Teclistamab Leads Ongoing Emergence of Bispecific Antibodies in Multiple Myeloma

Jeffrey Zonder, MD

Teclistamab-cqyv (Tecvayli) was the first bispecific antibody approved by the FDA for the treatment of patients with relapsed/refractory multiple myeloma, and other agents in this class that are under development, including those with non-BCMA targets, could represent additional treatment options for this patient population, according to Jeffrey Zonder, MD.

“The important thing is that we keep developing these new targets as we enter this time when patients are routinely going to have access to BCMA-targeted therapy. Whether it’s CAR T-cell therapy or bispecific antibody therapy, some patients don’t respond, and the responses to all approved agents are not indefinite,” said Zonder, who chaired an OncLive® State of the Science Summit™ on multiple myeloma.

In an interview OncLive following the event, Zonder discussed the ongoing development of other BCMA-targeted and non–BCMA targeted bispecific antibodies, toxicity management for these agents, how to navigate treatment decisions for patients eligible for CAR T-cell therapy, and ongoing research in multiple myeloma at the Barbara Ann Karmanos Cancer Institute. Zonder is the leader of the Multiple Myeloma and Amyloidosis Multidisciplinary Team at the Barbara Ann Karmanos Cancer Institute, and a professor of medicine in the Departments of Hematology and Oncology at Wayne State University School of Medicine in Detroit, Michigan.

OncLive^®: How has the emergence of bispecific antibodies begun to shift the treatment landscape for multiple myeloma?

Zonder: Teclistamab is the first of several BCMA-directed bispecific [antibodies] coming [down the pike] in multiple myeloma. Bispecific antibody therapy as a platform is quickly going to expand beyond just BCMA-targeted therapy. We have talquetamab [JNJ-64407564] coming, cevostamab [RG 6160] is [under] study, and other bispecific antibodies are also in development.

We need those next therapies, and the bispecific antibodies I mentioned [talquetamab and cevostamab] look like they have great promise in the [post-BCMA] setting.

What has been observed so far with the use of talquetamab and cevostamab in patients who have and have not received prior BCMA-targeted therapy?

The most exciting thing that we’re seeing with both talquetamab and cevostamab is response rates that are similar to response rates we have seen with BCMA-targeted bispecific antibodies. To be fair, the initial data with these newer targeted bispecifics were [from] patients who had not [received] BCMA-targeted therapy previously. However, what we are starting to get now are some early data regarding patients who [previously] had BCMA-targeted therapy. The response rates are still quite high, more than what we are used to seeing with other therapies in the past developed in the same space [for patients who] received 3, 4, or 5 lines of previous therapy or more.

It is hard to know for sure, because the numbers are still fairly small, but we are starting to get data [for talquetamab and cevostamab] post–BCMA-targeted therapy, and they look promising.

What toxicities are associated with bispecific antibodies, and how are they managed?

There are certain toxicities that are common to both cellular therapies and bispecific antibody therapies that are related to immune activation. Cytokine release [syndrome (CRS)] is a common and generally early adverse effect [AE] seen with both CAR T-cell therapy and bispecifics. The rates [of CRS] seem to be higher with CAR T-cell therapy and a little bit more variable with bispecifics.

The good news with the bispecific antibodies is that CRS, in nearly all cases, is limited to the early stages of therapy, often during a ramp-up dosing period, and generally is grade 1/2. [This] means that you are not using multiple pressors, [and] you are often not managing it in an intensive care unit setting. Although [CRS] may require steroids, tocilizumab [Actemra], or similar agents to manage the symptoms, with early recognition and prompt treatment if symptoms of sufficient severity start occurring, we can generally keep it in that milder range and keep patients safe.

The other thing we discussed was neurologic AEs. We specifically drilled down on immune effector cell–associated neurotoxicity syndrome [ICANS] events. These are often early neurologic symptoms, characterized by change in cognition, mentation, or level of alertness. When ICANS events are severe, it can be associated with seizures, although that is not common with bispecific antibodies. Fortunately, the frequency of ICANS events with bispecific antibodies is low, and they are generally grade 1/2. When ICANS occurs, prompt recognition and steroids are important. If the symptoms are severe enough, anti-seizure prophylaxis is often a consideration.

Andrew Kin, MD, of the Karmanos Cancer Institute, discussed how BCMA-targeted therapy has changed the treatment landscape for multiple myeloma. How do you choose which BCMA-targeting approach is appropriate for a given patient?

For a brief moment, there were 3 options [for BCMA-targeted therapy]. There was the antibody-drug conjugate belantamab mafodotin-blmf [Belamaf], there were emerging bispecific antibodies with teclistamab recently approved, and then there were 2 approved CAR T-cell therapies [idecabtagene vicleucel (ide-cel; Abecma) and ciltacabtagene autoleucel (cilta-cel; Carvykti)]. I believe there is a consensus that if a patient is a candidate for CAR T-cell therapy and is interested, then that is probably the preferred therapy.

The 2 CAR T-cell agents available, ide-cel and cilta-cel, and the currently approved bispecific antibody teclistamab, are approved in the same setting [for patients who received] 4 or more prior lines of therapy, [including] an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody. [Therefore, these agents] occupy the same general space in the treatment paradigm.

