JNJ-5322 Shows CAR T–Like Efficacy With Monthly Off-the-Shelf Dosing

All patients with anti-BCMA/-GPRC5D naïve multiple myeloma who received the recommended phase 2 dose (RP2D) of JNJ-5322 in phase 1 study achieved an objective response. This is a result which study investigators believe could potentially lead to a paradigm shift.

JNJ-5322 is a next-generation TsAb that targets BCMA and GPRC5D via T-cell redirection, and the rationale for exploring this therapy, according to study investigator, Rakesh Popat, MBBS, consultant hematologist at University College Hospital Macmillan Cancer Center in London, UK, is the known success of bispecific antibodies.

“We know that bispecific antibodies are effective in myeloma and the combination of teclistamab and talquetamab has a high level of activity.  This led to the development of the trispecific antibody that was designed to confer more specificity to myeloma due to its dual targeting and increase efficacy and reduce resistant.  The initial results show a 100% response rate at the recommended phase 2 dose for BCMA GPRC5D naive patients and 95% of patients alive and disease free at 12 months,” Dr. Popat told Blood Cancers Today.

A total of 126 patients were treated with JNJ-5322 in the study, including 36 patients who received the putative RP2D of 100 mg every 4 weeks. The median patient age was 64 years, and the median number of prior lines of therapy was 4. All patients were triple-class exposed, 56% were triple-class refractory, and 31% had high-risk cytogenetics. Among response-evaluable patients (n = 124), the objective response rate (ORR) was 73%, with 66% achieving a very good partial response (VGPR) or better. At the RP2D, the ORR was 86%, and among patients naïve to prior anti–BCMA or GPRC5D therapies (n = 27), 89% achieved VGPR or better. Median time to first response was 1.2 months, and all responses in the anti-BCMA/GPRC5D–naïve subgroup remained ongoing at a median follow-up of 8.5 months.

JNJ-5322 demonstrated a manageable safety profile. Cytokine release syndrome (CRS) occurred in 59% of patients, with all events graded 1 or 2; investigators did not report any grade 3 or higher CRS events. Additional adverse events (AEs) included nail disorders and taste alterations (both 56%; grade 1 or 2), neutropenia (48%; grade 3/4 in 41%), and non-rash skin AEs (47%).

“We noticed that the off tumor GPRC5D side effects, namely taste disturbance was lower as was weight loss. We think this might be due to the increased specificity of the antibody but need to work that out in larger studies,” explained Dr. Popat.

Infections were reported in 75% of patients, with 28% classified as grade 3 or 4. Weight loss and rash were each reported in 16% of patients, with no events grade 3 or higher. Immune effector cell–associated neurotoxicity syndrome occurred in 2% of patients, all of which were grade 1 in severity. Five patients experienced dose-limiting toxicities, and four deaths were attributed to AEs. Investigators noted that the monthly dosing schedule and early, deep responses support the potential of JNJ-5322 as an outpatient-administered, off-the-shelf T-cell redirecting therapy.

The results from this phase 1 study represent the largest data set for next-generation dual antigen T-cell redirecting TsAb. The efficacy of the agent was said to be similar to that of off-the-shelf chimeric antigen receptor T-cell therapies.