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

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

Sagar Lonial a,✉, Meletios A Dimopoulos b,c, Jesus G Berdeja d, Paul G Richardson e, Hang Quach f, Paula Rodríguez-Otero g, Paulo Maciag h, Kevin Hong h, Michael Amatangelo h, Min Chen h, Niels WCJ van de Donk i
PMCID: PMC12150652  PMID: 40346992

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: Relapsed/refractory multiple myeloma, clinical trial, phase III, iberdomide, CELMoD agent

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.

1. Introduction

1.1. Background & rationale

Multiple myeloma (MM) is a plasma cell neoplasm stemming from the malignant transformation of clonal plasma cells, which accumulate in the bone marrow [1]. Common manifestations and clinical sequelae of progressive MM include recurrent infections, cytopenias, renal insufficiency, hypercalcemia, bone pain, and pathologic fractures [2]. The most frequent causes of death are disease progression, infections, renal failure, and non-myeloma malignancies; to date, it remains incurable [2–5]. MM represents approximately 1.8% of all new cancer cases diagnosed annually in the US [6], and the annual age-adjusted incidence of MM is 5.6 cases per 100,000 people in Western countries [7]. With a median age at diagnosis of 70 years, MM affects mainly elderly individuals, although approximately 37% of newly diagnosed cases occur in individuals aged <65 years. As life expectancy of the general population increases and MM survival rates improve, the number of elderly patients with MM is likely to increase [7].

MM 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 [5,8]. A real-world, retrospective, longitudinal study of treatment patterns and outcomes in the US patients with relapsed/refractory MM (RRMM) found a median length of first-line treatment of approximately 3.0–7.5 months, which decreased with each subsequent line of therapy. The median time to next treatment was 5.7–14.3 months after first-line therapy, with treatment-free intervals shortening progressively with each successive line of therapy [9]. This suggests that despite advances in treatment for RRMM over recent years (e.g., chimeric antigen receptor [CAR]T cell therapies and T-cell engagers), new, safe, and convenient treatment options are needed to achieve deep and durable responses and extend remissions [5,9].

CELMoD™ agents modulate the E3 ubiquitin ligase cereblon (CRBN) by inducing conformational changes that enable CRBN to bind target neo-substrates, leading to their degradation and subsequent pharmacologic effects [5,10]. Iberdomide (IBER), an oral CELMoD agent shares structural similarities with the immunomodulatory drugs (IMiDs®) lenalidomide (LEN) and pomalidomide (POM); however, it binds CRBN with unique interactions and 20-fold higher affinity. These enhanced properties facilitate more efficient allosteric rearrangement of CRBN into the active/closed conformation required for substrate recruitment, resulting in more potent and efficient degradation of the hematopoietic transcription factors Ikaros and Aiolos compared with LEN and POM (Figure 1) [10–13]. Loss of Ikaros and Aiolos has been shown to be necessary and sufficient to induce apoptosis and inhibit proliferation of myeloma cells, and the improved potency of IBER results in greater tumoricidal and immunomodulatory effects compared with IMiD agents. Furthermore, IBER has also been shown to overcome IMiD-agent resistance and has in vitro synergy with standard-of-care agents in MM, including dexamethasone (DEX), daratumumab (DARA), and bortezomib (BORT) [14–19].

Figure 1.

Figure 1.

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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.

In the multicenter, multicohort, open-label, phase I/II CC-220-MM-001 trial (NCT02773030), the efficacy and safety of IBER in combination with DEX was evaluated in patients with RRMM who had received ≥2 previous lines of therapy, including LEN or POM and a proteasome inhibitor [20]. In the dose-expansion part of the trial, the overall response rate (ORR) was 26% (95% confidence interval [CI]: 18–36; 28 of 107 patients). Regarding safety, the Grade ≥3 adverse events (AEs) that occurred most frequently were neutropenia (45%), anemia (28%), infection (27%), and thrombocytopenia (22%), with approximately half of patients experiencing serious AEs. One (1%) treatment-related death from sepsis occurred and IBER was discontinued in five (5%) patients due to AEs [20].

