BCMA-Directed CAR-T Therapy Shows Promise in Pretreated MM

Jesus Berdeja, MD, Sarah Cannon Research Institute, Nashville, Tennessee, discusses the results of the CARTITUDE-1 trial exploring BCMA-directed CAR-T therapy in relapsed/refractory multiple myeloma (MM).



My name is Jesus Berdeja. I'm the Director of Multiple Myeloma Research at Sarah Cannon Research Institute in Nashville, Tennessee, United States of America. I presented the results of CARTITUDE‑1, which is a phase 1b/2 study of BCMA‑directed CAR-T therapy in relapsed/refractory multiple myeloma.

JNJ‑4528 is structurally different than other anti‑BCMA CAR-T therapies. It contains 2 BCMA‑targeting single‑chain antibodies which are designed to confer affinity, basically binding it to different places in BCMA, and perhaps lessening the potential for escape.

It is identical to the CAR construct used in the LEGEND‑2 study. The dose of CAR-Ts administered in this study was lower than those of some of the other BCMA CAR-T structures presented.

The dose here was .72x106 CAR‑viable T-cells per kilogram. We reported on 29 patients that were enrolled to the phase 1b portion of the study. These were heavily pretreated patients with median of 5 lines of prior therapy.

86% of these patients were triple‑refractory. We did see any unexpected safety singles. The majority of patients had cytokine release, as expected, but mostly grade 1 and 2, with only 2 patients having cytokine release grade 3 or higher.

Interestingly, the mean onset to CRS was 7 days, which is longer than what has been reported with other BCMA CAR products. Neurotoxicity was unusual and generally low‑grade, with only 1 grade 3 event.

Most of the patients experienced grade 3/4 cytopenias, but it was rare that any patient had not resolved by 60 days. There was no significant incidence of unusual infections beyond those expected in this patient population.

JNJ‑4528 was very effective, with 100% overall response rate, 86% stringent complete remission, 97% greater than or equal to VGPR, at a median follow-up of 11.5 months.

There were 16 patients in CR that were available for MRD assessments. Of these, 81% were MRD‑negative at 10‑5 or better, and 69% at 10‑6. The PFS at 9 months was 86%.

JNJ‑4528 has received breakthrough therapy designation. The phase 2 portion of the study is fully enrolled and phase 2/3 studies have been initiated. I think this data is very encouraging.

It provides lot of hope for our patients with multiple myeloma and is a strong candidate to become one of the first FDA‑approved CAR-T therapies for patients with myeloma. I think there are three specific characteristics of this CAR product that separate it from some of the others.

One is the fact that it has, again, it uses 2 BCMA‑directed antibodies to confer affinity, and I believe, perhaps, a stronger hold on BCMA, and perhaps less escape potential. The dose that is infused with this CAR product is much lower than with other products supported, at .72 CAR-T cells per kilogram on average, given in this phase 1b patient population.

Then finally, I think the late onset of CRS is actually quite intriguing. Most other products have CRS that starts immediately or within the first 2 days of infusion of the CAR product. Here, the median onset was 7 days, which perhaps lends itself well to outpatient dosing of this product, which hopefully will translate to increased availability to patients.

These are the results of the phase 1b portion of CARTITUDE‑1. The phase 2 portion is actually now fully enrolled. Those results have not been presented, but I think in aggregate, these data will hopefully make this product available for the FDA to evaluate and hopefully approve.

The phase 2/3 studies that are underway are actually more looking at treatment with this product in different phases of the disease, moving it perhaps earlier. There's going to be a phase 3 randomized trial, for example, in patients who had at least 2 prior lines of therapy.

We’re in that population comparing it to standard of care. There's also going to be a study, or one of the cohorts of the study, will be looking at even a consolidation with JNJ‑4528 in patients with high‑risk disease as part of their upfront treatment.

I think that's the hope, is that as we learn more from these studies and the effectiveness, as well as the toxicity profiles, it lends itself well to hopefully expanding it to different patients and not just the relapsed/refractory.    

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