Bispecific Antibodies Propel the Relapsed/Refractory Myeloma Paradigm Further Ahead

Timothy M. Schmidt, MD

Phase 1 data with novel bispecific antibodies, such as teclistamab (JNJ-64007957), talquetamab, and cevostamab (BFCR4350A), have demonstrated significant efficacy for patients with relapsed/refractory multiple myeloma (RRMM), suggesting that this class of agents could transform the paradigm, said Timothy M. Schmidt, MD. However, studies are needed to navigate the management of cytokine release syndrome (CRS) associated with these drugs and to optimize their sequencing with chimeric antigen receptor (CAR) T-cell therapy.

“Bispecific antibodies are emerging in multiple myeloma as really effective tools to gain control of the disease and [induce] impressive responses,” said Schmidt. “We don’t know which agent will demonstrate the most effectiveness and feasibility for patients, but we have many options [in development]. The more patients we can enroll on clinical trials using these drugs, the better we will understand the optimal way to use them.”

In an interview with OncLive^® during an Institutional Perspectives in Cancer webinar on multiple myeloma, Schmidt, an assistant professor in the Department of Medicine of the University of Wisconsin School of Medicine and Public Health, discussed the integration and utility of bispecific antibodies in treating patients with RRMM, as well as some of the most promising agents in clinical development.

OncLive^®: What sets bispecific antibodies apart from other agents in relapsed/refractory multiple myeloma?

Schmidt: Bispecific antibodies are a really interesting, off-the-shelf option that engage the immune system and control RRMM or other hematologic malignancies. They work somewhat similarly to CAR T-cell therapies in that they are products that activate patients’ T cells and bring them in closer proximity to cancer cells. [The T cells] then recognize the [cancer] cells as abnormal and induce cell death. 

What is unique about bispecific antibodies is that [they utilize] 2 targets. Monoclonal antibodies [mAbs] rely on passive immunotherapy, in which the immune system coordinates a response after the antibody binds to actively bring them together. Bispecific antibodies are different from CAR T-cell therapies that have a similar mechanism of action; bispecific antibodies don’t require engineering of autologous T cells. Bispecific antibodies can be given to the patient immediately [because they don’t] require weeks of processing [as CAR T-cell therapy does]. The CAR T-cell therapy process risks a patient progressing while waiting [for the product to be engineered] or failure of that product to be generated.

What was learned from the development of AMG 420?

AMG 420 provided proof of concept for the use of bispecific antibodies in multiple myeloma. AMG 420 was the first molecule [to be evaluated] in multiple myeloma with this mechanism of action. At more active doses of AMG 420, we saw some really excellent response rates and profound depths of response with durability. 

The problem with AMG 420 is that because of the way the agent was constructed—with a short linker—it was metabolized rapidly by the body and had a very short halflife. As such, it required continuous infusion. Although that is feasible, it is not necessarily convenient for patients or clinicians. 

Some of the newer technologies and newer designs of bispecific antibodies are more favorable [vs AMG 420].

What efficacy and safety data were observed with teclistamab?

A phase 1 study evaluated teclistamab, which is a bispecific antibody targeting CD3 on T cells and B-cell maturation antigen [BCMA] on the surface of myeloma cells. The dose- escalation study enrolled patients with RRMM, many of whom were in earlier dose cohorts. In this patient population, individuals were heavily pretreated with a median of 6 prior lines of therapy. The vast majority of patients were refractory to a CD38-directed mAb, an immunomodulatory agent, and a proteasome inhibitor, and more than one-third of patients were penta-refractory. 

We saw far superior efficacy vs what had been reported in the initial studies for currently approved drugs in this space. The overall response rate [ORR] was 73%, with a very good partial response [VGPR] rate of 55%. Many of these responses lasted 6 months or longer. 

In terms of safety, we saw CRS that was similar to what we’ve seen with other bispecific antibodies in other hematologic malignancies, as well as what has been seen with CAR T-cell therapy. [This makes sense] because the products have similar mechanisms of action. Importantly, the CRS tended to be low grade and no grade 3 CRS events were noted. We also saw hematologic toxicities, which were expected given the mechanism of action [in multiple myeloma]. This raises the confidence level that teclistamab could be a more feasible option [than other agents] for a broader spectrum of patients.

How did talquetamab perform, a? Why is it important to develop bispecific antibodies that target antigens other than BCMA?

Talquetamab performed very similarly to other bispecific antibodies [for which data] were presented during the 2020 American Society of Hematology Annual Meeting and Exposition and in previous years. The ORR was 69%, with a VGPR rate of 39% in the most active dose cohort. Therefore, this was a very similar response rate and similar toxicity [was observed compared with teclistamab], but with a novel target. That is important given the fact that there are so many agents targeting BCMA; we are looking for these newer targets that we can utilize in this space.

What activity did cevostamab demonstrate in this space, and what sets this agent apart from other bispecific antibodies in development?

Cevostamab is a first-in-class BsAb targeting FcRH5, which is a surface protein found on myeloma cells. [FcRH5’s] function is not entirely clear, but it presents at high levels basically just on lymphoid cells, the vast majority of which are myeloma cells.

In a phase 1 dose-escalation study, cevostamab showed an ORR in the active dose cohorts of 53%, with a VGPR or better rate of 32% and a complete response or better rate of 18%. The duration of follow-up is short, so we haven’t seen quite how long these responses are going to last. However, it is promising, especially considering that 21% of the patients who [remain on] study had been exposed to prior BCMA-directed therapy in addition to the other main classes of myeloma drugs.

In terms of toxicity, the rates of CRS were a little bit higher numerically [with cevostamab] compared with the BCMA-directed and GPRC5D-directed bispecific antibodies. However, cross-trial comparison is sometimes difficult, especially when we are dealing with such small numbers [of patients]. There were a couple of cases of grade 3 CRS events observed primarily with the initial dose of cevostamab. The rates of CRS dramatically decreased with time. 

Also, cevostamab was given in an intravenous infusion that had a step-up dose vs a subcutaneous administration with the other bispecific antibodies I’ve discussed.

What questions do you hope to see answered in ongoing phase 2 trials?

For bispecific antibodies in general, the question is: How feasible are these agents going to be for administration outside an academic center? The lower rates of CRS are encouraging, so it’s thought that we could do this in the community setting. However, until we have more data about how common CRS is and what we need to do to manage it, [community administration] is probably a decent way away. Potentially, bispecific antibodies will be easier than CAR T-cell therapies [to administer in the community setting].

The other big question is whether bispecific antibodies are best utilized on their own or in combination with other myeloma agents. Should they stay in the relapsed/refractory space or should they be moved earlier? For example, although blinatumomab [Blincyto] was initially approved in relapsed/refractory B-cell acute lymphoblastic leukemia, it’s had a significant effect among patients who are minimal residual disease [MRD] positive after their initial induction therapy in terms of helping them achieve MRD negativity or to move forward with transplant.

In myeloma, it is certainly possible that [blinatumomab] could be used for functionally high-risk patients with myeloma who don’t achieve MRD negativity or who need something more after transplant. We are a long way from that, and we need to have more data to learn about how to use these agents better.