A Phase I First-in-Human Study of ABBV-383, a B-Cell Maturation Antigen × CD3 Bispecific T-Cell Redirecting Antibody, in Patients With Relapsed/Refractory Multiple Myeloma

Abstract

PURPOSE ABBV-383, a B-cell maturation antigen × CD3 T-cell engaging bispecific antibody, has demonstrated promising results in an ongoing first-in-human phase I study (ClinicalTrials.gov identifier: NCT03933735 ) in patients with relapsed/refractory multiple myeloma (RRMM). Herein, we report safety and efficacy outcomes of this phase I dose escalation/expansion study. METHODS Patients with RRMM (≥ three prior lines including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody) were eligible. ABBV-383 was administered intravenously over 1-2 hours once every 3 weeks, without any step dosing. A 3 + 3 design with backfilling for dose escalation was used (intrapatient escalation to highest safe dose permitted) followed by initiation of dose expansion. RESULTS As of January 8, 2022, 124 patients (dose escalation [0.025-120 mg], n = 73; dose expansion [60 mg], n = 51) have received ABBV-383; median age was 68 years (range, 35-92 years). The most common hematologic treatment-emergent adverse events (TEAEs) were neutropenia (all grades: 37%) and anemia (29%). The most common nonhematologic TEAEs were cytokine release syndrome (57%) and fatigue (30%). Seven deaths from TEAEs were reported with all considered unrelated to study drug by the investigator. For all efficacy-evaluable patients (n = 122; all doses), the objective response rate (ORR) was 57% and very good partial response (VGPR) or better (≥ VGPR) rate was 43%. In the 60 mg dose expansion cohort (n = 49), the ORR and ≥ VGPR rates were 59% and 39%, respectively; and in the ≥ 40 mg dose escalation plus dose expansion cohorts (n = 79) were 68% and 54%, respectively. CONCLUSION ABBV-383 in patients with RRMM was well tolerated with an ORR of 68% at doses ≥ 40 mg. This novel therapy's promising preliminary antitumor activity in heavily pretreated patients warrants further clinical evaluation.

Bispecific Antibodies in Multiple Myeloma: Opportunities to Enhance Efficacy and Improve Safety

“…The seven studies shown in Table 1 include published data on 681 participants. CRS was reported in 59%, of which 1.3% was grade 3 [ 27 , 28 , 53 , 64 , 95 , 96 , 97 ].…”

“…In the phase 1 study of the BCMA BsAb ABBV-383, no step-up doses or premedications were administered. CRS occurred in 72% of patients receiving 60 mg of ABBV-383 (2% grade 3–4) [ 96 ]. Another means of reducing CRS may be to incorporate additional therapies with immunomodulatory capabilities.…”

Monoclonal Antibodies: The Greatest Resource to Treat Multiple Myeloma

“…Finally, ABBV-383 has standard availability, unlike CAR-T cell therapies, and a shorter hospitalization time than other BCMA and CAR-T cell therapies. The limitations of this study are related to the small number of patients enrolled [ 75 ]. Another ongoing phase 1/2 study (NCT03761108) involves REGN5458, which is a bispecific BCMAxCD3 antibody.…”

How We Manage Newly Diagnosed Multiple Myeloma With Circulating Tumor Cells

“…Data from a case series showing activity of CD38-targeting antibodies in pPCL, combined with improved clinical outcomes in high-risk MM with CD38 antibodies, 26 suggest that CD38 antibodies can be used as part of first-line treatment. Furthermore, because of the high efficacy of T-cell immunotherapies in extensively pretreated MM, including those with high-risk cytogenetics, [27][28][29][30][31] T-cell redirecting bispecific antibodies and chimeric antigen receptor T-cell therapies should also be evaluated in pPCL. Inclusion of patients with pPCL in trials, with early access to novel agents, should be encouraged.…”