<div>Abstract<p>The safety and efficacy of combining the isocitrate dehydrogenase-1 (IDH1) inhibitor ivosidenib (IVO) with the BCL2 inhibitor venetoclax (VEN; IVO + VEN) ± azacitidine (AZA; IVO + VEN + AZA) were evaluated in four cohorts of patients with <i>IDH1</i>-mutated myeloid malignancies (<i>n</i> = 31). Most (91%) adverse events were grade 1 or 2. The maximal tolerated dose was not reached. Composite complete remission with IVO + VEN + AZA versus IVO + VEN was 90% versus 83%. Among measurable residual disease (MRD)–evaluable patients (<i>N</i> = 16), 63% attained MRD-­negative remissions; <i>IDH1</i> mutation clearance occurred in 64% of patients receiving ≥5 treatment cycles (<i>N</i> = 14). Median event-free survival and overall survival were 36 [94% CI, 23–not reached (NR)] and 42 (95% CI, 42-NR) months. Patients with signaling gene mutations appeared to particularly benefit from the triplet regimen. Longitudinal single-cell proteogenomic analyses linked cooccurring mutations, antiapoptotic protein expression, and cell maturation to therapeutic sensitivity of <i>IDH1</i>-mutated clones. No IDH isoform switching or second-site <i>IDH1</i> mutations were observed, indicating combination therapy may overcome established resistance pathways to single-agent IVO.</p>Significance:<p>IVO + VEN + AZA is safe and active in patients with <i>IDH1</i>-mutated myeloid malignancies. Combination therapy appears to overcome resistance mechanisms observed with single-agent IDH-inhibitor use, with high MRD-negative remission rates. Single-cell DNA ± protein and time-of-flight mass-cytometry analysis revealed complex resistance mechanisms at relapse, highlighting key pathways for future therapeutic intervention.</p><p><i><a href="https://aacrjournals.org/bloodcancerdiscov/article/doi/10.1158/2643-3230.BCD-4-4-ITI" target="_blank">This article is highlighted in the In This Issue feature, p. 247</a></i></p></div>