Attaya Suvannasankha, MD, associate professor, clinical medicine, Indiana University School of Medicine, discusses addressing the incidence of cytokine release syndrome (CRS) in a first-in-human phase 1/2 trial (NCT04083534) for patients with relaped/refractory multiple myeloma.

Patients with multiple myeloma who are relapsed/refractory or intolerant to at least 3 prior lines of therapy, including an anti-CD38 monoclonal antibody, an immunomodulatory agent, and a proteasome inhibitor, need more effective treatment options, Suvannasankha begins. REGN5459 is a BCMAxCD3 bispecific antibody with low affinity to CD3 on T cells, and it was evaluated in a first-in-human phase 1/2 trial (NCT04083534) in this heavily pretreated population of patients with relapsed/refractory multiple myeloma who have already failed all meaningful therapy options, Suvannasankha notes.

REGN5459 is designed to bind onto myeloma cells and CD3 on T cells, engaging the T cells to kill the cancer cells, Suvannasankha expands. However, due to the agent’s low affinity for CD3, REGN5459 could reduce the burden of CRS without sacrificing efficacy, Suvannasankha notes. T cell–directed therapies, including CAR T-cell therapies and bispecific antibodies, are associated with CRS due to inflammation that occurs after T cells kill cancer cells.

In results from the first-in-human study presented at the 2023 AACR Annual Meeting, 53.5% of patients treated with REGN5459 across all dose levels experienced CRS. Notably, most instances (46.5%) were grade 1 events.

Preclinical models of REGN5459 utilized a platform to adjust the antibodies attaching to the T cells with varying binding strength. By downgrading the binding to T cells, less CRS occurred during the killing of the cancer cells, Suvannasankha explains. This led to the hypothesis that REGN5459 could represent an effective and well-tolerated treatment, Suvannasankha concludes.

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Attaya Suvannasankha, MD, discusses addressing the incidence of cytokine release syndrome in a first-in-human phase 1/2 trial for patients with relaped/refractory multiple myeloma.


Dr Suvannasankha on the Potential Mitigation of CRS With REGN5459 in R/R Myeloma

Attaya Suvannasankha, MD, associate professor, clinical medicine, Indiana University School of Medicine, discusses future research directions with bispecific antibodies in patients with multiple myeloma and potential methods for mitigating adverse effects (AEs) in this population.

Dr Suvannasankha on the Future of Bispecific Antibodies in Multiple Myeloma

Bispecific antibodies are contributing to a promising future for multiple myeloma treatment, and moving these agents to earlier lines would decrease the time patients would need to wait to receive these treatments, Suvannasankha says. Mitigating cytokine release syndrome (CRS), which may be accomplished through CD3 affinity adjustment, is key for safely administering bispecific antibodies in this population, and should be explored further, Suvannasankha explains. For instance, in a first-in-human phase 1/2 trial (NCT04083534), treatment with the BCMA-directed bispecific antibody REGN5459, which has a low affinity to CD3, resulted in grade 1, 2, and 3 CRS in 46.5%, 2.3%, and 4.7% of patients, respectively, with no reported instances of grade 4 or 5 CRS.

Bispecific antibodies are also under investigation in other cancers, and the safety benefits of CD3 binding adjustments may be broadly applicable beyond multiple myeloma, Suvannasankha notes.

Dr Suvannasankha on Anticipating and Mitigating AEs With Bispecific Antibodies in Multiple Myeloma

As bispecific antibodies are becoming a new standard of care (SOC) for patients with multiple myeloma, mitigating common AEs associated with these agents, such as CRS, is important to ensure the safe delivery of these therapies—particularly in older or frail patients, Suvannasankha says. Additionally, infection is a common AE associated with bispecific antibodies because patients are often immunocompromised by the time they are eligible to begin these treatments, Suvannasankha explains. Moving bispecific antibodies to earlier lines would allow patients to receive these agents while their immune systems are stronger, Suvannasankha emphasizes.

Beyond managing infections, infection prevention is another important practice; this can include proactively watching for infections, as well as administering intravenous immunoglobulin infusions, which have become a SOC in patients whose antibody levels fall when they receive bispecific antibodies, Suvannasankha concludes.

Attaya Suvannasankha, MD, discusses future research directions with bispecific antibodies in patients with multiple myeloma and potential methods for mitigating adverse effects in this population.

Dr Suvannasankha on Bispecific Antibodies in Multiple Myeloma

Attaya Suvannasankha, MD, Associate Professor of Clinical Medicine, Indiana University School of Medicine, Indiana University Health System, discusses the safety and efficacy of REGN5459, a BCMAxCD3 bispecific antibody with low affinity to CD3 on T cells, in relapsed/refractory multiple myeloma.

At the 2023 AACR Annual Meeting, Suvannasankha presented data from a first-in-human phase 1/2 trial (NCT04083534) of REGN5459 in patients with multiple myeloma who were relapsed/refractory or intolerant to at least 3 prior lines of therapy, including an anti-CD38 monoclonal antibody, an immunomodulatory agent, and a proteasome inhibitor, and who exhausted all treatment options.

Among evaluable patients across all dose levels (n = 43), the objective response rate (ORR) was 65.1%, including a very good partial response (VGPR) or better in 58.1% of patients and a complete response (CR) or better in 51.2% of patients. Within patients treated at higher doses between 480 mg and 900 mg (n = 21), the ORR was 90.5%, including a CR or better rate of 61.9% and a VGPR or better rate of 76.2%. These levels of response in a heavily pretreated and historically difficult-to-treat population were notable, Suvannasankha says, adding that this patient population typically has a tough time achieving a deep remission.

Among patients who had a CR or better who were evaluable for minimal residual disease (MRD; n = 19), 79.0% were MRD negative at the 10-5 threshold. MRD testing allowed investigators to better understand how deep remission was for this subset of patients, Suvannasankha continues.

Data from the phase 1 and 2 portions of the trial showed that REGN5459 had an acceptable safety/tolerability profile. Any-grade treatment-emergent adverse effects (TEAEs) were reported in 100% of patients, and grade 3/4 TEAEs occurred in 74.4% of patients across all dose levels. Any-grade cytokine release syndrome (CRS) occurred in 53.5% of patients; however, the majority of instances of CRS were low grade (grade 1, 46.5%; grade 2, 2.3%). Two patients (4.7%) experienced grade 3 CRS, and no grade 4/5 events were observed. One patient experienced grade 2 immune effector cell–associated neurotoxicity syndrome.

Other common TEAEs included cough, dyspnea, and infection, Suvannasankha notes. Infection occurred 62.8% of patients, and 30.2% of patients had grade 3/4 infection. The most common infections of any grade consisted of urinary tract infection, pneumonia, sinusitis, and upper respiratory infection. Two patients had grade 5 AEs, including 1 patients with pneumonia and 1 with COVID-19, Suvannasankha concludes.

Attaya Suvannasankha, MD, discusses the safety and efficacy of REGN5459, a BCMAxCD3 bispecific antibody with low affinity to CD3 on T cells, in relapsed/refractory multiple myeloma.

Attaya Suvannasankha, MD

Articles

Dr Suvannasankha on the Potential Mitigation of CRS With REGN5459 in R/R Myeloma

Dr Suvannasankha on Bispecific Antibodies in Multiple Myeloma

Dr Suvannasankha on the Safety/Efficacy of REGN5459 in R/R Multiple Myeloma