruits complement proteins that boost the killing power of antibodies and punch holes in the targeted myeloma cells. 
• It modulates the immune response by decreasing immune system suppression. 
• It inhibits CD38 from functioning as an enzyme that regulates calcium flux in the cell. Blocking the transfer of calcium ions is toxic to cancer cells but spares normal cells. 

What Are FDA-Approved Treatment Regimens That Use Darzalex? 

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

• In combination with Velcade® (bortezomib), Thalomid® (thalidomide), and dexamethasone [D-VTd] in newly diagnosed patients who are eligible for autologous stem cell transplant (ASCT)  
• In combination with Revlimid® (lenalidomide) and dexamethasone [DRd]
  • in newly diagnosed patients who are ineligible for ASCT and 
  • in relapsed or refractory myeloma patients who have received one prior therapy 
• In combination with Velcade (bortezomib), melphalan, and prednisone [D-VMP] in newly diagnosed patients who are ineligible for ASCT 
• In combination with Velcade (bortezomib) and dexamethasone [DVd] in patients who have received at least 1 prior therapy 
• In combination with Kyprolis® (carfilzomib) and dexamethasone [DKd] in relapsed or refractory myeloma patients who have received one prior therapy 
• In combination with Pomalyst® (pomalidomide) and dexamethasone [DPd] in patients who have had at east 2 prior therapies. These prior therapies include: 
  • Revlimid (lenalidomide) and a proteasome inhibitor such as Velcade (bortezomib), Kyprolis (carfilzomib), or Ninlaro® (ixazomib) 
• As a standalone therapy (monotherapy) in  
  • patients who have received at least 3 prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent such as Pomalyst (pomalidomide), Revlimid (lenalidomide), or Thalomid (thalidomide) or 
  • patients who are double-refractory to a proteasome inhibitor and an immunomdulatory agent 

How Is Darzalex Given?

The first dose of Darzalex is usually given over a period of up to 8 hours. Especially with the first dose, the slower the rate of infusion, the less likely it is that a severe administration-related reaction (ARR) will occur. 

If the first dose is well tolerated, subsequent doses may be given more rapidly at your doctor’s discretion. Medications can be given before and after each Darzalex infusion to help prevent a reaction.  

Splitting the first infusion of Darzalex over two consecutive days, also called a “split-dosing regimen,” is approved in both the United States and Europe. The concentration of Darzalex in the body was found to be comparable regardless of whether the first dose was administered as a single infusion or a split-dosing infusion.  

The dose of Darzalex, whether alone or as part of DRd or DPd regimens, is 16 mg/kg of body weight. It is given  

• weekly for weeks 1–8;  
• every 2 weeks for weeks 9–24; and  
• every 4 weeks for weeks 25 and thereafter until disease progression. 

As part of the DVd regimen, Darzalex is given at the standard dose. However, it is given

• weekly for weeks 1–9;  
• every 3 weeks for weeks 10–24; and  
• every 4 weeks for weeks 25 and thereafter until disease progression.  

As part of the twice-weekly DKd regimen, Darzalex is given

• at a dose of 16 mg/kg on days 1, 8, 15, and 22, of Cycles 1 and 2;  
• every two weeks during Cycles 3–6; and  
• every 4 weeks during Cycle 7 and thereafter.  

The initial dose of Darzalex can be split into two doses of 8 mg/kg each, given on two consecutive days.  

As part of the once-weekly DKd regimen, Darzalex is given

• at a dose of 8 mg/kg on days 1 and 2 of Cycle 1, and 
• if tolerated, at 16 mg/kg on days 8, 15, and 22.  
• On days 1, 8, 15, and 22 of Cycle 2, Darzalex is given at a dose of 16 mg/kg. 
• On days 1 and 15 of Cycles 3–6, Darzalex is given at a dose of 16 mg/kg.  
• On Day 1 of Cycle 7 and thereafter, Darzalex is given at a dose of 16 mg/kg 

What Are the Possible Side Effects of Darzalex? 

