Teclistamab Plus Nirogacestat Elicits Durable Responses in Relapsed/Refractory Myeloma

Jeffrey V. Matous, MD

The combination of teclistamab-cqyv (Tecvayli) and nirogacestat (Ogsiveo) produced high and deep responses in patients with relapsed/refractory multiple myeloma, according to data from the phase 1b MajesTEC-2 trial (NCT04722146) presented at the 2023 EHA Congress.

Findings showed that at a median follow-up of 14.7 months (range, 0.5-22.9), evaluable patients treated with the combination (n = 27) experienced an overall response rate (ORR) of 74.1%, including a complete response (CR) or better in 51.9% of patients. The rates of stringent CR, CR, and very good partial response were 22.2%, 29.6%, and 22.2%, respectively.

The median time to first response was 1.18 months (range, 1.1-2.7), and the median duration of response (DOR) was not yet reached. Notably, 87.2% of responders maintained their response for at least 12 months.

Regarding safety, no dose-limiting toxicities (DLTs) were observed at dose levels 2 or 3 of teclistamab (0.72 mg/kg or 1.5 mg/kg once per week, respectively) plus a delayed, reduced dose of 100 mg of nirogacestat per day. Three DLTs were reported in patients treated at dose level 1 of 0.72 mg/kg of teclistamab once per week plus concurrent nirogacestat at 100 mg twice per day. One patient experienced a grade 3 gastrointestinal bleed and grade 3 diarrhea, and another patient had grade 3 immune effector cell–associated neurotoxicity syndrome (ICANS).

Five grade 5 treatment-emergent adverse effects (AEs) were reported, including sepsis, septic shock, COVID-19, cardiac arrest, and Pneumocystis jiroveciipneumonia.

“The clinical profile of teclistamab plus nirogacestat in this phase 1b study suggests that careful evaluation is warranted when we’re combining BCMA-targeted bispecific therapies with a gamma-secretase inhibitor,” presenting study author Jeffrey V. Matous, MD, said in a presentation of the data. Matous is a member physician at the Colorado Blood Cancer Institute and a clinical professor of medicine at the University of Colorado in Denver.

The multicohort study enrolled patients with measurable multiple myeloma who received at least 3 prior lines of therapy, or were double refractory to a proteasome inhibitor and an immunomodulatory drug and were triple-class exposed. Patients also needed to have progressive disease within 12 months of their last line of therapy.

At dose level 1 (n = 8), patients received 0.72 mg/kg of teclistamab once per week after step-up doses of 0.06 mg/kg and 0.24 mg/kg, plus 100 mg of nirogacestat twice per day starting concurrently with the first step-up dose. Those treated at dose level 2 (n = 7) received the same regimen of teclistamab with nirogacestat started at 100 mg once per day following the first full dose of teclistamab without cytokine release syndrome (CRS). At dose level 3 (n = 13), patients received 1.5 mg/kg of teclistamab once per week following step-up doses of 0.06 mg/kg and 0.30 mg/kg, and 100 mg of nirogacestat per day was started following the first full dose of teclistamab in the absence of CRS.

Safety/tolerability and determining the optimal doses of each agent served as the trial’s primary end points. Secondary end points included ORR, rate of VGPR or better, rate of CR or better, DOR, time to response, and pharmacokinetics.

Among all treated patients (n = 28), the median age was 65.5 years (range, 46-80), 57.1% were male, and 78.6% were White. Twenty-five percent of patients had extramedullary plasmacytomas, and 20% had high-risk cytogenetics. Patients had International Staging System stage I (35.7%), stage II (39.3%), or stage III (25.0%) disease. The median time since diagnosis was 5.9 years (range, 1.3-15.5).

Patients received a median of 4.0 (range, 2-12) prior lines of therapy. Notably, 82.1% of patients underwent prior stem cell transplant. All patients were triple-class exposed, and 71.4% were penta-drug exposed. Additionally, 71.4% were triple-class refractory, 21.4% were penta-drug refractory, and 92.9% were refractory to their last line of therapy.

Additional safety data showed that all patients experienced at least 1 any-grade AE, and grade 3/4 AEs occurred in 92.9% of patients. The median duration of treatment of teclistamab and nirogacestat was 9.4 months (range, 0.03-22.9) and 4.7 months (range, 0.16-15.6), respectively. At data cutoff, 42.8% and 14.3% of patients were in ongoing treatment with teclistamab and nirogacestat, respectively. AEs led to discontinuation and dose reductions of teclistamab in 7.1% and 10.7% of patients, respectively. The rates of discontinuation and dose reductions with nirogacestat were 60.7% and 39.3%, respectively.

The most common hematologic AEs included neutropenia (any grade, 82.1%; grade 3/4, 75.0%), anemia (35.7%; 32.1%), and thrombocytopenia (25.0%; 14.3%). One patient discontinued treatment due to neutropenia. One patient experienced febrile neutropenia.

The most common non-hematologic AEs included CRS (any grade, 75.0%; grade 3/4, 3.6%), diarrhea (64.3%; 25.0%), injection-site erythema (53.6%; 0%), decreased appetite (50.0%; 0%), and fatigue (42.9%; 7.1%). One patient treated at dose level 2 also experienced grade 2 ICANS.

Regarding CRS, the median time to onset was 2 days (range, 1-3), and the median duration was 2 days (range, 1-33). Supportive measures for CRS included tocilizumab (Actemra; 35.7%), oxygen (14.3%), and a vasopressor (3.6%). Most CRS occurred during step-up dosing or cycle 1, and all CRS events resolved by data cutoff.

The most common infections included COVID-19 (any grade, 28.6%; grade 3/4, 7.1%), pneumonia (28.6%; 21.4%), bronchitis (21.4%; 0%), and upper respiratory tract infection (21.4%; 3.6%). One patient discontinued treatment due to pneumonia, and 4 infection-related deaths were reported.

Disclosures: Dr Matous reported serving on advisory committees for BeiGene and Janssen, and serving on a data monitoring board for BeiGene.

Reference

Offner F, Decaux O, Hulin C, et al. Teclistamab (TEC) + nirogacestat (NIRO) in relapsed/refractory multiple myeloma (RRMM): the phase 1b MajesTEC-2 study. Presented at: 2023 EHA Congress; June 8-11, 2023; Frankfurt, Germany. Abstract S194.