FDA Approves TECVAYLI® for Relapsed or Refractory Multiple Myeloma

SUMMARY: The FDA on October 25, 2022, granted accelerated approval to TECVAYLI® (Teclistamab-cqyv), the first bispecific B-Cell Maturation Antigen (BCMA)-directed CD3 T-cell engager, for adult patients with Relapsed or Refractory multiple myeloma who have received at least four prior lines of therapy, including a Proteasome Inhibitor, an Immunomodulatory agent, and an anti-CD38 monoclonal antibody. Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 34,470 new cases will be diagnosed in 2022 and 12,640 patients will die of the disease. Multiple Myeloma is a disease of the elderly, with a median age at diagnosis of 69 years and characterized by intrinsic clonal heterogeneity. Almost all patients eventually will relapse, and patients with a high-risk cytogenetic profile, extramedullary disease or refractory disease have the worst outcomes. The introduction of Proteasome Inhibitors, Immunomodulatory agents and CD 38 targeted therapies has resulted in higher Response Rates, as well as longer Progression Free Survival (PFS) and Overall Survival (OS), with the median survival for patients with myeloma approaching 10 years or more. Nonetheless, multiple myeloma in 2022 remains an incurable disease.

B-Cell Maturation Antigen (BCMA) is a member of the Tumor Necrosis Factor superfamily of proteins. It is a transmembrane signaling protein primarily expressed by malignant and normal plasma cells and some mature B cells. BCMA is involved in JNK and NF-kB signaling pathways that induce B-cell development and autoimmune responses. BCMA has been implicated in autoimmune disorders, as well as B-lymphocyte malignancies, Leukemia, Lymphomas, and Multiple Myeloma. At the time of writing, there are three BCMA-targeted therapies approved by the FDAfor patients with Relapsed or Refractory multiple myeloma with triple-class exposure. They include CARVYKTI® (Ciltacabtageneautoleucel) and ABECMA® (Idecabtagenevicleucel),which are B-Cell Maturation Antigen (BCMA)-directed genetically modified autologous T cell immunotherapies (CART-Cell therapies), and BLENREP® (Belantamabmafodotin-blmf), which is a B-Cell Maturation Antigen (BCMA)-directed antibody and microtubule inhibitor drug conjugate (Antibody Drug Conjugate). Even though CAR T-cell therapies have resulted in remarkable clinical responses, logistic challenges include at least 2 weeks of hospital stay, long manufacturing times, need for bridging therapy, and high cost of treatment.

TECVAYLI® is a bispecific antibody with dual binding sites, that targets both CD3 expressed on the surface of T cells and BCMA expressed on the surface of myeloma cells, and thereby mediates T-cell activation and lysis of BCMA-expressing myeloma cells. This effect occurs regardless of T-cell–receptor specificity or Major Histocompatibility Complex class I molecules on the surface of myeloma cells. This mechanism of action of TECVAYLI® is distinct from that of other available therapies for this patient group.

The present FDA approval was based on the efficacy and safety results from the pivotal, single-arm, multi-cohort, open-label, multi-center Phase 1/2 portion of MajesTEC-1 study, which enrolled 165 patients, who had Relapsed or Refractory myeloma after at least three therapy lines, including triple-class exposure to an Immunomodulatory drug, a Proteasome Inhibitor, and an anti-CD38 antibody. Patients received TECVAYLI® 1.5 mg/kg subcutaneously once weekly, after receiving step-up doses of 0.06 and 0.3 mg/kg separated by 2- 4 days and completed 2-4 days before the administration of the first full TECVAYLI® dose. Patients were hospitalized and premedicated with Dexamethasone, Acetaminophen, and Diphenhydramine for each step-up dose and for the first full dose of TECVAYLI®. Treatment was continued until disease progression, unacceptable toxicity, or the end of the study. The median age was 64 years, the median time between diagnosis and the first treatment dose was 6 years, 26% had at least one high-risk cytogenetic abnormality defined as del(17p), t(4;14), or t(14;16) among those with available cytogenetic data (N=148), 77.6% had triple-class refractory disease, and patients had received a median of 5 previous lines of therapy. The Primary end point was the Overall Response Rate (ORR), which was defined as a Partial Response or better according to the International Myeloma Working Group criteria, as assessed by an Independent Review Committee. Secondary end points included Duration of Response, Very Good Partial Response (VGPR) or better, Progression Free and Overall Survival, Minimal Residual Disease (MRD) status and Safety.

At a median follow-up of 14.1 months, the Overall Response Rate was 63%, with 39.4% having a Complete Response or better. Close to 60% of patients had a Very Good Partial Response or better. Approximately, 27% of patients had negative results for Minimal Residual Disease in bone marrow (<1 myeloma cell in 100,000 cells), and the MRD-negativity rate among the patients with a Complete Response or better was 46%. The median Duration of Response was 18.4 months, and the median duration of Progression Free Survival was 11.3 months. Common adverse events included Cytokine Release Syndrome (CRS) noted in 72% and were mostly Grade 1 or 2 and fully resolved. None of the patients discontinued TECVAYLI® due to CRS. Other common adverse events included neutropenia, anemia, and thrombocytopenia, as well as immune effector cell–associated neurotoxicity syndrome, but none of the patients discontinued therapy because of neurotoxic events.

It was concluded from this study that TECVAYLI® had substantial clinical activity, with a high rate of deep and durable response in patients with triple-class-exposed Relapsed or Refractory multiple myeloma. Toxic effects were common but were mainly of low grade and reversible. The researchers added that the efficacy of TECVAYLI® compared favorably with other FDA approved treatments that are currently available for later lines in multiple myeloma, including BLENREP® (Belantamabmafodotin-blmf), XPOVIO® (Selinexor), and CAR T-cell therapies.

Teclistamab in Relapsed or Refractory Multiple Myeloma. Moreau P, Garfall AL,van de DonkNW,et al. N Engl J Med 2022; 387:495-505