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BCMA-Targeted Therapies in MM
How to Apply BCMA-Directed Strategies and the Practical Use of BCMA-Targeted Therapies in Multiple Myeloma

Released: April 25, 2023

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Key Takeaways
  • Use of BCMA-targeted therapies, including CAR T-cell treatment and bispecific antibodies, is paramount in our fight against multiple myeloma.
  • Access to BCMA-targeted therapies for multiple myeloma has been challenging but may improve as we experience fewer manufacturing challenges and more availability at approved centers.
  • Real-world evidence suggests that patients excluded from registrational trials because of comorbidities such as existing cytopenias or renal insufficiency may do well with CAR T-cell treatment. 
  • Infection is a common adverse event with bispecific antibody therapies, but prophylactic care and dose delays may help alleviate concerns.

BCMA, B-Cell maturation antigen, is an antigen present on the surface of myeloma cells. It has become an important target for multiple immune therapies and is paramount in our fight against multiple myeloma (MM). Three strategies have emerged to target BCMA in patients with myeloma: CAR T-cell therapy, bispecific antibody therapy, and antibody‒drug conjugates (ADCs). 

CAR T-cell therapy involves collecting T-cells from a patient and manufacturing them in the lab so that they target BCMA on the surface of MM cells; the engineered product is then multiplied and reinfused into patients to help destroy malignant cells. Bispecific antibody therapies are off-the-shelf drugs designed to bind both a target on the malignant plasma cells by virtue of the BCMA and a target on T-cells (CD3) to help activate the T-cell to facilitate the destruction of the malignant plasma cells. ADCs comprise a monoclonal antibody that is tethered to a cytotoxic agent (also known as a “payload” or a “warhead”) by a chemical linker that is stable in the circulation but releases the cytotoxic agent in the target cell. ADCs are designed to deliver potent cytotoxic agents to targeted tumor cells while minimizing toxicity to normal tissue. 

The following discussion provides insight on access to and current use of these agents, how they may be used in the future, and other exciting new therapies in development for MM.

Access to BCMA-Targeted Therapies

Joseph Mikhael, MD, MEd, FRCPC, FACP: 
Two CAR T-cell therapies targeting BCMA—idecabtagene vicleucel and ciltacabtagene autoleucel—and 1 bispecific antibody targeting BCMA—teclistamab—currently are approved for relapsed/refractory (R/R) MM after ≥4 lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and a CD38-targeted monoclonal antibody. The ADC—belantamab mafodotin—was the first BCMA-targeted therapy to be approved, but in November 2022 it was withdrawn from the US market because of lack of confirmation of activity in a phase III trial. 

These novel treatment options are changing the landscape for R/R MM, but there have been challenges in accessing the 3 currently approved agents in clinical practice. The withdrawal of belantamab mafodotin from the market has further reduced the ease of access to BCMA-targeted therapy.

Suzanne Lentzsch, MD, PhD: 
The withdrawal of belantamab mafodotin is unfortunate because, in my experience, some patients did benefit from the drug, and it was well tolerated, especially in older patients. In clinical practice, we are still learning the best approach for treatment with teclistamab. It is difficult because a close to 10 day hospital stay is required to monitor for cytokine-release syndrome (CRS) after beginning this therapy. In New York, we are challenged to obtain bed availability for this period of time, and smaller practices struggle too with how to integrate teclistamab. Perhaps we will be able to shorten the duration of hospital stay as we gain more clinical experience and have additional data on the best practices for teclistamab administration, but this remains to be seen. Finally, we are not able to use CAR T-cell therapy as much as we would like to because of limited availability, both from a manufacturing capacity and availability at approved centers with a specialized medical team. 

Joseph Mikhael, MD, MEd, FRCPC, FACP: 
I agree. I have the privilege of being connected to multiple centers across the country in the work that I do, and many are trying to find different ways to reduce—or even eliminate—these hospitalization requirements for teclistamab while ensuring that patients do not experience significant CRS, particularly with the first few doses. My hope and goal with these advancements is that we will see bispecific therapies used more extensively in the community without the need to begin therapy in the hospital or academic setting.  