A side effect is an unwanted or unexpected effect caused by a drug. In the Darzalex registration trials evaluated by the FDA before approval, side effects that occurred in 20% or more of the patients were the following: 

• infusion-related reaction 
• fatigue 
• nausea 
• back pain 
• fever 
• cough 
• and upper respiratory tract infection (URI).  

In addition, Darzalex may cause blood cell counts to drop, with significant numbers of patients experiencing  

• anemia 
• thrombocytopenia 
• neutropenia 
• lymphopenia 

Blood counts are carefully monitored during treatment with Darzalex. If they are too low, your doctor will hold your dose of Darzalex until your counts improve. Your doctor may also provide you with supportive care in the form of transfusions or medications that stimulate the formation of new blood cells.  

Infusion-related reaction (IRR) for the IV formulation  

Monoclonal antibodies may cause IRR by the release of cytokines, sometimes called cytokine release syndrome (CRS). Reactions are often flu-like, and include nasal congestion, fever, chills, cough, throat irritation, difficulty breathing, low blood pressure, nausea, and rash. IRR occurred in 46% of patients in the registration trials for Darzalex. IRR was mostly mild to moderate, and mostly during or within 4 hours after the first infusion. IRR occurred in 5% of patients during or after the second infusion, and in 4% with subsequent infusions. IRR severe enough to require hospitalization occurred in 3% of patients. There were no life-threatening infusion reactions. To learn more about prevention and treatment of IRR, see page 13 of the IMF booklet Understanding Darzalex (daratumumab) and Darzalex FASPRO. 

Fatigue 

39% of the patients in the registration trials for Darzalex experienced fatigue. Yet, all but 2% of these fatigue issues were  mild to moderate and did not limit the patients’ ability to care for themselves. 

Caution is advised if you are operating machinery, including automobiles. For more detailed information, please see the IMF publication Understanding Fatigue. 

Nausea  

Approximately 25% of the patients in the registration trials had mild to moderate nausea. There were no cases of severe nausea.  

Pre- and post-infusion medications help to reduce the occurrence and severity of nausea. Your doctor may order an anti-nausea drug prior to your Darzalex infusion.  

Back pain  

Treatment-related (rather than myeloma-related) back pain can occur as a result of inflammatory cytokines released in reaction to the monoclonal antibody. Back pain may also occur because a patient receiving Darzalex has low levels of white blood cells (WBC) and develops an infection along with body aches and pains.  

Of the 25% of patients who experienced back pain in the Darzalex registration trials, only 2% experienced back pain that was severe enough to limit their ability to care for themselves. 

Pre- and post-infusion medications can reduce or prevent infusion-related back pain. Consult your doctor, who will determine if you require medication. 

Fever 

An oral temperature greater than 100.4°F (38°C) needs to be further evaluated immediately. Fever can be a sign of the interaction of the monoclonal antibody with the immune system.  

You can minimize the effects of fever in the following ways:  

• Check your temperature twice a day if you feel warm.  
• Notify your doctor immediately if you have a fever greater than 100.4°F (38°C).  
• If your doctor’s office is closed and you are not able to reach your healthcare team, go to an emergency room (ER) or urgent care facility.  
• Take medications to control the fever as directed by your doctor.  
• To avoid dehydration, drink a lot of non-alcoholic and non-caffeinated liquids.  

Your doctor may also do the following:  

• Recommend medication to treat fever related to flu-like symptoms. Do not take any medication without first consulting a doctor familiar with your medical history.  
• Prescribe antibiotics if you have a fever as a result of an infection. You may also be given a colony-stimulating factor (CSF) to stimulate the development and growth of while blood cells. 

Cough  

Cough can be best managed proactively with pre- and post-infusion medications. You can relieve symptoms of cough by: 

• maintaining good hydration 
• drinking hot liquids 
• taking lozenges 
• avoiding irritants in the air, and  
• breathing warm steam from a shower or humidifier. 

Cough can be best managed proactively with pre- and post-infusion medications.  

