(M-095) Population Pharmacokinetics and Exposure-response Analysis of Cemsidomide in Patients with Relapsed/Refractory Multiple Myeloma and Non-Hodgkin’s Lymphoma

Kavitha Bhasi – C4 Therapeutics, Inc.; Eunju Hurh – C4 Therapeutics, Inc.; Abagail Adam – C4 Therapeutics, Inc.; Amro Ali – C4 Therapeutics, Inc.; Rong Chu – C4 Therapeutics, Inc.; Anthony Fiorino – C4 Therapeutics, Inc.; Len Reyno – C4 Therapeutics, Inc.

Objectives: Cemsidomide (formerly CFT7455) is a novel, potent, cereblon-based IKZF1/3 MonoDAC® degrader rationally designed to enable rapid and deep target degradation. Cemsidomide is being evaluated in an ongoing phase 1 dose-escalation study in patients with relapsed/refractory multiple myeloma (MM) and non-Hodgkin’s lymphoma (NHL) [1, 2]. The objective of the analysis was to develop a population PK model for cemsidomide and to evaluate exposure-response relationships for dose selection in future studies.

Methods: PK data was collected from an ongoing phase 1 study CFT7455-1101 (NCT04756726), where cemsidomide was administered with 50 μg once daily (QD) 21 days on/7 days off (21/7), 25 μg to 75 μg Monday, Wednesday, and Friday (MWF) 14 days on/14 days off (14/14), or 37.5 μg to 100 μg QD 14/14 dosing schedules as monotherapy or in combination with dexamethasone (MM only). A preliminary population PK model for all patients was developed using NONMEM version 7.5. Any plasma cemsidomide concentration below the limit of quantification (BQL) was treated as censored and the data was analyzed with the full likelihood approach (M3 method). Individual exposure metrics for exposure-response analyses were generated using individual patient empirical Bayes estimates of PK parameters and dosing records. To evaluate the relationship between exposure and anti-myeloma activity in MM patients treated with cemsidomide and dexamethasone, an Emax model was developed for the nadir ratio of dFLC (difference between involved and uninvolved serum free light chain levels) normalized to baseline with cemsidomide exposure. For the analysis of exposure-neutropenia relationship in all patients, logistic regression was conducted for the decrease in absolute neutrophil count (ANC) levels below 500/mm3 or 1000/mm3 with the patients’ cemsidomide exposures. Emax and logistic regression analysis were conducted in R using the rstanemax package and glm function, respectively.

Results: A two-compartment model with first-order oral absorption and absorption lag time and first-order elimination best described cemsidomide PK. Exposure-dFLC analysis in MM patients with dexamethasone combination treatment showed that higher exposures of cemsidomide resulted in deeper reductions in light chains. The highest exposure quartile showed greater than 50% reduction from baseline in dFLC. These exposures were back-calculated to an average cemsidomide dose of approximately 78 µg QD 14/14. Univariate and multivariate (with baseline ANC as covariate) logistic regression showed no significant trend for decrease in patients’ ANC levels below 500/mm3 or 1000/mm3 over the range of exposures evaluated.

Conclusions: Results from exposure-response analysis indicate an increased anti-myeloma effect at higher exposure and lack of exposure-neutropenia relationship over the range evaluated and support cemsidomide doses of 75 µg QD or greater on a 14/14 schedule in combination with dexamethasone for patients with MM. These analyses will be updated when complete dose-escalation data in MM and NHL become available for dose selection for future studies.

Citations: [1] Dhakal et al., Initial 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. Blood (2024) 144 (Supplement 1): 3366. ASH 2024.

[2] Horwitz et al., Initial Results of a Phase 1 First-in-Human Study of Cemsidomide (CFT7455), a Novel MonoDAC® Degrader, in Patients with Non-Hodgkin’s Lymphoma. Blood (2024) 144 (Supplement 1): 467. ASH 2024.

Keywords: cemsidomide, population PK, exposure-response