The flurry of decisions from the U.S. Food and Drug Administration (FDA) on investigational anticancer therapeutics continued last week when the agency approved two new agents for treating certain patients with multiple myeloma: daratumumab (Darzalex) and ixazomib (Ninlaro).
Multiple myeloma is one of the most commonly diagnosed hematological malignancies, or blood cancers. In fact, the National Cancer Institute estimates that there will be 26,850 new cases of multiple myeloma and 11,240 multiple myeloma–related deaths in the United States this year. The development and FDA approval of new therapeutics—including proteasome inhibitors like bortezomib (Velcade) and carfilzomib (Kyprolis), and immunomodulatory agents like lenalidomide (Revlimid) and pomalidomide (Pomaylst)—have improved outcomes in recent years. However, the overall five-year survival rate remains under 50 percent creating an urgent need for new therapeutics.
Daratumumab: a new immunotherapeutic
The FDA approved daratumumab specifically for treating patients whose multiple myeloma has progressed despite treatment with at least three prior forms of therapy, including a proteasome inhibitor and an immunomodulatory agent, as well as those whose disease is not responsive to either a proteasome inhibitor or an immunomodulatory agent. This approval will help address a clear unmet need because these patients have a very poor prognosis, with median overall survival estimated to be about nine months.
Daratumumab is a monoclonal antibody that attaches to a protein called CD38, which is found at high levels on the surface of myeloma cells. It exerts its anticancer effects in a number of ways, including by flagging the myeloma cells for several types of immune cells. Once the immune cells have been directed to their target, they attack and destroy the myeloma cells.
According to the FDA, the agency approved daratumumab based on results from a phase II clinical trial. Specifically, the fact that 29 percent of the 106 patients enrolled on the trial had a complete or partial reduction in their tumor burden (that is to say 29 percent had an objective response) and that the median duration of the responses was 7.4 months. Because this approval was based on objective response rate data, rather than overall survival, daratumumab’s manufacturer, Janssen, is required by the FDA to conduct a study to confirm that the drug improves survival for patients compared with standard therapy.
Ixazomib: the first oral proteasome inhibitor
The FDA approved ixazomib specifically for use in combination with the immunomodulatory agent lenalidomide and dexamethasone to treat patients with multiple myeloma that has progressed despite treatment with at least one prior therapy.
Ixazomib is the first oral therapeutic in a class of anticancer therapeutics called proteasome inhibitors. These agents block the function of a cellular complex called the proteasome, which allows cells to break down proteins, a process that helps control key cellular processes such as cell division and survival. Preventing the natural breakdown of proteins can be highly toxic to myeloma cells, causing them to die.
According to the FDA announcement, the approval of ixazomib was based on results from a phase III clinical trial, which showed that adding ixazomib to lenolidamide and dexamethasone increased the time by almost six months before disease progressed.
More advances on the horizon
Daratumumab and ixazomib are the second and third new therapeutics, respectively, approved by the FDA in 2015 for treating multiple myeloma, the first being panobinostat (Farydak), which we highlighted previously on this blog. With one other investigational therapeutic under review at the FDA for the treatment of multiple myeloma—elotuzumab—there is hope that we will soon see more progress against this disease.
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