A Multi-Institution 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. It is typically dosed 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 of which 52% were grade 3 or 4 events (van de Donk et al, ASCO 2023) and several were fatal (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 multi-institution, 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, are offered monitored drug discontinuation (NCT05932680). Participants are monitored monthly off-drug for up to 24 months and are 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 assess whether the rate of treatment failure of limited-duration teclistamab 6 months after drug discontinuation is non-inferior to that of historical controls who received continuous therapy. 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 (using FACT-MM), and immune cell subset composition. A subset of patients are being enrolled in an optional biomarker sub-study for analysis of minimal residual disease (MRD) and bone marrow microenvironment parameters, which are being pursued as exploratory endpoints. 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 was observed 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. Target enrollment is 75 participants for a goal of 64 evaluable subjects. 20 patients have enrolled across three participating institutions between July 2023 and July 2024. The study is supported by the Leukemia Lymphoma Society Academic Clinical Trials Award (PI Garfall).

Conclusions: This multi-institution, 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 and is ongoing.