Durable Responses Found With Teclistamab in Relapsed or Refractory Multiple Myeloma

Article

Patients taking teclistamab for relapsed or refractory multiple myeloma saw durable response, and a well-tolerated toxicity profile.

Teclistamab was well tolerated and showed durable responses that deepened over time in patients with relapsed or refractory multiple myeloma treated on the phase 1 MajesTec-1 study (NCT03145181), according to a study published in The Lancet.

The median duration of response was not met at the recommended phase 2 dose. Most of the 40 patients treated at that dose level (85%) were still alive and continuing treatment after a median follow-up of 7.1 months (interquartile range [IQR], 5.1-9.1). However, teclistamab, at the phase 2 dose exposure was maintained above target exposure levels and consistent with T-cell activation.

The trial enrolled 157 patients to receive at least 1 dose of teclistamab. In total, 64% of patients that discontinued treatment, 49% due to progressive disease, 6% because of adverse effects (AEs), 6% because of physician decision, 2% because of patient withdrawal, and 1% because of death.

All patients had previously received a median of 6 lines of therapy (IQR, 4-7) with 82% being triple-class refractory, 39% penta-drug refractory, and 90% refractory to their last line of therapy.

Teclistamab was given intravenously (IV) once every 2 weeks in 12 patients, IV once every week in 72, and subcutaneously in 73. Patients in the once every 2 weeks IV group received a dose of 0.3 to 19.2 μg/kg, the once per week IV group received a dose of 19.2 to 720 μg/kg, and the subcutaneous group received 80 to 3000 μg/kg with step-up dosing used for full-doses 38.4 μg/kg or higher.

Patients in the once per week intravenous cohort experienced 2 dose-limiting toxicities of grade 4 delirium at the 20.0 μg/kg step-up dose in a patient assigned to the 120 μg/kg cohort and grade 4 thrombocytopenia at the 180 μg/kg full dose. There were no dose-limiting toxicities in the subcutaneous group and the maximum tolerated dose of teclistamab was not reached.

In the once per week subcutaneous group, collective safety, efficacy, pharmacokinetic, and pharmacodynamic data were used to find the recommended phase 2 dose of 1500 μg/kg of teclistamab. This dosing level was the first one to be consistently above the target level from an ex vivo cytotoxicity assay, and the higher exposure did not affect the safety profile compared with the next highest dose.

The entire population had AEs, with 85% (n = 134) being grade 3 or 4 treatment-emergent AEs. All 40 patients in the recommended phase 2 dose had a treatment-emergent AE, with 80% (n = 32) having at least 1 that was grade 3 or 4 in severity. In 50% of patients (n = 78) in all cohorts and 58% (n = 23) in the phase 2 dose group, grade 3 or 4 treatment-emergent AEs were found to be treatment related.

In 52% of patients overall (n = 81) and in 43% (n = 17) of patients in the phase 2 dose group, serious treatment-emergent AEs occurred. In 18% of patients (n = 29), serious treatment-emergent AEs were related to teclistamab, with 13% (n = 5) in the phase 2 cohort.

During the study, 55 patients died, 38) due to disease progression, 7 due to AEs that occurred 100 days or fewer after the last teclistamab dose or before the start of subsequent therapy, 9 after the start of subsequent therapy, and 1 for unknown reasons.

The median duration of follow-up was 16.6 months (IQR, 6.2-16.7) in the intravenous cohorts and 8.8 months (IQR, 3.8-11.1) in the subcutaneous dosing cohorts. There were 35 patients with confirmed partial responses (PRs) that switched from once per week to once every 2 weeks, with 1 patient had disease progression that occurred 1 month after switching.

For all patients treated with the recommended phase 2 dose, the median follow-up was 6.1 months (IQR, 3.6-8.2). The overall response rate (ORR) was 65% (9% CI, 48-79), with 58% achieving very good PR and 40% with a complete response (CR).

The ORR for patients who were triple-class refractory was 61% with median time to first confirmed response at 1.0 month (IQR, 1.0-1.6), first good PR at 1.0 month, and first confirmed CR was 3.0 months. The PFS for patients treated with the recommended phase 2 dose was 67% (95% CI, 49%-80%).

For all 5 dose levels, the ORR was 67% with 63% having a good PR or better. The mean duration of response was not reached.

There were 26 patients who were evaluable for minimal residual disease (MRD) that had a CR, 69% (n = 18) of whom were MRD negative. There were 2 patients who sustained MRD negativity for more than 12 months after a CR. For all 6 patients in the recommended phase 2 dose cohort, MRD-negative CR response was achieved (≤10–5 sensitivity level).

The increased frequency of T-cells was found in the once per week subcutaneous teclistamab group and consistent T-cell activation was found in the recommended phase 2 dose. These findings were similar to the T-cell immunoglobulin and mucin domain–containing protein 3, which are markers of T-cell activation.

Low titers for anti-teclistamab antibodies were found in 2% (n = 2) patients, 1 in the 80 μg/kg intravenous cohort and one in the 240 μg/kg subcutaneous cohort. This had no effect on safety or pharmacokinetics in these patients.

Reference

Usmani SZ, Garfall AL, van de Donk NWCJ, et al. Teclistamab, a B-cell maturation antigen × CD3 bispecific antibody, in patients with relapsed or refractory multiple myeloma (MajesTEC-1): a multicentre, open-label, single-arm, phase 1 study. Lancet. 2021;398(10301):665-674. doi:10.1016/S0140-6736(21)01338-6

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