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. 2025 Jun;21(14):1761-1769.
doi: 10.1080/14796694.2025.2501920. Epub 2025 May 10.

EXCALIBER-RRMM: a phase III trial of iberdomide, daratumumab, and dexamethasone in relapsed/refractory multiple myeloma

Sagar Lonial  1 , Meletios A Dimopoulos  2   3 , Jesus G Berdeja  4 , Paul G Richardson  5 , Hang Quach  6 , Paula Rodríguez-Otero  7 , Paulo Maciag  8 , Kevin Hong  8 , Michael Amatangelo  8 , Min Chen  8 , Niels W C J van de Donk  9
Affiliations

EXCALIBER-RRMM: a phase III trial of iberdomide, daratumumab, and dexamethasone in relapsed/refractory multiple myeloma

Sagar Lonial et al. Future Oncol. 2025 Jun.

Abstract

Multiple myeloma (MM) is a plasma cell neoplasm that stems from the malignant transformation of clonal plasma cells. It is characterized by multiple periods of remission and relapse requiring multiple lines of therapy, with response to treatment and survival decreasing with each successive relapse. To achieve deep and durable responses in relapsed/refractory MM (RRMM), novel treatments are required. Iberdomide (IBER), an oral CELMoD™ agent, is associated with greater tumoricidal and immune-stimulatory effects than immunomodulatory drugs (IMiDs®). IBER has been shown to have synergy with dexamethasone (DEX) and daratumumab (DARA) in vitro. In a phase I/II trial, IBER in combination with DARA and DEX (IberDd) was well tolerated and demonstrated promising preliminary efficacy in patients with heavily pretreated RRMM, including patients refractory to IMiD agents, DARA, and proteasome inhibitors. EXCALIBER-RRMM is a unique confirmatory phase III trial that incorporates a 2-stage seamless design to firstly address dose optimization of IberDd, and secondly, to compare the efficacy and safety of the selected IberDd dose with DARA, bortezomib, and DEX in patients with early-line (1 or 2 prior lines of therapy) RRMM.Clinical trial registration: www.clinicaltrials.gov identifier is NCT04975997.

Keywords: CELMoD agent; Relapsed/refractory multiple myeloma; clinical trial; iberdomide; phase III.

Plain language summary

Multiple myeloma (MM) is a type of cancer that affects a group of blood cells called plasma cells, found in the bone marrow, which become abnormal and grow uncontrollably. Eventually, these cells crowd out healthy blood cells and cause various problems in the body, including bone pain, tiredness, weakness, and frequent infections. A cancer is referred to as “relapsed” when the disease reappears or grows again after a period of remission, and as “refractory” when it does not respond to, or stops responding to, treatment. While treatment options for MM have continued to get better, unfortunately MM is still not curable, and there is a need for new treatment options to prevent it from relapsing and to provide long-term control of the disease. Researchers wanted to see whether adding a new treatment called iberdomide (IBER) to a combination of established treatments can stop relapsed/refractory MM from getting worse and help patients live longer. To answer this question, they have started a unique large, international, phase III study called EXCALIBER-RRMM comprising two stages. The first stage will select the appropriate dose of IBER (dose optimization), and the second stage will evaluate whether treating patients with the selected dose of IBER in combination with daratumumab (DARA) and dexamethasone (DEX), compared with a combination of DARA, bortezomib, and DEX, can help stop the cancer from getting worse and help patients live longer.

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Conflict of interest statement

Sagar Lonial reports a consulting or advisory role with AbbVie, Amgen, BMS, Genentech, GSK, Janssen, Novartis, Pfizer, Regeneron, and Takeda; research support for clinical trials from BMS, Janssen, Novartis, and Takeda; and is on the board of directors with stock for TG Therapeutics. Meletios A. Dimopoulos reports honoraria from Amgen, AstraZeneca, Beigene, BMS, GSK, Janssen, Menarini, Regeneron, Sanofi, Swixx, and Takeda for lectures, presentations, and speakers bureaus; support for travel from Amgen, BMS, Janssen, and Takeda; and participation on advisory boards for AstraZeneca, Amgen, Beigene, BMS, GSK, Janssen, Menarini, Regeneron, Sanofi, Swixx, and Takeda. Jesus G. Berdeja reports grants or contracts from 2 Seventy Bio, AstraZeneca, BMS, C4 Therapeutics, Caribou Biosciences, CARsgen, Cartesian Therapeutics, Celularity, Genentech, Gracell, GSK, Ichnos Sciences, J&J, Juno Therapeutics, K36 Therapeutics, Karyopharm, Kite, Moderna, Pfizer, Regeneron, Roche, Sanofi, and Takeda; consulting fees from AstraZeneca, BMS, Galapagos, Genentech, J&J, Karyopharm, Kite Pharma, Kyowa Kirin, Pfizer, Regeneron, Roche, and Sebia; and payment for lectures from Janssen. Paul G. Richardson reports grants or contracts from Oncopeptides; consulting fees from Celgene/BMS, GSK, Karyopharm, Oncopeptides, Regeneron, and Sanofi. Hang Quach reports consulting fees, honoraria, and participation on advisory boards for AbbVie, BMS, GSK, Janssen, Roche, and Pfizer. Paula Rodríguez-Otero reports honoraria from BMS, GSK, J&J Innovative Medicines, Pfizer, Regeneron, and Sanofi; participation in advisory boards for BMS, GSK, H3 Biomedicine, Janssen, Oncopeptides, Pfizer, Regeneron, Roche, and Sanofi; and is a consultant for AbbVie, BMS, J&J Innovative Medicines, Pfizer, and Roche. Paulo Maciag, Kevin Hong, Michael Amatangelo, and Min Chen are employees of BMS and hold stock in the company. Niels W.C.J. van de Donk reports research support from Amgen, BMS, Celgene, Cellectis, Janssen Pharmaceuticals, and Novartis; has participated in advisory boards for AbbVie, Adaptive, Amgen, Bayer, BMS, Celgene, Janssen Pharmaceuticals, Kite Pharma, Merck, Novartis, Pfizer, Roche, Sanofi, Servier, and Takeda, all paid to institution. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Professional medical writing and editorial assistance were provided by Mauro Locati, PhD, of Excerpta Medica, and was funded by Bristol Myers Squibb. The authors are fully responsible for all content and editorial decisions.

Figures

Figure 1.
Figure 1.
IBER mechanism of action. Chemical structures reprinted (adapted) with permission from Matyskiela, 2018 [11]. Copyright 2018 American Chemical Society. c-Myc: cellular Myc; CUL4: cullin 4; DC: dendritic cell; DDB1: DNA damage-binding protein 1; IBER: iberdomide; IFN: interferon; IL: interleukin; IRF4: interferon regulatory factor 4; LEN: lenalidomide; MM, multiple myeloma; NK: natural killer; ROC1: regulator of cullins-1; Ub: ubiquitin.
Figure 2.
Figure 2.
Study design. EXCALIBER-RRMM is a phase III study evaluating the efficacy and safety of IberDd versus DVd in patients with RRMM.
Figure 3.
Figure 3.
Map of countries where clinical study sites are located.
See this image and copyright information in PMC

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