In the CC-220-MM-001 trial, IBER + DARA + DEX (IberDd) also demonstrated promising efficacy and safety in patients with RRMM, with increased natural killer (NK)- and T-cell proliferation [19]. The most frequent hematologic Grade 3 or 4 treatment-emergent AEs (TEAEs) experienced by patients receiving IberDd were neutropenia (63%), anemia (28%), leukopenia (28%), and lymphopenia (25%). The occurrence of Grade 3 or 4 non-hematologic TEAEs was low. In this heavily pretreated (≥2 prior anti-myeloma regimens) patient population with IMiD-agent – refractory disease, the ORR was 41% (12 of 29 patients: 1 stringent complete response, 2 complete responses [CRs], 2 very good partial responses, 7 partial responses) [19]. Furthermore, analysis of molecular data from patients in the CC-220-MM-001 trial demonstrated IBER’s ability to restore T-cell function without triggering exhaustion. This is especially important in patients with late-line RRMM, who often show significant T-cell exhaustion due to prior lines of treatment [21], making the restoration of T-cell activity a critical step in enhancing therapeutic outcomes.

Taken together, the results from the CC-220-MM-001 trial support further investigation in the phase III EXCALIBER-RRMM trial. EXCALIBER-RRMM is a unique inferentially seamless 2-stage, phase III trial that integrates dose optimization prior to efficacy and safety evaluation of the treatment. Dose optimization is key to maximizing efficacy and minimizing toxicity for patients, as inadequate dose optimization can result in unnecessary toxicity, decreased treatment effectiveness, reduced quality of life, leading to challenges in developing combination therapies [22]. To date, dose selection has often been based on the maximum tolerated dose (MTD) [23]. However, Project Optimus, initiated by the US Food and Drug Administration in 2021, shifted the focus from MTD to optimal biological dose in oncology trials, providing a framework for dose optimization. This approach helps trial designs prioritize effective dosing to improving patient outcomes and reduce toxicity through investigation of dose– and exposure–response relationships, enhancing treatment efficacy [22–24]. Accordingly, the objectives of the EXCALIBER-RRMM trial are to conduct a dose-optimization stage of the trial of IberDd and then compare the efficacy and safety of the confirmed optimal dose of IberDd with DARA + BORT + DEX (DVd) in patients with RRMM.

1.2. Trial design

EXCALIBER-RRMM is a global, multicenter, open-label, inferentially seamless, adaptive phase III study conducted in two stages. Stage 1 will determine the dose of IBER in combination with DARA and DEX and stage 2 will compare the efficacy and safety of IberDd versus DVd in patients with RRMM. The study design is shown in Figures 2 and 3 shows a map of the countries where the clinical study sites are located.

Figure 2.

Figure 2.

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Study design. EXCALIBER-RRMM is a phase III study evaluating the efficacy and safety of IberDd versus DVd in patients with RRMM.

aThe recommended dose for stage 2 will be determined by an independent data monitoring committee.

DVd: daratumumab + bortezomib + dexamethasone; IBER: iberdomide; IberDd: iberdomide + daratumumab + dexamethasone; RRMM: relapsed/refractory multiple myeloma.

Figure 3.

Figure 3.

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Map of countries where clinical study sites are located.

In stage 1 of the study, patients will be randomized initially 1:1:1:1 to 1 of 3 IBER dose levels in combination with DARA and DEX, or to the DVd comparator arm. One dose level of IBER will be selected for continued evaluation in stage 2 based on the totality of efficacy, safety, pharmacokinetic (PK) and pharmacodynamic data, and additionally supported by a benefit–risk score. In stage 2, patients will be randomized 1:1 to receive IberDd or DVd. The IberDd treatment arm will consist of 28-day cycles, and the DVd treatment arm will consist of 21-day cycles (Cycles 1–8) or 28-day cycles (Cycle 9 onward). The dose schedule by treatment arm is shown in Table 1.

Table 1.

Dose schedule by treatment arm.

Treatment Arm A: IberDd Treatment Arm B: DVd
IBER (oral): 1.0 mg (A1)/1.3 mg (A2)/1.6 mg (A3) on D1 − 21 DARA (SC): 1800 mg C1 − 3 on D1, 8, and 15; C ≥ 4 on D1
DARA (SC): 1800 mg C1 − 2 on D1, 8, 15, and 22; C3 − 6 on D1 and 15; C ≥ 7 on D1 BORT (SC): 1.3 mg/m2 C1 − 8 on D1, 4, 8, and 11
DEX (oral): 40 mg on D1, 8, 15, and 22a DEX (oral): 20 mg C1 − 8 on D1, 2, 4, 5, 8, 9, 11, and 12b
28-day cycles 21-day cycles (C1–8)
28-day cycles (C ≥ 9)
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aTreatment arm A: for patients who are aged <75 years, are underweight (BMI <18.5 kg/m2), have poorly controlled diabetes, or have prior intolerance/AE to steroid therapy, DEX may be administered at a dose of 20 mg weekly on D1, 8, 15, and 22; bTreatment arm B: for patients who are aged >75 years, are underweight (BMI <18.5 kg/m2), have poorly controlled diabetes, or have prior intolerance/AE to steroid therapy, DEX may be administered at a dose of 10 mg on D1, 2, 4, 5, 8, 9, 11, and 12.