CAR T-cell therapies have the advantage of being a one-and-done type of therapy [with] high response rates. Even the CAR T-cell therapy which seems to have a slightly lower response rate [ide-cel] compares well against bispecific antibody therapy, and cilta-cel probably has a significantly higher response rate [than both agents].

The problem with CAR T-cell therapy is that not every patient is a candidate, [and] there are a couple of bottlenecks in the process of getting [patients this therapy]. There is a line to the front door at most centers in terms of having T cells collected and then sent for manufacturing, and manufacturing slots are limited right now. Just getting patients to the apheresis unit to have the cells collected usually [involves] a significant time lag built into that part of the process.

Then once the cells are collected, there is another several weeks–long manufacturing window. Between those 2 time points, a patient who has rapidly progressing disease after 4 prior lines of therapy might not be a great candidate for CAR T-cell therapy, or, at the least, will need some kind of bridging therapy to keep the disease under control during that months-long waiting period. That is where bispecifics have an edge for some patients.

Bispecifics are an off-the shelf therapy, and they are not a one-time treatment. For teclistamab, after a ramp up, it is subcutaneous weekly dosing on an ongoing basis. Optimal duration of therapy has not been defined, and right now, it is used until progression. However, it can be started right away, and the response rates, although certainly not higher than CAR T-cell therapy, are still a significant leap forward compared with other [treatment options] in that space. If you think about [the expected response rates for] immunomodulatory agents, XPO1 inhibitors, anti-CD38 antibodies, or proteasome inhibitors [in this setting], they are much lower than what we see with teclistamab. All the available BCMA platforms right now are a leap forward.

In terms of picking between [CAR T-cell therapy and a bispecific antibody], for me, it comes down to how urgently therapy is needed. For me, that is a major deciding factor between them.

Abhinav Deol, MD, of the Karmanos Cancer Institute, covered CAR T-cell therapy in multiple myeloma. Could you expand on deciding between the 2 available FDA approved anti-BCMA CAR T-cell therapies, ide-cel and cilta-cel?

The truth is that in most cases, [we do not get to] pick between CAR T-cell therapies. It is hard for patients to get their head around that sometimes, but the reality is, with the limited manufacturing slots available, most patients end up getting whatever [CAR T-cell therapy] is available first.

The response rates seen with cilta-cel are reported to be a bit higher and more durable than with ide-cel, [based on] the studies that led to the approvals of both agents. From the patient perspective, it is easy to understand why one might be preferred over the other. Having said that, putting both CAR T-cell therapies in perspective, both are better than anything else available in that same space, and both have that one-and-done advantage to them. Both CAR T-cell therapies that are available represent excellent treatment options.

I have yet to see a patient who opts for some other therapy because the first CAR T-cell therapy that became available to them was ide-cel rather than cilta-cel. I have had a few patients who have decided to hold out for cilta-cel. That is usually a patient-driven decision. Our program and I believe most programs are comfortable [saying] that both CAR T-cell therapies represent excellent therapy options, and our center and many others have both available. With the waiting lists that we have, we are using both.

Craig Emmitt Cole, MD, of the Karmanos Cancer Institute, discussed proteasome inhibition in multiple myeloma. What real-world data have been observed with ixazomib (Ninlaro)-based therapy compared with what was previously seen in clinical trials?

Dr Cole talked about the INSURE study, which was a [pooled analysis] of 3 different real-world datasets. One of the primary areas of interest in this analysis was how patients who received ixazomib-based therapy in the real-world setting compared with patients who were treated on [clinical trials].

This is always an important question because study patients are often optimal patients. [Clinical trials typically] exclude patients with health problems that many of our patients have. Those same issues that disqualify patients from studies can have real health consequences and make it harder to deliver myeloma therapy. For example, the patient may be less able to tolerate therapy, and you might get less mileage out of that therapy.

The analysis showed encouraging data that when ixazomib is used in that real-world setting, you get similar outcomes to what has been recorded in studies. That reassures us that we can believe the results of the study. When we tell a patient, this is what you can expect, we can do that with confidence.

Is there any ongoing or planned research at Karmanos Cancer Institute that you would like to highlight?

We, and many other centers, are involved in the ongoing work with different bispecific antibodies, and we are very excited about that. Another area of interest in our program is newer cellular therapies, including allogeneic CAR T cells or CAR natural killer cells. Allogeneic products could have the advantage of being available off the shelf. [With autologous CAR T-cell therapy], the two time gaps are the line to the front door and the manufacturing period, both of which [can contribute] to a patient’s risk of disease progression. An allogeneic product eliminates that second issue because you have cells ready to go.

There is also ongoing work on new and more rapid manufacturing processes. Even for autologous CAR T-cell therapy, the manufacturing process is going to be becoming much shorter in the future.

In terms of new classes of medications, the one that deserves the most attention are cereblon E3 ligase modulators [CELMoDs]. Iberdomide [formerly CC-220] and mezigdomide [CC-92480] are being developed in multiple myeloma with different time points, ranging from initial therapy in combination with other standard products, to the maintenance setting, and then to the relapsed setting. These are cereblon-targeting agents, which is the same target as immunomodulatory drugs, but they have more potent binding. [Iberdomide and mezigdomide] have been studied in patients that have been exposed to previous immunomodulatory drugs and, in most cases, are refractory to previous therapy.