Outcomes in RRMM: The Modern Treatment Paradigm and BCMA

Ola Landgren, MD, PhD:Welcome to thisTargetedOncology™ presentation in precision medicine called “BCMA-Targeted Therapy for Relapsed-Refractory Multiple Myeloma.” I am Dr Ola Landgren, a professor of medicine and the chief attending physician at the myeloma service at Memorial Sloan Kettering Cancer Center in New York, New York. I’m here with my colleague Dr Nina Shah, an associate professor at the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco. Targeted therapies have really come to the forefront of treatment of cancer. Today we’re going to talk about an important therapeutic approach, the targeted B cell maturation antigen, orBCMA, which has shown great promise in treating relapsed-refractory multiple myeloma.

Several types of BCMA-targeted therapies are currently being investigated, and these represent the potentially paradigm-changing advance in precision oncology and drug development for patients with relapsed-refractory myeloma. Thanks for joining us. Let’s begin.

Welcome, Nina. It’s a pleasure having you here today.

Nina Shah, MD:I’m really happy to be here. Thanks for having me.

Ola Landgren, MD, PhD:Before we start talking about theBCMA-targeted therapies I would like to start a bit broader and talk a little about the treatment landscape for patients with relapsed-refractory myeloma. There’s so much going on.

Nina Shah, MD:Yeah, definitely.

Ola Landgren, MD, PhD:What’s your perspective?

Nina Shah, MD:There have been more drugs than we’ve had time to know exactly what to do with them. A clear example of that is daratumumab, which only 3 or 4 years ago was thought to be a drug only for relapsed myeloma, and now we’ve moved it to the front. That’s opened the way for a lot of other different drugs to be developed in relapsed myeloma, including, as you mentioned, theBCMA-targeting agents, other antibody-drug conjugates, and other modes of targetingBCMA. They include CAR [chimeric antigen receptor] T-cell therapy, BiTEs [bispecific T-cell engagers], ADCs [antibody-drug conjugates], and other non-BCMA, small-molecule inhibitors, and then repurposing of things like venetoclax.

Ola Landgren, MD, PhD:In your opinion, what’s the biggest unmet clinical need we have in the relapsed setting for myeloma?

Nina Shah, MD:We have never been able to cure myeloma in general, right? We’ve done really well in the up front, and we’ve extended people’s lives, the time of progression, and the time they’re actually living. But most of that we’re doing up front. We’re not doing as much in the relapsed-refractory setting, and we know that with each subsequent line of therapy, the rate of response goes down, and the time or duration of response goes down. We haven’t made as many moves on that time as I’d like to see.

Ola Landgren, MD, PhD:I agree with that. In the big picture, I think it’s important to emphasize that although there are a lot of issues we still have, we’re dealing with it. If you look at the big picture, patients with myeloma these days live for a very long time compared with just what we saw around the turn of the century. I think the overall survival used to be around 3 or so years from diagnosis.

Nina Shah, MD:Right.

Ola Landgren, MD, PhD:Today patients in the United States probably have an expected overall survival of maybe 10 or 20 years, or something like that.

Nina Shah, MD:Yeah, I think you’re right. And that’s made a huge difference where we really changed myeloma to be a chronic disease that maybe you don’t die from but that you live with. And all these drugs that have been developed, as time goes on we’re learning how to use them better in better patient populations and allowing them to make a bigger impact on the actual individual myeloma patient’s life.

Ola Landgren, MD, PhD:Let’s talk about theBCMA-directed therapies. What’s the rationale? Why would one think about usingBCMAas the drug target in myeloma? Can you talk a little about that?

Nina Shah, MD:Yeah. As you mentioned,BCMAstands for B-cell maturation antigen, and it’s a protein that is expressed pretty exclusively on plasma blast and plasma cells. And it’s involved in signal for proliferation and activation of the plasma cells. It interacts from its exterior service on the plasma cell with APRIL and BAFF on effector cells. And as I mentioned before, this would be involved in proliferation and downstream signaling. The reason it’s thought to be a very good target for myeloma is that it’s very specific for the plasma cell. It’s actually not found on non—plasma cell or physically hematopoietic elements, which we always worried about for cytopenias, etc. It turns out to be a really nice sort of Holy Grain antigen and target for us to target for things like cellular therapy.

Ola Landgren, MD, PhD:BCMAis expressed on the plasma cells; myeloma is a plasma cell disorder. It’s not expressed on the other cells. Maybe it’s a little expressed but very little.

Nina Shah, MD:Correct.

Ola Landgren, MD, PhD:What about levels of expression. Is there a need to test individual patients for high or low expression levels on the myeloma cells? Could you talk about that?

Nina Shah, MD:Yeah. You know, it’s been a confusing situation, because in order to know whether high or lowBCMAmakes a difference, you have to have the right test to do that. Traditionally we used things like IHC [immunohistochemistry] and now there are more advanced ways to look at that. I’d say that all we know from the sort of dirty looks is that whether you have some or a lot of theBCMAprobably doesn’t make a difference. I think you’re right, though. We don’t know the full sense of which cells may not haveBCMA. What do you think about that?

Ola Landgren, MD, PhD:I think all the data, at least the data that’s being presented and published in different settings, I think has been derived from expression of RNA, and the target we’re talking about is a protein. So DNA, RNA protein—that’s the chain. So I guess the ultimate test would be probably to do some form of single-cell proteomics and looking at proteins. I don’t think that has been done in myeloma to identify potential other proteins and also to study the exact details of how it is expressed on every single cell.

And we know that we can achieve deep responses with the cell therapies—we will talk about that in a bit. Unfortunately, patients will still continue to relapse.

Nina Shah, MD:Right.

Ola Landgren, MD, PhD:There probably is some more information that we are missing.

Nina Shah, MD:Right. It’s a great target, but it’s not the end-all, be-all, because there’s room for us to grow. We know that there isn’t a plateau on these curves yet. I’d be interested to see what proteomics will reveal, both between individual patients who may have differences and within the patient, because there’s clonal heterogeneity.

Transcript edited for clarity.