AE: adverse event; BMI: body mass index; C: Cycle; D: Day; DARA: daratumumab; DEX: dexamethasone; DVd: daratumumab + bortezomib + dexamethasone; IBER: iberdomide; IberDd: iberdomide + daratumumab + dexamethasone; SC: subcutaneous.

Patients will be randomized using an Interactive Response Technology and stratified by number of prior lines (1 vs 2), age (≤70 vs >70 years), and International Staging System at study entry (I or II vs III).

2. Methods

2.1. Participants, procedure, and intervention

In stages 1 and 2 of the study, ≥200 and approximately 664 patients, respectively, will be randomized; approximately 764 patients are required for primary efficacy analysis. The target sample size of this study was determined through comprehensive analysis to ensure a clinically meaningful assessment of IBER anti-myeloma activity and safety at each dose level, as well as PK and pharmacodynamic data in stage 1, and power the test of primary efficacy endpoint in stage 2.

Patients with RRMM who have received 1 or 2 prior lines of anti-myeloma therapy will be enrolled. Patients refractory to CD38-directed therapy or to BORT are excluded. Patients with prior CD38-directed antibody therapy are excluded in stage 1; in stage 2, approximately 10% of these patients may be enrolled in each arm. Table 2 summarizes key inclusion and exclusion criteria.

Table 2.

Key eligibility criteria.

Inclusion criteria Exclusion criteria

  • Age ≥18 years

  • ECOG PS 0–2

  • Measurable disease

  • 1 or 2 prior lines of therapy

  • ≥PR achieved with ≥1 prior therapy

  • PD during or after last regimen

  • Prior therapy with IBER

  • Plasma cell leukemia, Waldenström’s macroglobulinemia, or POEMS syndrome

  • Peripheral neuropathy Grade 2 (with pain), 3, or 4

  • Stage 1: prior treatment with CD38-directed therapy; stage 2: prior treatment with CD38-directed therapy with best response <PR, PD <60 days from last dose, discontinuation of therapy due to AE, and last dose of DARA <3 months before joining the study

  • Prior treatment with BORT with best response <MR, PD <60 days from last dose
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AE: adverse event; BORT: bortezomib; DARA: daratumumab; ECOG PS: Eastern Cooperative Oncology Group performance status; IBER: iberdomide; MR: minimal response; PD: progressive disease; POEMS: polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes; PR: partial response.

The study comprises screening, treatment, and follow-up periods. The screening period may not exceed a 28-day window prior to randomization, and the treatment period begins after randomization and continues until discontinuation of all study treatment. Treatment will continue until confirmed progressive disease (PD), unacceptable toxicity, or withdrawal of consent. All patients will have an end of treatment visit to collect safety and efficacy assessments. The follow-up period consists of the 28-day follow-up visit to collect safety assessments. A progression-free survival (PFS) follow-up phase is applicable for patients who discontinue study treatment permanently for any reason other than confirmed PD, death, or withdrawal of consent. During this time, patients will be monitored every 28 days for response assessment until PD, at which time a PFS discontinuation visit will be performed. No other anti-myeloma therapy may be started during the PFS follow-up phase prior to PD. All patients will be followed in the long-term follow-up for survival status, subsequent anti-myeloma therapy, and second primary malignancy every 4 months for ≥5 years from the date of last patient randomized in the study. European Quality of Life 5 dimensions 5 levels (EQ-5D-5 L) assessments will be conducted every 4 months for 1 year in the long-term follow-up.

