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: 

• 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 + 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.

How Is Darzalex Given?

The first dose of Darzalex is usually given over a period of up to eight 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 four 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 

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?

Infusion-related reaction (IRR) with Darzalex IV

Clinical trial data show that IRR was documented in approximately 37% of patients during their first infusion of Darzalex IV, then 5% during the second infusion, and 6% during subsequent infusions. 

Reactions are typically mild to moderate and usually occur during or within 4 hours of the first infusion. Severe reactions requiring hospitalization occurred in 3%; none were life-threatening.

Symptoms may include:

• Nasal congestion
• Throat irritation
• Cough
• Fever
• Chills
• Difficulty breathing
• Low blood pressure
• Nausea
• Rash

IRR is triggered by cytokine release (cytokine release syndrome), a known response to monoclonal antibodies like Darzalex.

To reduce IRR risk, patients receive pre- and post-infusion medications before every Darzalex IV infusion. If dexamethasone is part of the treatment regimen, it may double as the pre-medication. Any reaction during infusion will prompt an immediate stop.

Studies in 2018 and 2022 found that adding montelukast (10 mg) as a pre-medication further reduced IRR rates and shortened first-infusion duration.

Risk of herpes zoster infection

Darzalex can reactivate varicella-zoster virus (VZV), causing shingles. Patients should start antiviral medication within 1 week of beginning Darzalex and continue for 3 months after the last dose.

Risk of hepatitis B virus reactivation

Darzalex can reactivate hepatitis B virus (HBV) in rare cases (<1% in trials), with some fatal outcomes. Regular long-term monitoring is required, and preventive strategies may be recommended. Ask your doctor for specific instructions.

Neutropenia, lymphopenia, and thrombocytopenia

Darzalex commonly causes low blood cell counts, including neutropenia (low neutrophils), lymphopenia (low B, T, and NK cells), and thrombocytopenia (low platelets). Low platelets can increase bleeding risk, particularly below 50,000/µL, with major bleeding risk below 10,000/µL.

Your doctor will monitor your blood counts regularly with a CBC. If counts drop too low, your dose may be delayed. Alternatively, you may receive transfusions or medications to stimulate blood cell production.

Interference with blood tests

Darzalex IV can interfere with blood compatibility testing (including cross-matching for transfusions) and myeloma monitoring tests (SPEP and IFE). Before starting treatment, your doctor should establish your blood type, and blood banks should be notified of your Darzalex use. For myeloma monitoring, an FDA-approved test (2018) is available to more accurately detect M-protein in patients on Darzalex.

Embryo-fetal toxicity

Females of reproductive potential and males with female partners of reproductive potential should use effective contraception during treatment with Darzalex and for 3 months after stopping Darzalex treatment. 
 

Darzalex Combinations in Clinical Trials

In December 2019, at the annual meeting of the American Society of Hematology (ASH), the GRIFFIN phase II clinical trial of VRd vs. DVRd introduced adding Darzalex to the VRd combination. It did so in induction therapy and for 2 Cycles of consolidation therapy after ASCT.

In June 2022, the post hoc analysis of sustained minimal residual disease(MRD) from the GRIFFIN study was presented at the annual meeting of the American Society of Clinical Oncology (ASCO). Adding Darzalex to VRd during induction and consolidation, followed by Revlimid maintenance, may improve outcomes. This approach may help patients achieve durable MRD negativity.
Benefits were seen in:

• ASCT-eligible patients with newly diagnosed multiple myeloma (NDMM)
• Patients with high-risk cytogenetics
• Those with ISS stage III disease
• Patients who reach complete response (CR) or stringent complete response (sCR)

In December 2023, at the annual meeting of ASH, the primary results of the PERSEUS phase III study showed that DVRd significantly improved progression-free survival (PFS) in ASCT-eligible patients with NDMM and increased depth of response (DpR) across relevant study subgroups.

These results support the use of DVRd followed by maintenance therapy with Darzalex and Revlimid [D-R] as a new standard of care for ASCT-eligible patients with NDMM when compared to VRd alone followed by maintenance with Revlimid. 

Before the FDA approval, DVRd was included in the National Comprehensive Cancer Network (NCCN) guidelines for the management of myeloma.

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™ .