Building on BCMA-Directed Therapies in Multiple Myeloma

Luciano J. Costa, MD, PhD

Antibody-drug conjugates (ADCs) and bispecific T-cell engagers (BiTEs) are 2 of the latest treatment modalities that have emerged in relapsed/refractory multiple myeloma, further augmenting an already rich landscape of BCMA-directed therapy, explained Luciano J. Costa, MD, PhD.

“We’re seeing an immunotherapeutic revolution in multiple myeloma. There is a plethora of new and very exciting approaches that deliver a real chance of disease control for patients who, until recently, did not have any therapeutic opportunity,” said Costa. “We should all be mindful of those options when we’re treating a patient who is no longer responding to the approved agents. Reach out to your colleagues who are in myeloma centers because they’re very likely to have 1 or more clinical trials that could be a good fit.”

In an interview with OncLive^® during the 2020 Institutional Perspectives in Cancer webinar on Multiple Myeloma, Costa, an associate professor of medicine in the Blood and Marrow Transplantation and Cell Therapy Program at the University of Alabama’s Birmingham School of Medicine, discussed emerging data regarding the use of BCMA-directed BiTEs and ADCs in multiple myeloma.

OncLive^®: Could you discuss the excitement surrounding BiTEs in myeloma?

Costa: An exciting [area of therapeutic development in] myeloma has to do with bispecific antibodies, which are mostly T-cell engagers. It’s premature to try to dissect the differences between them. So far, we have seen clinical data for 3 different BCMA-directed T-cell engagers: AMG 420, CC-93269, and more recently teclistamab. They all have a very different structure.

AMG 420 is really a BiTE; it’s a very small molecule, which is the end of the Fab portion of an anti-CD3 and an anti-BCMA antibody put together. Because of that, [AMG 420] has a very short half-life and requires continuous infusion. [The drug] was active at the optimal dose, and the majority of patients responded. These patients were not so heavily pretreated. The drug is being developed further with a half-life extender.

CC-93269 and teclistamab are large IgG-like antibodies or modifications of antibodies with the same specificity to CD3 and BCMA, allowing for intermittent dosing with weekly or less frequent schedules. Even if you take a population that is triple-class refractory at the optimal doses or the doses that are being tested currently, we’re seeing that the majority of patients do respond.

We do see cytokine release syndrome (CRS). I always provide an analogy between CAR T-cell therapy and bispecifics. We’re essentially trying to get the same end result, which is engaging T cells that have some other random specificity, into the cancer cell. However, instead of inserting a gene and modifying those T cells ex vivo, we’re putting an antibody that connects the T cell with the myeloma cell in vivo. That proximity leads to activation, degranulation, and ultimately cell kill. As a result, we see CRS as we do with CAR T-cell therapy. The difference here is that we can modulate the toxicity by modulating the dose of the antibody or the frequency of the doses.

A lot of work is being done on finding the optimal way to safely administer those bispecific antibodies to get the maximum effect. The majority of patients had grade 1/2 CRS, which is very manageable. Higher grades of CRS have been very rare. We do see some hematologic toxicity, mostly neutropenia that responds to growth factor support, as well as transient thrombocytopenia. We also see infection [with all of these agents], mostly respiratory infection. At this point, it’s unclear if that is intrinsic to the class of agents, or if it reflects the population of patients we’re treating.

Since you can dose patients [with T-cell engagers] for a long period of time, [the hope is that patients] will [experience] longer-lasting responses; that’s their appeal. However, more patients and larger trials are going to be needed [to prove that].

The other thing that is very stimulating is that there are several other non-BCMA bispecific antibodies in development, binding to, for example, GPRC5D or FcRH5, in addition to other immunotherapeutic targets and plasma cells. That’s going to become highly relevant. We’ll want to see which of those immunotherapy targets performs better, but also how patients respond to immunotherapy after [patients progress], particularly after CAR T-cell therapy.

What research is being done with regard to ADCs?

Another immunotherapeutic avenue are the ADCs. One in particular, belantamab mafodotin-blmf (Blenrep), was recently approved by the FDA for treatment of patients with multiple myeloma who have disease that is refractory to multiple lines of therapy. Belantamab mafodotin is a monospecific that has a monomethyl auristatin F payload, which is a tubulin poison, very much like the old vincristine. The idea is if we can attach the payload to the antibody, we can deliver that payload in higher concentrations to the cell of interest with very little toxicity.

Belantamab is targeted against BCMA, so it has the same targets as all the CAR T-cell therapies we have seen data for and most of the bispecifics. However, it doesn’t have the T-cell engagement nature that CAR T-cell therapy and bispecifics have. Therefore, CRS is not a toxicity. In that regard, it’s very safe and very easy to administer.

Most of the clinical data that led to its approval came from the DREAMM-2 trial, which enrolled patients who had prior immunomodulatory drugs, proteasome inhibitors, and CD38 monoclonal antibodies. A significant proportion of patients were triple-class refractory. The trial evaluated two doses: 2.5 mg/kg and 3.4 mg/kg every three weeks. The response rates were a little over 30%, and the progression-free survival (PFS) was between 2.5 and 4.5 months. Some patients can experience durable responses, but unfortunately, they’re not well reflected by the median PFS.

The main concern about this agent is the toxicity. We see some hematologic toxicity, particularly thrombocytopenia and a little bit less neutropenia. However, the signature toxicity is corneal toxicity, [also known as] keratopathy. The mechanism of [keratopathy] is not completely clear. Though, it seems to be that the payload itself, even small concentrations can lead to keratopathy that can present in many different ways, including dry eye, burning eye, and blurry vision. Patients can experience quite a bit of corneal damage that does not match symptoms and vice versa. The corneal toxicity appears to be reversible over time, although the frequency and the chronology of that reversibility is not very well understood. The challenge is that most hematologists are not accustomed to eye toxicity, so that’s a little bit of an unfamiliar territory for most of us.

The drug is being rolled out as part of a very complex, comprehensive Risk Evaluation and Mitigation Strategy program that really requires a very close partnership with an ophthalmologist. Patients will have to have a detailed eye exam and hematologic exam before each dose. It’s certainly great that we have a new agent in myeloma. I think it remains to be seen how well this agent can be utilized given the logistics and toxicity restraints [it has] and how well we can combine it with other agents.

Now, we have 3 different approaches to BCMA: ADCs, T-cell engagers, and CAR T-cell therapy. There’s a lot of curiosity and urgency in understanding how those therapies perform in sequence. These are the things we hope to see in the years to come.