Belantamab Mafodotin Induces Responses in Relapsed/Refractory Myeloma, But Calls for Multidisciplinary Approach

Sagar Lonial, MD, FACP

The antibody-drug conjugate (ADC) belantamab mafodotin demonstrated durable responses in patients with relapsed/refractory multiple myeloma, according to Sagar Lonial, MD, FACP, and although the agent was found to be well tolerated, partnering with an ophthalmologist can help ensure its optimal use.

In the open-label, multicenter, phase 2 DREAMM-2 trial, 196 patients with relapsed/refractory multiple myeloma were randomized 1:1 to receive either 2.5 mg/kg (n = 97) or 3.4 mg/kg (n = 99) of belantamab mafodotin intravenously every 3 weeks until disease progression or unacceptable toxicity.

Updated results from a 13-month follow-up analysis of the trial presented at the 2020 ASCO Virtual Scientific Program showed an overall response rate (ORR) of 32% (97.5% CI, 21.7%-43.6%) in patients who received the recommended 2.5 mg/kg dose. Meanwhile, patients who received the 3.4 mg/kg dose experienced an ORR of 35% (97.5% CI, 23.9%-46.0%). The duration of response (DOR) was not reached in either arm. The median DOR was 11 months (95% CI, 4.2-not reached [NR]) in the 2.5 mg/kg arm and 6.2 months (95% CI, 4.8-NR) in the 3.4 mg/kg arm.

With regard to safety, keratopathy was reported in 75% of patients who received the 2.5 mg/kg dose of the ADC versus 77% of those who received the 3.4 mg/kg dose. The median time to onset of the first event was 37.0 days and 22.5 days, respectively.

“The keys to successful use of belantamab mafodotin are partnering with your ophthalmologist early on and ensuring that you have their input in terms of whether or not a dose needs to be held, skipped, or modified,” said Lonial. “At the end of the day, a lot of this comes down to the oncology’s comfort with delivering the therapy. Corneal events are something that, as oncologists, we’re not often used to dealing with. There is a little bit of a learning curve.”

In January 2020, the FDA granted a priority review for the biologics license application seeking approval for the ADC as a treatment for patients with relapsed/refractory multiple myeloma who received prior therapy with an immunomodulatory drug (IMiD), a proteasome inhibitor, and an anti-CD38 antibody. The decision was based on earlier data from DREAMM-2.

In June 2020, the agency scheduled an Oncologic Drugs Advisory Committee hearing for July 14, 2020, to discuss data supporting the BLA.

In an interview with OncLive, Lonial, a professor and chair of the Department of Hematology and Medical Oncology at Emory University School of Medicine and the chief medical officer of Emory University’s Winship Cancer Institute, discussed the updated data from DREAMM-2 with belantamab mafodotin, associated toxicities to be aware of, and future directions for research.

OncLive: Could you provide some background on belantamab mafodotin?

Lonial: Belantamab mafodotin is an antibody-drug conjugate that targets a protein called BCMA on the surface of plasma cells. The chemotherapy moiety that is linked to the antibody is something called MMAF, a known potent chemotherapy agent that is delivered to the plasma cell by this BCMA-directed antibody.

We know that from previous studies, particularly DREAMM-1, that belantamab mafodotin is pretty active in the context of relapsed/refractory myeloma. We also know that for many of those patients, responses [to the agent] can be quite durable, with a median PFS in other trials of up to 11 months. That was the rationale for the early trials trying to evaluate how to use the agent in a refractory myeloma patient population.

What was the design of the phase 2 trial and what were the updated findings from the 2 dosing cohorts?

[DREAMM-2] was a randomized phase 2 trial evaluating the phase 1 decided dose of 3.4 mg/kg of belantamab mafodotin, given every 3 weeks, and then a lower dose of 2.5 mg/kg on the same schedule, to try and understand whether there was any difference in AEs or efficacy between those 2 doses.

