Intriguing BCMA-Targeted Therapies Move Through Myeloma Pipeline

David E. Avigan, MD

Investigators are exploring various treatment modalities in the multiple myeloma pipeline, many of them using BCMA as a target because of its high expression on myeloma cells, explained David E. Avigan, MD.

“[BCMA] is a highly expressed, conserved target in plasma cells that is not seen in epithelial tissues and other areas where you would see toxicity from cross-reactivity,” said Avigan, a professor of medicine at Harvard Medical School and active staff in Hematology-Oncology at Beth Israel Deaconess Medical Center, both in Boston, Massachusetts.

For example, the phase I DREAMM-1 trial explored the BCMA-targeted antibody—drug conjugate (ADC) belantamab mafodotin (GSK2857916) in patients with relapsed/refractory disease. Results showed that the overall response rate (ORR) was 60.0% and included 3 complete responses and 2 stringent complete responses.¹ Additionally, the median progression-free survival was 12 months, and the median duration of response was 14.3 months. Common adverse events were thrombocytopenia and corneal events. However, the drug was well tolerated overall and demonstrated a rapid, deep, and durable response in heavily pretreated patients with relapsed/refractory multiple myeloma.

For the phase II DREAMM-2 study, GlaxoSmithKline, manufacturer of belantamab mafodotin, announced that the ADC met the primary end point of a clinically meaningful ORR in patients who were refractory to treatment with an anti-CD38 antibody, a proteasome inhibitor, and an immunomodulatory drug.²

In an interview with OncLive during the 17th International Myeloma Workshop, Avigan discussed the different modalities targeting BCMA and other targets in multiple myeloma.

OncLive: Could you provide an overview of the modalities being investigated in multiple myeloma?

Avigan: This is a transformative time for these immune-based therapies in multiple myeloma. We are still in a discovery phase, but we are seeing really exciting results that we have to understand, integrate, and ultimately adopt as part of how we approach our treatment paradigm for patients. We need to look at a variety of strategies, consider them individually, and then decide how we would use them or sequence them together.

Chimeric antigen receptor (CAR) T-cell therapy has been transformative in lymphoproliferative diseases, specifically acute lymphocytic leukemia and non-Hodgkin lymphoma. [CAR T-cell therapy] is now being examined in multiple myeloma, specifically with a focus on BCMA as a target. BCMA is expressed predominantly in plasma cells, making it a good [target].

The results, to date, with CAR T cells have been somewhat variable, depending on the exact construct. We have seen very high response rates, even in patients with advanced disease. The real question now is how durable the response is. Results of one of the longer follow-up studies had suggested a median time of response of about 12 months, with a little bit less [duration of response] in patients with advanced disease. That is exciting and offers a tool we didn’t have previously to take care of patients. It shows there is progress to be made in terms of understanding why patients are relapsing and what we can do to preserve response.

A lot of focus is on understanding how we would integrate CAR T cells into those patients with advanced disease and understanding patterns of resistance, as well as what we could change in terms of relapse. Additionally, we are exploring whether a role exists for moving [CAR T-cell therapy] up in the therapeutic sequence and whether that will provide a longer response. There is real potent activity [with this approach], but we still need to answer some questions.

Other approaches that we’re looking at include bispecific T-cell engagers (BiTEs). This is very exciting [area of research], with evidence of response in patients with advanced disease showing a real clinical meaning to the immunologic response that we’re seeing. We still need to consider durability of response and toxicity.

Work is also being done with ADCs, which are a different type of therapy. The antibody binding has a poison tail that helps target BCMA-expressing cells. We have seen exciting data, and we’re getting some response rates, but some toxicity issues exist. No studies have examined how to integrate these different approaches [into practice], but there is some promise that newer targets and molecular poisons will be [further investigated].

Lastly, vaccines are trying to drive immune responses within the patient. One of the most prominent examples involves the dendritic cell with a fusion vaccine, which is a hybrid between dendritic cells and the patient’s own tumor. This [approach] was shown to improve response rates in patients who had partial responses after a homologous transplant. Additionally, [vaccines] are now being evaluated in a large randomized trial with cooperative groups to compare vaccine plus maintenance therapy versus maintenance therapy alone.

