Sequencing BCMA-Targeted Therapies in RRMM

Current combination approaches, including BCMA-targeting agents like belantamab mafodotin, being explored to address treatment gaps in relapsed/refractory multiple myeloma.

Natalie Callander, MD: We know that patients with relapsed and refractory [multiple] myeloma tend to have higher levels of soluble B-cell maturation antigen [BCMA]. That’s B-cell maturation antigen that’s been clipped off the surface of myeloma cells. One concern is that soluble BCMA can serve as a sink for drugs that are targeting BCMA. That may be 1 mechanism. A strategy that’s being utilized, both looking at belantamab [mafodotin] and other BCMA-targeted therapies, is to bring in a gamma-secretase inhibitor. That’s supposed to try to inhibit cleavage of BCMA off of the cell surface so that interference mechanism may not happen.

In other BCMA-targeted therapies, CAR [chimeric antigen receptor] T-cell therapy, there have been some investigations that show that there can be a loss or downregulation of BCMA. If patients experience a deletion of 16p where BCMA is encoded, that may be a mechanism. There may be some patients who are showing a biallelic deletion of the BCMA gene. That could be another mechanism. There are some investigations that show that once a BCMA-directed therapy is withdrawn, you start to see BCMA expression return on myeloma cells. This is an area that we’re still in the very early stages of understanding. Another strategy to try to help with resistance is to combine these BCMA agents with other drugs. That may help as well.

[Belantamab (mafodotin)-based combination regimens] are a very exciting area. This is a common theme in myeloma, that you take the drugs you have and combine them with new drugs. In particular, there’s the combination of belantamab [mafodotin] with the ICOS [investigational inducible T-cell co-stimulatory] agonist feladilimab. I had the privilege of presenting those preliminary data showing a response rate of about 52%. This is a very small pilot study of 25 patients, but it had some intriguing findings, including that the ICOS agonist, which is like a T-cell stimulator, didn’t create any more adverse effects, which is terrific.

One of the other studies that was presented was by Suzanne Trudel, MSc, MD, [Princess Margaret Cancer Centre] where she combined belantamab [mafodotin] with pomalidomide [Pomalyst] and dexamethasone. This study had a quite high response rate of about 83%. One of the features of her study is that she dosed the belantamab [mafodotin] in an every 8-week fashion. The incidence of keratopathy and ocular toxicity in this particular trial was quite low, which was great. I believe it was in the 20% to 30% range. That’s a very exciting study.

There were a couple of very interesting studies presented at ASH [American Society of Hematology annual meeting] this year. One is called the DREAMM-9 study. This is where a bortezomib [Velcade]/lenalidomide [Revlimid]/dexamethasone [VRd] backbone was combined with belantamab [mafodotin] in patients with newly diagnosed non–transplant eligible myeloma. They were looking at various doses and schedules. The VRd backbone was very much a standard one, with dosing of bortezomib on days 1, 4, 8, and 11. It was a 21-day cycle of VRd. The belantamab [mafodotin] was added in at various doses and schedules.

They were able to show really high response rates in the neighborhood of 85% to as high as 100% in some of the cohorts. There wasn’t the sense that there’s more toxicity. Part of the dosing strategy is to try to back off of the Q3-week [every 3 weeks] dosing of belantamab [mafodotin] to try to minimize toxicity. This looks very promising.

The Greek Myeloma [Study] Group presented data using belantamab [mafodotin] with lenalidomide and dexamethasone in newly diagnosed non-transplant patients. They had quite impressive results, well into the 90% range, with very acceptable toxicity. That 3-drug regimen is looking very interesting. We’ll probably see more of these upfront belantamab [mafodotin] combinations in the future.

A theme that often happens in myeloma is we have new drugs developed and they’re first tested in patients with relapsed and refractory myeloma, but for obvious reasons, we then start testing them in the upfront setting and they often look like they bring a lot of value there. That certainly happened with bortezomib when it was added to lenalidomide and dexamethasone in the SWOG 777 study published 10 years ago. It certainly looks like it may happen with the addition of an anti-CD38 antibody to upfront regimens in some of the preliminary data that are showing higher response rates, although it’s still not translating to survival. I think that will happen with many of the BCMA-targeted drugs. That’s 1 theme that will happen.

The second [theme] is trying to understand sequencing of BCMA-targeted therapies. We have the antibody-drug conjugate. There’s another 1 that’s BCMA-directed that was also presented at ASH. There are the bispecifics that we talked about. And then there are BCMA-directed CARs. Knowing the proper sequence is [important]. One of the interesting publications at ASH was a small retrospective study from Mount Sinai where they were looking at the results of people who had received bispecifics as part of a study and whether they could be retreated with another BCMA-targeted agent. Their results were promising. They saw about a 50% response rate on retreatment, in this case with either a bispecific or CAR T. Trying to figure out what we can do with sequencing is going to be critical in the next couple of years so that we can offer patients the best choices that we can.

Transcript edited for clarity.

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