Regarding CAR T-cell therapy, although availability has been challenging, I think we are close to overcoming some of the issues. In terms of manufacturing, we are now competing less with vaccine manufacturing than we have in the past, and I estimate that the challenges in employing qualified individuals to produce the CAR T-cells are likely to be diminished by the end of 2023. In addition, the number of available slots at approved CAR T-cell centers should increase along with the increase in manufacturing capability.

Real world Experience 

CAR T-Cell Therapy Eligibility 

Suzanne Lentzsch, MD, PhD: 
In terms of how we use these available therapies in clinical practice, I think the majority of the data should come from clinical trials, but there have been some helpful studies using real-world data to help confirm some of our clinical decisions. An excellent study by Hansen and colleagues was published recently on 196 patients with R/R MM receiving idecabtagene vicleucel. CRS was observed in 82% of patients, and neurotoxicity was observed in 18%, both of which are consistent with that observed in clinical trials. Response rates also were similar to those observed in clinical trials; the best overall and complete response rates were 84% and 42%, respectively. Furthermore, the median progression free survival (PFS) was 8.9 months, consistent with clinical trial data. Of importance, 77% of patients included in this analysis would not have been eligible for the KarMMa trial based on the inclusion/exclusion criteria. The most common reasons patients would have been ineligible were comorbidities, cytopenias, and prior BCMA-targeted therapy. I think this is very important to note because these represent the patients we see every day, and it is comforting that they can achieve the same outcomes with CAR T-cell therapy.

Sequencing Therapies

Suzanne Lentzsch, MD, PhD: 
Unfortunately, we do not have data from clinical trials to answer the question of whether BCMA-targeted therapies can be used in sequence because in most trials, patients who have received previous BCMA-targeted therapy were excluded. However, some real world data from a study presented at ASH 2022 with 49 patients who received idecabtagene vicleucel after BCMA-targeted therapy showed that the PFS was only 3.2 months after previous BCMA-targeted ADCs and 2.8 months after a BCMA-targeted bispecific antibody. Therefore, these data would suggest that we should not use CAR T-cells after ADCs or bispecific antibodies. 

Joseph Mikhael, MD, MEd, FRCPC, FACP: 
For balance, I think we should mention the data presented by Adam Cohen that assessed use of ciltacabtagene autoleucel after previous BCMA directed therapy. In that study, 20 patients previously exposed to BCMA directed therapy received ciltacabtagene autoleucel, and the overall response rate (ORR) was 60%, which is lower than that seen for patients not exposed to BCMA directed therapy—but still encouraging. I think the lesson from these studies is that it is not ideal to proceed immediately from one BCMA strategy to another, but it can be done, especially when a patient has limited options. 

We have generated some preliminary data in my lab suggesting that different BCMA therapies may have different patterns of resistance—so we may be able to sequence these therapies in some way once we better understand the biological drivers behind resistance. 

Suzanne Lentzsch, MD, PhD: 
One caveat I would like to mention is that one study used idecabtagene vicleucel and the other used ciltacabtagene autoleucel, so there may be differences between these agents.  

Joseph Mikhael, MD, MEd, FRCPC, FACP: 
Yes, we still have more to learn about both of these agents, but in the meantime—and especially for patients who have not been exposed to BCMA therapy—I like to tell patients that it is very much like comparing a Ferrari to a Lamborghini. They are both very good choices, and the overwhelming majority of patients who are eligible will benefit from either CAR T-cell approach.

Renal Insufficiency

Joseph Mikhael, MD, MEd, FRCPC, FACP: 
Although excluded from registrational clinical trials, we also have some real-world evidence of patients with renal insufficiency receiving idecabtagene vicleucel. This is important because approximately one third of patients with R/R MM will have significant renal insufficiency over the course of their disease.

Suzanne Lentzsch, MD, PhD: 
Yes, in the study by Sidana and colleagues, outcomes of patients with renal insufficiency receiving idecabtagene vicleucel vs those without renal insufficiency were similar. Indeed, PFS for patients with vs without renal insufficiency was 8.1 months vs 6.5 months, respectively. These data are important to present not only to patients, but also to insurance companies to increase the probability of coverage. 

