BCMA-Targeted Therapy for Relapsed/Refractory Multiple Myeloma - Episode 4

Potential Sequencing of BCMA-Directed Therapies in RRMM

December 10, 2019

Ola Landgren, MD, PhD:If we look at individual studies we are not comparing the details. We’re not looking at the decimals here but, as I mentioned, the drug approval for the daratumumab and carfilzomib. There was a paper published in 2019, regarding the first CAR [chimeric antigen receptor] T-cell therapy, the bb2121, the bluebird bio CAR T cell. And that is a drug that targetedBCMA. They had about a year or so of progression-free survival [PFS] follow-up. But those patients were a little more heavily pretreated.

Nina Shah, MD:Yeah. I think that it’s a really good point. We only have the data we have, right? So of course we’re going to look at studies between studies and see what are the differences. No one wants to compare these 2 very exciting drugs with each other just yet because there are too much exciting data coming out that are early. So in the CAR [T-cell] study, the bb2121 study, the patients received a median prior of 7 lines. It’s a little more heavily pretreated. They had to have had 3 lines before going on the study.

Their response rate there was over 80%, around 85%. As you mentioned, the PFS was comparable, 11.8 months versus the 12 months we’re seeing that theBCMAADC [antibody-drug conjugate] drug. That’s comparable. I think it’s a different science that the CAR T cells are working with versus theBCMAADCs. I’m hoping we can put these things together eventually to get a better PFS, whether it’s going to be sequencing or combining them. But they’re definitely 2 different patient populations. The differences we’re seeing in the data reflect that. However, the similarities in the PFS also bring to mind that maybe these are things that can be used for similar patient populations eventually, and it will be a question of who is best fit for what.

Ola Landgren, MD, PhD:The current protocols that are in our clinics for both the CAR T cells and the antibodies, these ADCs, exclude patients with the exposure to priorBCMA-targeted therapies. You cannot receive CAR T cell therapy and go on antibody, or you cannot receive antibody and go to CAR T cell. Do you think once these drugs are FDA approved that clinicians will use them after one another?

Nina Shah, MD:Yeah, actually I do, because my opinion—and we have some hints of this, although it has not been completely proven—is that having a progression afterBCMACAR T cells does not necessarily mean that you lostBCMA. It’s that whatever cell was in there isn’t working anymore. As long as you have that protein on the surface target tumor cell, then it’s worth looking at another modality to target it. I would advocate for even having a cohort of patients in a clinical trial that are BCMA exposed, and some trials are doing this now, and then having those patients go on to get either the bispecific therapy or theBCMAADC therapy. I think it makes sense if you can prove whatever it means we have—IHC [immunohistochemistry] or RNA or protein mix—that still haveBCMA, then it’s worth giving them another shot.

There was an ASCO [American Society of Clinical Oncology] abstract presented this past year in which patients had received aBCMACAR T-cell therapy that was humanized after; 4 of those 10 patients who were presented had previously received aBCMACAR T-therapy that was murine, and actually all 4 of those patients did respond to this new CAR T. So it lends the idea that maybe we do have an opportunity to re-treat people but with differentBCMA-directed therapy.

Ola Landgren, MD, PhD:This concept is not really new to think about re-treatment. If we think about the FDA-approved classes of drugs we have, the first so-called novel class of drugs was bortezomib, a proteasome inhibitor. There are now 3 FDA-approved proteasome inhibitors, and they all go after the same 20S subunits.

Nina Shah, MD:Right.

Ola Landgren, MD, PhD:We have bortezomib, we have carfilzomib, and we have ixazomib. There are data that even led to the registration that you can use them after one another, and we know that in clinical practice. The same is true for the IMiDs [immunomodulatory imide drugs].

Nina Shah, MD:Exactly.

Ola Landgren, MD, PhD:Again, also FDA approved. You can use palmiest after you have used, or pomalidomide after you had used lenalidomide.

Nina Shah, MD:Right, which we do.

Ola Landgren, MD, PhD:Yes, which we do. And that was also how it led to its approval.

Nina Shah, MD:Right.

Ola Landgren, MD, PhD:We know that you can recycle different drugs. You can go back to the same drug even if you give a little bit of a break probably.

Nina Shah, MD:Yeah. And these are different mechanisms of action. Maybe the same target, but different mechanisms of action. So I think it’s worth sequencing them and at least trying it, because these patients do need other options after the CAR T failure.

Transcript edited for clarity.