When to Implement Innovative New Therapies

  • It is sometimes difficult to determine whether a patient should begin treatment with a CAR T-cell therapy or a bispecific antibody. Several factors must be considered in making the choice.
  • Dr. Joshua Richter, of Mount Sinai, tells SurvivorNet Connect that sometimes the choice comes down to what’s available. CAR T therapy tends to yield better results, but it takes time to prepare and comes with more severe side effects.
  • “In an optimal environment, we try to place CAR T in front of bispecific antibodies,” Dr. Richter explains. “But sometimes we can’t wait for the four to eight weeks to manufacture and quality check a CAR T. Sometimes patients need treatment immediately.”

CAR-T cells and bispecific antibodies have revolutionized the treatment of relapsed and refractory multiple myeloma, providing new hope for patients who have exhausted other treatment options. While each approach has its advantages and challenges, the development of these therapies marks a significant step forward in the battle against this incurable disease.

SurvivorNet Connect spoke to Dr. Joshua Richter, an associate professor of medicine at the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, and the director of myeloma at the Blavatnik Family Chelsea Medical Center at Mount Sinai, about the benefits and further expectations with these therapies.

“With all of these different options, we do not always know what the optimal path is. And we do say that anything from a Tylenol to a transplant carries risks and benefits. So with multiple answers at each transition point we discuss the different options in their individual risks and individual benefits. But ultimately as we try to think about each potential option, we want to try to put our best foot forward. Because even though we have had multiple approvals from the FDA across the last decade, the average myeloma patient in the United States only gets three to four lines of therapy.

“And what this really means is: if you’re saving a drug or a therapy, that you think is optimal, and you’re saving it for a rainy day, the problem is that rainy day doesn’t always come. So if you think you have an option for a patient that is ideal, don’t save it for fourth, fifth or sixth line, they’re not likely to get there. Move this up to earlier lines of therapy, which is exactly our approach for CAR Ts.”

Comparing CAR T-Cells and Bispecific Antibodies

Among the most promising of these newer therapies are Chimeric Antigen Receptor (CAR) T-cell therapies and bispecific antibodies. Both treatments offer a more targeted approach, aiming to improve patient outcomes, but they differ in terms of their administration, efficacy, and safety profile:

  • Efficacy: CAR T therapies generally offer higher response rates and deeper remissions compared to bispecific antibodies, but this comes at the cost of more severe side effects.
  • Toxicity: Both treatments are associated with cytokine release syndrome, but the risk is higher and more severe with CAR T therapies.
  • Accessibility: Bispecific antibodies are more accessible, both in terms of cost and ease of administration, as they do not require individualized manufacturing.
  • Duration of Response: CAR-T therapies often provide durable responses, with some patients experiencing long-term remissions. However, ongoing studies are evaluating how bispecific antibodies perform over longer periods.

“When it comes to deciding between things like the bispecific antibodies and the CAR Ts, one of the principles we think is what is available to you at the moment. What you have is the best one,” Dr. Richter explains.

“What we know at the moment is that in an optimal environment we try to place CAR T in front of bispecific antibodies. But sometimes we can’t wait for the four to eight weeks to manufacture and quality check a CAR T. Sometimes patients need treatment immediately. So if you need treatment immediately today, I can’t give you a CAR T today. I can give you a bispecific antibody today. And we really need to kind of focus on what is the optimal strategy in the short term as well as the long term”

Chimeric Antigen Receptor (CAR)-T Cells: A Revolution

CAR T-cell therapy involves modifying a patient’s own T cells to recognize and attack cancer cells. In multiple myeloma, the most prominent targets for CAR-T cell therapies are B-cell maturation antigen (BCMA), a protein expressed on myeloma cells. The two FDA-approved CAR-T cell therapies for multiple myeloma, Abecma (drug name ide-cel) and Carvykti (drug name cilta-cel), have shown remarkable efficacy in heavily pretreated patients​.

In the process, T cells are collected from the patient, genetically engineered to express CARs that specifically target BCMA, and then expanded and reinfused into the patient after a lymphodepleting regimen. This approach enables the modified T cells to seek out and destroy myeloma cells that express BCMA.