There are also exciting ideas for integrating some of these treatments. [For example,] a vaccine and a CAR [could] work together to avoid escape and resistance with checkpoints, but the combination has not been effective in myeloma and has toxicity issues. However, other combinations create more durable responses.

How is BCMA currently being used as a biomarker?

In trying to understand the best approach to an immune-based therapy, you must ask whether you have an ideal target, which is defined as something that differentiates between malignant cells and normal cells. We can tolerate some targeting of normal cells, such as B cells or plasma cells, if they are the only cells being targeted and not more vital tissue; however, we have seen issues over time if a patient never has B-cell or plasma cell recovery.

One of the aspects of the target is how to differentiate between the normal and abnormal cells, which would give you the therapeutic windows. How uniform are the expressions? It might be expressed, but does that mean 100% or 50% of the tumor cells expressed it? What is the susceptibility to the development of antigen-negative variants? For example, a whole cell vaccine that’s hitting multiple targets may be better than a single-antigen target.

The target is important, and BCMA is a good target in terms of differentiating plasma cells from many other cells in the body. However, it is not perfect. Eliminating all BCMA cells for a long period has toxicity consequences. We’re trying to figure out whether we need to combine targets and how to best work with that.

What makes BCMA an ideal biomarker?

We are looking at other targets in malignant plasma cells, but [BCMA] is expressed at relatively high levels. There was some thought that [targeting CD19] might be effective because it targets the more primitive stem cell population in myeloma, but the majority of cells didn’t express it, which created challenges. BCMA is richly expressed and might be important to the myeloma cell life cycle, but it probably is not perfect as a single antigen.

The DREAMM-1 trial reported responses in patients with relapsed/refractory multiple myeloma who were treated with belantamab mafodotin, an ADC against BCMA. What is the significance of these early data?

[The agent] has a promising initial response rate. We’re still trying to understand the durability of response. There was some toxicity that we’re now trying to figure out. From what I understand, the toxicity is relatively transient, but it still can affect some vital function aspects of quality of life for patients. We’re still trying to understand how to manage the toxicity and learn how durable the response is.

How is a deeper understanding of BCMA changing the multiple myeloma landscape?

[We must consider] each of these strategies in their own context. If the question is “How do BCMA CAR T cells affect the landscape?” Then we now have a tool that is highly potent in terms of inducing responses. [Toxicity] tends to be relatively manageable, at least in the majority of patients. Patients with advanced disease have these dramatic responses, and then many of them [experience a] relapse; that period of response is not trivial.

In at least 1 of the studies, you have responses that are coming out in close to 1 year in heavily pretreated patients, but it’s not that the disease is now gone or we don’t have to deal with it anymore. Whether there is a tail, we’re still going to learn, but patterns of relapse have become the focus when trying to improve on this pretty striking therapy.

What other investigational agents are hitting different targets in myeloma?

The vaccine trial that targets the whole myeloma cell induces the polyclonal response. It is hitting multiple targets, including neoantigens, that are unique to individual tumors. CS1 is another target that [investigators are looking] at with elotuzumab (Empliciti). There was some discussion of NKG2D ligand as a protein expressed on myeloma cells that is being targeted by CAR natural killer cells [and with other approaches]. CD38 and CD138 are also potential targets, but they overlap with other normal cell populations. The number of potential targets is growing.

References

1. Trudel S, Lendvai N, Popat R, et al. Antibody—drug conjugate, GSK2857916, in relapsed/refractory multiple myeloma: an update on safety and effi cacy from dose expansion phase I study. Blood Cancer J. 2019;9(4):37. doi: 10.1038/s41408-019-0196-6.
2. GSK announces positive headline results from the pivotal DREAMM-2 study for multiple myeloma [news release]. London, United Kingdom: GlaxoSmithKline; August 23, 2019. bit.ly/30ul1qB. Accessed August 23, 2019.