Study Moves CAR-T Therapy Forward in Myeloma

Chimeric antigen receptor (CAR) T-cell therapy could be on the horizon for the treatment of relapsed/refractory (R/R) multiple myeloma, according to findings from the phase 1b/2 CARTITUDE-1 study.

Using an approach that targets the B-cell maturation antibody (BCMA) protein that is overexpressed in myeloma, an investigational CAR T-cell therapy produced early, deep, and high responses among patients who had progressed on ≥3 prior regimens. Additionally, minimal residual disease (MRD) negativity was achieved in all evaluable patients.

“It was thought initially that CAR T-therapy was going to cure these patients,” said Deepu Madduri, MD, from the Tisch Cancer Institute at Mount Sinai, New York, who presented the results of the study. “Maybe ‘cure’ is not the right word yet, but perhaps we can give a one-time treatment for these patients who come once or twice a week for infusions.”

Although numerous treatment advances have been made in recent years, resulting in prolonged survival in patients with multiple myeloma, there is currently no approved CAR T-cell therapy for patients with R/R disease. Patients who have failed on all approved therapeutic options have a median overall survival of less than a year.

“Every single patient on the study responded to therapy, for an overall response rate of 100%, with 66% showing stringent complete responses,” Dr Madduri reported. “Considering these patients have all received multiple prior therapies, these results are extremely encouraging.”

The product is JNJ-4528, a structurally differentiated CAR T-cell therapy that contains 2 BCMA-targeting antibodies.

To participate in the study, patients had to have progressive disease as well as measurable disease in their blood or bone marrow, and must have received all 3 classes of available agents (prior proteasome inhibitor, immunomodulatory drug, and CD38 therapy). T-cells from eligible patients were collected and genetically engineered to express JNJ-4528. Patients then received bridging therapy (as needed) followed by lymphodepletion chemotherapy before having the new cells re-infused.

In total, 29 patients with a median age of 60 years were infused with JNJ-4528 at a median administered dose of 73,000 CAR T-cells (targeted dose was 0.75 × 106 CAR+ cells/kg). Dr Madduri noted that this particular CAR T-cell therapy is given as a weight-based dose as opposed to a flat dose. In the phase 1b portion of the study, median follow-up was 6 months at data cutoff.

“The median prior lines of therapy in this study was 5, but it ranged from 3 to 18,” she noted. “These patients are quite refractory.”

Breaking the 100% overall response rate down further, Dr Madduri reported that 69% of patients were in complete response, meaning they had no evidence of myeloma cells in their bone marrow or blood, while 86% of patients were in very good partial response or better.

Median time to first response was 1 month, as was the median time to complete response or better. Of 17 evaluable patients, all 17 were MRD-negative. At data cutoff, 27 of 29 patients remained progression-free.

The most frequently reported adverse events were cytokine release syndrome (93%), the majority being grade 1/2 (86%).

Dr Madduri noted that the median time to onset of cytokine release syndrome was 7 days, with >90% between 5 and 9 days. Most other CAR T-cell therapies have rapid expansion, resulting in faster onset of cytokine release syndrome.

Also frequent were neutropenia (93%), anemia (86%), and thrombocytopenia (86%). Hematologic adverse events grade ≥3 included neutropenia (93%), thrombocytopenia (69%), and anemia (55%). Nonhematologic adverse events were very uncommon.

Every patient demonstrated consistent expansion of JNJ-4528 CAR+ T-cells, with peak expansion around day 10.

“What we think makes this product more unique is the preferential expansion of CD8+ central memory phenotype,” she explained. “CD8+ cells are used to kill myeloma cells, but these central memory cells have a way—we think—of not getting exhausted as often, and therefore having sustained effector function.”

“Collectively, these results demonstrate that JNJ-4528 at the target dose delivers early and deep responses, including MRD negativity,” Dr Madduri commented. “This was a very safe and tolerated product.”

The safety and efficacy results from the ongoing CARTITUDE-1 study are consistent with results seen in the LEGEND-2 study (with LCAR B38M) conducted in a Chinese population, confirming the reliability of this chosen dose as the drug moves forward to the phase 2 portion of the study, she noted.

Just days ago, JNJ-4528 received breakthrough designation from the US Food and Drug Administration. The phase 2 portion of the study is now fully enrolled, and phase 2 and 3 studies have been initiated.

Madduri D. ASH Abstract 577.

Related Items