Sequencing BCMA Therapies with Dr. Joshua Richter

Dr. Joshua Richter, a multiple myeloma specialist at Mount Sinai in New York, sees treating multiple myeloma as a chess game. Although he admits he's horrible at the game of pawns and queens, years of practice and participation in key myeloma research have allowed him to be a talented player in treating today's myeloma. 

"It's really about thinking several moves ahead," says Richter, "I never plan a line of therapy for a patient without thinking what I'm going to do next, or what I'm going to do after that, or even after that." 

With this philosophy, it's no surprise that Dr. Richter stays current with the latest treatments in multiple myeloma, including the BCMA-targeted immunotherapies that are starting to change how myeloma is treated. 

Watch his presentation on this important topic here or read the summary below: 

What is Immunotherapy? 

Immunotherapy is the general term for relatively new and innovative cancer treatments that come after years of dominance from drug classes such as proteasome inhibitors (like Velcade), immunomodulatory drugs (like Revlimid), and monoclonal antibodies (such as Darzalex). While these "old-school" drugs still have an important role to play when treating multiple myeloma, these new immunotherapies (BCMA targeted or not) provide new and exciting stand-alone or combination treatments to fight myeloma. 

Did you know? Every person's body creates cancerous cells within our body every day. But because of our immune systems, most of those cancer cells are eradicated or kept at bay by our excellent immune systems. Just think about it! In this new age of myeloma therapy, the best cancer fighter is being recognized as our own immune system.

Which of These Immunotherapies Target BCMA? 

The following are currently approved FDA therapies (as of April 2023) that are considered to be BCMA-targeting immunotherapies: 

CAR T-Cell Therapies 

• idecabtagene vicleucel (ABECMA, approved March 2021) 
• ciltacabtagene autoleucel (CARVYKTI, approved February 2022)

Bispecific Antibody Therapies 

• teclistamab (TECVAYLI, approved October 2022) 

Another treatment targeting BCMA on myeloma cells was Blenrep, an antibody-drug conjugate. It was recently withdrawn from the market in November of 2022 but could potentially return. 

While these are the only currently approved myeloma therapies specifically targeting BCMA, many more are likely to be approved if their pending clinical trials show promising results. This is exciting news for myeloma patients whose options used to be slim but now seem ever-expanding.

Understanding Anti-BCMA Bispecific Antibody Therapy 

As of April 2023, there is currently only one FDA-approved bispecific antibody targeting BCMA in myeloma cells, teclistamab. It's had successful results in myeloma. 

Many others are on their way to approval. For example, Elrantamab has been filed with the FDA, and specialists hope to see its approval in late summer or early fall of 2023. Another contender, Alnuctamab, is expected to be submitted to the FDA this year, and others remain in the works with clinical trials. 

Currently, CAR T-cells are taking a long time to remanufacture. They often take longer than myeloma patients can afford (although this is something that is being worked on). Theoretically, bispecific antibody therapies have an advantage over CAR T-Cell therapy because they are off-the-shelf therapies. This means there is a shorter turnaround time from the time that your doctor prescribes your medication/treatment to the time that you actually receive it.

However, bispecific therapy administration is not without inconvenience. Those receiving bispecific therapy for the first time must receive their first doses in the hospital to be monitored for any CRS (cytokine release syndrome) effects. This is something that they are working to improve and is not expected to be a permanent solution.

Teclistamab, available at myeloma centers, is administered subcutaneously (an injection). This drug shows relatively high response rates (63%) in those who have received many previous lines of therapy. It's given once a week until progression or intolerability; however, in ASCO and EHA this year, data will be presented supporting administration every two weeks and potentially every four. They also hope to find a point at which therapy can be stopped, and patients can be monitored without drug interference. 

Elrantamab is the second BCMA antibody before the FDA, awaiting approval. It also shows exceptional response rate levels in those with heavily treated multiple myeloma at 64%. The median duration of remission with this therapy is 17 months. Be aware that this treatment, like many other immunotherapies, does put you at risk for infection. That said, as always, specialists will be mindful of this risk and provide prophylactic prescriptions to lower that risk and hospital administration for your first doses. 

Bispecific therapies also show incredible promise when combined with other existing myeloma therapies. The response rates are shooting up in the early relapse setting at incredibly successful rates (93%). These promising results really give hope for the future. 

Understanding CAR T-Cell Therapy

As mentioned above, there are two currently approved CAR T-Cell therapies. Because they've had more time on the market than bispecific therapies, more clinical trials have been done to indicate the success of their use earlier in myeloma treatment. 

The KARMA 3 study showed that when the disease returns in an earlier setting, it is more efficacious to give a CAR T-Cell therapy instead of the typical Dara/Pom regimen many specialists prescribe for relapsed/refractory myeloma.

The CARTITUDE-2 study yielded a 100% response rate for patients who experienced early relapse. This means they received standard-of-care treatment, but their responses did not last. This level of response is not only incredibly exciting for patients and community members alike, but it's monumental in being able to provide CAR T at earlier intervals of myeloma treatment and not waiting to use it as an end-of-the-line procedure. 

How Do We Sequence These Therapies? 

Now that we are familiar with these anti-BCMA therapies, the question remains, "How do we sequence them?" 

Researchers used to be concerned that targeting BCMA through different therapies would lead to antigen loss. In other words, the myeloma cell would outsmart the medications by removing the BCMA antigen/marker from its surface, thus making it impossible to target. However, the mechanism of resistance for a lot of these therapies is not antigen loss, and the problem actually resides with T-Cell exhaustion. 

Therefore, theoretically, BCMA therapies can be given back to back without risk of antigen loss, but we still need answers on how to sequence them most effectively. 

Should specialists give a bispecific and a CAR T? Or a CAR T and then a bispecific? And does it matter? 

To answer this question, Dr. Cohen at UPenn and other international collaborators looked at patients receiving CAR-T Therapy Cilta-Cel (CARVYKTI) who had previously received another BCMA-targeted therapy. These previous treatments were either belatamab-mafadotin (BLENREP) or another bispecific therapy. 

While the response rate for those that had received previous BCMA targeted therapy (particularly those that received a bispecific therapy) were marginally lower, the response rates for those patients remained optimal, many achieving a durable response from their CAR T. 

The time from the last BCMA therapy plays a significant role in how successful your second BCMA-targeted therapy will be. For example, if you received a CAR T a year or two ago and are now relapsing, you could expect a good response from a bispecific.

Many trials remain in the works to answer not only this but similar questions that could change the way we treat myeloma as a whole. Stay tuned and look for clinical trials near you to accelerate this type of myeloma research. 

Learn more as you hear questions from our audience and Dr. Richter's excellent answers to those questions here: 

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