Novel Combos With Belantamab Mafodotin May Move the Needle in Myeloma

The approval of belantamab mafodotin-blmf (Blenrep) addressed an unmet need in relapsed/refractory multiple myeloma, according to Sagar Lonial, MD, FACP, and to build off the efficacy observed with the agent, research efforts are dedicated to examining its use in other novel combinations and moving it earlier on in the treatment journey.

“BCMA is the ‘it’ target of 2020,” said Lonial, a professor and chair of the Department of Hematology and Medical Oncology at Emory University School of Medicine. “Belantamab mafodotin provides an off-the-shelf [opportunity] to target BCMA; the agent not only elicits responses in a highly-resistant patient population, but these responses are also durable. The agent also has a reasonable safety profile.”

Results from the phase 2 DREAMM-2 study (NCT03525678) served as the basis for the August 2020 FDA approval of the antibody-drug conjugate (ADC) in the treatment of patients with relapsed/refractory disease who have received 4 prior therapies, including an immunomodulatory drug (IMiD), a proteasome inhibitor (PI), and an anti-CD38 antibody.

Updated data from a 13-month follow-up analysis presented during 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 of belantamab mafodotin and an ORR of 35% (97.5% CI, 23.9%-46.0%) in those who received the 3.4 mg/kg dose of the agent.

“Several combination studies [with belantamab mafodotin] will emerge,” said Lonial, who is also the chief medical officer of Emory University’s Winship Cancer Institute. “The is whether we should use a different dose or schedule to be able to combine [the ADC] with additional agents. There is also a big push to use the agent up front in combination with the 3-drug induction regimen of lenalidomide, bortezomib, and dexamethasone (RVd).”

In an interview with OncLive, Lonial discussed the role of belantamab mafodotin in relapsed/refractory multiple myeloma and emerging BCMA-targeted agents that are generating excitement in this setting.

OncLive: What is the significance of the regulatory approval of belantamab mafodotin in multiple myeloma?

Lonial: Belantamab mafodotin provides patients with a new treatment modality, particularly those who have exhausted most [available] treatment approaches. Despite all the great advances that we've seen, with median overall survivals now exceeding 10 to 12 years, there are patients who become triple-class refractory; these patients are resistant to IMiD, PIs and anti-CD38 antibodies and. For these patients, treatment options are relatively limited.

Could you shed light on findings from the phase 2 DREAMM-2 trial that served as the basis for the approval of this agent?

In this randomized phase 2 trial, [investigators] evaluated 2 different doses of belantamab mafodotin. The lower dose of 2.5 mg/kg, which is now the FDA-approved dose, was requested by the [regulatory agency] to see whether it would have a different safety profile.

Although on the surface it appeared that the response rates were somewhat similar, and the adverse effects (AEs) were somewhat similar [between the doses], results showed that more patients had grade 1/2 AEs versus grade 3/4 AEs [with the lower dose]. The ORR was 32% with a median progression-free survival (PFS) of 2.9 months and a DOR of 11 months [in those who received this dose]. The DOR truly showed that in the patients for whom this therapy appears to be working, you can safely keep them on this agent despite the AEs that occur.

Could you speak to the administration of this agent along with the safety profile?

Belantamab mafodotin is an intravenous BCMA ADC. The agent is administered intravenously, and it is very well tolerated from an infusion reaction perspective. The ADC is much easier to give with acetaminophen and Benadryl prophylaxis; it doesn’t require steroid premedication. The agent doesn't take very long to administer and is given every 3 weeks.

The safety profile has 2 [notable toxicities]. The first is hematologic toxicity; we have seen suppression of the white blood count and some level of anemia; a lot of that is often disease related but it can be attributed to belantamab mafodotin, as well. The second is keratopathy, which is the development of microcysts within the cornea. Notably, microcysts occur in about 70% of patients who receive belantamab mafodotin.

Notably, only about 50% of patients are symptomatic and the most common AE was dry or itchy eyes, which can be addressed with lubricating eyedrops. People are most worried about changes in visual acuity; however, only approximately 20% of patients on the trial experienced these changes. The optimal way to administer belantamab mafodotin is by partnering with an ophthalmologist, who can see the patient before each dose is given to ensure that the keratopathy is not significant or severe enough that it does warrant adjustment or holding of to allow for that [toxicity] to improve.

Are there any other elements of the trial that you wanted to elaborate on? What was the significance of this research?

