CAR-T Cell Therapy May Have ‘Big Future’ in Relapsed/ Refractory Multiple Myeloma

Carvykti (ciltacabtagene autoleucel), a chimeric antigen receptor T (CAR-T) cell therapy, has induced early, durable responses and manageable side effects in patients with relapsed/refractory multiple myeloma who were previously heavily treated. The results led to an approval by the Food and Drug Administration (FDA) on February 28, 2022, making Carvytki the second CAR-T cell therapy available for this patient population.

The phase 1/2b study included 97 patients (58.8% male; median age, 61 years) who had at least three prior lines of therapy or were refractory to a proteasome inhibitor and immunomodulatory drug. Dr. Thomas G. Martin, lead author on the study and associate director of the myeloma program at the University of California, San Francisco, said in an interview with CURE® that most patients in this study had six prior lines of therapy and became refractory, “which is where we get into trouble.” The patients had exhausted all other treatment options, so to have another option was important for this population.

In the study, patients received a single Carvykti infusion five to seven days after chemotherapy.

Martin explained that CAR-T cell therapy is an immunotherapy where T cells are taken from the patients and, using gene therapy, are trained to be “professional myeloma killers,” by now targeting a protein, BCMA, on the outside of the cell surface. This is one of the first studies using BCMA-targeted CAR-T cells for these patients, he said.

“It’s the first step in what’s hopefully going to be a big future for these CAR-T cells in the treatment of multiple myeloma,” he added.

DURABLE RESULTS

Study results, which were presented at the 2021 American Society of Hematology (ASH) annual meeting, demonstrated an objective response rate (the rate of measurable response to treatment) of 97.9%. Additionally, 82.5% of patients achieved stringent complete response and 94.9% achieved a very good partial response (a decrease in tumor size or the amount of cancer in the body as a response to treatment) or better.

“This study shows the highest response rate in these patients that’s ever been achieved,” Martin said.

He explained that only two patients did not qualify as having a response, and one of them was deemed as having unmeasurable disease in the beginning. However, that patient still remains in remission. “Honestly, there’s only one patient who perhaps did not have a response to this therapy. (This is) amazing in this really heavily pretreated population,” he said.

The median time to first response was one month, 2.6 months to best response and 2.9 months to complete response or better. The median dura- tion of response was not estimable. And of 61% of patients who were evaluable for minimal residual disease (MRD; the small number of cancer cells in the body after treatment), 91.8% were negative.

The 18-month progression-free survival (or time during and after treatment when the patient lives without disease progression) was 66%, and for those who sustained MRD for at least six months and at least 12 months, it was 96.3% and 100%, respectively. The overall survival rate (patients with cancer who are still alive after treatment) was 80.9%.

Results demonstrated that 60.5% of patients remained in remission at a 24-month follow-up. Martin said the average remission duration is going to be more than 24 months and may approach 30 months or beyond.

“What we showed at the ASH meeting was that responses were again durable, essentially lasting longer than any other therapy tested in this relapsed/refractory population. ... This is really dramatic and the best responses and the best results ... we’ve ever seen in this population,” he explained.

SIDE EFFECTS

The most common severe side effects occurred in at least 25% of patients and included low white blood cell counts such as neutropenia (94.8%), leukopenia (60.8%), thrombocytopenia (8%), lymphopenia (49.5%) and anemia (68%).

Martin said that patients are often apprehensive because the side effects can be significant. However, when he asks patients which had worse side effects, the CAR-T cell therapy or autologous stem cell transplant, they uniformly say the transplant.

Mild or moderate cytokine release syndrome (when a particular protein overstimulates the immune system so that it attacks healthy organs) occurred in 94.8% of patients but was resolved within two to seven days with medicines, Martin said, compared with side effects from a transplant, which can last one to three months.

“I don’t worry so much about the side effects. We have great treat- ments, and we generally have ways to mitigate all the side effects of CAR-T cell therapy,” he added.

Martin explained that prior to CAR-T cell therapy, patients receive chemotherapy that suppresses the immune system to create room for the incoming T cells, also contributing to the ongoing immunosuppression. But it is necessary for T-cell expansion and allows the T cells to better kill the myeloma.

“I tell people that the initial chemotherapy acts to rid the ‘immune bunkers’ that are sitting all over your body and in lymph nodes, bone marrow, etc., to make space for those CAR-T cells, which grow and amplify in those bunkers and then kill the myeloma cells,” Martin said. “We have to do this chemotherapy, but it also makes people’s immune system quite low.”

When CAR-T cells are given, they are strictly focused on targeting myeloma, not other infections such as the flu or COVID-19. Additionally, the CAR Ts can knock off normal plasma cells, and these cells make antibodies to protect one’s body against viruses. Many of these patients require supplemental intravenous gamma globulin infusions (IVIG) in the first six months of CAR-T cell therapy and will also utilize antibiotics to help prevent a shingles reactivation or pneumonia.

“The first three to six months after a CAR-T (therapy), people are at risk for infection and we want them to just be careful. ... Patients feel well and feel like doing a lot of stuff, but in today’s world, they have to focus on being safe and staying local. ... Patients can certainly go outside, can still exercise and spend time with family but need to discuss additional freedoms with their CAR-T cell providers,” he said.

LIMITATIONS AND OPTIMISM FOR THE FUTURE

One downside to CAR-T cell therapy is that it is recommended that patients visit a cancer center with experience in administering these treatments. There are only 70 to 100 of those in the United States, so not everyone has access to it, Martin said. It’s also not an “off-the-shelf” therapy; thus, it takes time to prepare and manufacture the CAR-T cells. In fact, it could take up to four to six weeks, and some patients cannot wait that long for this therapy.

However, Martin said, this is not the only therapy that is performing well in this patient population, and there is much to look forward to.

“What’s exciting is that now we (have) many other immune therapeutics that are being developed in this patient population. Many are being tested in phase 1 trials, but several have progressed to phase 2. Most exciting are the T-cell-engaging antibodies, where one arm of the antibody targets and anchors
the antibody to a protein on themyeloma cell surface like BCMA, and the other arm binds to and activates T cells in the local environment. The activated T cells kill the myeloma cells. These agents are showing remarkable responses and thus optimism for their use” he said.

He said these other therapies can take the place of CAR-T cell therapy, especially for those who don’t have access or may not be fit enough for CAR-T cell therapy. Early results suggest that patients can still achieve a deep remission with these T-cell- engaging or bispecific antibodies.

Martin remains very optimistic about the future of multiple myeloma treatment because of these early positive results. All the currently approved drugs for multiple myeloma have previously shown single-agent responses rates between 20% and 30%; that was the previous bar for drug development, Martin said. So, to have this CAR-T cell therapy show responses rates greater than 90% as a single agent is a big advance for myeloma. Other studies testing different CAR-T’s have also demon- strated good results with response rates between 80% and 90%. He also highlighted bispecific T-cell-engaging antibodies, which are demonstrating single-agent response rates between 55% and 85%.

“This is a whole new level of activity with all of these new drugs and therapies,” he added.

Martin explained that when they test these drugs in patients with refractory disease and it works so well, they want to bring it to earlier lines of therapy. So, these drugs are now being used in patients who previously received one to three lines of therapy, and soon they will be tested in newly diagnosed multiple myeloma, he said. Martin noted the future is quite bright for these therapeutics throughout the myeloma treatment continuum.

“I don’t think there’s ever been a time in myeloma therapy where we have such optimism for our next generation of drugs,” he concluded.

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