Belantamab Mafodotin Emerging as Novel Option for Relapsed/Refractory Myeloma

Sagar Lonial, MD, FACP

Belantamab mafodotin is emerging as a novel BCMA-targeted therapeutic option to treat patients with heavily relapsed/refractory multiple myeloma, a population that continues to be an unmet need, explained Sagar Lonial, MD, FACP.

The DREAMM-1 trial evaluated the safety, pharmacokinetics, pharmacodynamics, immunogenicity, and clinical activity of belantamab mafodotin in patients with relapsed/refractory myeloma and other advanced BCMA-expressing hematologic malignancies. These data elicited an overall response rate (ORR) of 60.0%, with 3 complete responses (CRs) and 2 stringent CRs.1 The median progression-free survival (PFS) was 12 months (95% CI, 3.1—not estimable), and the median duration of response was 14.3 months (95% CI, 10.6-NE).

The DREAMM-2 trial compared different doses of belantamab mafodotin in patients with relapsed/refractory myeloma. The agent showed an ORR of 31% (97.5% CI, 20.8-42.6) in patients receiving the recommended 2.5-mg/kg dose. In those who received belantamab mafodotin at 3.4 mg/kg, the ORR was 34% (97.5% CI, 23.9-46.0).

Based on the DREAMM-2 data, the FDA granted a priority review designation to belantamab mafodotin in January 2020 as a treatment for patients with relapsed/refractory multiple myeloma who received prior therapy with an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 agent.

“Having an off-the-shelf BCMA targeted therapy is a really easy and simple way to talk about treating [patients] when you don't have a lot of other options,” said Lonial. “I suspect other [BCMA-targeted therapies] will start to move [into] the treatment paradigm as well.”

Data show that belantamab mafodotin is associated with ocular adverse events (AEs), which are typically manageable with supportive care and dose modifications. Monitoring and treating these AEs allows patients to continue with treatment, sometimes with a brief pause.

The next steps to take with belantamab mafodotin will involve searching for other agents to pair with the antibody-drug conjugate (ADC).

In an interview with OncLive, Lonial, professor and Anne and Bernard Gray Family Chair in Cancer at Emory University School of Medicine, as well as chief medical officer at Winship Cancer Institute of Emory University, discussed the encouraging activity with the BCMA-targeted agent belantamab mafodotin in multiple myeloma.

OncLive: What novel therapies are being explored in multiple myeloma?

Lonial: The novel approaches involve the use of BCMA-targeted therapy, including ADCs—such as belantamab mafodotin—bispecific antibodies, or CAR T-cell therapy. [BCMA] is the next new big target in myeloma. We are trying to figure out the best approach, when to use [these BCMA-targeted therapies], and how to maximize their benefit to eventually discuss curing patients.

How will ADCs transform the myeloma landscape?

ADCs, particularly those targeting BCMA, have the ability to come off the shelf, meaning you don't have to wait for [the ADCs] to be available. They don't necessarily have the inpatient hospitalization that you might see with bispecific T-cell engagers (BiTEs) in terms of cytokine release syndrome (CRS) or other potential complications. As we're learning from early-phase studies, [ADCs] are able to be combined with other standard anti-myeloma drugs. Figuring out how to use [ADCs] and position them in a way that is effective immediately and can translate into long-term immunity is an exciting part of ADCs.

Could you discuss the DREAMM-1 and DREAMM-2 trials and their impact on the paradigm?

What we know about belantamab mafodotin comes from 2 trials: DREAMM-1 and DREAMM-2. The first was the DREAMM-1 study, which was a phase I trial designed to identify the dose that should go forward in trials. We saw that the ORR was around 60%. The median PFS was somewhere between 11 and 12 months. In that same trial, if you look at a penta-refractory patient population, these numbers are much smaller [compared with the overall DREAMM-1 population]. We demonstrated that the response rate was somewhere around 35% to 40% and the median PFS was around 4 months.

In DREAMM-2, we tested 2 different doses of belantamab mafodotin. One dose was 2.5 mg/kg and the other was 3.4 mg/kg; we tried to identify which was the safer dose to move forward. The ORR was relatively similar, at about 30% in both cohorts, which is similar to what we have seen for every other approved drug in the refractory myeloma setting. The median PFS is somewhere around 3 months. It looks like the duration of response is going to be much longer, suggesting that the responses patients get are durable.

If you begin to look at AEs, there were 2 big categories that came up. One was ocular toxicity, which can be managed with dose modifications and adjustments. The second was hematologic toxicity, which was not unexpected, given that it's an ADC. The hematologic toxicity is easily manageable by most hematologists and belantamab mafodotin hopefully will be a very active drug for us. The ability to combine belantamab mafodotin with other drugs is what we're looking at in current trials.

You want to partner with an ophthalmologist who can give you some early clues as to what's going on in the cornea, and then make decisions based on symptoms and AEs—regarding whether you want to hold the dose, give the dose, make dose adjustments, or dose modifications. Those are probably the biggest issues. Much of the other toxicity is infusion related, which is standard for most of us in hematology. There is also thrombocytopenia or hematologic toxicity, which most of us are used to dealing with in this disease.

If belantamab mafodotin receives FDA approval, what impact will it have on the myeloma landscape?

As good as we've gotten in myeloma, unfortunately, there still are a lot of patients who run out of available treatment options. Having something for those heavily relapsed and refractory patients will be a huge step forward.

What are the next steps of this research with belantamab mafodotin?

Beyond FDA approval, the next steps include combining belantamab mafodotin with standard drugs, such as bortezomib (Velcade), lenalidomide (Revlimid), pomalidomide (Pomalyst), and carfilzomib (Kyprolis). There are also other studies combining belantamab mafodotin with checkpoint inhibitors to see whether or not you can take that immunogenic cell death and use that to spur on an immune response that may last longer than the time that you're giving the drug. That is an exciting concept if we can prove that it works.

References

1. Trudel S, Lendvai N, Popat R, et al. Antibody—drug conjugate, GSK2857916, in relapsed/refractory multiple myeloma: an update on safety and efficacy from dose expansion phase I study. Blood Cancer J. 2019;9(37). doi: 10.1038/s41408-019-0196-6
2. 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. Lancet Oncol. 2020;21(2):207-221. doi: 10.1016/S1470-2045(19)30788-0