Substantial Clinical Activity of Teclistamab in Patients with Heavily Pretreated Relapsed or Refractory Multiple Myeloma

In a phase I/II study, teclistamab showed substantial clinical activity that compares favourably with that of existing therapies in 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. Side effects were also common, but were mainly of low grade and reversible. Updated efficacy and safety data of the MajesTEC-1 study were presented at ASCO 2022 Annual Meeting along with a simultaneous publication on 5 June in The New England Journal of Medicine authored by Dr. Philippe Moreau of the Hematology Clinic, University Hospital Hotel-Dieu in Nantes, France and colleagues.

The authors wrote in the background that standard treatment for patients with multiple myeloma includes the administration of immunomodulatory agents, proteasome inhibitors, and anti-CD38 antibodies. However, available therapies for patients who have had disease progression after receiving these agents are limited, and outcomes are generally poor. B cell maturation antigen (BCMA) represents a promising new target and three BCMA-directed therapies (belantamab mafodotin, an antibody-drug conjugate, and two CAR T cell therapies, idecabtagene vicleucel and ciltacabtagene autoleucel) have been approved for the treatment of patients with myeloma who have received immunomodulatory agents, proteasome inhibitors, and anti-CD38 antibodies.

Teclistamab is a bispecific antibody that targets both CD3 expressed on the surface of T cells and BCMA expressed on the surface of myeloma cells, thus mediating T cell activation and subsequent lysis of BCMA-expressing myeloma cells. In phase I MajesTEC-1, the investigators identified the recommended phase 2 dose of teclistamab as a weekly subcutaneous injection of 1.5 mg per kilogram of body weight. At this dose level, teclistamab showed promising efficacy in 40 patients, with 65% of patients having a partial response or better.

In the latest article, the authors reported the efficacy and safety results from the pivotal phase I/II portion of MajesTEC-1 involving 165 patients with triple-class–exposed (an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 antibody) relapsed or refractory myeloma. They cover in the report pharmacokinetics, immunogenicity, and biomarkers of response and progression. Patients received a weekly subcutaneous injection of teclistamab at a dose of 1.5 mg per kilogram of body weight after receiving step-up doses of 0.06 mg and 0.3 mg per kilogram. The primary endpoint was the overall response, defined as partial response or better.

Among 165 patients who received teclistamab, 77.8% had triple-class refractory disease. With a median follow-up of 14.1 months, the overall response rate was 63.0%, with 65 patients (39.4%) having a complete response or better. 

A total of 44 patients (26.7%) were found to have no minimal residual disease (MRD). The MRD-negativity rate among the patients with a complete response or better was 46%. The median duration of response was 18.4 months (95% confidence interval [CI] 14.9 to not estimable). The median duration of progression-free survival was 11.3 months (95% CI 8.8 to 17.1).

Common adverse events included cytokine release syndrome in 72.1% of the patients with grade 3 in 0.6% and no grade 4, neutropenia in 70.9% patients with grade 3 or 4 in 64.2%, anaemia in 52.1% patients with grade 3 or 4 in 37.0%, and thrombocytopenia in 40.0% patients with grade 3 or 4 in 21.2%. Infections were frequent in 76.4% with grade 3 or 4 in 44.8%. Neurotoxic events occurred in 24 patients (14.5%), including immune effector cell–associated neurotoxicity syndrome in 5 patients (3.0%), but in all of grade 1 or 2.

The authors commented that it is important to put the study results in context of new and emerging therapies for multiple myeloma. Although cross-trial comparisons are challenging to interpret owing to differences in study design and patient populations, the response rates observed with teclistamab (63%) compare favourably with those of belantamab mafodotin, which has an overall response rate of 31% in patients with triple-class refractory disease. In a matching-adjusted indirect comparison of data from the DREAMM-2 study, teclistamab provided a substantial efficacy benefit over belantamab mafodotin in patients with relapsed or refractory multiple myeloma who had received at least three previous lines of therapy. 

Overall response rates of 67-83% have been observed with approved CAR T cell therapies in patients who have undergone apheresis. CAR T therapy requires that patients have access to specialised centres and can wait the minimum 4 week period for production, which can result in attrition rates of approximately 10-15%, factors that underscore the need for effective off-the-shelf treatment options for patients with relapsed or refractory myeloma. Teclistamab is readily available and has been associated with rapid onset of response after a median of approximately 1 month of treatment.

The authors concluded that teclistamab resulted in a high rate of deep and durable response in patients with triple-class–exposed relapsed or refractory multiple myeloma. Cytopenias and infections were common; side effects that were consistent with T cell redirection were mostly grade 1 or 2.

The study was funded by Janssen Research and Development.

Reference

Moreau P, Garfall AL, van de Donk NWCJ, et al. Teclistamab in Relapsed or Refractory Multiple Myeloma. NEJM; Published online 5 June 2022. DOI: 10.1056/NEJMoa2203478

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