Adverse Events

Joseph Mikhael, MD, MEd, FRCPC, FACP: 
In terms of adverse events (AEs), we know there are challenges with both of these drug classes, namely, CRS, neurotoxicity and immune effector cell‒associated neurotoxicity syndrome (ICANS), risk of infections, and hematologic toxicities. Could you share some guidance regarding these AEs with both CAR T-cell and bispecific therapy?

Suzanne Lentzsch, MD, PhD: 
I think we focus so much on CRS and ICANS that we sometimes overlook a prominent AE of bispecific antibodies, which is infection. We learned this from several clinical trials assessing BCMA-targeted bispecific antibodies that had a percentage of patients who became sick, and we were managing infections we had never seen before, such as Epstein-Barr virus, cytomegalovirus, and pneumocystis pneumonia caused by Pneumocystis jirovecii. Based on these experiences, all of the patients in my practice who are receiving a bispecific antibody receive IV immunoglobulin, and patients who are high risk for infection, such as those who are older and frail, receive prophylactic antibiotics. Finally, we counsel patients to let us know if they are experiencing any fever or do not feel well. This is an important message to share with the community, as we anticipate more widespread use of teclistamab. For patients who do experience infection while receiving teclistamab, dose delays until the infection improves to grade ≤1 are effective.

In most of the clinical trials, patients receiving a bispecific antibody were treated indefinitely until progression, and one question we are currently investigating is whether indefinite treatment is necessary. Once remission is induced, it may be possible to stop treatment for a period of time to limit the frequency and/or severity of infections.

Joseph Mikhael, MD, MEd, FRCPC, FACP: 
I agree. As you know, investigators of many of the BCMA directed bispecific antibodies in development are looking at either less-frequent dosing or treatment for only a defined period of time. One of the greatest benefits of CAR T-cell therapy is the fact that it is administered one time and the patient has long-term benefit, so it would be nice if we could get closer to that strategy with bispecific antibodies.  

Future Directions and Concluding Remarks

Joseph Mikhael, MD, MEd, FRCPC, FACP: 
In the future, I think we also will see some data on using these therapies earlier in the disease course. In fact, we already have seen data from the KarMMA 2 Cohort 2A study that were presented at ASH 2022, where idecabtagene vicleucel showed a very strong signal of response in 37 patients who experienced progressive disease within 18 months of initiation of frontline therapy.  

I also think we will see new data on 2 other targets that are being heavily developed in myeloma: GPRC5D and FcRH5. Do you think those agents will have a big role in our use of both CAR T-cells and bispecifics?

Suzanne Lentzsch, MD, PhD: 
I do. Talquetamab is a new GPRC5D bispecific antibody that targets T-cells, and this may allow us to circumvent the problems with BCMA drug resistance. In the MonumenTAL trial, talquetamab demonstrated a promising ORR of >70% in heavily pretreated patients (N = 288), with a nearly 60% very good partial response rate. Of importance, GPRC5D is not expressed on B-cells, so it specifically targets GPRC5D-expressing myeloma cells, resulting in less infection. 

Joseph Mikhael, MD, MEd, FRCPC, FACP: 
I think it is very exciting that if we exhaust BCMA, we may have another target in GPRC5D, both with bispecific antibodies, as mentioned, and with CAR T-cell technology.  

Yet another potentially valuable target for patients with previous experience with BCMA-targeted therapy is FcRH5. Cevostamab, a bispecific T-cell engager antibody that targets both the tumor-associated antigen Fc receptor‒like protein 5 and CD3 on T-cells, is under investigation in clinical trials for patients previously treated with BCMA-targeted therapy.  

Finally, promising data were presented for modakafusp alfa, a first-in-class immunocytokine that uses a fusion protein with a monoclonal antibody targeting CD38 and interferon α-2b to deliver interferon α-2b to MM cells. In that study, the ORR was >40%, despite enrolling several patients with prior BCMA experience.

To conclude, although I think access is a problem in the short term and we need to find ways to sequence BCMA-targeted therapies, having these additional targets will be helpful in the future.  The future is particularly bright in myeloma.  

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