A Phase 2, Single-Arm, Non-Inferiority Study of Limited-Duration Teclistamab for Relapsed and Refractory Multiple Myeloma (LimiTec)

Background and Significance: Teclistamab, a BCMA-directed T-cell engager (anti-BCMAxCD3 bispecific antibody), is currently approved for relapsed/refractory multiple myeloma (MM) patients with ≥4 prior lines of therapy, including an IMID, proteasome inhibitor, and CD38 antibody. Teclistamab is typically dosed on a regular schedule (every 1-4 weeks) indefinitely until disease progression. Yet continuous exposure, as reported on the phase 1/2 MajesTEC-1 study, was associated with infectious complications in 78% of patients, with 52% grade 3 or 4 events (van de Donk et al, ASCO 2023) and several fatal infections (Moreau et al., NEJM 2022). Sustained off-drug responses have been observed in patients who discontinued teclistamab for reasons other than progression and have also been reported with cevostamab, an anti-FcRH5xCD3 bispecific antibody under investigation as a limited-duration regimen (17 cycles) in MM (Lesokhin et al, ASH 2022). These findings raise the possibility that limited-duration teclistamab might provide comparable efficacy with lower risk compared to continuous therapy. Therefore, we hypothesize that monitored discontinuation of teclistamab in patients with deep response after 6-9 months of continuous therapy, with option to resume upon early sign of MM growth, will be non-inferior to that of historical controls [from the MajesTec-1 trial] who were treated with continuous teclistamab dosing.

Study design and methods: This is a single-arm, non-inferiority study in which patients who have achieved a very good partial response (VGPR) or better, according to International Myeloma Working Group (IMWG) response criteria, following 6-9 months of standard-of-care teclistamab, will be offered monitored drug discontinuation. Patients will be monitored monthly off-drug for up to 24 months and will be allowed to resume commercial teclistamab on-study in the event of early disease growth (defined as increase in involved free light chain >20 mg/L with ratio >5) or progression (as defined by IMWG criteria). The primary objective is to preliminarily assess whether the rate of treatment failure of limited-duration teclistamab after 6 months of drug discontinuation is non-inferior to that of historical controls who received continuous therapy, where treatment failure is defined as any of the following events: (1) disease progression after teclistamab re-initiation (for subjects who resume teclistamab for early disease growth), (2) failure to achieve at least minimal response to teclistamab re-initiation (for patients who resume teclistamab for IMWG progression), (3) initiation of non-teclistamab systemic MM therapy, or (4) death due to complications of MM, teclistamab, or infection. Secondary endpoints will evaluate time to progression, rates of re-response, the rate and severity of infections, types of clinical complications with progression, patient reported outcomes, and immune cell subset composition. Analysis of minimal residual disease (MRD), tumor features, and bone marrow microenvironment parameters, which will be pursued as exploratory correlative analyses in this study, may identify factors that predict durable response to limited-duration therapy and thereby enable more precise selection of patients likely to benefit from this approach. A subset of patients will be enrolled in an optional biomarker sub-study for analysis of these exploratory endpoints. We will enroll ~75 subjects to reach the target of 64 evaluable subjects assuming 15% will be not evaluable. The sample size was calculated based on a non-inferiority test for the primary outcome of failure-free probability at six months after the date of discontinuation of teclistamab against the null value of 0.79 that estimated from a historical cohort with 80% power, 0.05 alpha level, and a non-inferiority margin of -0.15. The power was evaluated at the value such that no difference between the historical and early discontinuation values using a one-sided one-sample continuity-corrected Z-test for testing a binomial proportion (normal approximation) with the standard deviation estimated under the null value.

Conclusions: This single-arm, phase 2 study is exploring whether limited-duration teclistamab is non-inferior to continuously administered therapy in patients who have received 6 to 9 months of teclistamab and have achieved at least a very good partial response. Accrual started in July 2023.