BCMA-Targeted Approaches Revolutionize Relapsed/Refractory Myeloma Treatment

Elisabet E. Manasanch, MD

The relapsed/refractory multiple myeloma treatment landscape is in the process of undergoing a major revolution, with the emergence of novel BCMA-targeted approaches comprised of antibody-drug conjugates (ADCs), bispecific T-cell engagers (BiTEs), and CAR T-cell therapies, according to Elisabet E. Manasanch, MD.

“I really feel that the way we treat [patients with] myeloma will be completely different 5 years from now because many of these [new] drugs will be on the market,” said Manasanch. “There was a big revolution in this disease when we started to use proteasome inhibitors (PIs). When bortezomib (Velcade) came along, that was another revolution [because] there were not many medications that were effective. Right now, we are [witnessing] another revolution with CAR T-cell therapies, BiTEs, and ADCs.”

With regard to ADCs, belantamab mafodotin-blmf (Blenrep) demonstrated an overall response rate (ORR) of 31% (97.5% CI, 20.8-42.6) when given at a dose of 2.5 mg/kg in patients with relapsed/refractory multiple myeloma who had previously received 4 therapies, including an immunomodulatory drug (IMiD), a PI, and an anti-CD38 antibody. The ORR was even higher, at 34% (97.5% CI, 23.9-46.0), when patients received the higher dose of 3.4 mg/kg. These data led to the August 2020 FDA approval of the agent in this patient population.

BiTEs are also generating excitement in the relapsed/refractory treatment setting. AMG 701, a half-life–extended anti-BCMA BiTE demonstrated encouraging preclinical in vitro antitumor activity and characteristics suitable for once-weekly dosing in patients with multiple myeloma.²

Additionally, the agent REGN5458 elicited responses in 57% of heavily pretreated patients (n = 4/7) who received a dose of 3 mg; 75% (n = 3/4) who received a higher dose of 6 mg achieved a response.3 Moreover, 50% of those who received the higher dose also achieved minimal residual disease negativity. Participants had received a median of 7 prior lines of systemic therapy and had all progressed on anti-CD38 treatment.

“One of the main advantages [with BiTEs] is that you can just give [the drug to the patient]. You could be in the hospital and see a patient who has relapsed myeloma and if BiTEs are approved, you can give them that agent in the same afternoon,” added Manasanch. “That’s very attractive because you get immediate access to [an efficacious drug]. That will be one of the potential advantages of BiTEs over CAR T-cell therapies.”

In an interview with OncLive, Manasanch, an associate professor in the Department of Lymphoma/Myeloma and Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, discussed novel modalities that are emerging in relapsed/refractory multiple myeloma.

OncLive: How do you identify patients with BCMA expression? Are you testing for this to decide who should receive BCMA-targeted agents?

Manasanch: I don't think that it’s important to check whether the patient expresses BCMA because most of them will have it. Plus, there's a lot of data saying that the response to BCMA-targeted agents is not directly related to the BCMA expression. You can test for BCMA through immunohistochemistry and flow cytometry, but it’s not something that we do clinically; we do this in a clinical trial setting, if anything. Also, for belantamab mafodotin, for example, you don’t need to do BCMA staining.

Belantamab mafodotin is an antibody-drug conjugate. In just 3 to 4 years, they [brought] the drug from a phase 1 study to an FDA approval. [Investigators have] done an excellent job and this drug is very good; it has a response rate of approximately 30% as a single agent without steroids in patients who have received many [prior] therapies. The patients who do respond [to the agent] seem to respond very well. These patients also seem to have a prolonged response; it's not just that they respond and it lasts for a couple of months. These patients can experience responses that last for 1 or 1.5 years. This is very valuable for these patients [who are so heavily pretreated].

Belantamab mafodotin is approved for patients who have relapsed myeloma and who have had at least 4 prior therapies. There is nowhere in the approval that you have to test for BCMA expression. Any patient who has relapsed myeloma and received 4 prior lines of therapies, you can start on belantamab mafodotin. We don’t really check for BCMA clinically.

I asked a couple months ago [about obtaining] validated tests to test for BCMA because if there's any relationship, we want to know about it. [That test is also] good at identifying plasma cells and so on. They’re now doing a test to validate this, so that we can test for it clinically but this it’s not ready; it’s very new. I don’t believe that [something like this] will be available in smaller centers [anytime soon].

Could you expand on the approval of belantamab mafodotin in this setting?

The FDA approval of belantamab mafodotin is a major one in the field of myeloma because it is the first BCMA-targeted agent approved and it had a response rate of about 30%. Patients who do respond can have a duration of response that is quite long. I don’t know if this has been talked about too much, but based on some of the data that have been [reported], we see some of the patients can be on this treatment for 1 year or longer. That’s very important.

[However], this approval has several limitations. The main limitation is that this drug [can cause] corneal changes because the payload of the ADC can deposit in the cornea. When this happens, some patients can be very uncomfortable. I don’t know that it’s necessarily painful, but it’s definitely annoying. Patients can also have dry eyes. However, the FDA has implemented an ocular risk evaluation and mitigation strategy (REMS) program, so that this drug can be given safely.

The REMS program requires the physician and the patient to sign up along with the infusion center. An ophthalmologist or optometrist is also needed to do an eye exam. These are very detailed examinations [pertaining to the cornea and visual acuity] that have to be done within 2 weeks of receiving the drug.

In the clinic, the physician looks at the evaluations from the optometrist and ophthalmologist. If [results fall] within [an acceptable] range, then the physician prescribes the medication. It's only when you go on the website and [input the necessary information] that you get a code that indicates to the infusion center that you can infuse the drug.

Beyond the program, how do you suggest that these toxicities be mitigated in practice?

