BCMA and CD3 T-cell–Engaging Bispecific Antibody Shows Promise in R/R Multiple Myeloma

ABBV-383 was effective and well tolerated at all administered doses in patients with relapsed/refractory multiple myeloma, according to safety and efficacy results from an ongoing first-in-human, phase 1 dose-escalation/-expansion study (NCT03933735).

Among the 122 efficacy-evaluable patients in the overall population, the overall response rate (ORR) was 57% (n = 69), and the rate of very good partial response (VGPR) or better was 43% (n = 52). In the dose-expansion cohort (n = 49), the ORR was 59% (n = 29) and the rate of VGPR or better was 39% (n = 19). Of the 79 patients in the combined dose-escalation and dose-expansion cohorts who received at least 40 mg of study drug, the ORR was 68% (n = 54) and the rate of VGPR or better was 54% (n = 43).

The most common hematologic treatment-emergent adverse effects (TEAEs) in the overall population were neutropenia (all grades, 37%; grade ≥ 3, 34%) and anemia (all grades, 29%; grade ≥ 3, 16%). The most common all-grade nonhematologic TEAEs were cytokine release syndrome (CRS; 57%), fatigue (30%), nausea (29%), and diarrhea (27%).

“The unique design of ABBV-383 maximizes [multiple myeloma] target-cell killing while potentially minimizing off-target toxicity and cytokine release, as demonstrated in preclinical studies,” lead study author Anita D’Souza, MD, of Medical College of Wisconsin in Milwaukee, and colleagues, wrote. “These results may translate to the improved tolerability and efficacy in vivo.”

BCMA, a novel multiple myeloma target, has highly selective expression on malignant plasma cells. ABBV-383 is a next-generation, fully human, monoclonal, IgG4 T-BsAb, BCMA-targeted therapy that uses a low-activating CD3 to preclinically decouple T-cell activation from cytokine release and preferentially activate effector T cells over regular T cells.

Patients ages 18 years and older were eligible for this trial if they had multiple myeloma that was relapsed or refractory to at least 3 prior lines of therapy, including a proteasome inhibitor, an anti-CD38 monoclonal antibody, and an immunomodulatory drug. Patients needed to have an estimated glomerular filtration rate of at least 30 mL/min and an ECOG performance status of 2 or less.

Patients who had received a prior BCMA-targeted therapy or who were candidates for beneficial multiple myeloma treatments were ineligible.

In the dose-escalation phase, patients received intravenous (IV) ABBV-383 at a fixed dose over 1 to 2 hours once every 3 weeks. For cycle 1, patients were premedicated with 10 mg of IV dexamethasone or equivalent once on day 1 prior to receiving ABBV-383 for cycle 1. For subsequent cycles, patients could receive dexamethasone prior to ABBV-383 once every 3 weeks. Patients who did not experience an infusion-related reaction or immune-mediated toxicity could receive a reduced dexamethasone dose of 5 mg IV once on day 1 prior to receiving ABBV-383. Patients who did not experience an infusion-related reaction or immune-mediated toxicity while receiving 5 mg of dexamethasone could discontinue dexamethasone on subsequent cycles.

ABBV-383 was evaluated at the following dose levels: 0.025 mg, 0.075 mg, 0.2 mg, 0.6 mg, 1.8 mg, 5.4 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 90 mg, and 120 mg.

Patients received the study drug until progressive disease (PD), unacceptable toxicity, or up to 3 years after the last patient’s first dose.

As of January 8, 2022, 124 patients have received ABBV-383 through this study. The dose-escalation cohort included 73 patients who received 0.025 mg to 120 mg of the study drug. The dose-expansion cohort included 51 evaluable patients, 49 of whom received 60 mg of the study drug. Enrollment to the expansion cohort is complete, and the investigators are evaluating a dose of 40 mg once every 3 weeks in an additional expansion cohort.

The primary end points of this trial were safety and tolerability to determine the maximum tolerated dose or recommended phase 2 dose and to evaluate the clinical pharmacology of ABBV-383 monotherapy.

The secondary end point was the evaluation of the clinical activity of ABBV-383 monotherapy, including ORR, partial response (PR), overall survival, progression-free survival (PFS), time to response, and duration of response (DOR).

The median DOR and PFS were not reached in the 40-mg or greater escalation plus expansion or 60-mg expansion cohorts. The Kaplan-Meier estimates for the 6- and 12-month DOR rates for the 60 mg expansion cohort were 79.9% (95% CI, 53.8%-92.2%) and 79.9% (95% CI, 53.8%-92.2%), respectively. The Kaplan-Meier estimates for the 6- and 12-month DOR rates for the 40-mg or greater escalation plus expansion cohorts were 74.8% (95% CI, 59.0%-85.2%) and 72.2% (95% CI, 56.1%-83.2%), respectively. The median PFS was 10.4 months (range, 5-19.2) in the overall population.

