C4 Therapeutics reported a 50% overall response rate at 100 µg and 40% at 75 µg for cemsidomide plus dexamethasone in a Phase 1 dose-escalation study of relapsed/refractory multiple myeloma. Across all dose levels, 34% of evaluable patients achieved a partial response or better, with a median duration of response of 9.3 months; the median duration has not been reached at the two highest doses. Safety readouts were consistent with on-target cytopenias but remained manageable: febrile neutropenia occurred in 4% (Grade 3) and 1% (Grade 4), thrombocytopenia in 7% (Grade 3) and 4% (Grade 4), with no Grade 5 events reported. Dose reductions were infrequent (6%), and there were no discontinuations attributed to cemsidomide.
The dataset, presented with enrollment complete (n=72), reflects a heavily pretreated population with a median of seven prior regimens; 75% had received BCMA-directed therapy, and 75% had prior CAR-T or T-cell engagers. Pharmacodynamic measures showed >50% degradation of IKZF1 and >80% of IKZF3 with associated T-cell activation, supporting the mechanistic rationale for combination use. At 100 µg, one patient achieved an MRD-negative complete response, and another converted from a very good partial response to a complete response after the cutoff. C4T plans to advance two paths grounded in these data: a single-arm Phase 2 in fourth line or later evaluating cemsidomide plus dexamethasone aiming for accelerated approval, slated to start in Q1 2026 with initial ORR data in H2 2027; and a Phase 1b starting Q2 2026 combining cemsidomide and dexamethasone with a BCMA bispecific, with mid-2027 data guiding a single randomized Phase 3 intended to support full approval. The recommended Phase 2 dose alignment with the FDA is targeted by year-end 2025.
Strategically, this is a dual-track bet. The later-line, single-arm route follows precedent where ORR and durability have supported accelerated approvals in myeloma, but it comes amid a shift toward tighter FDA scrutiny and faster confirmatory expectations. The earlier-line combination path with a BCMA BiTE hedges that risk, positioning cemsidomide as a tolerable immunomodulatory backbone designed to amplify T-cell activity without compounding the operational burdens of step-up dosing and inpatient monitoring common to T-cell engagers. The company is effectively challenging entrenched IKZF1/3 degraders by leaning into combination flexibility and a safety profile that could sustain multi-agent regimens.
For sites, the operational signal is favorable: a once-daily oral regimen with low discontinuation pressure, manageable neutropenia, and durability emerging at higher doses suggests outpatient feasibility and fewer protocol-driven interruptions. If the BiTE combination moves forward, sites should anticipate layered infection prophylaxis and hematologic monitoring typical of TCE regimens, but the absence of cemsidomide-related discontinuations in Phase 1 may reduce dose-management complexity. Sponsors and CROs will note the program’s focus on post-BCMA populations, aligning with regulator and payer expectations that new agents demonstrate value after exposure to cell and T-cell–redirecting therapies. Vendors supporting immunomonitoring and cytokine analytics may see increased demand given the mechanistic readouts anchoring the combination rationale.
Near term, the key watch items are the RP2D decision, consistency of the 100 µg response and tolerability signal in expansion cohorts, and maturing duration data at the top doses. The BiTE combination will need to show that additive cytopenias and infection risk remain manageable while translating the pharmacodynamic synergy into clinically meaningful response depth and durability. Competitive pressure from other IKZF1/3 degraders and evolving standards in earlier lines may compress the window for differentiation. Ultimately, regulators will weigh cross-trial comparisons cautiously; robust post-BCMA efficacy, clean safety in combinations, and a crisp confirmatory strategy will determine whether cemsidomide can secure a place as a backbone partner rather than a late-line placeholder.
Jon Napitupulu is Director of Media Relations at The Clinical Trial Vanguard. Jon, a computer data scientist, focuses on the latest clinical trial industry news and trends.
