FDA Accepts NDA for Bristol Iberdomide Plus Daratumumab-Dexamethasone in Multiple Myeloma

 The FDA accepted a new drug application (NDA) for iberdomide (CC-220) in combination with daratumumab (Darzalex) and dexamethasone (IberDd) for patients with relapsed or refractory multiple myeloma (RRMM), assigning a Prescription Drug User Fee Act (PDUFA) date of August 17, 2026.1 The filing is supported by minimal residual disease (MRD) negativity data from the phase 3 EXCALIBER-RRMM trial (NCT04975997). The agency also granted breakthrough therapy designation (BTD) and priority review for the regimen.

The application is notable for its reliance on MRD negativity as a dual primary end point alongside progression-free survival (PFS), underscoring the growing regulatory interest in MRD as a surrogate end point supporting drug approval in multiple myeloma. Whether MRD improvement in this setting will translate into durable survival benefit remains a key clinical question.

Drug and Class Background

Iberdomide is a cereblon E3 ligase modulator (CELMoD), a next-generation agent designed to enhance degradation of Ikaros and Aiolos transcription factors more potently than earlier immunomodulatory drugs (IMiDs). Preclinical and early-phase clinical studies suggested activity in heavily pretreated myeloma, including in patients with myeloma refractory to lenalidomide (Revlimid) and pomalidomide (Pomalyst).2

IMiDs, including thalidomide, lenalidomide, and pomalidomide, form a backbone of myeloma therapy and exert immunomodulatory and anti-myeloma effects through cereblon-mediated ubiquitin pathways.³ Iberdomide aims to build on this mechanism with enhanced cereblon binding and downstream target degradation.4

Trial Overview

EXCALIBER-RRMM is a global, randomized, open-label, phase 3 trial evaluating iberdomide plus daratumumab and dexamethasone in patients with RRMM who received 1 or 2 prior lines of therapy.4

Stage 1 of the study identified 1.0 mg of iberdomide as the optimal dose based on safety, pharmacokinetic, and preliminary efficacy data after comparing it with 1.3 mg and 1.6 mg daily on days 1 to 21 of a 28-day cycle in at least 200 patients.1,4 In stage 2, approximately 664 patients were randomly assigned to IberDd vs daratumumab, bortezomib, and dexamethasone (DVd) on a 1:1 basis.

Patients are stratified by number of prior lines of therapy, age of 70 or higher vs lower than 70, and International Staging System status of 1, 2, or 3 at study entry. Patients whose myeloma was refractory to anti-CD38 therapy or bortezomib were excluded, and in stage 2 only approximately 10% of patients in each arm could have received prior anti-CD38 therapy.4

The trial’s dual primary end points are PFS and MRD negativity in patients achieving a complete response. MRD was assessed using next-generation sequencing at high sensitivity thresholds (10⁻⁵ to 10⁻⁶), consistent with International Myeloma Working Group (IMWG) criteria.² Secondary end points include overall survival (OS), overall response rate (ORR), duration of response, time to progression, time to next treatment, and health-related quality of life.

According to results announced in September 2025, the IberDd arm demonstrated a statistically significant improvement in MRD negativity compared with DVd at the prespecified interim analysis.5 PFS data remain immature, and patients continue to be followed for time-to-event outcomes. Detailed hazard ratios for PFS have not yet been fully reported in peer-reviewed publication, limiting definitive conclusions regarding long-term benefit.

The safety profile of IberDd was consistent with known toxicities of the agents based on previous studies. In the previous phase 1/2 CC-220-MM-001 trial (NCT02773030) of iberdomide plus dexamethasone, the most frequent grade 3 or higher adverse events included neutropenia (45%), anemia (28%), infection (27%), and thrombocytopenia (22%).2

Clinical Context and Limitations

Multiple myeloma remains incurable despite significant therapeutic advances over the past decade. The integration of proteasome inhibitors, IMiDs such as lenalidomide and pomalidomide, and anti-CD38 antibodies such as daratumumab has extended survival; however, most patients ultimately relapse. Treatment selection in the relapsed setting depends on prior exposure, refractoriness, and patient comorbidities.

The DVd regimen used as the control arm in EXCALIBER-RRMM is an established standard in previously treated myeloma, supported by the phase 3 CASTOR trial (NCT02136134), which demonstrated improved PFS with daratumumab plus bortezomib and dexamethasone compared with bortezomib and dexamethasone alone.6 As patients are exposed to lenalidomide in early lines of therapy, there remains a need for effective oral immunomodulatory agents with activity in lenalidomide-refractory disease.

MRD negativity has emerged as a strong prognostic marker in myeloma across treatment settings. Regulatory agencies, including the FDA, have provided guidance for considering MRD as a surrogate end point in for accelerated approval, although it is not accepted as a basis for full approval.7

The FDA’s acceptance of the NDA, along with BTD, reflects the potential clinical relevance of improved MRD rates in RRMM. Mature PFS and OS data will be critical to determine whether MRD improvements translate into meaningful clinical benefit.

The review is being conducted under Project Orbis, enabling concurrent review by international regulatory authorities. Final regulatory decisions will depend on the totality of efficacy and safety data.

“The FDA’s acceptance of this application is a testament to the potential of iberdomide, in combination with anti-CD38 monoclonal antibodies, as a novel, potent, oral treatment option, with a manageable safety profile, for patients with multiple myeloma,” said Cristian Massacesi, executive vice president and chief medical officer of Bristol Myers Squibb in a news release.1 “Furthermore, our filing for iberdomide based on the MRD end point underscores our commitment to pioneering new ways of advancing life-saving therapies for patients living with cancer.”

https://www.targetedonc.com/view/fda-accepts-nda-for-iberdomide-plus-daratumumab-and-dexamethasone-in-rrmm