JNJ-4528 Boasts High Response Rate in Relapsed/Refractory Myeloma

Deepu Madduri, MD

The anti-BCMA CAR T-cell therapy JNJ-4528 led to a 100% overall response rate (ORR) with a manageable toxicity profile in patients with heavily pretreated relapsed/refractory multiple myeloma, according to Deepu Madduri, MD, who added that ongoing research efforts will determine the durability of these responses.

“[In the phase Ib/II CARTITUDE-1 trial], we showed that JNJ-4528 is safe and has a manageable toxicity profile,” said Madduri, who is the lead author of the study. “The ORR was 100%, so we're pretty excited and hope these [responses] continue as we evaluate more patients in the phase II portion of the trial.”

According to results from the trial (NCT03548207) presented at the 2019 ASH Annual Meeting, the 100% ORR consisted of a 66% stringent complete response (CR) rate, 3% CR rate, 17% very good partial response rate, and 14% partial response rate. Additionally, all 17 patients evaluable for MRD had MRD negativity.

In the trial, JNJ-4528 was administered to patients at a dose of 0.73 x 10⁶ (0.52-0.89 x 10⁶) CAR+ viable T cells/kg.

To be eligible for enrollment, patients had to have measurable and progressive disease; an ECOG performance status of ≤1; received ≥3 prior therapies or disease that is double refractory; and prior treatment with a proteasome inhibitor, immunomodulatory drug, and anti-CD38 therapy. Patients received a median of 5 (range, 3-18) prior lines of therapy, and 25 (86%) patients had prior autologous transplantation.

In terms of safety, all-grade cytokine release syndrome (CRS) occurred in 27 patients, with 2 reports of grade ≥3 CRS and 1 report of progressive grade 4 CRS. The rate of neurotoxicity was low, with 3 all-grade events and 1 grade ≥3 event.

Based on these data, the FDA granted JNJ-4528 breakthrough therapy designation for the treatment of patients with relapsed/refractory multiple myeloma.

The phase II portion of the trial, which will evaluate the recommended phase II dose of 0.75 x 10⁶ CAR + viable T cells/kg, has completed accrual. Additionally, the CARTITUDE-4 trial (NCT04181827), which has yet to open, will compare JNJ-4528 with pomalidomide (Pomalyst), bortezomib (Velcade), and dexamethasone, as well as daratumumab (Darzalex), pomalidomide, and dexamethasone in patients with relapsed or lenalidomide (Revlimid)-refractory myeloma.

In an interview with OncLive, Madduri, assistant professor of medicine, hematology and medical oncology, Mount Sinai Hospital, discussed the results of the CARTITUDE-1 trial and the next phase of development with JNJ-4528.

OncLive: Could you provide a rationale for the trial?

Madduri: Patients with multiple myeloma who have been exposed to 3 or more prior lines of therapy have an overall survival of less than 12 months. With this in mind, we wanted to see if we could use a one-time treatment to get sustained and durable responses.

How was the trial designed?

The trial consisted of 2 portions: a phase Ib and phase II portion. The phase Ib portion characterized the safety [of JNJ-4528] and confirmed the recommended phase II dose. The phase II portion characterized the efficacy [of JNJ-4528]. [At the 2019 ASH Annual Meeting], I presented the data from the phase Ib portion, which consisted of 29 patients.

What differentiates JNJ-4528 from other products that are under investigation in myeloma?

JNJ-4528 is quite unique; in fact, it has a different construct. The product has 2 BCMA-binding domains. We also noticed that there was a slow expansion of the CAR T cells [with JNJ-4528]. We noticed a median CRS period of about 7 days. Most CAR T-cell products expand very quickly and result in early onset CRS. The other interesting thing we noticed is that JNJ-4528 had a preferential memory like CD8 phenotype, which we believe is causing the sustained effector function.

What were the results?

We found that the most common grade ≥3 adverse events (AE) were hematological; non-hematological grade ≥3 AEs were very uncommon. Neurotoxicity was also very uncommon, occurring in 10% of patients. Three of 29 patients experienced any-grade neurotoxicity. One patient had a grade 3 neurotoxic event, which was concurrent with a grade 3 CRS event. However, both events resolved very quickly with the administration of tocilizumab (Actemra) and steroids. All but 2 patients experienced CRS, and 86% of patients had grade 1/2 CRS. One patient had a grade 3 CRS event, and 1 patient had a prolonged grade 4 CRS event, which turned into a grade 5 event at day 99.

Patients [enrolled on the trial] were heavily pretreated and received a median of 5 prior lines of therapy. However, we saw a 100% ORR [with JNJ-4528]. Every single patient experienced a reduction in their paraprotein, and 27 out of the 29 patients are still progression free at a median of 6 months of follow-up.

All 17 patients who were evaluable for MRD were MRD negative. MRD assessment has been used as a diagnostic tool in most multiple myeloma clinical trials. [In CARTITUDE-1], we showed that all evaluable patients were MRD negative. Nine patients had MRD negativity of 10^-6, 5 patients had MRD negativity of 10^-5, and 3 had MRD negativity of 10^-4.

What are the next steps regarding this research?

We confirmed the recommended phase II dose, and [enrollment for] the phase II portion of the study has been completed. In that portion, we are evaluating what the long-term responses are as well as the durability of those responses. Additional phase II and phase III studies have also been initiated, and with those studies, we're going to move this therapy earlier on [in the treatment journey] and evaluate how that impacts responses.

Madduri D, Usmani SZ, Jagannath S, et al. Results from CARTITUDE-1: a phase Ib/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). Blood. 2019;134(suppl 1):577. doi: 10.1182/blood-2019-121731.