Iberdomide maintenance after autologous stem-cell transplantation in newly diagnosed multiple myeloma: An update from the phase 2 EMN26 trial

Abstract Clinical Background. Iberdomide is a novel, potent, oral CELMoD with clinically meaningful activity and favorable toxicity profile in patients (pts) with MM, including those with newly diagnosed and IMiD-refractory disease. We previously showed that iberdomide maintenance improves response post-transplant with a manageable safety profile, compared with historical data. Aims. Here we present an updated analysis with a median follow-up of 30.2 months. Methods. The EMN26 study (NCT04564703) enrolled MM pts aged ≥18 years, who had achieved at least a partial response (PR) after induction therapy containing a proteasome inhibitor (PI) plus an IMiD +/- anti-CD38 antibody followed by 1 or 2 autologous stem-cell transplants (ASCT) +/- consolidation, into one of 3 different cohorts (iberdomide 0.75, 1.0, or 1.3 mg on days 1–21 of each 28-day cycle; 40 pts in each cohort). The primary outcome was improvement in response within 6 months, and secondary outcomes included response rate, rate of minimal residual disease conversion (MRD; by next-generation flow; sensitivity 10-5), safety, and progression-free survival (PFS). Results. At data cut-off (May 20, 2025), 40 pts were enrolled in each of the 3 cohorts (total of 120 pts). Median follow-up was 23.4, 33.4, and 33.4 months for the 0.75, 1.0, and 1.3 mg cohorts, respectively (the 0.75 mg cohort was activated 15 months later than the other two cohorts). Baseline characteristics were generally well balanced among the 3 cohorts, except for more frequent quadruplet use in the 0.75 mg cohort. Median age of these 120 pts was 59 years; 54% were male. At diagnosis, 29% of pts presented with Revised International Staging System (R-ISS) stage 1 disease, 56% with stage 2, and 12% with stage 3 (only in 3% R-ISS was missing at study entry). High-risk disease del(17p), t(4;14), and/or t(14;16) was present in 21%. All pts received a PI/IMiD-containing induction regimen, which also included daratumumab in 53% of pts. Quadruplet induction was more frequently used in the 0.75 mg cohort (88%), compared to the other 2 cohorts (35% and 38%). Double ASCT was administered to 17% and post-ASCT consolidation to 21%. At enrollment (prior to start of maintenance), complete response or better (≥CR) was achieved by 35%, 23%, and 28% of pts in the 0.75, 1.0, and 1.3 mg cohorts, respectively. After 6 treatment cycles, there was substantial deepening of response in all 3 cohorts, with response improvements observed in 59% (90% CI 43%–74%) of pts in the 0.75 mg, 37% (24%–52%) in the 1.0 mg, and 38% (23%–54%) in the 1.3 mg cohorts. These response improvements were significantly higher than the null hypothesis of ≤20% response improvement within 6 months. Best response achieved during iberdomide maintenance was ≥CR in 78% in the 0.75 mg cohort, 60% in the 1.0 mg cohort, and 70% in the 1.3 mg cohort. During iberdomide maintenance, conversion from positive to negative MRD status occurred in 50%, 42%, and 53% of pts in in the 0.75, 1.0, and 1.3 mg cohorts, respectively (overall 48%). MRD negativity sustained over a period of ≥12 months was achieved in 62%, 55%, and 57% of pts. PFS at 2 years was 92%, 82%, and 84% in these 3 cohorts. The median relative dose intensity of iberdomide was 91%, 88%, and 84% in the first 24 cycles with dose reductions occurring in 38%, 55%, and 65% of pts in the 0.75 mg, 1.0, and 1.3 mg cohorts, respectively. The most common grade ≥3 adverse event (AE) during cycles 1–24 was neutropenia (48% in the 0.75 mg, 58% in the 1.0 mg, and 60% in the 1.3 mg cohorts), followed by infections (8%, 18%, and 18%; mostly respiratory infections). Grade ≥3 rash was more frequent in the 1.3 mg cohort (10%), compared to 0.75 mg (0%) and 1.0 mg (3%) cohorts. There were no grade ≥3 AEs of thrombocytopenia, anemia, or venous thromboembolism. Only 1 of 120 pts (0.8%) developed grade ≥3 neuropathy (1.3 mg), and 1 (0.8%) developed grade 3 diarrhea (1.0 mg). Conclusions. Iberdomide represents a novel effective maintenance strategy with a favorable safety profile and superior response improvement than what has been historically observed with lenalidomide maintenance. These data support the investigation of iberdomide versus lenalidomide maintenance in the ongoing phase 3 registrational EXCALIBER Maintenance trial. The dose of 0.75 mg iberdomide was chosen as the recommended maintenance dose for further evaluation, based on comparable efficacy with superior tolerability, compared to higher doses of iberdomide.