In stage 1, an Independent Data Monitoring Committee (IDMC) will recommend the optimal IBER dose in combination with DARA and DEX that will be further evaluated in stage 2. An Executive Oversight Committee comprised of sponsor representatives will liaise with the IDMC to determine the optimal IBER dose selection. The sponsor representatives will not be involved in trial conduct or management. The study team will remain blinded to the aggregate study results by dose level. An independent statistician external to the sponsor will provide data to the IDMC throughout the study. In addition, an independent internal unblinded team may provide data to the IDMC in stage 1 for dose selection, if applicable. In stage 2, alongside the regular review of cumulative safety data, the IDMC will also review the prespecified interim results of the study and recommend that the study be continued, modified, stopped for superiority, or stopped for futility.

Dose selection will occur in interim analysis 1, when approximately 50 patients in each arm have been treated for ≥3 cycles or discontinued earlier from treatment, and be based on the totality of efficacy, safety, and PK and pharmacodynamic data. Pharmacodynamic analyses included IBER induction of T-/NK-cell proliferation and activation, decrease in absolute B cells, and decrease in serum-free light chains (sFLCs) over time by dose. Additionally, a benefit–risk score was adapted to aid in dose selection. The benefit–risk score is an average of the parameters listed below:

Proportion of patients:

  1. With ≥90% reduction in serum M-protein or sFLC

  2. With a decrease in absolute neutrophil count (ANC) to <1000 cells/µL

  3. With a decrease in platelet count to <50,000 cells/µL

  4. With Grade ≥3 or any serious infections (System Organ Class)

  5. Who discontinue study treatment permanently due to AEs

  6. With dose interruption due to AEs

  7. With dose reduction due to AEs

To quantify the anti-myeloma activity of each IBER dose-level arm, the reduction in M-protein and sFLC, which serve as markers of disease activity, will be assessed at each cycle by a central laboratory. For safety parameters, absolute neutrophil and platelet counts will be included to assess hematologic toxicities and will be monitored routinely in this study. Infections are common in MM and one of the leading causes of hospitalization and death. Other parameters indicative of overall tolerability included in the algorithm are the proportion of patients who discontinue therapy prematurely, interrupt treatment, or reduce the dose of IBER due to AEs.

Following IBER dose selection at interim analysis 1, sites and study personnel will be informed of the selected dose for stage 2. Patients enrolled in the treatment arms corresponding to doses not selected for stage 2 may switch to the selected dose of IBER based on pre-specified criteria and investigator assessment. If the selected dose of IBER is higher than the dose the patient is receiving, then a dose switch will be allowed only if the patient did not have any dose reduction of IBER, the patient did not experience any Grade ≥3 AEs considered related to IBER within the previous three cycles; and ANC is ≥1000 cells/µL. If the IBER dose is changed to the selected dose, the dose change should occur on Day 1 of the next cycle. If the selected dose of IBER for stage 2 is lower than the dose the patient is receiving, patients may elect to remain on their current dose, unless otherwise specified by the IDMC. Stage 1 patients enrolled initially in the selected IBER dose level arm or in the DVd arm will contribute to the efficacy and safety analyses of stage 2 of the study.

In stage 1, to determine the dose of IBER in combination with DARA + DEX, patients will be treated with 1, 1.3, or 1.6 mg oral IBER (Treatment Arm A1, A2, or A3, respectively) once daily on Days 1–21 of a 28-day cycle in combination with DARA + DEX. In stage 2, IBER will be administered at the selected dose level once daily on Days 1–21 of a 28-day cycle, in combination with DARA + DEX (Treatment Arm A). A co-formulation of DARA 1800 mg and 30,000 units recombinant human hyaluronidase (rHuPH20) will be administered subcutaneously on Days 1, 8, 15, and 22 of a 28-day cycle (Cycles 1 and 2); Days 1 and 15 of a 28-day cycle (Cycles 3–6); and Day 1 of a 28-day cycle (Cycle 7 onward). DEX 40 mg (total dose) will be given orally on Days 1, 8, 15, and 22. Among older patients (aged >75 years), those who are underweight (body mass index [BMI] <18.5), have insufficiently regulated diabetes, or have experienced intolerance to/AEs following steroid treatment, DEX 20 mg may be given orally on Days 1, 8, 15, and 22. DEX may also be administered intravenously.

