Teclistamab demonstrates clinical activity for R/R MM

The T-cell-redirecting bispecific antibody teclistamab induced deep and durable responses in patients with triple-class-exposed relapsed or refractory multiple myeloma (R/R MM), findings from the phase I/II MajesTEC-1 trial have shown.

“After a median follow-up of 14.1 months … responses occurred in 63 percent of patients, with 39 percent having a complete response or better despite a history of extensive previous treatment and disease that was refractory to currently available therapies,” said the researchers. [N Engl J Med 2022;doi:10.1056/NEJMoa2203478]

The responses were consistent across subgroups*, except for those with extramedullary disease, stage III disease, and at least 60 percent plasma cells in the bone marrow. “The lower response rate in patients with extramedullary plasmacytomas probably reflects the poor prognosis in this population, which is historically challenging to treat,” they said.

Moreover, MRD**-negativity rate was 27 percent in the overall cohort and 46 percent among those with complete response or better. Evidence shows that MRD negativity is tied to improved survival in MM. [Blood Adv 2020;4:5988-5999; Blood 2022;139:492-501; Sci Rep 2021;11:21916]

Low-grade, reversible toxicities

Seventy-six percent of participants had infections (45 percent grade 3/4), but the researchers underlined that this is a patient population that is highly susceptible to infection owing to the immunodeficiency tied to the disease and the immunosuppression from prior treatments.

Apart from one grade 4 seizure in a patient with bacterial meningitis, most neurotoxicities were low grade. Cytokine release syndrome (CRS), though frequent (72 percent), was also mostly grade 1/2 and fully resolved. “[T]he lower-grade profile of CRS with teclistamab supports the potential for outpatient administration,” said the researchers.

There were no treatment cessations owing to neurotoxic events or CRS development.

Of the 68 deaths, 41 were due to progressive disease. Nineteen deaths were from adverse events (12 from COVID-19), while five were deemed related to teclistamab.

Need for effective alternatives

Participants (n=165; median age 64 years, 58 percent male) received SC teclistamab 1.5 mg/kg of body weight weekly after step-up doses of 0.06 and 0.3 mg/kg. They had progressive disease after at least three therapy lines, including triple-class exposure to an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody – which is the standard treatment regimen for MM.

For patients with disease progression even after receiving the standard regimen, treatment options are limited, and outcomes are usually poor. [Hemasphere 2021;5:e528; J Natl Compr Canc Netw 2020;18:1685-717; Leukemia 2022;36:1371-1376]

Two of the three BCMA***-directed therapies approved for heavily pretreated MM are CAR-T^# therapies (idecabtagene vicleucel and ciltacabtagene autoleucel), which have shown favourable response rates. [N Engl J Med 2021;384:705-716; Leukemia 2020;34:985-1005; Lancet 2021;398:314-324] However, these require access to specialized care centres and waiting time due to production, which can lead to attrition rates of up to 15 percent.

“[These] underscore the need for effective off-the-shelf treatment options for patients with R/R MM. Teclistamab is readily available and has been associated with rapid onset of response after a median of ~1 month of treatment,” said the researchers.

Teclistamab targets not only BCMA expressed on myeloma cell surfaces but also CD3 expressed on T cell surfaces. “[Its bispecific mechanism mediates] T-cell activation and subsequent lysis of BCMA-expressing myeloma cells,” they continued.

“[Overall, our findings showed that] teclistamab had substantial clinical activity that compares favourably with that of existing therapies for patients with heavily pretreated R/R MM … Toxic effects were also common but were mainly of low grade and reversible,” said the researchers.

“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,” they added.