Abstract
Background. Inobrodib (CCS1477; Ino) is a first-in-class, potent, selective, orally bioavailable inhibitor of the bromodomains of p300 and CBP, histone acetyltransferases with oncogenic roles in haematologic malignancies. Inobrodib demonstrates anti-tumor activity in multiple myeloma cell lines and synergistic activity with pomalidomide (Pom). The combination of Ino with pomalidomide and dexamethasone (dex; InoPd) has previously shown manageable safety and clinical activity in heavily pretreated relapsed/refractory multiple myeloma (RRMM).
Methods. Eligible patients with RRMM had exhausted standard-of-care options or received ≥2 prior therapies including lenalidomide and a proteasome inhibitor (if pomalidomide-naïve). Patients were randomized to inobrodib 20 mg, 30 mg, or 40 mg twice daily on a 4-days-on/3-days-off schedule, combined with pomalidomide 4 mg and dexamethasone 20–40 mg (age-dependent), administered in 28-day cycles. Randomization was stratified by prior pomalidomide exposure. Adverse events were graded per CTCAE v5.0 and responses were Investigator-assessed using IMWG criteria.
Results. At a data cutoff of 6 October 2025, 61 patients were enrolled. Median age was 70 years (range 44–83), and 79% had ECOG performance status <1. Thirty-six percent had high risk disease by IMWG Consensus Genomic Staging. The median number of prior therapies was 5 (range 2–17); 53% were pomalidomide-refractory, 71% were triple-class refractory, and 66% had received prior BCMA- or T-cell engager–directed therapy. Grade 3/4 treatment-emergent adverse events occurred in 71% of patients and were predominantly haematologic (neutropenia 34%, thrombocytopenia 36%, anemia 20%). Thrombocytopenia was the primary overlapping toxicity; at the 20-mg dose, its frequency and severity were comparable with published pomalidomide/dexamethasone data. Among 44 response-evaluable patients, overall response rates were 69%, 54%, and 33% in the 20-, 30-, and 40-mg cohorts, respectively. High response rates were observed in a high-unmet-need population (pomalidomide-refractory and post-BCMA/T-cell engager patients), with 60% and 75% ORR in the 20-, and 30-mg cohorts, respectively. Overall, the 20-mg dose demonstrated the most favorable benefit–risk profile.
Conclusions. InoPd demonstrates a manageable safety profile and promising clinical activity in heavily pretreated RRMM. Initial results support selection of the 20-mg dose for future registrational studies. Additional trial arms evaluating inobrodib in combination with elranatamab and teclistamab are ongoing.
Footnotes
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