In Treatment Arm B, patients will be treated with DVd. A co-formulation of DARA 1800 mg and 30,000 units rHuPH20 will be administered subcutaneously on Days 1, 8, and 15 of a 21-day cycle (Cycles 1–3); Day 1 of a 21-day cycle (Cycles 4–8); and Day 1 of a 28-day cycle (Cycles 9 onward). BORT at a starting dose of 1.3 mg/m2 will be administered subcutaneously on Days 1, 4, 8, and 11 of a 21-day cycle (Cycles 1–8; doses should be ≥72 h apart). Oral DEX will be administered at a starting dose of 20 mg on Days 1, 2, 4, 5, 8, 9, 11, and 12 of a 21-day cycle (Cycles 1–8). Among older patients (aged >75 years), those who are underweight (BMI <18.5), have insufficiently regulated diabetes, or have experienced intolerance to/AEs following steroid therapy, DEX 10 mg may be given orally on Days 1, 2, 4, 5, 8, 9, 11, and 12. DEX may also be administered intravenously.

For all treatment arms, on DARA administration days, DEX will be utilized as the treatment dose of steroid for that day, as well as the required pre/post medication for DARA administration. If necessary, due to timing constraints, all oral pre-injection medications may be administered outside of the clinic on the day of the injection, provided they are taken within 1–3 h (within 24 h for montelukast) before the injection (Table 1).

Neutropenia has been the most frequently reported AE with IBER and specific guidance for the management of neutropenia is provided in the study. If Grade 4 neutropenia (defined as ANC <500 cells/μL) or Grade 3 febrile neutropenia (defined as ANC <1000 cells/μL with a single temperature >38.3°C [101°F] or with a sustained temperature ≥38°C [100.4°F] for >1 h), IBER treatment should be interrupted, and the complete blood counts should be followed at least weekly. If the patient was not receiving granulocyte colony-stimulating factor (G-CSF), G-CSF therapy should be initiated. The dose of IBER may be maintained if neutropenia was the only IBER-related toxicity requiring a dose modification and G-CSF treatments are continued. ANC must return to ≥1000 cells/μL to resume dosing. If a dose reduction is appropriate, IBER is interrupted for the remainder of the cycle and the reduced dose given on Day 1 of the next cycle. For DARA, individual dose modifications are not permitted. However, delaying the dose is recommended as the main approach to manage toxicities related to DARA, which include febrile neutropenia (any grade) and neutropenia with clinically significant infection (any grade). The DARA dose can be paused and restarted when toxicities have returned to Grade ≤2 or baseline. Aside from on Day 1 of a cycle, if DARA is not restarted within a pre-specified period of the scheduled administration date, the dose will be deemed a missed dose; administration is permitted to restart at the next scheduled dosing date, and a missed dose will not be compensated for.

2.2. Endpoints & outcomes

The dual primary endpoints of the EXCALIBER-RRMM trial will compare the efficacy of IberDd with DVd in patients with RRMM in terms of minimal residual disease (MRD) negativity at any time in patients achieving CR or better, and PFS. The key secondary endpoint is overall survival (OS), and additional secondary endpoints include determination of the dose of IberDd to continue in stage 2 of the study, and PK. Cancer-related symptoms and quality of life will also be evaluated using the European Organization for Research and Treatment of Cancer – Quality of Life C30 (EORTC QLQ-C30) questionnaire and the European Quality of Life Multiple Myeloma Module (EORTC QLQ-MY20). The primary and secondary endpoints are outlined in Table 3.

Table 3.

Study endpoints.

Dual primary endpoint

  • PFS: time from randomization to PD or death, whichever occurs first

  • MRD-negative CR at any time

Key secondary and exploratory endpoints

  • Determination of recommended IBER dose in combination with DARA + DEX (stage 1 only)

  • OS

  • ORR

  • Duration of response

  • Time to progression

  • Time to response

  • PK analyses

  • Time to next treatment

  • PFS2

  • Sustained MRD-negativity rate

  • Safety

  • Health-related quality of life

  • Biomarker analyses (exploratory)
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CR: complete response; DARA: daratumumab; DEX: dexamethasone; IBER: iberdomide; MRD: minimal residual disease; ORR: overall response rate; OS: overall survival; PD: progressive disease; PFS: progression-free survival; PFS2: time from randomization to progression on first subsequent therapy; PK: pharmacokinetic.