This trial addressed the unmet medical need in myeloma. Patients had received a median of 6 prior lines of therapy, and both 100 patients were on each arm [of the trial]; thus, it provided a fairly robust experience.

I believe it reflects the real-world practice of seeing patients with triple-class refractory multiple myeloma. It’s important to remember that, just because patients develop keratopathy, doesn't mean it will always impact their vision. In patients who have changes in visual acuity, the median time to recovery is about 22 days, so missing a dose could allow for them to recover back to baseline.

Moreover, in the majority of patients who had to miss a dose or reduce their dose, the disease actually didn't grow out of proportion. Over 80% of these patients maintained their disease response or deepened their response, likely because of the very long half-life of the antibody. It's a different drug in a number of different ways than most are used to dealing with.

What are the next steps for research with this agent?

As with every drug that we use in myeloma, we often try to move these agents [to examine their use] earlier on in the course of disease; these trials are currently ongoing. For example, the DREAMM-6 study combined bortezomib (Velcade) with belantamab mafodotin and demonstrated a significantly high ORR with a similar keratopathy rate to what was shown in the DREAMM-2 study. 

Other ongoing are trials examining belantamab mafodotin in combination with new immunologic targets. Some are looking at belantamab mafodotin in combination with pomalidomide (Pomalyst), lenalidomide (Revlimid), or carfilzomib (Kyprolis).

With quadruplet therapies emerging in the frontline setting, have sequencing strategies been impacted? Do you foresee the ADC being used in second-line setting?

Quadruplet therapies are being used more frequently in the newly diagnosed setting, particularly for patients who are transplant eligible. I do foresee antibody strategies, other than daratumumab, potentially moving into the second-line setting.

The strategy at Emory University’s Winship Cancer Institute is to use daratumumab with RVd in the first 4 cycles of therapy, but not after transplant. In those cases, the use of daratumumab after transplant, is a reasonable approach, especially in the context of relapse. If you’re giving continuous daratumumab, [investigators will start to examine] belantamab mafodotin, isatuximab (Sarclisa), or other antibodies more frequently in first relapse.

What are some of the other BCMA-targeted therapies that are currently under investigation?

Belantamab mafodotin is an ADC and others are currently under development. Additionally, we have seen a lot of data on BiTEs. [With regard to BiTEs], AMG 420 led the way early on, but there are now BiTEstargeting BCMA that have a longer half-life. Also, [data with] bispecifics have been reported by several companies. At higher doses, there seems to be ORRs ranging anywhere from 60% to 90%; this is very exciting, especially for relapsed/refractory multiple myeloma where we have been worried about T-cell health being a limiting factor for the efficacy of these bispecifics. However, this does not appear to be the case in small phase 1 studies.

Compared with lymphoma and chronic lymphocytic leukemia, we have been behind with regard to CAR T-cell therapy. [We know that] CAR T cells elicit high ORRs and minimal residual disease negativity rates along with longer DOR and PFS. The product that is furthest along in research is probably idecabtagene vicleucel. We're hoping that [this product] will be approved in the next few months based on results from the KarMMA study. Right behind this are other products that seem to have similar efficacy. We’ll have to see more information on PFS to determine which of these CAR T-cell products are optimal.

One of the differences between myeloma CARs and CD19 CARs has to do with both efficacy and toxicity. We see much less grade 3/4 cytokine release syndrome with myeloma CARs as well as less grade 3/4 neurotoxicity. This is great, because those toxicities are challenging to deal with; this differentiates CD19 from BCMA as a target.

How do you plan on sequencing these BCMA-targeted therapies?

We are often asked whether we plan on sequencing these agents. Which one will we give if we can only give one? In reality, we're going to end up giving multiple. Having off-the-shelf options is really important, particularly for older or frailer patients or those who present with acute relapse and action needs to be taken immediately.

The CAR T-cell approach may be more effective in younger patients and I suspect that we'll be giving more than one of these BCMA-targeting drugs to patients. Most trials excluded prior BCMA exposure from enrollment but, with belantamab mafodotin, we are going to be able to see whether patients who progress on a CAR T-cell therapy will respond to the ADC. For patients who respond to belantamab mafodotin and have progressed, can they respond to a CAR T-cell therapy or a BiTE? The next year will be filled with many of these anecdotal examples that will hopefully provide us with a sense of how best to sequence or if all can be used in a given patient.

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 refractory to proteasome inhibitors, 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