Highlights
Clinically Meaningful Efficacy
The ICON study demonstrated a median progression-free survival (PFS) of 17.6 months in patients with relapsed and refractory multiple myeloma (RRMM) who were refractory to lenalidomide, a significant outcome for this difficult-to-treat population.
All-Oral Regimen
The combination of iberdomide, low-dose cyclophosphamide, and dexamethasone (IberCd) provides a potent, entirely oral treatment option, reducing the treatment burden associated with parenteral therapies.
Manageable Safety Profile
While neutropenia and infections were common, the safety profile was consistent with the known effects of cereblon-modifying agents, and treatment-related deaths were rare.
Introduction: The Evolving Landscape of Multiple Myeloma Therapy
The treatment landscape for multiple myeloma has undergone a paradigm shift over the last decade with the introduction of proteasome inhibitors, monoclonal antibodies, and immunomodulatory drugs (IMiDs). However, the majority of patients eventually experience disease progression and become refractory to standard-of-care agents, particularly lenalidomide. For patients who have exhausted three or more lines of therapy—frequently referred to as triple-class exposed or refractory—the need for novel agents with distinct mechanisms of action is urgent.
Iberdomide represents a next-generation approach. As a cereblon E3 ligase modulator (CELMoD), it is designed to bind to cereblon with significantly higher affinity than older IMiDs like lenalidomide or pomalidomide. This higher affinity translates into more efficient degradation of target transcription factors Ikaros (IKZF1) and Aiolos (IKZF3), leading to enhanced tumor cell apoptosis and more robust immunostimulatory effects. The ICON study was designed to evaluate whether combining iberdomide with low-dose cyclophosphamide and dexamethasone could provide a synergistic and convenient solution for these patients.
The ICON Study: Trial Design and Methodology
The ICON study was a prospective, multicentre, single-arm, phase 2, open-label trial conducted at eight specialized hospitals in the Netherlands. The study targeted a specific and clinically relevant niche: patients (aged 18 or older) with RRMM who were specifically refractory to lenalidomide and had received between two and four prior lines of systemic therapy.
Patient Population
A total of 61 patients were enrolled between February 2021 and July 2023. The cohort was heavily pretreated, with a median of three prior lines of therapy. Notably, 85% of patients were triple-class exposed (to IMiDs, proteasome inhibitors, and anti-CD38 monoclonal antibodies), and 44% were triple-class refractory, representing a high-risk population with limited remaining options.
Treatment Protocol
Patients received a 28-day cycle of the IberCd regimen:
– Iberdomide: 1.6 mg orally once daily on days 1–21.
– Cyclophosphamide: 50 mg orally once daily on days 1–28 (continuous low-dose).
– Dexamethasone: 40 mg orally once weekly (reduced to 20 mg for patients over 75).
– Thrombosis Prophylaxis: Standard aspirin or carbasalate calcium, with low-molecular-weight heparin reserved for those with a prior history of VTE.
The primary endpoint was progression-free survival (PFS), defined as the time from treatment initiation to disease progression or death from any cause.
Key Findings: A New Benchmark for Oral Therapy
The results of the ICON study, after a median follow-up of 25.4 months, suggest that the IberCd combination is remarkably active in the post-lenalidomide setting.
Efficacy and Progression-Free Survival
The median PFS was 17.6 months (one-sided 95% CI 16.6–19.9). This result is particularly striking when compared to historical benchmarks for other regimens in similar populations. For instance, pomalidomide-based triplets in the RRMM setting typically yield a median PFS in the range of 4 to 11 months. The 17.6-month figure highlights the potency of iberdomide when combined with low-dose cyclophosphamide, which likely acts as a sensitizing agent by altering the tumor microenvironment and providing a separate pathway of cytotoxicity.
Response and Disposition
While 39 of the 61 patients eventually discontinued treatment due to progressive disease, the duration of response was sustained for many. All 61 patients were included in the primary analysis, ensuring a rigorous intent-to-treat evaluation of the regimen’s utility.
Safety and Tolerability Profile
As with most intensive myeloma therapies, hematologic toxicity and infection risk were the primary safety concerns. The safety analysis for the 61 patients revealed the following:
Adverse Events (AEs)
– Neutropenia: The most common grade 3–4 adverse event, occurring in 56% of patients. This is expected given the myelosuppressive nature of both CELMoDs and cyclophosphamide.
– Infections: Grade 3–4 infections occurred in 34% of patients. This remains a significant concern in the RRMM population, particularly as these patients are often functionally immunosuppressed.
– Serious Adverse Events (SAEs): Treatment-related SAEs were reported in 41% of patients, with infections accounting for 71% of these serious events.
– Mortality: One treatment-related death (2%) occurred due to COVID-19, emphasizing the continued vulnerability of this patient group to respiratory pathogens.
Despite these events, the all-oral nature of the therapy allowed for home-based administration, which is a significant quality-of-life benefit compared to regimens requiring frequent clinic visits for infusions.
Expert Commentary: Mechanistic Synergies and Clinical Context
The ICON study’s results underscore the potential of iberdomide to overcome resistance to earlier generations of IMiDs. Mechanistically, iberdomide’s ability to achieve deeper degradation of Ikaros and Aiolos allows it to remain effective even when the cereblon levels in myeloma cells are relatively low, a common mechanism of lenalidomide resistance.
Experts note that the addition of low-dose cyclophosphamide is a strategic choice. Cyclophosphamide at low doses has known immunomodulatory properties, including the depletion of regulatory T cells, which may complement the T-cell and NK-cell activation induced by iberdomide. This “chemo-immunotherapy” approach appears to be more than the sum of its parts.
However, limitations must be acknowledged. This was a single-arm study, making direct comparisons to other regimens like carfilzomib-dexamethasone or newer bispecific antibodies difficult. Furthermore, the high rate of neutropenia suggests that clinical implementation will require proactive management, likely including the use of granulocyte colony-stimulating factors (G-CSF) and rigorous infection monitoring.
Conclusion and Future Directions
The IberCd regimen represents a highly active, all-oral combination for patients with RRMM who have failed lenalidomide and other prior lines of therapy. With a median PFS of 17.6 months, it offers a compelling alternative to more invasive treatments. As the field moves toward more complex therapies like CAR-T and bispecifics, the availability of a potent oral triplet remains essential for maintaining patient autonomy and managing disease in a sustainable, long-term fashion.
Future research will likely focus on moving iberdomide into earlier lines of therapy and combining it with other agents, such as daratumumab or bortezomib, to further improve outcomes in the frontline and early relapse settings.
Funding and ClinicalTrials.gov
This study was funded by Bristol Myers Squibb. The trial is registered at ClinicalTrials.gov under the identifier NCT04392037.
References
1. Korst CLBM, Plattel W, de Kort EA, et al. Iberdomide plus low-dose cyclophosphamide and dexamethasone in patients with relapsed and refractory multiple myeloma (the ICON study): a multicentre, single-arm, phase 2 trial. Lancet Haematol. 2026;13(1):e30-e40. doi:10.1016/S2352-3026(25)00298-4.
2. Lonial S, Popat R, Hulin C, et al. Iberdomide plus dexamethasone in patients with relapsed or refractory multiple myeloma: a multicentre, open-label, 1/2 trial. Lancet Haematol. 2022;9(11):e822-e832.
3. Richardson PG, Perrot A, San-Miguel J, et al. Iberdomide in combination with dexamethasone and daratumumab, bortezomib, or carfilzomib in patients with relapsed or refractory multiple myeloma. Blood. 2020;136(Supplement 1):14-15.
