Novel BCMA-Directed CAR T-Cell Therapy Had Excellent Responses in Heavily Pretreated Patients with Multiple Myeloma

JHOP - February 2020 Vol 10, No 1 - ASH Highlights, CAR T-Cell Therapy, Multiple Myeloma

The investigational B-cell maturation antigen (BCMA)-­directed chimeric antigen receptor (CAR) T-cell therapy known as JNJ-4528 induced responses in 100% of 29 evaluable patients with heavily pretreated relapsed or refractory multiple myeloma, according to the results of the phase 1b/2 CARTITUDE-1 clinical trial reported at ASH 2019. 

The responses were deep and durable, with a median number of 5 previous treatments that included the full arsenal of current therapies used for the treatment of multiple myeloma.

The objective response rate included a 66% stringent complete response rate, a 3% complete response rate, a 17% very good partial response rate, and a 14% partial response rate. The median follow-up was 6 months (range, 3-14 months), with a median 1-month period to first response and to complete response or better. All but 2 patients remained progression-­free at 6 months, and all 17 patients evaluable for minimal residual disease (MRD) had MRD-­negative status. 

“We are seeing a high response rate, with most patients achieving MRD-negativity,” said the study’s lead investigator Deepu Madduri, MD, Assistant Director, Cellular Therapy Service, Center of Excellence for Multiple Myeloma, Tisch Cancer Institute and the Icahn School of Medicine at Mount Sinai, New York City.

“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,” she added.

“We are learning that every CAR-T therapy is different,” Dr Madduri explained. JNJ-4528 is a novel CAR T-cell therapy that binds to BCMA, a protein found on the surface of multiple myeloma cells, and features 2 BCMA-­targeting single-domain antibodies. JNJ-4528 is preferentially enriched to bind to CD8 T-cells, one of the most important T-cells in killing cancer.

This agent is being developed in the United States and in Europe under the designation of JNJ-4528; in China, the same therapy is being developed using the designation LCAR-B38M.

The CARTITUDE-1 Study

Of the 29 patients, 25 (86%) patients had undergone autologous transplant, and the median number of previous lines of therapy was 5 (range, 3-18). The median age of the patients was 60 years (range, 50-75 years), 7 (25%) patients had a high-risk cytogenetic profile, and the median number of years since diagnosis was 6 (range, 2-16 years).

All 29 patients had been exposed to 3 drug classes, including a proteasome inhibitor, immunomodulatory drug (IMiD), and anti-CD38 therapy. In all, 25 (86%) of the patients had triple-refractory disease, 21 (72%) were penta-exposed (ie, received ≥2 proteasome inhibitors, ≥2 IMiDs, and anti-CD38 therapy), and 9 (31%) patients had penta-refractory disease.

JNJ-4528 was given at a median dose of 0.73 × 106 (0.52-0.89 × 106) CAR+ viable T-cells/kg, and the study supported a recommended phase 2 dose of 0.75 × 106 CAR+ viable T-cells/kg.

“Every single patient expanded their T-cells,” Dr Madduri said.

As with other current CAR T-cell therapies, cytokine release syndrome (CRS) of any grade was common and occurred in 17 (93%) patients. The median time to onset of CRS was 7 days, with more than 90% of the cases occurring on days 5 to 9. In all, 1 patient died at day 99, which was attributed to grade 4 CRS and 76% of the patients received treatment with tocilizumab (Actemra) for CRS.

Neurotoxicity of any grade occurred in 3 patients, with 1 patient having grade ≥3 neurotoxicity.

Common hematologic adverse events across all grades included neutropenia (93%), anemia (86%), thrombocyto­penia (86%), leukopenia (52%), and lymphopenia (45%). Frequent grade ≥3 hematologic events included neutro­penia (93%), thrombocytopenia (69%), anemia (55%), leukopenia (52%), and lymphopenia (31%).

Grade ≥3 nonhematologic adverse events included increased aspartate aminotransferase (7%), increased alanine aminotransferase (3%), and diarrhea (3%). 

Breakthrough Therapy for Multiple Myeloma

Based on the CARTITUDE-1 findings presented at ASH 2019, the FDA granted JNJ-4528 a breakthrough therapy designation in December 2019 for the treatment of patients with relapsed or refractory multiple myeloma.

The phase 2 portion of CARTITUDE-1 is fully enrolled; the phase 3 CARTITUDE-4 trial has been initiated. The phase 3 clinical trial will investigate the use of JNJ-4528 combined with pomalidomide (Pomalyst), bortez­omib (Velcade), and dexamethasone compared with daratumumab (Darza­lex), pomalidomide, and dexamethasone in patients with relapsed and lenalidomide-refractory multiple myeloma.

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