Efficacy and Safety of Teclistamab in Patients with Relapsed/Refractory Multiple Myeloma

Oncology Medicine Life Sciences Hematology Immunology
Multiple Myeloma Teclistamab BCMA-targeted therapy Relapsed/Refractory Clinical Trial

Interpretation of Research on the Efficacy and Safety of Teclistamab in Patients with Relapsed/Refractory Multiple Myeloma Following Anti-BCMA Therapies

Academic Background

Multiple myeloma (MM) is a malignancy stemming from plasma cells within the bone marrow. Recent advancements in treatment have significantly improved overall survival rates. However, challenges remain for patients with relapsed/refractory multiple myeloma (R/RMM). When patients become resistant to the three primary treatment modalities—immunomodulatory drugs, proteasome inhibitors, and anti-CD38 monoclonal antibodies—and disease progression or relapse occurs, their options become severely limited.

B-cell maturation antigen (BCMA) serves as a vital therapeutic target for MM. Therapies targeting BCMA, including antibody-drug conjugates (ADCs), chimeric antigen receptor (CAR-T) therapies, and bispecific antibodies, represent breakthroughs for R/RMM patients. Teclistamab, a bispecific BCMA×CD3 antibody, is a groundbreaking option in BCMA treatments, featuring weight-based dosing and being the first approved medication of its class.

Although BCMA-targeted therapies have shown significant efficacy, patients previously treated with such therapies may develop resistance and face treatment dilemmas. Researchers aimed to investigate the efficacy and safety of Teclistamab in such previously treated populations, providing scientific insights to enhance clinical practice.

Source of the Study

This study, authored by Cyrille Touzeau and colleagues, was published in the December 2024 issue of Blood. The research team hails from prestigious global institutions, including University Hospital Hôtel-Dieu (Nantes, France); City of Hope Comprehensive Cancer Center (California, USA); and Memorial Sloan Kettering Cancer Center (New York, USA).

Part of the MajesTEC-1 trial, this phase 1⁄2 open-label, multi-center, single-arm study was registered under NCT03145181 and NCT04557098. The primary objective was to assess the efficacy and safety of Teclistamab in R/RMM patients, including those who had previously undergone BCMA-targeted therapies.

Study Design and Methods

1. Study Population and Design

This study’s Cohort C focused on R/RMM patients previously treated with anti-BCMA therapies (either ADCs or CAR-T therapies). Inclusion criteria required: - Diagnosis of R/RMM per International Myeloma Working Group (IMWG) criteria. - Prior treatment with three therapy classes (immunomodulators, proteasome inhibitors, anti-CD38 antibodies). - Progressive or measurable disease and an Eastern Cooperative Oncology Group performance status of 0 or 1.

Before treatment, patients underwent two step-up dosing regimens, followed by weekly subcutaneous injections of 1.5 mg/kg Teclistamab. Patients achieving complete response (CR) or better for more than six months could switch to a biweekly dosing schedule.

2. Sample Size and Follow-Up

The cohort included 40 patients, 62.5% of whom were male, with a median age of 64 (range: 32–82). Patients had received an average of six prior treatments, including 29 with BCMA-ADC, 15 with CAR-T, and four with both ADC and CAR-T therapies. Median follow-up was 28 months, and the median treatment duration was six months.

3. Data Collection and Key Endpoints

The primary endpoint was the overall response rate (ORR), defined as the proportion of patients achieving a partial response (PR) or better, per IMWG criteria. Secondary endpoints included: - Proportion achieving very good partial response (VGPR) or better. - Duration of response (DoR). - Progression-free survival (PFS) and overall survival (OS). - Adverse event (AE) incidence and severity.

The study also assessed changes in soluble BCMA (sBCMA) levels in serum, bone marrow BCMA expression, and immunological changes induced by the treatment.

Study Results

1. Efficacy

  • Response Rates:
    Among 40 patients treated with Teclistamab, the ORR was 52.5%, with 47.5% achieving VGPR or better and 30% achieving complete response (CR) or better. Notable findings included:

    • ORR of 55.2% among patients previously treated with ADC and 53.3% among those treated with CAR-T.
    • ORR of 33.3% in patients with high-risk cytogenetics, demonstrating potential efficacy in challenging cases.

  • Durability of Response:
    The median DoR was 14.8 months, with response durability reaching 16.7 months among patients achieving CR or better.

  • Survival Outcomes:
    Median PFS was 4.5 months, and median OS was 15.5 months. Patients who responded to treatment demonstrated progressive reductions in sBCMA levels, suggesting a correlation between therapeutic efficacy and biomarker changes.

2. Safety

  • Adverse Events (AEs):
    All patients experienced at least one treatment-emergent adverse event (TEAE). The most common events were:

    • Cytokine release syndrome (CRS): 65% (all grades 1-2, median duration: two days).
    • Infections: 70% incidence, including 10% grade 5 infections (primarily COVID-19-related).

  • Hematologic Toxicities:
    Common AEs included neutropenia (70%), anemia (50%), and lymphopenia (45%). While the AE incidence was high, only 7.5% of patients discontinued treatment due to side effects, and the overall toxicity profile was consistent with prior MajesTEC-1 data.

Clinical Significance and Value

1. Scientific Contribution

This study systematically explores the efficacy and safety of Teclistamab in patients previously treated with BCMA-targeted therapies. It underscores that different BCMA therapeutic constructs should not preclude positive responses to subsequent bispecific antibody treatment. This finding provides important guidance for sequencing therapies in clinical practice.

2. Practical Implications

For R/RMM patients, Teclistamab offers practical therapeutic value with its >50% response rate and durable CR intervals. It provides hope for patients who may have limited options after exhausting previous BCMA-targeted treatments.

3. Future Directions

Although the study highlights promising results, further randomized controlled trials with larger patient samples are necessary to: - Optimize timing between BCMA-targeted therapies. - Explore combinational treatments. - Evaluate long-term infection control measures and dosing schedule modifications to enhance patient safety.

Summary and Highlights

The MajesTEC-1 Cohort C results demonstrate that Teclistamab effectively offers deep and durable responses for heavily pretreated R/RMM patients, including those with prior BCMA therapy. Its manageable toxicity profile and consistent efficacy make it a valuable therapeutic option as resistance to BCMA-targeted therapies becomes an increasingly common clinical challenge.

These findings lay a critical foundation for advancing treatment strategies and optimizing care for a growing population of patients with complex R/RMM.