pci2On November 16th, 2016 the U.S. Food and Drug Administration (FDA) granted accelerated approval for Darzalex® (daratumumab) to treat patients with multiple myeloma who have received at least three prior treatments. Darzalex® is the first monoclonal antibody approved for treating multiple myeloma.

Multiple myeloma is a form of blood cancer that occurs in infection-fighting plasma cells (a type of white blood cell) found in the bone marrow. These cancerous cells multiply, produce an abnormal protein and push out other healthy blood cells from the bone marrow. The disease may result in a weakened immune system and cause other bone or kidney problems. The National Cancer Institute estimates there will be 26,850 new cases of multiple myeloma and 11,240 related deaths in the United States this year.

Daratumumab (Darzalex®) is the first human anti-CD38 cytolytic antibody approved for use in cancer and induces tumor cell death through multiple immune-mediated mechanisms of action, including complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity and antibody-dependent cellular phagocytosis, as well as through apoptosis, in which a series of molecular steps in a cell lead to its death. A subset of myeloid-derived suppressor cells, CD38+ regulatory T cells and CD38+ B cells were decreased by daratumumab, according to Janssen Pharmaceuticals filing with the FDA. Daratumumab received breakthrough therapy designation from the FDA for this indication.

Daratumumab is indicated for use with lenalidomide (Revlimid®, Celgene) and dexamethasone, or bortezomib (Velcade®, Millennium) and dexamethasone for patients with MM who have already received treatment for the cancer, including a protease inhibitor (PI) and an immunomodulatory agent, or who are double refractory to a PI and an immunomodulatory agent.

Approval was based on two Phase II open-label studies showing consistent and pronounced clinical benefit with daratumumab used in combination with two of the most widely used treatment classes. According to results from the open-label POLLUX clinical study, the median progression-free survival (PFS) in the daratumumab arm has not been reached, compared with a median PFS of 18.4 months in patients who received lenalidomide-dexamethasone alone, with a median follow-up of 13.5 months. In addition to meeting the primary end point of improved PFS, daratumumab significantly increased the overall response rate (ORR) (91% vs. 75%; P<0.0001), compared with lenalidomide-dexamethasone alone, including doubling the rates of complete response (CR) (25% vs. 12%; P<0.0001) and significantly increasing very good partial response (VGPR) (32% vs. 24%; P<0.0001) (N Engl J Med 2016;375[14]:1319-1331).Approval was based on two Phase II studies showing consistent and pronounced clinical benefit with daratumumab used in combination with two of the most widely used treatment classes.

According to results from the open-label CASTOR clinical study, the median PFS in the daratumumab arm has not been reached, compared with a median PFS of 7.2 months in patients who received bortezomib-dexamethasone alone, with a median follow-up of 7.4 months. In addition to meeting the primary end point of improved PFS, daratumumab also significantly increased ORR (79% vs. 60%; P<0.0001), compared with bortezomib-dexamethasone alone, including doubling rates of CR (14% vs. 7%; P<0.0001) and significantly increasing VGPR (38% vs. 19%; P<0.0001) (N Engl J Med 2016;375[8]:754-766).

The most common side effects of Darzalex® were infusion-related reactions, fatigue, nausea, back pain, fever and cough. Darzalex® may also result in low counts of infection-fighting white blood cells (lymphopenia, neutropenia, and leukopenia) or red blood cells (anemia) and low levels of blood platelets (thrombocytopenia).Blood banks should be informed that patients are receiving Darzalex® because the drug may interfere with certain tests that are done by blood banks (such as antibody screening) for patients who need a blood transfusion. Women who are pregnant should not use Darzalex®, and women planning to become pregnant should use effective contraceptives during and for at least three months after treatment.

Readers of this blog are highly encouraged to read the sources/references listed below thoroughly and in full to contextualize the complete information provided. Additionally, interested parties on this topic should seek further information on this topic from scientific and medical information readily available in the public domain.

Links/References:

  1. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm472875.htm
  2. http://www.pharmacypracticenews.com/New-Drug-Approvals/Article/11-16/FDA-Gives-New-Indication-for-Darzalex-With-2-Standard-Treatments-for-MM-/38644/ses=ogst?enl=true
  3. New England Journal of Medicine 2016;375[8]:754-766).