, by NCI Staff

Two CAR T cells binding to a multiple myeloma cell

The two CAR T-cell therapies approved by FDA for treating multiple myeloma bind to the BCMA protein (blue) on the surface of myeloma cells.

Credit: Adapted from Frontiers in Immunology. August 2018. https://doi.org/10.3389/fimmu.2018.01821. CC BY 4.0.

Patients with advanced multiple myeloma now have a second option for CAR T-cell therapy, a type of personalized immunotherapy. On February 28, the Food and Drug Administration (FDA) approved ciltacabtagene autoleucel (Carvykti) for adults with multiple myeloma that is not responding to treatment (refractory) or has returned after treatment (relapsed).

Under the approval, ciltacabtagene autoleucel, also called cilta-cel, can be taken by people who have already received four or more lines of therapy, including treatment with three major classes of multiple myeloma drugs (an immunomodulating agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody).

The approval was based on results from a small clinical trial in which cilta-cel reduced the amount of cancer in nearly every participant and, for many, kept their cancer in check for more than a year. Like the first FDA-approved CAR T-cell therapy for multiple myeloma, cilta-cel targets a protein on myeloma cells called BCMA.

“Although we do have a lot of treatment options for myeloma … for the majority of patients, the disease still comes back” after each treatment, said Faith Davies, M.D., director of the Center for Blood Cancers at NYU Langone Health’s Perlmutter Cancer Center. Once the available treatments have been exhausted, patients typically live less than a year.

“So having another therapeutic approach in our toolbox is so important,” Dr. Davies added. CAR T-cell therapy “works in a completely different way than our standard treatments and, therefore, it offers a different way of killing [drug] resistant myeloma cells, which really is the key,” she said.

But cost, availability, and the time it takes to manufacture the treatment are limiting factors for CAR T-cell therapy. Cilta-cel has a list price of $465,000 for a one-time infusion, although the final cost to a patient will depend on their insurance coverage. 

Cilta-cel is currently only available at a limited number of hospitals that are certified to offer the complex treatment, though additional hospitals will be added to the list as the manufacturer, Janssen Pharmaceutical, scales up production, according to a company press release. 

Plus, it takes around 1 month to make the personalized treatment—a wait time that may be too long for some patients with very aggressive cancer.

“Impressive” results with cilta-cel

Multiple myeloma is a cancer of blood cells that make antibodies. The cancer can form tumors in the bones and other organs.

The FDA approval was based on findings from CARTITUDE-1, an ongoing clinical trial evaluating cilta-cel in people with multiple myeloma who had already received multiple treatments. 

The 97 study participants received a single infusion of cilta-cel. Nearly all of them (98%) responded to the treatment, meaning it reduced the amount of cancer in their body, at least partially. For 78% of participants, there were no signs of the cancer in their bone marrow or blood on sophisticated tests—what’s called a stringent complete response. Overall, responses lasted for a median of 22 months. 

“To compare, other drugs to date that have been approved [for multiple myeloma] were in the neighborhood of a 30%” response rate , said the trial’s lead investigator, Sundar Jagannath, M.D., of the Tisch Cancer Institute in New York.

For patients who have already received multiple lines of therapy, “having response rates nearing 100% is absolutely unprecedented and is amazing,” Dr. Davies said. And to have responses that lasted for close to 2 years “is very impressive,” she added. 

Importantly, Dr. Jagannath noted, patients typically don’t need additional cancer treatments while they are in remission after cilta-cel. 

“Most of them have been constantly on treatment [because] continuous therapy is important for myeloma,” he explained. For many, the interval after cilta-cel treatment is their first real break from cancer treatment since being diagnosed, which greatly improves their quality of life and well-being, he said. 

What are the side effects of cilta-cel?

Cilta-cel led to side effects that are typical for a CAR T-cell therapy, such as cytokine release syndrome, infections, and nerve problems like pain or tingling (neuropathy).

It “didn’t appear to cause any different side effects compared with other CAR T-cell therapies, so that’s a good thing,” Dr. Davies said.

Side effect Frequency
Cytokine release syndrome 95%
Infections 59%
Low blood platelet count 41%
Low neutrophil count 30%
Nerve problems 26%
Low antibody levels 12%

Some side effects appeared days or weeks after the cilta-cel infusion. In addition, there were seven deaths attributed to the treatment.

Cytokine release syndrome is caused when revved-up CAR T cells dump inflammatory signals into the blood, leading to flu-like symptoms. Although nearly all of the study participants had cytokine release syndrome, the majority of those cases were mild and treatable with steroids or other medicines. 

“We have all learned how to handle [cytokine release syndrome] better. As experience has improved, safety has increased,” Dr. Jagannath explained.

Cilta-cel comes with a boxed warning for six potentially life-threatening or fatal side effects including HLH/MAS (hemophagocytic lymphohistiocytosis/macrophage activation syndrome), a condition also caused by inflammatory signals from CAR T cells. HLH leads to dangerously low blood pressure and multiorgan dysfunction but can be treated if recognized early.

There is also a boxed warning for Guillain-Barre syndrome and parkinsonism, a condition with symptoms that are similar to Parkinson’s disease, such as tremors and slow movement. The research team put a mitigation plan in place for parkinsonism, Dr. Jagannath explained, which appears to be helping to reduce the condition in ongoing studies.

The other warnings are for severe cytokine release syndrome, prolonged periods of low blood counts, and ICANS (immune effector cell–associated neurotoxicity syndrome), a neurologic syndrome that causes alterations in consciousness and problems with brain function.

Two options for CAR T-cell therapy

To make cilta-cel, a patient’s own immune cells are collected and genetically modified to be able to find and kill cancer cells. The souped-up immune cells, called CAR T cells, home in on BCMA, a protein found in high amounts on multiple myeloma cells and a very small subset of healthy blood cells. 

Idecabtagene vicleucel (Abecma), or ide-cel, was the first CAR T-cell therapy to be FDA-approved for multiple myeloma. Ide-cel also targets BCMA, but cilta-cel differs slightly in that the CAR T cells grab onto two sections of BCMA rather than one. 

Now that there are two CAR T-cell therapy options, the big question everyone is asking, Dr. Davies said, is “what are the differences and potential benefits of one over the other?”

It’s too early to know that answer. But the most important thing, Dr. Jagannath said, is that “both CAR T [therapies] work well. Both are serving and helping patients.” 

Right now, the option will simply come down to which one is available, Dr. Davies added. “The demand for ide-cel was so huge, we weren’t able to meet it. So being able to have a second [CAR T-cell therapy] available to use is so important,” she said. 

The possibility of a cure?

According to Dr. Davies, there’s another big question about CAR T-cell therapy for multiple myeloma: Given that the therapies work well for people who have had four or more treatments, would they work even better for people who have had fewer or no prior treatments?

“These therapies work by using the patient’s natural immune system. And with myeloma, by the time patients receive four therapies, their immune system is a little bit beat up,” she explained. A patient who is newly diagnosed and hasn’t received any treatment yet probably has an immune system that is in better shape, she said. 

Another potential advantage of treating newly diagnosed patients with the CAR T-cell therapy, Dr. Jagannath said, is that they are less likely to have cancer cells that are resistant to the treatment.

Dr. Davies mused, “There’s a lot of discussion about if we were to use these therapies earlier in the disease course, would patients maybe have better responses, longer responses, and in some cases be cured?”