PFS has been used widely to assess clinical efficacy in MM pivotal studies and is, therefore, one of the primary endpoints in this trial. In addition, in April 2024, the Oncologic Drugs Advisory Committee voted unanimously in favor of MRD as an intermediate endpoint in MM clinical trials [25,26]. MRD-negative CR is recognized increasingly as a critical marker in assessing the efficacy of treatments in MM. MRD-negative status is a key early indicator of clinical benefit and improved outcomes in MM, and studies show that MRD negativity correlates with prolonged PFS and OS regardless of disease setting (newly diagnosed MM or RRMM) [27,28]. The strong prognostic value of MRD-negative CR justifies its use as an appropriate intermediate endpoint likely to predict clinical benefit in MM. EXCALIBER-RRMM is among the first randomized, phase III studies to evaluate MRD-negative CR as a dual primary endpoint alongside PFS, providing evaluation of both early- and long-term efficacy in MM. Here, MRD negativity is assessed by a 2-tube, 8-color next-generation flow cytometry assay at a threshold of 10−5 based on EuroFlow markers that has been globally validated for implementation in this trial [29,30].

Additionally, exploratory analysis of gene and protein expression of relevant biomarkers will be performed to investigate any potential correlation to clinical outcomes and association with development of resistance to IBER-containing regimens. This includes expression of CRBN (and other potential biomarkers, such as Ikaros, Aiolos, and CD38), mutations in the CRBN gene and other immune biomarkers, and their utility for determining response to treatment with IBER in combination with DARA.

2.3. Statistical analysis

All efficacy analyses will be performed based on the intent-to-treat (ITT) population (all randomized patients), except efficacy analyses related to MRD negativity, which will be done in a subset of the ITT population based on the sample size planned for MRD-negative CR analysis.

For the dual primary endpoints of MRD-negative CR at any time and PFS, the MRD-negative CR is defined at a sensitivity of a minimum of 1 in 105 nucleated cells by next-generation flow cytometry in bone marrow aspirate for patients who achieve ≥CR. The PFS is calculated as the time from randomization to the first documented progression or death due to any cause, whichever occurs first. Clinical responses to study treatment and PD will be independently evaluated by an Independent Review Committee. Response assessments will be based on the International Myeloma Working Group Uniform Response Criteria for Multiple Myeloma 2016 [31]. The Kaplan–Meier method will be used to estimate the distribution of overall PFS for each treatment. Treatment comparison of the overall distribution of PFS will be based on a stratified log-rank test. Hazard ratio and its 95% CI will be estimated based on a stratified Cox’s regression model with treatment as the only explanatory variable. Comparisons of MRD-negative CR between treatment arms at any time will be performed using the stratified Miettinen–Nurminen test by adjusting for the stratification fact.

Safety analysis will be performed based on the safety population (all patients who received ≥1 dose of study treatment). AEs will be summarized using the Medical Dictionary for Regulatory Activities classification system. The severity of the toxicities will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.

In stage 1, 1 interim analysis will select the IBER dose in combination with DARA and DEX. In stage 2, one MRD-negative CR final analysis, two interim analyses for PFS, and four interim analyses for OS are planned. The MRD-negative CR analysis is planned when ≥420 patients are randomized and followed for ≥12 months or discontinued early. During this analysis, a non-binding futility analysis of PFS will be performed. The interim analysis for PFS superiority will be performed when approximately 344 (75%) events have accumulated. A final analysis for PFS will occur after approximately 458 events have been observed. For OS, the interim analyses will be performed at the MRD analysis time (futility analysis), 75% PFS event analysis time (futility analysis), PFS final analysis time (futility and superiority analysis), and 75% OS events time (futility and superiority analysis). Final OS analysis will occur when 507 deaths have been observed.

The study family-wise type I error rate will be controlled by multiplicity adjustment. There will be no statistical testing in stage 1, and thus no type I error rate adjustment will be applied for stage 1. In stage 2, the fallback procedure will be used to control the overall type I error for dual primary endpoints. The initial alpha allocation of testing MRD-negative CR at any time and PFS will be 0.005 (1-sided) and 0.02 (1-sided), respectively. With the projection that MRD-negative CR at any time will be tested first then followed by PFS testing, if the MRD test demonstrates superiority of the IberDd arm over the DVd arm, PFS will be tested using 0.025 (one-sided) alpha level overall. Alpha spending between PFS futility/superiority interim analysis and final analysis will follow O’Brian–Fleming alpha spending function by the Lan–DeMets method. If the testing of the primary endpoint of PFS is statistically significant at interim analysis 3 (PFS superiority analysis) or interim analysis 4 (PFS final analysis), the key secondary efficacy endpoint of OS will then be tested at the same overall alpha level used for PFS testing. The family-wise type I error rate will be controlled by the stepdown approach from PFS to OS comparison. Additionally, in stage 2, to control for potential type I error inflation for dose selection in stage 1, the rank-based Dunnett’s p value adjustment method will also be applied [32].