The drug is effective as a single agent in the relapse [setting]; it’s going to help a lot of patients. There are going to be some patients with myeloma who don’t have many treatment options who can go on this medication and do really well for quite some time. This is very important despite the limitations that I have mentioned. As we get used to giving this medication outside of clinical trials, it will become easier and easier [to manage]. As long as we follow the REMS program and patients undergo evaluations and go to the ophthalmologist, these [AEs] should not be a real issue. It also very important to know that the corneal changes that we have seen usually resolve within a couple of months.

Some patients are going to have symptoms and some may not even though they have some changes in the cornea. There could be an incident where the ophthalmologist says that you have to halt the drug because there are some changes [even though] the patient's vision may be perfectly fine; that can happen. The other thing important [to note] is that even if you hold the medication, that doesn't mean the patient is going to relapse right away.

You give a patient a couple of doses, which is a dose every 3 weeks; they receive cycle 1, day 1 and cycle 2, day 1. Then, if they come for cycle 3, day 1 and they have some epithelial cornea changes or a little bit of blurry vision and it's determined that they cannot receive the drug that day because those ocular need to be watched, you can hold the drug. If the patient has a response within the first 2 doses, it's very possible that you can carry this response through for the next 2 to 6 weeks and you can dose the patient later, once these changes have resolved. You may be able to put the patient on the medication again [at that time].

Depending on the severity of the changes in the cornea, you can also [reduce] the [dose of the] drug. If the patient has very high-grade changes in the cornea or severe diminishing of visual acuity, then you can decrease the dose of the medication, as well. [We have a lot to] learn [about] how to manage the drug. Overall, I'm very happy that we have this drug on the market right now.

Is there anything you would like to add on the Driving Excellence in Approaches to Multiple Myeloma (DREAMM) program?

It’s a nice program. I haven't used it personally yet, but it doesn't seem very difficult to use. We have support staff in our clinic who can help patients work closely with an ophthalmologist or optometrist to get the scores that we need, and the nurses and infusion centers can call us. I don’t think it’s going to be a big issue; I just think it’s going to need some logistical setup to get it up and running. However, once it starts, I don’t believe it’s going to be [problematic]. I think it was really well set up. It’s very functional, and it’s online, so it’s easy to access. The [program has] a lot of information available for patients, which is good. It’s all for the safety of the patients.

Shifting to other BCMA-targeted agents, could you speak to some of the recent developments that have been made with BiTEs?

AMG 420 was 1 of the first [BiTEs] that had data presented in a past medical meetings and the efficacy was really good, but I don’t think this drug is [still] being developed by Amgen. AMG 420 was a medication that was [given as] a continuous intravenous infusion and the half-life of the drug was very short. The development of AMG 701 followed. This agent does not have such a short half-life; it can be given once a week. This is still [under] development so there are not a lot of data [with regard to its efficacy], but the expectation is that the response will be very good. [AMG 701] is under evaluation in a phase 1 trial.

One of the nice things about this study is that there's an escalation of the dose. As you know, BiTEs can have similar toxicities to that of CAR T cells. Cytokine release syndrome is 1 of the dangerous toxicities that can occur. One of the things that we have realized in drug development is that perhaps some of the studies can start with a very low dose in the first week, then they can ramp up the dosage each week if a patient doesn't experience AEs. That probably makes the drug much easier to give, but it's still early.

Another BiTE [is being developed] by Regeneron Pharmaceuticals: [REGN5458]. Some of the data on that drug were presented and looked very promising in terms of efficacy. BiTEs are most likely going to move forward in development for multiple myeloma; it could be another revolution. There’s definitely going to be a market for this approach because these drugs can be given off-the-shelf. You don't have to do T-cell collection; with CAR T, you have to collect T-cells and then you have to manufacture the cells.

What is some of the work that is being done with CAR T-cell therapies? Are there benefits to this modality over BiTEs?

The good thing about CAR T-cell therapy is that usually it's given once and a patient could achieve a very good response from it; it is then followed with observation. Patients usually like this because they get a break from treatment. With BiTEs, you really need continuous dosing. Usually [patients] get repeated dosing either every week or every couple of weeks, so they’re not going to receive a treatment once and then be done. That would be 1 of the [reasons] why CAR T-cell therapy may be preferable [to BiTEs] for patients.

Are any other agents under exploration that you are excited about?

There is a drug called iberdomide (formerly CC-220), which is a drug from Bristol Myers Squibb and it is a new generation of IMiD that looks very promising. The phase 1 study of the agent focused on [establishing] the toxicity and efficacy [of the agent]. The response rate was around [30%], which is very good, especially in patients who [have progressed on] almost all of the therapies [available to them]. The agent was also found to be safe. The [patients] went through dose escalation without [experiencing] toxicities; it took a while for them to find [the recommended] dose. That's a good thing.

References

1. Lonial S, Lee HC, Badros A, et al. Belantamab mafodotin for relapsed or refractory multiple myeloma (DREAMM-2): a two-arm, randomised, open-label, phase 2 study. Published online December 16, 2019. Lancet Oncol. doi:10.1016/S1470-2045(19)30788-0
2. Cho S-F, Lin L, Xing L, et al. AMG 701, a half-life extended anti-BCMA BiTE, potently induces T cell-redirected lysis of human multiple myeloma cells and can be combined with IMiDs to overcome the immunosuppressive bone marrow microenvironment. Presented at: The 17th International Myeloma Workshop; Sept. 12-15, 2019; Boston, MA. AB169.
3. First clinical data for REGN5458 (BCMAxCD3) show positive preliminary results in multiple myeloma. News release. Regeneron Pharmaceuticals, Inc. December 8, 2019. Accessed September 24, 2020. https://prn.to/2RXqt2Q.