Teclistamab Achieves Clinical Benefit in Relapsed/Refractory Multiple Myeloma

Promising responses including a positive safety profile were seen with teclistamab when used as treatment for patients with relapsed/refractory multiple myeloma.

High rates of deep and durable responses were seen with teclistamab in patients with triple-class-exposed relapsed/refractory multiple myeloma, according to updated findings from the phase 1/2 MajesTEC-1 trial (NCT04557098, NCT03145181).1

Data published in the New England Journal of Medicine revealed that at a median follow-up of 14.1 months (range 1.2-15.2), the overall response rate (ORR) was 63.0%, with 65 patients (39.4%) having a complete response (CR) or better.

Teclistamab also had a positive safety profile. While cytopenias and infections were common, toxic effects consistent with T-cell redirection were mainly grade 1 or 2. Overall, findings were consistent with results of the phase 1 study.

“In this phase 1–2 study, teclistamab had substantial clinical activity that compares favorably with that of existing therapies for patients with heavily pretreated relapsed or refractory multiple myeloma. The high rate of deep and durable responses in this population indicates the potential for teclistamab to provide substantial clinical benefit to a broader population of patients. Toxic effects were also common but were mainly of low grade and reversible,” wrote the study investigators led by Philippe Moreau, MD, head of the Hematology Department at the University Hospital of Nantes, France.

Teclistamab is a novel, off-the-shelf, T-cell redirecting, bispecific antibody targeting both B-cell maturation antigen (BCMA) and CD3. The agent works by redirecting CD3-positive T-cells to BCMA-expressing myeloma cells, inducing tumor cell death.

The first-in-human, open-label, dose-escalation phase 1/2 MajesTEC-1 study aimed to evaluate teclistamab as a treatment option for patients with relapsed or refractory multiple myeloma. Eligible patients were those aged 18 years and older, who had previously received at least 3 lines of therapy, progressive, measurable disease at screening, and an ECOG score of 0 or 1. Previous treatment with a BCMA-targeted therapy was not allowed.

Patients were administered a weekly subcutaneous injection of teclistamab at a dose of 1.5 mg/kilogram of body weight after receiving step-up doses of 0.06 mg and 0.3 mg/kg. In phase 1, the cycle duration was 21 days and in phase 2 it was 28 days. Patients continued to receive teclistamab until the occurrence of disease progression, unacceptable toxicity, withdrawal of consent, death, or the end of the study.

The primary end point of the trial was overall response defined as a partial response or better with secondary end points including duration of response (DOR), the time until response, progression-free (PFS), and overall survival.

Among the patients treated in MajesTEC-1, the median age was 64.0 years (range, 33–84) and 15% of patients were 75 years and older. A total of 59% of the cohort was male, the median number of prior lines of therapy among patients in the study was 5 (range, 2–15), and 100% were triple-class, 69% were penta-drug exposed, 77% were triple-class refractory, and 30.3% were penta-drug refractory.

Between March 3, 2020, to August 13, 2021, 165 patients were enrolled at 35 sites in 9 countries where they were given teclistamab at the recommended phase 2 dose of 1.5 mg per kilogram. Among these patients, 40 were enrolled in phase 1, and 125 were enrolled in phase 2.

Seventy patients (42.4%) continued receiving treatment as of March 16, 2022 with a median treatment duration of 8.5 months (range, 0.2-24.4). A total of 98 patients (59.4%) received at least 6 months of teclistamab treatment, and 79 patients (47.9%) received at least 9 months of treatment. Further, the median relative dose intensity for all treatment cycles, including step-up doses, was 93.7%.

Findings revealed that along with the median follow-up of 14.1 months and response in 63.0% of patients, the median time until the first response was 1.2 months (range, 0.2-5.5), and the median time until achievement of a best response was 3.8 months (range, 1.1-16.8).

There were 44 patients (26.7%) who had no minimal residual disease (MRD). The MRD-negativity rate among the patients with a CR or better was 46%. The median DOR was 18.4 months (95% CI, 14.9-not estimable). Additionally, the median duration of PFS was 11.3 months (95% CI, 8.8-17.1). Response rates were consistent across most clinically relevant subgroups, including patients with high-risk cytogenetic abnormalities and those with penta-drug refractory disease.

In regard to safety, each of the 165 patients reported having an adverse event (AE) with 156 patients (94.5%) having a grade 3 or 4 AE. The most common AEs were cytokine release syndrome (72.1%), neutropenia (70.9%), anemia (52.1%), and thrombocytopenia (40.0%). Cytokine release syndrome was grade 3 in 0.6% of patients with no grade 4, neutropenia was grade 3 or 4 in 64.2%, anemia was grade 3 or 4 in 37.0%, and thrombocytopenia was grade 3 or 4 in 21.2%.

Infections were frequent in 76.4% of patients with grade 3 or 4 infections having occurred in 44.8%. Neurotoxic events were reported in 24 patients (14.5%), including immune effector cell–associated neurotoxicity syndrome in 5 patients (3.0%), all of which were grade 1 or 2.

Among those enrolled, 1 patient had a dose reduction during cycle 21 due to recurrent neutropenia, and 104 patients (63.0%) skipped a dose as a result of their AEs. Teclistamab was discontinued by 2 patients because of AEs, including grade 3 adenoviral pneumonia and grade 4 progressive multifocal leukoencephalopathy.

A total of 68 patients (41.2%) died, most deaths (41) of which were attributed to progressive disease (Table S9). There were 19 patients who died from AEs including 12 deaths from Covid-19, and 5 deaths considered to be related to teclistamab, including 1 who had discontinued teclistamab due to progressive multifocal leukoencephalopathy, 2 patients who had contracted Covid-19, 1 patient who had hepatic failure, and 1 patient who had streptococcal pneumonia.

Additionally, teclistamab exposure was sustained over the predetermined target level and there was a low peak-to-trough ratio. None of the 146 patients who had received the recommended phase 2 dose and could be evaluated for immunogenicity were found to have antibodies against teclistamab.

Overall, this phase 1/2 study showed teclistamab to have substantial clinical activity which compares to existing therapies for this patient population. With a high rate of deep and durable responses for patients with relapsed/refractory multiple myeloma, teclistamab has the potential to provide these patients with significant clinical benefit.

Reference:
Moreau P, Garfall AL, van de Donk NWCJ, et al. Teclistamab in Relapsed or Refractory Multiple Myeloma. N Engl J Med. 2022;387(6):495-505. doi:10.1056/NEJMoa2203478