C4 Therapeutics Doses First Patient in Phase 2 Myeloma Trial, Targets 2028 NDA Submission

C4 Therapeutics has dosed the first patient in its Phase 2 MOMENTUM trial evaluating cemsidomide in combination with dexamethasone for the treatment of relapsed/refractory multiple myeloma. The company is targeting enrollment completion in the first quarter of 2027 and a registrational dataset and NDA submission by 2028, supported by financing through end-2028.

The MOMENTUM Phase 2 single-arm study will enroll approximately 100 patients in the fourth-line or later setting. Cemsidomide will be evaluated at the 100 µg dose level with a daily dosing schedule of 14 days on and 14 days off, and dexamethasone is dosed once a week. The primary endpoint is the overall response rate per the International Myeloma Working Group response criteria as assessed by an independent review committee. Secondary endpoints will evaluate a range of additional safety and efficacy measures.

Approximately 100 patients who have received at least three prior anti-myeloma regimens that must have included an IKZF1/3 degrader, a proteasome inhibitor, an anti-CD38 antibody, and a T-cell engager or CAR-T therapy will be enrolled in the trial. Management is targeting a roughly 12-month enrollment period and is expanding beyond the U.S.-only footprint of the Phase 1 study by activating sites in Europe and other regions.

Phase 1 results showed a 36% overall response rate across all studied doses, with response rates increasing at higher doses to 53% at 100 micrograms. The Phase 1 study enrolled what was described as a contemporary, heavily pretreated population: 100% triple-class exposed, 100% previously treated with anti-CD38 therapy, and 75% previously treated with BCMA-directed therapies or CAR-T.

Cemsidomide showed a safety profile consistent with class effects, including transient neutropenia, but demonstrated relatively low rates of neutropenia versus other CELMoDs and low use of G-CSF. The study saw very few dose reductions and almost zero discontinuations due to drug-related side effects.

The company is prioritizing durable responses and MRD-negative complete responses as potential endpoints to support accelerated and pivotal filings. Management described an approach built around a threshold response rate: in this late-line population, the company assumed off-the-shelf regimens could deliver at least a 20% response rate and designed the 100-patient trial to be able to show a higher level, targeting at least a 40% response rate.

C4 will initiate a Phase 1b combination study with Pfizer's elranatamab to inform a Phase 3 confirmatory trial. The Phase 1b trial of cemsidomide in combination with elranatamab is on track to initiate in the second quarter of 2026. Elranatamab is an FDA-approved B-cell maturation antigen CD3 targeted bispecific antibody.

The Phase 1b study is designed to evaluate the safety, tolerability and preliminary efficacy of cemsidomide in combination with elranatamab. The study will evaluate different cemsidomide dose levels beginning with 75 µg, with the opportunity to simultaneously explore 50 µg and 100 µg in patients who have received one to four prior lines of therapy, which must have consisted of at least one IKZF1/3 degrader. Exclusion criteria for patients include those who have received prior treatment with a BCMA-directed T-cell engager or BCMA-directed CAR-T therapy. The goal is to move quickly and identify a dose suitable for a phase 3 trial within about 18 months of opening the study.

Cemsidomide is an investigational, orally bioavailable molecular glue degrader of IKZF1/3, transcription factors foundational to multiple myeloma biology. Management described two mechanisms as important for the class: effects on hematopoietic stem cell differentiation impacting plasma cell formation and T-cell activation through increased IL-2 production.

Further analysis of the completed Phase 1 trial of cemsidomide in combination with dexamethasone is expected in mid-2026. The company completed a financing in October that provides runway through the end of 2028.