A total of 196 patients were randomized and between those 2 [cohorts]; 97 patients received 2.5 mg/kg and 99 patients received 3.4 mg/kg. With regard to eligibility criteria, [patients had to have disease that was] refractory to IMiDs, proteasome inhibitors, and a CD38 antibody. Some of those patients were intolerant, but for the most part, a majority of them were resistant to a CD38 antibody. If you start to look at who these patients were, in terms of median prior lines of therapy, it was over 5 for both arms. [As such, this was a] very heavily pretreated refractory myeloma patient population.

We saw about a 32% ORR in the 2.5 mg/kg group and a 35% ORR in the 3.4 mg/kg group. In this longer-term follow-up, we saw that the PFS was right around 3 months for both of those arms—not statistically different. However, what was quite Interesting was the DOR [observed with the agent], because that's where the differences [between the arm] really began to play out; in the 2.5 mg/kg arm, it was 11 months in the 3.4 mg/kg group, it was 6.2 months.

The reason that I'm spending so much time focusing on the DOR curve, is that DOR is an amalgamation of both the response rate and the tolerability of the drug. What we learned is that the 2.5 mg/kg appears to be a better-tolerated [dose], and the response duration was much longer with the lower dose than with the higher dose.

What does the safety profile of this agent look like?

When we looked at the safety [of the agent] overall, no new findings [were reported]. What we did see was that keratopathy was an issue as we had expected; it's a known on-target effect of MMAF. We also know that very few patients discontinued because of keratopathy, and with appropriate dose modifications and dose holding, patients were able to stay on therapy and continue to benefit from it. In fact, a significant fraction of patients actually deepened their response while the dose was being held for grade 2 or greater keratopathy.

Another point to mention is that this study used very intense ophthalmologic exams. A number of patients had grade 1 keratopathy that was only detectable by an eye exam for which they had no symptoms. That was counted in the number because the frequency of keratopathy is over 70%, but a significant proportion of those were grade 1 where the patient really experienced no symptoms at all.

Did dose modifications or dose adjustments impact patient responses?

What we know is that many of the patients continued to deepen their response, even while the dose was being held. A very small proportion progressed during that period of time, but that's why the DOR point is so important. Even when withholding a dose, where the average time to resolution was about 22 days or 1 cycle of therapy, even missing 1 cycle of therapy, the DOR was still 11 months; this is quite long. In fact, [the DOR observed with this agent is] as long, if not longer, than any of the other drugs that have been approved in a similar accelerated approval fashion.

What are the next steps for this research?

The next steps involve combinations. Several trials, such as DREAMM-4, DREAMM-5, DREAMM-6, are looking at combinations with other standard anti-myeloma drugs, including bortezomib (Velcade) and lenalidomide (Revlimid). Another very interesting trial is looking at [combining the agent] with pembrolizumab (Keytruda) to try to take advantage of the immunogenic cell death, which is a unique mechanism for belantamab mafodotin. [Other next steps would include conducting] phase 3 trials to try and bring the agent into earlier lines of therapy to see whether that benefit is even [greater].

Is there anything else about the trial that you would like to emphasize?

Partnering with your ophthalmologist is key to help you get through the learning curve. [By learning from them, you will eventually get] to the point of knowing whether you’re going to give a dose based on what a patient tells you, before you even get that formal ophthalmological exam review. [To get there] just takes time; that partnership is needed to learn the ropes.

Reference

Lonial S, Lee HC, Badros A, et al. Pivotal DREAMM-2 study: Single-agent belantamab mafodotin (GSK2857916) in patients with relapsed/refractory multiple myeloma (RRMM) refractory to proteasome inhibitors (PIs), immunomodulatory agents, and refractory and/or intolerant to anti-CD38 monoclonal antibodies (mAbs). J Clin Oncol. 2020;38(suppl 15):8536. doi:10.1200/JCO.2020.38.15_suppl.8536