Influencing Factors to Initially Targeting BCMA in MM

Sagar Lonial, MD, FACP: As we begin to see multiple agents that will target BCMA with multiple mechanisms of action, the obvious question comes up about sequencing. How do you choose which one to use when? The reality is that, while many of the cell therapy enthusiasts may say, “CAR [chimeric antigen receptor] T cells are the answer. That is the only way we should go,” we know that certain patients cannot wait 6 to 8 weeks to get CAR T-cell therapy. We know, for instance, that not every patient wants to go in the hospital and experience the potential risk of cytokine release syndrome [CRS], or even be in the hospital at all. Each of these 3 mechanisms that target BCMA have their own relative advantages or disadvantages.

For instance, belantamab mafodotin is an easy off-the-shelf administered approach that does not require hospitalization, but it does require partnering with an eye care professional, and it can be associated with some keratopathy or ocular toxicity. There are pros and cons of each of those drugs.

CAR T cells require a manufacturing period and a strategy for bridging for many patients who may have refractory myeloma. They also require admissions to the hospital, chemotherapy for lymphodepletion therapy, and potential complications associated with CRS, including ICU [intensive care unit] stays or other potential prolonged hospitalizations as well.

The bispecifics or T-cell engagers, while they may not be as intense as the CAR T cells, they may often require hospital stays as well, and many patients, again, do not necessarily want to do that. There is a risk of CRS, but again, it is an immune-based therapy that appears to be potentially easier to give than a CAR T cell. It is a decision and a discussion that we are going to have with our patients about where they are in their specific journey as to which agent we choose at which different time.

I cannot tell you that I have an ideal patient for each of these drugs, but we make those decisions. It is unlike other drugs where, if you target 1 antigen, such as CD19 or CD20, you do not necessarily come back with a different drug. As I mentioned earlier, we do not lose BCMA expression with progression in most cases. If one drug does not work, you may be able to go to a second class or a third. You are not precluding exposure to one of these different mechanisms by using one of them earlier or later.

When we talk about the ultimate goal, it is to bring these treatments to earlier and earlier lines of therapy and eliminate the need for treatment for relapsed disease. Understanding how CAR T cells, bispecifics or T-cell engagers, and antibody-drug conjugates may be best used in the newly diagnosed setting will require us to revisit a total therapy-like approach. It may be that the ultimate treatment is an IMiD [immunomodulatory drug], a PI [proteasome inhibitor], and BCMA-directed therapy for a few cycles, then consolidation with an anti-CD38 antibody, then consolidation with high-dose melphalan, and a maintenance approach to get patients to MRD [minimal residual disease]-negativity. These may all involve different drugs, so by using these different noncross-reactive drugs, we may ultimately be able to get patients to MRD-negativity and cure them earlier in the disease course. How do we bring all of these approaches into earlier lines of therapy? This is the challenge for me and many others who deal in myeloma, and it is a challenge I look forward to because more treatment options are always better than fewer.

Natalie Callander, MD: As researchers, we would always recommend that a patient be considered for a clinical trial of some BCMA-targeting agent if it is available. If it is not, then how people end up making some of these decisions has to do with the state of the patient. Most of the available CAR T products need some time for the manufacture of the cell, so if a person has an aggressive relapse and is not particularly stable, then an off-the-shelf product is probably a better approach, and right now, that is belantamab, so that is what a lot of people would turn to.

What we do not yet know is if there is an ideal order for these different BCMA-targeting therapies. Should you use one before another, or will that make a difference? Because of the way CAR T is being used in earlier lines of therapy, we are going to soon have an opportunity to find out if that BCMA-targeting approach does not last, or if we can use another BCMA-targeting agent if a patient relapses. There are data that BCMA can be downregulated on myeloma cells but that they come back. This has been researched a bit in patients who have received CAR T-targeting BCMA, and it has been shown that, over time, their myeloma cells will lose BCMA. But with further observation, that antigen comes back again, so that means that another BCMA-targeting drug would be useful, we would hope.

Everybody is interested in getting into that area of using BCMA for newly diagnosed patients. As I mentioned, there is a belantamab mafodotin trial that is looking at VRd [bortezomib, lenalidomide, dexamethasone] for patients with newly diagnosed myeloma. There is the KarMMa-2 study that is looking to incorporate CAR T for patients who have high-risk myeloma who we know are subject to relapse fairly quickly after an autologous transplant. The BMT CTN [Blood and Marrow Transplant Clinical Trials Network] is planning to use CAR T for either an early biochemical progression after an autologous transplant, or lack of having more than a VGPR [very good partial response].

We are hopefully going to have a high-risk trial as well, so that question is going to be answered. We are ultimately hoping to have a design where one of the bispecific engagers like teclistamab could be incorporated as an additional consolidation step following treatment either with or without an autologous stem-cell transplant. I suspect that, for all of those areas, we are going to see lots of research in the next couple of years.

With this whole area of specifically targeting antigens on myeloma cells, we have had 2 already available. We have had anti-CD38 drugs, and anti-SLAMF7, which are daratumumab, isatuximab for CD38, SLAMF7 for elotuzumab respectively. We now have belantamab mafodotin for BCMA. You are going to be seeing other targets emerging. There is GPRC5D, which is being developed as a CAR T target, and some others. We are going to see more and more of this kind of immunotherapy. It is not going to replace some of our good drugs like IMiD drugs or proteasome inhibitors, but more and more, this is going to be a step that patients receive treatment, either in the first line or early after a progression.

Transcript Edited for Clarity