Clinical Efficacy

Clinical trials for both ide-cel and cilta-cel have demonstrated impressive results. For example, ide-cel has shown response rates of around 80% in patients who had received at least three prior lines of therapy, including an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 antibody​. Cilta-cel has produced even more robust outcomes, with some trials reporting response rates as high as 97%, including a significant proportion of patients achieving a stringent complete response (sCR).

Adverse Effects and Considerations

The most significant adverse effect associated with CAR T cell therapy is cytokine release syndrome (CRS), which results from a rapid and massive immune response to the activated T cells. CRS can range from mild flu-like symptoms to life-threatening conditions, including severe hypotension and multi-organ dysfunction. Tocilizumab, an IL-6 receptor antagonist, is often used to manage severe CRS. Neurological toxicities, including confusion, seizures, and encephalopathy, have also been reported in a subset of patients.

Given the complexity of manufacturing and administering CAR T therapies, these treatments are available only at specialized centers. The process involves a long lead time for manufacturing the CAR T cells, and patients must be closely monitored for several weeks post-infusion.

Bispecific Antibodies: Dual-Targeting for Enhanced Efficacy

Bispecific antibodies are another innovative treatment for multiple myeloma, designed to simultaneously engage T cells and myeloma cells. These antibodies have two distinct binding sites: one attaches to BCMA on myeloma cells, while the other binds to CD3 on T cells. This dual targeting directs the patient’s immune system to attack and kill the myeloma cells directly.

One of the most notable bispecific antibodies in development for multiple myeloma is teclistamab (brand name Tecvayli), which targets BCMA and CD3. By recruiting T cells to attack myeloma cells, teclistamab creates an immune synapse, facilitating the destruction of the cancer cells

Clinical Efficacy

Clinical trials have demonstrated promising results with bispecific antibodies. Teclistamab, for example, has shown response rates of 60-70% in patients with relapsed or refractory multiple myeloma who had previously been treated with a proteasome inhibitor, immunomodulatory drug, and anti-CD38 antibody​. These response rates, though slightly lower than CAR-T cell therapies, offer a significant option for patients who may not be candidates for CAR T therapy due to age, comorbidities, or logistical reasons.

Safety and Administration

Bispecific antibodies, like CAR-T cells, are associated with a risk of cytokine release syndrome (CRS). However, CRS with bispecific antibodies tends to be milder and easier to manage than with CAR T-cell therapies. Infections, particularly viral infections such as herpes zoster, are also common, making prophylactic antiviral therapy a standard part of treatment with bispecific antibodies​.

The administration of bispecific antibodies is generally easier than CAR-T cell therapy since they do not require complex manufacturing and can be given as an outpatient infusion. This makes them a more accessible option for a wider range of patients.

Determining Which Bispecific or CAR T to Use

This is the million dollar answer. Dr. Richter explains that if all the circumstances are right, CAR T therapy is the first choice. But there are many circumstances when it simply cannot be given.

“This is an evolving field. At the time of this recording, we have five FDA approved T-cell redirection therapies: two CAR Ts and 3 bispecific antibodies. Both CAR Ts target BCMA. Two of the three bispecifics target BCMA and one of the bispecifics targets GPRC5D, which is another antigen that’s expressed on all plasma cells.

“So if I need to treat someone today who’s relapsing and I have all five of these in front of me, if the relapse is slow and we have time to make this decision and the patient is young enough and fit enough for a CAR T, I will push towards a CAR T first,” he explains.

“If the patient is never going to get a CAR T because they’re older or frailer, then I typically give one of the BCMA-directed bispecific antibodies first, either elranatamab (brand name Elrexfio) or teclistamab (brand name Tecvayli).

“But if the patient is young enough and fit enough for a CAR T, but their disease is growing fast and we don’t have time to get them a CAR T. I will start off with Talvey (drug name talquetamab), which targets the GPRC5D and allows us to not only gain control of the patient’s disease but save that BCMA targeting for a little further down the line when their disease may be a little more controlled and allow us the time to create and administer either Carvykti (drug name ciltacabtagene autoleucel) or Abecma (drug name idecabtagene vicleucel).”