If you develop a cough as a result of an upper respiratory infection, your doctor will recommend medications, if appropriate, to treat the infection.  

Upper respiratory tract infection (URI)  

In the registration trials for Darzalex, 20% of the patients experienced URI; all but 1% were mild to moderate. URIs can be a bacterial or viral infection of the nose, throat, sinuses, or larynx.  

Report your symptoms to your doctor immediately. If your infection is serious and your white blood cell count is low, the doctor may hold your Darzalex infusion until you recover or support you with medications to stimulate the production of new white blood cells. 

Warnings and Precautions with Darzalex 

Interference with blood tests  

Darzalex binds to the CD38 cell surface antigen on red blood cells and interferes with blood compatibility testing, including antibody screening and cross-matching done prior to blood transfusions. 

Your doctor should type and screen your blood before you start treatment with Darzalex in case you need a blood transfusion subsequently.  

Darzalex has been known to interfere with the results of serum protein electrophoresis (SPEP) and immunofixation electrophoresis (IFE) tests myeloma.org 11 used to monitor myeloma. This led to false positive test results for patients with IgG kappa myeloma protein, leading to inaccuracies in detecting complete response and disease progression. In January 2018, the FDA approved a new assay for evaluating monoclonal protein in serum by IFE for myeloma patients treated with Darzalex.  

Risk of hepatitis B virus reactivation  

Darzalex can cause the hepatitis B virus (HBV) to become active again. In clinical trials with Darzalex, HBV reactivation has been reported in less than 1% of patients, but there were fatal cases. HBV reactivation can occur at any treatment phase. That is why regular monitoring is required on a long-term basis. Ask your doctor if prevention strategies are recommended for you.  

Risk of herpes zoster infection  

Herpes zoster (“shingles”) is caused by the reactivation of the varicella-zoster virus (VZV), the same virus that causes varicella (“chickenpox”). Before starting treatment with Darzalex, ask your doctor about preventive antiviral medication. A small percentage of patients in clinical trials with Darzalex developed reactivation of VZV, which frequently affects nerves. Therefore, all patients should receive preventive treatment with an antiviral medication within 1 week after starting Darzalex. Also, they should continue taking an antiviral medication for 3 months following treatment with Darzalex.  

Pregnancy  

To avoid exposure to the fetus, women of reproductive potential should use effective contraception during treatment and for 3 months after stopping Darzalex treatment.  

Darzalex Combinations in Clinical Trials  

Darzalex (daratumumab), Velcade (bortezomib), Revlimid (lenalidomide), and dexamethasone [D-VRd] is not formally approved by the FDA. Yet, it is included by the National Comprehensive Cancer Network (NCCN) in its guidelines for the management of myeloma.  

At the December 2023 annual meeting of the American Society of Hematology (ASH), a late-breaking abstract presented the primary results of the PERSEUS phase III clinical trial of D-VRd in newly diagnosed multiple myeloma (NDMM) patients eligible for ASCT. This trial demonstrated that D-VRd (with SQ administration of Darzalex Faspro) significantly improved progression-free survival (PFS) and increased depth of response (DoR) with consistent and clinically meaningful PFS benefit across clinically relevant subgroups. The PERSEUS safety profile was consistent with the known safety profiles for Darzalex Faspro and VRd. These data, together with the previously presented results from the GRIFFIN phase II clinical trial, support the use of D-VRd followed by maintenance with Darzalex and Revlimid [D-R] as a new standard-of-care for ASCT-eligible newly diagnosed multiple myeloma.  VRd alone followed by maintenance with Revlimid is outdated by this new regimen. 

For more information about VRd, read the IMF’s publication Understanding the VRd Regimen for Newly Diagnosed Myeloma. Darzalex continues to be studied in numerous clinical trials as part of a wide spectrum of combination therapies and across myeloma disease settings. Contact the IMF InfoLine or visit clinicaltrials.gov for up-to-date information. 

Janssen CarePath Program

Please call 1-844-553-2792 or visit darzalex.com for more information.

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