Bispecific antibodies have 2 distinct binding domains, which interact with either CD3 on T cells or a tumor-associated antigen on the tumor cell surface.
Combining a case study with available data, the authors of a new report concluded that T-cell immunotherapy using bispecific antibodies could significantly improve outcomes in patients with multiple myeloma.
T cell-engaging bispecific antibodies have shown substantial activity in heavily pretreated patients with multiple myeloma, a patient population with significant needs for new, improved treatments. The overall response rate (ORR) for B-cell maturation antigen (BCMA)-targeting bispecific antibodies is between 60% and 70%, and many patients also have very good partial or complete responses. Comparable results have been found with bispecific antibodies targeting GPRC5D or FcRH5.
The study authors presented a case involving a 64-year-old male with multiple myeloma who was experiencing his 11th relapse. He was heavily pretreated and refractory to 3 immunomodulatory drugs, 1 cereblon modifying drug, 2 proteasome inhibitors, 1 CD38-targeting antibody, alkylating drugs, and 1 checkpoint inhibitor.
The authors emphasized that triple-class refractory patients should always be considered for participation in a clinical trial, which allows them to access novel agents with new mechanisms of action. However, they acknowledged that there are frequently limitations to this participation. For patients not previously treated with pomalidomide or carfilzomib, the authors said regimens with these drugs are a good option. Alternatively, patients could be treated with drugs used in prior lines in a different, potentially synergistic combination. Conventional chemotherapy regimens could also be useful for patients with high tumor burden or extramedullary disease as a bridge toward another therapy, such as CAR T-cell therapy or a clinical study.
In the case study, the patient was enrolled in a phase 1, dose-escalation trial with teclistamab (MajesTEC-1). At the time, he received only a fraction of the recommended phase 2 dose, which was identified later. He received premedication to prevent severe cytokine release syndrome (CRS) prior to treatment, although he developed a fever 1 hour after administration of the first priming dose. He was diagnosed with grade 1 CRS and he was treated with 1 infusion of tocilizumab before continuing treatment with teclistamab as planned.
Bispecific antibodies have 2 distinct binding domains, which interact with either CD3 on T cells or a tumor-associated antigen on the tumor cell surface. This redirects the T cell to the tumor cell and enables the formation of an immunological synapse, thus activating the T cell and carrying out effector functions. Commonly targeted antigens of bispecific antibodies for multiple myeloma are BCMA, GPRC5D, and FcRH5.
Notably, trispecific antibodies are also under investigation in both preclinical studies and clinical trials. In addition to binding CD3, these antibodies either target 2 antigens on the myeloma cell in order to prevent antigen escape, or they activate T cell co-stimulatory molecules to prevent T cell anergy.
The immunoglobulin G (IgG)-like bispecific antibody teclistamab is the first FDA-approved bispecific antibody in multiple myeloma. It received FDA approval to treat patients who have received at least 4 prior lines of therapy, including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody.
In the first-in-human, dose-escalation study, the recommended phase 2 dose for teclistamab was established as a subcutaneous dose of 1.5 mg/kg with 2 step-up doses to mitigate CRS. In total, 165 patients (78% with triple-class refractory disease) received teclistamab at the recommended phase 2 dose with at least partial response in 63% and complete response in 39% of patients. The median progression-free survival (PFS) was 11.3 months and median response duration was 18.4 months.
Elranatamab is another BCMA-targeting antibody in development for the treatment of multiple myeloma. It was administered via subcutaneous injections to 123 heavily pretreated patients at the recommended phase 2 dose of 76 mg, preceded by 2 step-up doses. With a follow-up of 10.4 months, the ORR was 61% and the 12-month PFS was 58.8%.
Other IgG-like BCMA-targeting bispecific antibodies in clinical development are alnuctamab, HPN217, WVT078, ABBV-383, and REGN-5458. Development of the half-life extended BiTE AMG 701 was recently halted.
The investigators also reviewed GPRC5D-targeting bispecific antibodies and FcRH5-targeting bispecific antibodies. Talquetamab is a first-in-class GPTC5D-targeting bispecific antibody that was tested in a first-in-man, dose-escalation study in heavily pretreated patients with multiple myeloma. Partial response was achieved in 74.1% of patients treated at the 400 mg/kg subcutaneous dose every week, including complete response in 33.6%. Comparable results were seen in patients treated at an 800 mg/kg weekly dose, with partial response in 73.1% and complete response in 32.4%.
Forimtamig, another GPRC5D T-cell engaging bispecific antibody, induced rapid responses in heavily pretreated patients with multiple myeloma. Participants had a partial response of ≥71.4% with intravenous administration and ≥63.6% with subcutaneous administration.
Finally, cevostamab is a bispecific antibody that targets the membrane-proximal region of FcRH5 on the multiple myeloma cell surface. The first-in-human dose-escalation study with cevostamab has shown promising activity in heavily pretreated patients. At higher dose levels (132-198 mg), at least partial response was achieved by 56.7% including complete response in 8.4%. The single step-up cohorts had a median duration of response of 11.5 months.
Approximately 4 years after starting treatment with teclistamab, the patient in the case study still receives this agent once monthly and remains in a stringent complete remission. He has achieved the deepest and most durable remission since his diagnosis, highlighting the significant potential for these bispecific antibodies.
O’Neill C, van de Donk NWCJ. T-cell redirecting bispecific antibodies in multiple myeloma: Current landscape and future directions. EJHaem. 2023;4(3):811-822. doi:10.1002/jha2.729