BCMA Loss After Multiple Myeloma CAR T Infusion and What it Means for Del17 Patients

We read more and more about the success of various CAR-T treatments for multiple myeloma. Over the past two months The Myeloma Crowd by HealthTree has posted a number of articles about ide-cel, cilta-cell, CAR-T ddBCMA and other prospective treatments that target different and/or multiple proteins on the surface of myeloma cells. At the same time, however, there are also outcomes that raise questions about the long-term efficacy of CAR-T treatment and later relapse.

In a recent post Dr. Nikhil Munshi, medical oncologist at Dana Farber Cancer Institute, replied to a question about why, at times, CAR-T fails:

“So, this is a very important question, which is, why do CAR-T  fail? Almost 80–90%—in some cases over 90%—of patients respond. But for example, [for the CAR T therapy] ide-cel currently the progression free survival (PFS) is nine months. Now, yes, these are very advanced patients. The median line of treatment patients listed before [initiating treatment] were six, but still, with somebody getting deep responses, why do they relapse? So, if we understand that, we can improve the benefit of CART T cells.”

A Myeloma Patient's Experience

Dr. Munshi was co-author of a recently published article in the journal Nature Communications and he discussed the investigation that was started after a patient that participated in the Phase I clinical trial for ide-cel that was part of the clinical data set submitted to secure the recent FDA approval for this product.

The patient in question

“ … got a CAR T cell, had a very good partial response (VGPR), more than 90% reduction; [then] after nine months, patient relapsed. And we gave the same CAR T to the patient again and did not respond to that. So why did the patient relapse and why the second CAR T cell that work first time did not work second time?”

This investigation can be summarized as follows:

• The research team had 8 different bone marrow samples from different time points of the patient’s treatment (before the first CAR-T, during the CAR-T, at time of relapse, and after the second CAR-T.
• Single cell genomics were performed on these samples and no significant differences were found in the patient’s immune profile.
• The research team then started to look closer at the myeloma cells of the patient and discovered the following : “… the 16th p, the arm of the chromosome, where BCMA is located, was deleted on one side and the second chromosome 16p where BCMA is, there was a mutation which inhibits production of BCMA.” [Emphasis added] In other words, the patient stopped making BCMA and, therefore, the CAR-T treatment lost its treatment target, leading to the treatment failure.

The article continues with a discussion of a data set of 300 newly diagnosed myeloma patients showing that patients with deletion(s) in part of chromosome 16p will also have a high likelihood (77 %) of deletion(s) in chromosome 17p, and in reverse, patients with deletion(s) in 17p will have a 36% likelihood of deletion(s) in part of chromosome 16p.

The authors conclude:

“This may highlight the need to carefully examine for BCMA gene alterations in patients being retreated with subsequent BCMA targeting therapy at relapse from initial BCMA CAR T-cell treatment.”

Simply put, if myeloma re-occurs after treatment with BCMA-targeted CAR-T, it may NOT be appropriate for that patient to be retreated with the same CAR-T product and that genetic study of such patient needs to confirm that BCMA is still being produced in adequate quantities.

In addition:

“The co-occurrence of 16p deletion in patients with del 17p also underscores the need to further evaluate the role of BCMA targeted therapies in high-risk del17p MM.”

Simply put, the medical community needs to learn more whether BCMA targeted therapies are the optimal treatment path for some patients with del 17p.

The authors also conclude: 

“Recently, CAR T-cell therapy approach simultaneously targeting dual antigens BCMA and GPRC5D was shown as one approach to prevent BCMA escape-driven relapse.” [Emphasis added].

(The Myeloma Crowd by HealthTree recently published a post about the bi-specific antibody talquetamab that targets both GPRC5D as well as CD3 (and stays away from BCMA altogether).

BCMA-targeted CAR-T treatments are giving many of us additional hope for longer survival. At the same time, medical science is also learning more about what drives (or does not drive) success as clinical trials unfold for these treatment programs. This should give us additional hope that future developments in treatment will become more targeted to the specific genetic make-up of our disease so that will receive the optimal treatment plan for our individually specific needs.