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 IB2 study of PCMA directed CAR T therapy in relapse refractory multiple myeloma. JNJ 4528 is structurally different than other anti BCMA CAR T therapies. It contains two BCMA targeting single chain antibodies which are designed to confer avidity, 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 0.72 times 10 to the 6th CAR viable T cells per kilogram. We reported on 29 patients that were enrolled to the phase IB portion of the study. These were heavily pretreated patients with median five lines of prior therapy. 86 percent of these patients were triple refractory. We did not see any unexpected safety singles. The majority of patients had cytokine release, as expected, but mostly grade one and two, with only two patients having cytokine release grade three or higher. Interestingly, the median onset to CRS was seven days, which is longer than what has been reported with other BCMA CAR products. Neurotoxicity was unusual, and generally low grade, with only one grade three event. Most of the patients experienced grade three/four 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 percent overall response rate, 86 percent stringent complete remission, and 97 percent 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 percent were MRD negative at 10 to the minus 5 or better, and 69 percent at 10 to the minus 6. The PFS at 9 months was 86 percent. JNJ 4528 has received breakthrough therapy designation. The phase II portion of the study is fully enrolled, and phase II/III studies have been initiated. I think this is data is very encouraging. It provides lot of hope for our patients with multiple myeloma, and it's a strong candidate to become 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 two BCMA directed antibodies to confer avidity, and I believe perhaps a stronger hold on BCMA, perhaps less escape potential. The dose that is infused with this CAR product is much lower than with other products supported, at 0.72 CAR T cells per kilogram on average, given in this phase IB 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 two days of infusion of the CAR product. Here, the median onset was seven days, which perhaps lends itself well to patient dosing of this product, which hopefully will translate to increased availability to patients. These are the results of the phase IB portion of CARTITUDE I. The phase II portion is actually now fully enrolled, and so those results have not been presented. I think, in aggregate, these data will make this product available for the FDA to evaluate and hopefully approve. The phase II/III studies that are underway are actually more looking at treatment with this product and in different phases of the disease, moving in perhaps earlier. There is going to be a phase III randomized trial, for example, in patients who had at least two prior lines of therapy, or in that population, comparing it to standard of care. There's also going to be the 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 relapse refractory.