Three new therapeutic targets have been identified in the late-relapse setting: BCMA, GPRC5D, and FcRH5; however, there are many questions that still need to be answered with regard to these targets, with sequencing being an obvious one. I think that the real challenge over the next few years will lie in gaining an understanding of how to organize our approach with these great new targets, so that we will ultimately have a different paradigm of curative therapy. 

How do we identify which patients may benefit more from one target vs another, or from one modality vs another (eg, bispecific antibodies vs chimeric antigen receptor [CAR] T-cell therapy)? Currently, there is still a lot to be learned in this area. We also need to determine the role of the new cereblon E3 ligase modulators (also known as CELMoDs), such as iberdomide, in augmenting or sustaining a response to a bispecific antibody or even to a CAR T-cell agent. 

We are fortunate to have new targets in multiple myeloma, and the hope is that we would have the opportunity to intervene against these targets in most patients. However, dedifferentiation can occur in very late-stage multiple myeloma, whereby the multiple myeloma cells begin to lose more of their resemblance to plasma cells. These cells have lost that innate programming to do what plasma cells would normally do in that situation. Complicated molecular changes of both the tumor and the immune cells in the bone marrow may be taking place, leading to resistance. In that situation, we need to learn what the resistant cells are really being driven by. How can we better understand this to, perhaps, tailor treatment earlier in the disease course and eliminate those clones from ever being left over?  

To me, probably the most promising research area in immuno-oncology is immunogenic cell death, which can be described as the process of the dying multiple myeloma cell triggering an immune response against multiple myeloma. We are learning about how some of the current agents that we use in multiple myeloma, such as proteasome inhibitors, can induce immunogenic cell death. We are also learning that there is an absence of immunogenic cell death in high-risk multiple myeloma that is multiply relapsed. 

It appears that this lack of immunogenic cell death is, at least in part, mediated by genes on chromosome 17p, with p53 being the traditional one. While the concept of immunogenic cell death is relevant in multiple myeloma, it is also important in other cancers, as p53 mutation and 17p deletion are high-risk features of many other different types of cancers. Thus, understanding how we can induce this immune response in patients against their own multiple myeloma is a very promising future research area. 

We have seen that we can get to minimal residual disease (MRD) negativity with or without transplantation, with bispecific T-cell engagers and with CAR T cells. Now, I think that we need to focus on the ability to induce an immune response in these patients, preferably a memory immune response. If that occurs, we could not only reach MRD negativity but also have prolonged MRD negativity and even a potential cure for patients with multiple myeloma. 

So, in conclusion, I think that the future is exciting with the new drugs that have been mentioned, but we need to think outside the box and try to exploit our natural immune system as well. The best is yet to come in multiple myeloma.

Determining how to best sequence the various agents that we currently have available is very difficult. Trials assessing sequencing are challenging to conduct for many reasons; for instance, they require careful planning and flexibility, and they take time to generate actionable data. It will also take time to determine where in the disease course CAR T-cell agents and bispecific antibodies should be added to the treatment pathway. 

Another challenge lies in determining how to sequence different approaches that make use of the same target. For example, idecabtagene vicleucel, ciltacabtagene autoleucel, and teclistamab all target BCMA and have been approved by the US Food and Drug Administration for late-relapsed multiple myeloma. How should these different agents and modalities be used in patients with relapsed or refractory disease? To what extent should their availability and convenience guide decision making? Are there data indicating that one approach, or sequence, might be better than another? Further, if one treatment is not working, what is the possibility that the other treatment would work? And if it does work, how long will it work? 

Currently, we do not have definitive answers to these questions, nor do we have data on cost-effectiveness. These are some of the issues that we will be wrestling with in terms of the competitive landscape.