Multiple myeloma eventually becomes refractory to current treatments, and new therapeutic options with convenient dosing and improved safety are needed to enhance patient adherence, access, and outcomes. ABBV-383 is a distinctive next-generation BCMA x CD3 bispecific antibody composed of 2 high-affinity BCMA-binding domains, a low-affinity CD3-binding domain designed to reduce cytokine release syndrome (CRS) risk, and a silenced Fc tail for an extended half-life allowing convenient dosing. ABBV-383 monotherapy has shown promising activity in the ongoing first-in-human phase I trial in Relapsed/Refractory Multiple Myeloma (RRMM).

In data presented during EHA 2024, the optimal therapeutic dose of 60mg Q4W ABBV-383 monotherapy demonstrated promising efficacy. In a 60 mg every 4 weeks cohort, the Overall response rate (ORR) was 65% with ≥very good partial response or better (VGPR) of 55%. Median duration of response (DOR) and median progression-free survival (PFS) were not reached at a median duration of follow-up of 12.1 months.

Patients treated with 60 mg Q4W ABBV-383 had lower incidence (43%) and severity (Grade 1: 38%, Grade 2:  5%) of CRS compared with Q3W dose cohorts. In addition to this, at 60mg Q4W, incidence of Grade 3/4 infections was 19% (4/21). Infections consisted primarily of pneumonia (2/21), urinary tract infection (UTI) (1/21) and sepsis (1/21). 

The extended interval of Q4W, with a shortened CRS monitoring period in cycle 1, is designed to improve convenience and reduce treatment burden for patients.

KOL insights

“Encouraging preliminary antitumor activity observed in heavily pretreated patients with relapsed refractory multiple myeloma supports further clinical evaluation. Bispecifics are primed to play a significant role in the community setting compared to CAR T-cell therapy.”– MD, United States.

Conclusion 

Pharmaceutical companies are now aiming to enter early treatment settings following FDA approvals of bispecific antibodies in later lines. However, predicting patient outcomes and performance remains premature. The bispecific antibody market is expected to become crowded due to numerous approvals and robust pipeline activities. Intense competition is anticipated among drugs targeting similar pathways; for instance, several BCMA-targeting therapies, two CAR-T cell therapies, and two bispecific antibodies are already on the market, with additional approvals expected next year. Key players like J&J and Pfizer are actively pursuing label expansions for their bispecific antibodies, conducting extensive clinical trials across various treatment settings with and without combination therapies.

In June 2021, AbbVie acquired the Teneobio subsidiary of TeneoOne and its lead asset, TNB-383B (ABBV-383), based on an interim analysis of an ongoing Phase I study for the potential treatment of RRMM. Under the terms of the agreement, AbbVie made an exercise payment of USD 400 million, which was recorded to acquire IPR&D and milestones expense in the consolidated statement of earnings in the third quarter of 2021. The agreement also included additional payments of up to USD 250 million upon achieving certain development, regulatory, and commercial milestones.

AbbVie recently started a Phase III trial of ABBV-383. The CERVINO Phase III trial will evaluate the efficacy, safety, and tolerability of ABBV-383 monotherapy compared with standard available therapies (SATs) in patients with RRMM who have received at least two lines of prior therapy.

Both CAR T-cell therapies and bispecific therapies are increasingly popular due to their ability to induce profound and long-lasting responses in relapsed/refractory patients, a phenomenon unprecedented in previous treatments. The debate centers on which treatment—CAR T-cell therapy or bispecific therapy—offers greater benefits to patients. CAR T-cell therapy is a single infusion treatment, whereas bispecific therapies require ongoing administration. While CAR T-cell therapies demonstrate impressive efficacy in multiple myeloma, they come with risks such as cytokine release syndrome (CRS), a potentially life-threatening inflammatory response. Bispecific antibodies can also cause CRS, but typically with less severity compared to CAR T-cell therapies.