Darzalex (Daratumumab)

Darzalex (daratumumab) is a laboratory-made antibody against a specific protein, CD38.  It is approved by the U.S. Food and Drug Administration (FDA) to treat newly diagnosed, and relapsed and/or refractory myeloma patients, either alone or in combination with other approved treatments.

Janssen Pharmaceuticals developed and markets the treatment as an intravenous (into the bloodstream) infusion, and in a subcutaneous (under-the-skin) injection formulation. The subcutaneous formulation, Darzalex Faspro, allows for a faster and easier administration.

How does Darzalex work?

Darzalex recognizes a cell surface protein called CD38. This protein is abundantly present on the surface of myeloma — also called multiple myeloma — cells. It is also present on regulatory immune cells that diminish or suppress the activity of such immune cells as T cells and neutrophils. These cells have the ability to act against malignant myeloma cells.

Darzalex binds to multiple myeloma cells and induces their death. It also suppresses regulatory immune cells and allows other immune cells, including T cells and neutrophils, to grow robustly, and to identify and kill the myeloma cells.

Darzalex in clinical trials

Researchers conducted a Phase 2, open-label clinical trial (NCT00574288) testing the safety and effectiveness of Darzalex in patients with multiple myeloma who had relapsed or were resistant to at least two previous therapies. In part 1 of this study, patients received an infusion with Darzalex doses of 0.005 to 24 mg per kg of their body weight. In part 2, 30 patients were given 8 mg per kg of Darzalex, and another 42 patients 16 mg per kg of Darzalex, once weekly for eight times, twice-monthly eight times, and once monthly for up to 24 months.

Study results were published in the New England Journal of Medicine. They showed that patients tolerated all doses well. The most common adverse side effects were pneumonia and thrombocytopenia (low blood platelet counts). The overall response rate (ORR, the percentage of patients with a complete or partial response to treatment) was 10% for the 8 mg per kg group, and 36% for the 16 mg per kg group. Median progression-free survival (PFS) for the 16 mg per kg group was 5.6 months, with 65% of the patients not showing any progression for up to 12 months. Researchers concluded that Darzalex monotherapy is safe, well-tolerated, and effective in people with heavily pretreated and refractory myeloma.

A Phase 3 study (NCT02076009) compared a triple-combination therapy regimen of Darzalex, Revlimid (lenalidomide), and low-dose dexamethasone (DRd) with a double-combination regimen of Revlimid and low-dose dexamethasone (Rd) in 569 patients with relapsed or refractory multiple myeloma.

An interim analysis of the results at 13.5 months appeared in the New England Journal of Medicine. These early trial results found evidence of disease progression or death in 18.5% of patients in the triple-combination DRd group, compared to 41% in the Rd group. The PFS rate at 12 months was 83.2% in the DRd group and 60.1% in the Rd group. Complete response rates were 43% in the DRd group and 19.2% in the Rd group. In the triple-combination DRd group, 22.4% of patients showed minimal residual disease compared with 4.6% for the double-combination Rd group. The most common side effects were thrombocytopenia, anemia, and neutropenia. This trial’s researchers concluded that Darzalex significantly enhanced PFS when combined with Revlimid and dexamethasone in myeloma patients with relapsed and refractory disease.

Researchers also published the results of a Phase 3 clinical trial (NCT02136134) in the New England Journal of Medicine. They showed that Darzalex in combination with Velcade (bortezomib) and dexamethasone was more effective in treating relapsed and refractory myeloma than the standard treatment regimen of Velcade and dexamethasone only.

Results of an open-label Phase 1 study (NCT01998971) that included people with relapsed or refractory multiple myeloma, all who had already been given two or more previous therapies, were published in the Blood journal. They showed that treatment with Darzalex in combination with Pomalyst (pomalidomide) and low-dose dexamethasone significantly improved PFS and ORR. At a median follow-up time of 13.1 months, the median progression-free survival was 8.8 months, and median overall response rate was 17.5 months. The estimated 12-month survival rate was 66%. In total, 29% of patients with a complete response had minimal residual disease.

Another study, also published in the New England Journal of Medicine, reported the results of a Phase 3 trial (NCT02195479) in 706 previously untreated multiple myeloma patients (treatment naive) who were ineligible for autologous stem-cell transplantation (ASCT). All were treated either with a combination of Darzalex plus Velcade-Alkeran (melphalan)-prednisone (DVMP) or with a Velcade-Alkeran-prednisone (VMP) combination only. Results showed significantly improved PFS (71.6% vs. 50.2% at 18 months) and ORR (90.9% vs. 73.9%) in patients given Darzalex compared to those treated with VMP only. In the Darzalex group, 22.3% of patients were negative for minimal residual disease compared with 6.2% in the VMP group.

Ongoing clinical trials

Several clinical trials are ongoing in multiple myeloma patients that include the use of Darzalex.

Among them, an open-label, multi-center Phase 1b study (NCT01998971) is evaluating the safety, tolerability, and dosing of Darzalex given in combination with various treatment regimens. These include Velcade plus dexamethasone (VD), Velcade plus Alkeran and prednisone (VMP), Pomalyst plus dexamethasone (Pom-dex), Velcade plus Thalomid (thalidomide) and dexamethasone (VTD), Kyprolis (carfilzomib) plus dexamethasone (CFZ-dex), and Kyprolis plus Revlimid and dexamethasone (CFZRd).

This study enrolled about 250 patients, and is due to fully conclude in July 2022. Researchers are assigning participants non-randomly to these treatment regimens, with treatment given for a maximum of one year. The trial includes a minimum follow-up of 15 months, and researchers will be monitoring measures of treatment efficacy and safety throughout.

Other details

The FDA gave accelerated approval to Darzalex in November 2015 as a monotherapy for multiple myeloma patients who previously received at least three prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent.

In 2016, the FDA approved Darzalex in combination with Revlimid and dexamethasone, or in combination with Velcade and dexamethasone, to treat people with multiple myeloma after at least one prior therapy.

The FDA approved Darzalex in combination with Pomalyst and dexamethasone in 2017 for  multiple myeloma patients who have received at least two prior therapies, including Revlimid and a proteasome inhibitor such as Velcade, Kyprolis, or Ninlaro (ixazomib).

In May 2018, the agency approved Darzalex in combination with Velcade plus Alkeran plus prednisone (VMP) for people with newly diagnosed myeloma who are ineligible for ASCT.

Most common side effects of Darzalex include fatigue, nausea, back pain, fever, cough, upper respiratory tract infection, and infusion site reactions. The treatment can also cause anemia, thrombocytopenia (low platelet counts), and neutropenia (low counts of neutrophils, a type of white blood cell) and lymphopenia (low lymphocyte counts, also a type of white blood cell).

Since Darzalex can reactivate the herpes zoster virus, patients should be given anti-viral medication as a preventive treatment before taking Darzalex. Herpes zoster is the virus that causes shingles or chickenpox.


Last updated: May 8, 2020


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