The BCMA-directed CAR T-cell therapy JNJ-4528 achieved a 100% overall response rate with early and deep responses in 29 patients with heavily pretreated relapsed/refractory myeloma.
Deepu Madduri, MD
The BCMA-directed CAR T-cell therapy JNJ-4528 achieved a 100% overall response rate (ORR) with early and deep responses in 29 patients with heavily pretreated relapsed/refractory myeloma, according to data from the phase Ib/II CARTITUDE-1 trial reported at the 2019 ASH Annual Meeting.
The ORR comprised a 66% stringent complete response (CR) rate, 3% CR rate, 17% very good partial response (PR) rate, and 14% PR rate. The median follow-up was 6 months (range, 3-14), with  the median time to first response and median time to ≥CR both being 1 month. All but 2 patients remained progression-free at 6 months, and all 17 patients evaluable for minimal-residual disease (MRD) were MRD-negative.
“Sixty-nine percent of the patients were in complete response, meaning that they had no evidence of myeloma cells in their bone marrow or in their blood. Eighty-six percent of the patients were in very good partial remission or better,” said lead study author Deepu Madduri, MD, Mount Sinai Medical Center.
Based on the CARTITUDE-1 findings, JNJ-4528 has received an FDA breakthrough therapy designation for the treatment of patients with relapsed/refractory multiple myeloma. The designation will expedite the development and regulatory review of the anti-BCMA CAR-T treatment in this setting.
Eligibility criteria for CARTITUDE-1 included measurable and progressive disease; an ECOG performance status of ≤1; at least 3 prior therapies or double-refractory status; and prior treatment with a proteasome inhibitor (PI), immunomodulatory drug (IMiD), and anti-CD38 therapy.
The median administered dose in the trial was 0.73 x 106 (0.52-0.89 x 106) CAR+ viable T cells/kg, and the study supported a recommended phase II dose of 0.75 x 106 CAR+ viable T cells/kg.
The median patient age was 60 years (range, 50-75), 25% (n = 7) of patients had a high-risk cytogenetic profile, and the median number of years since diagnosis was 6 (range, 2-16). Twenty-five (86%) patients had prior autologous transplantation and the median number of prior lines of therapy was 5 (range, 3-18). All 29 patients were triple-exposed (received a PI, IMiD, and anti—CD-38 therapy), with 86% (n = 25) being triple-refractory, and 72% (n = 21) of patients were penta-exposed (received ≥2 PIs, ≥2 IMiDs, and anti–CD-38 therapy), with 31% (n = 9) being penta-refractory.
Madduri noted that this heavily pretreated population has a high unmet medical need, with a median overall survival of less than 1 year. “We really need a product that we can give to these patients that will [induce] deep, sustained responses.”
Commenting on the efficacy findings, Madduri said, “Every single patient expanded their T cells,” adding, “What we think makes this product unique is the preferential expansion of the CD8+ central memory phenotype. CD8 cells are used to kill myeloma cells [and] these central memory cells, we think, have a way of not getting exhausted as often and having sustained effector function.”
Regarding safety, cytokine release syndrome (CRS) across all grades occurred in 93% (n = 27) of patients, with 2 patients experiencing grade ≥3 CRS. The median time to the onset of CRS was 7 days, with more than 90% of CRS starting at day 5 to 9.
“Most other [CAR-T] products have rapid expansion and you notice CRS happening within the first couple of days. But with this one, there’s slow expansion, causing the CRS to happen at closer to 7 days,” said Madduri.
There was 1 dose-limiting toxicity of grade 4 CRS, which “converted to a grade 5 event, and the patient passed away from complications at day 99,” said Madduri.
Neurotoxicity was uncommon, occurring at any grade in 3 patients, with 1 patient having grade ≥3 neurotoxicity.
Common (≥25%) hematologic AEs across all grades included neutropenia (93%), anemia (86%), thrombocytopenia (86%), leukopenia (52%), and lymphopenia (45%). Nonhematologic AEs reported in ≥25% of patients included increased AST (31%), increased ALT (28%), diarrhea (28%), and upper respiratory tract infection (28%).
Frequent grade ≥3 hematologic AEs included neutropenia (93%),  thrombocytopenia (69%), anemia (55%), leukopenia (52%), and lymphopenia (31%). Grade ≥3 nonhematologic AEs included increased AST (7%), increased ALT (3%), and diarrhea (3%).
Madduri said the phase II portion of CARTITUDE-1 is fully enrolled and a phase III trial, CARTITUDE-4 (NCT04181827), has been initiated. CARTITUDE-4 is comparing JNJ-4528 with pomalidomide (Pomalyst), bortezomib (Velcade), and dexamethasone (PVd), or daratumumab (Darzalex), pomalidomide, and dexamethasone (DPd) in patients with relapsed and lenalidomide (Revlimid)-refractory multiple myeloma.
Madduri D, Usmani SZ,2 J, et al. Results from CARTITUDE-1: a phase 1b/2 study of JNJ-4528, a CAR-T cell therapy directed against B-cell maturation antigen (BCMA), in patients with relapsed and/or refractory multiple myeloma (R/R MM). Presented at: 2019 ASH Annual Meeting; December 7-10, 2019; Orlando, FL. Abstract 577.
The CARTITUDE-1 study design was informed by the earlier phase I LEGEND-2 study (NCT03090659), a first-in-human study that used an identical CAR construct in a slightly different patient population.