SOHO 2020 | BCMA targeting agents in myeloma

BCMA is a very interesting target for myeloma. And the reason is that it is expressed on myeloma cells and normal plasma cell, but almost not anywhere else. So it is very myeloma specific target and also myeloma cells depend on BCMA for its survival partly. So when we use BCMA as a target myeloma cell, very seldom can survive without BCMA, and so resistance mechanism are not so easy to get. And that has made BCMA as a very important target.

Now because of that, BCMA has been targeted using multiple approaches. One of the approach which is now already approved by FDA for commercial purpose, is targeting BCMA through an antibody conjugated with an immunotoxin, and the drug which is approved, now is belantamab mafodotin, it’s a BCMA antibody conjugated with an auristatin molecule. And so when myeloma cells binds to this antibody or antibody binds to a myeloma cell through BCMA, the drug is delivered and the myeloma cells are killed. And there was a large Phase II study done with this agent. And that showed in very advanced patient population patients who were beyond the five and six cycles on a median with almost 40% patients with high-risk cytogenetic et cetera, there was a 30% response rate with a significant proportion, half more than 50% of those patients had VGPR or better.

So as a single agent, this was very effective treatment. And also a very interesting both overall survival median was around 14 months, a little bit above 14 months, and the duration of response was around 11 months with a 2.5 milligram per kg dose. And so this has made targeting BCMA through antibody as an important thing.

I must mention that the response, there’s a very curious toxicity of corneal keratopathy, that needs to be closely monitored and it’s all discussed in my presentation. But the second and probably very interesting targeting of BCMA is through CAR T-cells and CAR T-cells are produced with antibody, which is specifically binding to BCMA. And the three major studies presented at ASCO this year for example, one of the largest study was the molecule called ide-cel or the product ide-cel. And each of these three studies showed a very important finding. The response rates were from 70 plus percent to a hundred percent. And these are the patients who were between five to six to seven median lines of prior treatments already advanced disease.

There were a majority of them were, almost all of them were triple refractory, majority were penta refractory, et cetera. And the response, it was such a high number. And if you look at the duration of response in one of the study, the ide-cel study, it was close to nine months and the others had not yet reached or it’s a little bit early. And number of these responses were MRD negative. So there’s a great excitement about that. And then finally, of course, safety is an important concern and we can discuss about it. But cytokine release syndrome is one of the toxicity. And then the third way of targeting BCMA has been using what is called BiTE or bi-specific antibody, which is where this conjugated antibody has one end that is recognizing BCMA, but other end recognizing some part of the T cell, the most common being CD3.

So it’s a CD3/BCMA antibody, that brings the immune cells closer to the myeloma cells and thereby leads to immune mediated killing of myeloma cells. And also there are a number of molecules now in various forms of development and stages, Phase II. And for example, a molecule called CC-93269 is a bivalent bi-specific T-cell engager now which had what was considered to be a therapeutic dose or a higher dose had close to 90% response rate. Again, in bi-specifics also you will end up seeing CRS as one of the toxicity to keep in mind.

So the point ends up being that BCMA is an excellent target and we can pursue various matters to go after it. And some anecdotal studies recently published more single to three patient experiences is that when patients have relapsed from one kind of BCMA targeting treatment, you could utilize a different BCMA targeting treatment. So for example, a patient had CAR T-cells and they relapse. You can use belantamab and possibly get response as well. And so one relapse from BCMA targeting drug does not rule out using BCMA again in this patient population.