The study can be claimed successful if ≥1 primary endpoint is statistically significant after multiplicity adjustment.

3. Conclusion

MM, particularly RRMM, remains a challenging disease with limited treatment options for achieving deep and durable responses. Despite treatment advancements, new therapeutic strategies are crucial to extend remission and improve patient outcomes, including quality of life. IBER, an oral CELMoD agent, with greater tumoricidal and immunomodulatory effects than IMiD agents, was well tolerated and demonstrated promising preliminary efficacy in a phase I/II trial in patients with heavily pretreated RRMM, including patients refractory to IMiD agents, DARA, and proteasome inhibitors. EXCALIBER-RRMM is a unique, inferentially seamless, 2-stage, confirmatory, phase III study supporting dose optimization of IberDd and comparing the efficacy and safety of IberDd with DVd in patients with RRMM who had received one or two prior lines of therapy. Enrollment began in June 2022 and is ongoing. The clinical implications of this study are significant, as the need for convenient, accessible, and safe drugs remains critical for MM, especially with the advantage of an orally bioavailable agent that facilitates a successful translational process into real-world practice [33,34]. IBER represents a highly attractive agent for use as a backbone in combination therapies for MM. As such, the outcomes of EXCALIBER-RRMM may establish IberDd as a transformative treatment in early-line RRMM and potentially broaden its role in combination regimens across the disease spectrum.

Funding Statement

This manuscript was funded by Bristol Myers Squibb. The EXCALIBER-RRMM trial was funded by Bristol Myers Squibb, which was involved in the decision to publish and the preparation of the manuscript.

Article highlights

  • Background

    • Iberdomide in combination with daratumumab and dexamethasone demonstrated promising preliminary efficacy and was well tolerated in a phase I/II trial, showing potential as a treatment in heavily pretreated patients with relapsed/refractory multiple myeloma (RRMM)

  • Trial design

    • EXCALIBER-RRMM is a confirmatory phase III study that incorporates a 2-stage seamless design to firstly find the optimal dose of iberdomide in combination with daratumumab and dexamethasone (IberDd) and then to compare the efficacy and safety of IberDd with daratumumab, bortezomib, and dexamethasone (DVd) in patients with early-line (1 or 2 prior lines of therapy) RRMM

    • The dual primary endpoints of the EXCALIBER-RRMM trial will compare the efficacy of IberDd with DVd in patients with RRMM in terms of progression-free survival and minimal residual disease negativity at any time in patients achieving a complete response or better

    • The key secondary endpoint is overall survival, and additional secondary endpoints include determination of the dose of IberDd to continue in stage 2 of the study, and pharmacokinetics

  • Conclusions

    • If results are positive, EXCALIBER-RRMM may establish IberDd as a key treatment in early-line RRMM and potentially broaden its role in combination regimens for multiple myeloma

Author contributions

Sagar Lonial: Conceptualization, Resources, Writing – review & editing. Meletios A. Dimopoulos: Conceptualization, Resources, Writing – review & editing. Jesus G. Berdeja: Conceptualization, Resources, Writing – review & editing. Paul G. Richardson: Conceptualization, Resources, Writing – review & editing. Hang Quach: Conceptualization, Resources, Writing – review & editing. Paula Rodríguez-Otero: Conceptualization, Resources, Writing – review & editing. Paulo Maciag: Conceptualization, Methodology, Writing – review & editing. Kevin Hong: Conceptualization, Methodology, Writing – review & editing. Michael Amatangelo: Conceptualization, Methodology, Writing – review & editing. Min Chen: Conceptualization, Methodology, Writing – review & editing. Niels W.C.J. van de Donk: Conceptualization, Resources, Writing – review & editing.

Disclosure 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.

Ethical considerations

The study will be conducted in accordance with the International Council for Harmonisation guidelines on Good Clinical Practice and the general principles outlined in the Declaration of Helsinki. The study will receive approval from an Institutional Review Board/Ethics Committee prior to commencement. The Investigator will conduct all aspects of this study in accordance with applicable national, state, and local laws of the pertinent regulatory authorities. All patients will provide written informed consent.

Data sharing statement

Data sharing is not applicable to this article as no new data were created or analyzed in this study.

References

Papers of special note have been highlighted as either of interest (•) or of considerable interest (••) to readers.

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