(OA-52) Updated Results of a Phase 1 First-in-Human Study of Cemsidomide (CFT7455), a Novel MonoDAC® Degrader, with Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma (RRMM)
Associate Professor/Hematologist Medical College of Wisconsin Milwaukee, Wisconsin
Introduction: Cemsidomide is a highly potent Ikaros Family Zinc Finger Protein 1/3 (IKZF1/3) cereblon-based degrader. Cemsidomide has demonstrated best-in-class activity in multiple myeloma (MM) preclinical models and has also been shown to stimulate immune activation.
Methods: CFT7455-1101(NCT04756726) is an open-label, phase 1/2, multi-center, first-in-human study evaluating safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of cemsidomide in patients (pts) with RRMM and R/R NHL. MM eligible pts must have received lenalidomide, pomalidomide, a proteasome inhibitor, and an anti-CD38 antibody. The primary objective of this portion of the phase 1 study is to characterize the safety of cemsidomide with dexamethasone (DEX) and to determine the maximum tolerated dose and/or recommended doses for phase 2. Secondary objectives include overall response rate (ORR) according to the International Myeloma Working Group (IMWG) response criteria, PK, and PD. Dose escalation was guided by a Bayesian logistic regression model.
Results: As of April 30, 2025, 64 pts have been treated with cemsidomide at various doses on a 14 day on/14 day off schedule plus DEX (20 or 40 mg weekly) in the dose escalation study. The median age was 67 (range 39-82) and pts had a median of 7 prior lines (range 3-22). 45/64 pts (70%) received prior CAR-T or a bispecific antibody. 20/64 pts (31%) had high-risk disease at screening and 19/64 pts (30%) had extramedullary disease. Systemic exposure of cemsidomide increased dose proportionally. At all dose levels, cemsidomide produced high levels of degradation of IKZF1 and IKZF3 (greater than 50% and 80%, respectively). 4 dose-limiting toxicity events have been observed (one pt in the 62.5 µg cohort and 3 pts in the 100 ug cohort). 77% of pts experienced grade ≥3 TEAEs. Grade 3-4 TEAEs occurring in ≥10% of pts included neutropenia (56%), anemia (25%), infections (28%), lymphopenia (11%), and thrombocytopenia (11%). The majority of grade ≥3 TEAEs occurred in cycles 1-2. 39% of pts received G-CSF and only 8% of pts experienced grade 3-4 febrile neutropenia. 1 pt had an AE resulting in dose reduction and 1 pt had an AE resulting in discontinuation. The ORR among efficacy evaluable pts is 33% (21/63) with 10 additional pts achieving minimal response for a clinical benefit rate of 49%. The ORR is 40% (8/20) at 75 ug and 50% (5/10) at 100 ug, where 1 pt had an MRD (-) CR. 100 ug has been declared safe with 10 additional patients enrolling, and no further dose escalation is planned.
Conclusions: Cemsidomide with DEX demonstrates compelling efficacy and tolerability as an all-oral therapy in a heavily pre-treated RRMM population, the majority of whom had received a CAR-T or bispecific antibody. Grade 3-4 toxicities consist largely of cycle 1-2 myelosuppression, which has been manageable with limited dose reductions and discontinuations. 100 ug is the maximum administered dose for planned further development.