In a preliminary pharmacokinetic analysis that included 99 patients, ABBV-383 demonstrated dose-proportional pharmacokinetics at doses between 5.4 mg and 120 mg, supporting the dosing schedule of once every 3 weeks.

Of the triple-class refractory patients, the ORRs were 51% in the overall population (n = 100), 63% in the 40-mg or greater escalation plus expansion cohorts (n = 64), and 54% in the 60-mg expansion cohort (n = 41). Of the patients in the 40-mg or greater escalation plus expansion cohorts with high-risk cytogenetics (n = 11), the ORR, complete response (CR) or higher, stringent CR, VGPR, and PR rates were 82%, 27%, 18%, 73%, and 9%, respectively.

Most adverse effects (55%) were grades 1 or 2. A total of 98%, 99%, and 98% of patients experienced any-grade TEAEs in the overall population, 40-mg or greater escalation plus expansion cohorts, and 60-mg expansion cohort, respectively. Additionally, 72%, 77%, and 78% experienced a grade 3 or higher TEAE in the overall population, 40-mg or greater escalation plus expansion cohorts, and 60-mg expansion cohort, respectively.

The most common all-grade nonhematologic TEAEs in the 40-mg or greater escalation plus expansion and 60-mg expansion cohorts, respectively, were CRS (73%; 71%), nausea (35%; 31%), diarrhea (32%; 29%), and fatigue (30%; 29%).

In the overall population, 53% of patients (n = 66) had serious TEAEs, 59% (n = 48) of the 40-mg or greater escalation plus expansion cohorts and 61% (n = 31) of the 60-mg expansion cohort. Overall, 41% (n = 51) of patients experienced infection as a TEAE, 44% (n = 31) of the 40-mg or greater escalation plus expansion cohorts and 47% (n = 24) of the 60-mg expansion cohort. Infections of grade 3 or higher in the overall population included pneumonia (6%), sepsis (6%), COVID-19 (6%), and urinary tract infections (5%).

In total, 10% (n = 12), 37% (n = 46), and 5% (n = 6) of the overall population experienced TEAEs leading to study treatment discontinuation, interruption, or dose reduction, respectively. Decreased neutrophil count (12%; n = 15) and CRS (2%; n = 3) were the most common TEAEs leading to dose interruption and reduction, respectively.

Three patients experienced dose-limiting toxicities of grade 4 decreased platelet counts at 60 mg of ABBV-383 and grade 3 CRS at 90 mg and 120 mg of ABBV-383.

All CRS events were related to ABBV-383. CRS of grade 3 or higher occurred in 3 patients, 1 each at 60 mg, 90 mg, and 120 mg. Eighteen percent (n = 22) of the overall population experienced serious CRS events, 26% (n = 21) of whom were in the 40-mg or greater escalation plus expansion cohorts. One patient in the 40-mg or greater escalation plus expansion cohorts had recurrent CRS after cycle 1. A total of 14% (n = 17) of patients, all of whom were in the 40-mg or greater escalation plus expansion cohorts, received tocilizumab.

Seven deaths (6%) from TEAEs occurred in the overall population. Deaths occurred from COVID-19 (n = 3 at 0.025 mg, 0.2 mg, and 60 mg of ABBV-383), sepsis (n = 1 at 5.4 mg), liver injury (n = 1 at 50 mg), subdural hematoma (n = 1 at 90 mg), and plasma cell myeloma (n = 1 at 60 mg). In total, 33 deaths were reported.

In total, 36% (n = 45) of patients in the overall population are still receiving the study treatment, and 64% (n = 79) discontinued the study treatment, with 76% (n = 60/79) discontinuing because of PD. Additionally, 44% (n = 55) of patients stopped study participation, for reasons including death (27%; n = 33), withdrawal of consent (12%; n = 15), and being lost to follow-up (1%; n = 1).

“ABBV-383 doses of 60 mg once every 3 weeks as well as 40 mg once every 3 weeks have been selected for further dose exploration and optimal-dose selection. The safety and efficacy of ABBV-383 will be investigated further in this ongoing phase 1 study,” the study authors concluded.

Reference

D’Souza A, Shah N, Rodriguez C, et al. A phase I first-in-human study of ABBV-383, a B-cell maturation agent x CD3 bispecific T-cell redirecting antibody, in patients with relapsed/refractory multiple myeloma. J Clin Oncol. 2022;40(31):3576-3586. doi:10.1200/JCO.22.01504