FDA Accepts Iberdomide NDA; New Data on Myeloma Quadruplet Therapy and Ferroptosis Research

The FDA has accepted a new drug application for iberdomide in combination with anti-CD38 monoclonal antibodies for treating relapsed or refractory multiple myeloma. This regulatory development coincides with other advances in myeloma treatment, including promising long-term data for a quadruplet therapy regimen and novel research on a ferroptosis-inducing agent.

The FDA's acceptance of the application for iberdomide (Bristol Myers Squibb) is based primarily on data from the phase 3 EXCALIBER-RRMM trial (NCT04975997). The study evaluated iberdomide, a next-generation cereblon E3 ligase modulator (CELMoD), in combination with anti-CD38-based therapy in patients with relapsed or refractory multiple myeloma (RRMM) who had received multiple prior lines of therapy. Key end points included measurable residual disease (MRD) negativity, overall response rate, progression-free survival, and safety. The submission emphasizes MRD as a clinically meaningful endpoint for treatment monitoring.

In another development, a phase 2 study presented at the ASCO Annual Meeting 2026 showed that the quadruplet therapy daratumumab plus carfilzomib, pomalidomide, and dexamethasone (DaraKPd) is effective and tolerable for long-term treatment of RRMM. The study included 28 patients who had received a median of 1 prior line of therapy; 85.7% had previously undergone autologous stem cell transplantation. The rate of near complete response after 4 cycles was the primary endpoint, reaching 39%. Median progression-free survival was 38.4 months, while median overall survival was not reached.

Assessment using flow cytometry for MRD was performed in 26 patients, with 65% achieving MRD-negativity and 42% sustaining that status for at least a year. For patients whose best response was MRD-negativity, median progression-free survival was 69.4 months, compared to 14.0 months for those with MRD-positivity. Consensus genomic staging classified 8 of 25 evaluable patients as high-risk; their median progression-free survival was 18.4 months versus 69.4 months for standard-risk patients. No new safety signals or treatment-associated deaths were recorded; treatment-emergent adverse events included febrile neutropenia in 21% and high-grade infections in 32%.

Separately, research published in Nature demonstrates that the selective third-generation retinoid X receptor (RXR) agonist IRX4204 sensitizes multiple myeloma cells to ferroptosis, an iron-dependent cell death pathway. In mechanistic studies, IRX4204 induces HMOX1 transcription via PPARα-RXRα binding and decreases GPX4 levels, leading to iron buildup, lipid peroxidation, and ferroptosis. In vivo, IRX4204 enhanced lenalidomide's effectiveness, reduced tumor burden, and extended survival without added toxicity. Clinically, high HMOX1 expression correlates with improved overall survival in multiple myeloma patients, supporting the potential of combining RXR agonists with ferroptosis-based treatments.