Darzalex (daratumumab) is a laboratory-made antibody against a specific protein, CD38. It is approved by the U.S. Food and Drug Administration (FDA) for the treatment of newly-diagnosed, relapsed, and/or refractory myeloma patients, either alone or in combination with other approved treatments. It is developed and marketed by Janssen Pharmaceuticals as an injection into the bloodstream under medical supervision in the hospital.

How does Darzalex work?

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

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

Darzalex in clinical trials

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

Results of the study were published in the New England Journal of Medicine. All doses were well-tolerated. The most common adverse events (side effects) were pneumonia and thrombocytopenia (low blood platelet counts). The overall response rate (ORR — the percentage of patients with complete or partial response) was 10% for the 8 mg/kg group and 36% for the 16 mg/kg group. The median progression-free survival (PFS) for the 16 mg/kg group was 5.6 months with 65% of the patients not showing any progression for up to 12 months. So, Darzalex monotherapy was found safe, well-tolerated, and effective in patients with heavily pretreated and refractory (hard-to-manage) myeloma.

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

Interim analysis of the results at 13.5 months was reported in the New England Journal of Medicine. They showed disease progression or death in only 18.5% of patients in the DRd group compared with 41% in the Rd group. The PFS rate at 12 months was 83.2% in the DRd group compared with 60.1% in the Rd group. The rate of complete response was 43% in the DRd group compared with 19.2% in the Rd group. In the DRd group, 22.4% of patients showed minimal residual disease, which is defined as one tumor cell per 100,000 white cells, compared with 4.6% for the Rd group. The most common side effects were thrombocytopenia, anemia, and neutropenia. The researchers concluded that Darzalex significantly enhanced PFS when combined with Revlimid and dexamethasone in myeloma patients with relapsed and refractory disease.

The results of a Phase 3 clinical trial (NCT02136134), also reported in the New England Journal of Medicine, 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.

The results of an open-label Phase 1 study (NCT01998971) reported in the Blood journal showed that treatment of relapsed or refractory multiple myeloma patients who had already received two or more previous therapies with Darzalex in combination with Pomalyst (pomalidomide) and low-dose dexamethasone significantly improved PFS (survival time without the disease) and ORR (patients with complete or better response). At a median follow-up time of 13.1 months, the median PFS was 8.8 months and median ORR was 17.5 months. The estimated 12-month survival rate was 66%. Moreover, 29% of patients with a complete response had minimal residual disease.

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

Several clinical trials are ongoing in myeloma patients that include Darzalex.

For example, an open-label, multi-center, Phase 1b study (NCT01998971) is evaluating the safety, tolerability, and dose regimen of Darzalex when administered in combination with various treatment regimens such as Velcade plus dexamethasone (VD), Velcade plus Alkeran plus prednisone (VMP), Pomalyst plus dexamethasone (Pom-dex), Velcade plus Thalomid (thalidomide) plus dexamethasone (VTD), Kyprolis (carfilzomib) plus dexamethasone (CFZ-dex), and Kyprolis plus Revlimid plus dexamethasone (CFZRd). The study expects to enroll approximately 250 patients assigned  non-randomly to all these different treatment regimens. The study includes treatment for a maximum of one year and follow-up for at least 15 months after the last patient receives the first dose of Darzalex. The study will seek to monitor clinical efficacy outcomes and safety throughout and is expected to be completed by Dec. 31, 2020.

Other details

Darzalex was granted accelerated approval in November 2015 as monotherapy for patients with multiple myeloma who have 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 Velcade and dexamethasone, for the treatment of patients with multiple myeloma who have received at least one prior therapy. The following year, Darzalex was approved in combination with Pomalyst + dexamethasone for treating patients with myeloma who have received at least two prior therapies, including Revlimid and a proteasome inhibitor such as Velcade, Kyprolis, or Ninlaro (ixazomib). Finally, in May 2018, the agency approved Darzalex in combination with Velcade plus Alkeran plus prednisone (VMP) for treating patients with newly diagnosed myeloma who are ineligible for ASCT.

The main side effects of Darzalex include fatigue, nausea, back pain, fever, cough, and upper respiratory tract infection. The treatment also can cause anemia, thrombocytopenia, and neutropenia and lymphopenia (low white blood cell counts). Since Darzalex can reactivate the herpes zoster virus that causes shingles or chickenpox, patients should receive anti-viral medication as a preventive treatment before taking Darzalex.


Last updated: Nov. 16, 2019


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