Нацеливание на Икароса и Айолоса: следующие циклоны Цереблона Е3 Ligase Modulars в MM.

Introduction

Multiple myeloma (MM) is a clonal malignancy of plasma cells that accumulates in the bone marrow, leading to progressive immune dysfunction, end‐organ damage, and a complex interplay between the malignant clone and its microenvironment. It accounts for ~1% of all cancers and nearly 10% of hematologic malignancies, with a median age at diagnosis of around 70 years [ 1 ].

Although major therapeutic advances over recent decades have substantially improved survival, MM remains characterized by repeated cycles of remission and relapse. Its clinical course is intrinsically heterogeneous, driven by genetic lesions, epigenetic reprogramming, and microenvironmental interactions that shape disease behaviour and treatment response [ 2 ].

MM typically arises from an asymptomatic premalignant stage known as monoclonal gammopathy of undetermined significance (MGUS), which progresses into smouldering multiple myeloma and eventually symptomatic MM. Each transition corresponds to increased genomic complexity and profound remodelling in the bone marrow niche [ 3 ].

Malignant plasma cells promote immune escape by impairing T‐cell activation, downregulating antigen presentation pathways, expanding regulatory T cells (Tregs), recruiting myeloid‐derived suppressor cells (MDSCs), and reshaping macrophage polarization. These immunosuppressive mechanisms are central to both disease persistence and treatment resistance [ 4 ].

MM disproportionately affects older adults, with a median age at diagnosis of ~69–70 years. Age‐related comorbidities and immune decline frequently complicate therapeutic decisions and limit tolerance to intensive regimens. Despite markedly improved outcomes in younger and fitter patients, the disease remains essentially incurable, and cumulative treatment burden, frailty, and immune dysfunction significantly contribute to morbidity and mortality [ 5 , 6 , 7 ].

Historically, treatment relied on cytotoxic chemotherapy; however, current paradigms integrate proteasome inhibitors, IMiDs, CD38‐ and SLAMF7‐directed monoclonal antibodies, steroids, and, more recently, XPO‐1 inhibitors, conjugate antibodies, immune effector cell therapies such as CAR‐T cells and bispecific T‐cell engagers. IMiDs—thalidomide, lenalidomide, and pomalidomide—have been particularly transformative, providing durable responses through immune activation and microenvironment modulation [ 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ]. A frontline therapy increasingly incorporates lenalidomide‐based quadruplets and extended maintenance strategies; IMiD resistance has emerged as an early and more prominent clinical challenge. Many patients who fail lenalidomide first relapse rapidly develop triple‐class refractoriness, often within only a few treatment lines [ 19 ]. This therapeutic bottleneck underscores the need for agents capable of restoring cereblon‐dependent degradation pathways and reactivating downstream immune and transcriptional networks [ 20 , 21 , 22 , 23 ].

CELMoDs such as iberdomide and mezigdomide were developed to overcome these limitations. Engineered to bind cereblon with higher affinity, they promote more efficient degradation of IKZF1 (Ikaros) and IKZF3 (Aiolos), resulting in greater suppression of IRF4 and c‐MYC—central transcriptional regulators aberrantly co‐opted in MM to sustain malignant plasma cell survival. Unlike their tumor‐suppressive role in other hematologic contexts, IKZF1 and IKZF3 are highly expressed and functionally required in myeloma cells, where they maintain oncogenic transcriptional programs centered on the IRF4–c‐MYC axis. IRF4 and c‐MYC form a tightly interconnected, self‐reinforcing regulatory loop that drives proliferation, metabolic fitness, bone marrow retention, and resistance to apoptosis. Through enhanced cereblon engagement, CELMoDs induce deeper and more sustained depletion of Ikaros and Aiolos, leading to marked downregulation of IRF4 and c‐MYC, collapse of pro‐survival transcriptional programs, and induction of myeloma cell apoptosis. Concurrently, IKZF degradation reshapes the tumor–immune interface by enhancing interferon signaling, increasing susceptibility to immune effector mechanisms, and amplifying T‐ and NK‐cell–mediated antitumor activity [ 24 ]. Therefore, beyond direct cytotoxicity, CELMoDs enhance immune activation, boost T‐cell effector function, and strengthen NK‐cell–mediated antibody‐dependent cellular cytotoxicity (ADCC), making them particularly well‐suited partners for monoclonal antibodies, bispecific immunotherapies, and post–CAR‐T strategies (Figure 1 ) [ 25 ].

CELMoDs: Mechanism of Action and Pharmacology

The central mechanism of action of both IMiDs and CELMoDs is based on modulation of cereblon (CRBN), the substrate receptor within the CUL4‐RBX1‐DDB1 E3 ubiquitin ligase complex. Thalidomide analogues function as “molecular glue degraders,” creating new protein–protein interfaces that enable the recruitment of transcription factor neosubstrates. The discovery that IKZF1 (Ikaros) and IKZF3 (Aiolos) are primary cereblon‐dependent degradation targets of IMiDs fundamentally transformed the understanding of their antimyeloma activity [ 26 ].

CELMoDs were engineered to enhance ligand‐CRBN interactions through several structural innovations. While lenalidomide and pomalidomide bind CRBN primarily through a glutarimide ring, iberdomide and mezigdomide incorporate additional chemical extensions that enlarge the interaction surfaces and engage residues beyond the classical tri‐tryptophan pocket. These modifications promote a more stable CRBN–ligand conformation and induce an allosteric shift toward a fully closed, active CRBN state, optimizing the interface required for neosubstrate recruitment and ubiquitination [ 27 ].

This improved CRBN engagement achieved by CELMoDs results in significantly deeper and faster degradation of IKZF1 and IKZF3. These transcription factors regulate the expression of IRF4 and MYC, which together sustain proliferation, inhibit apoptosis, and maintain plasma cell differentiation. Degradation of IKZF1/3 dismantles oncogenic enhancer networks and disrupts the IRF4–MYC feedback loop, leading to transcriptional collapse and potent induction of apoptosis in malignant plasma cells [ 28 ].

The immunomodulatory properties of CELMoDs arise from the same molecular mechanism. IKZF1 and IKZF3 degradation reprograms T‐ and NK‐cell function, increases IL‐2 production, enhances T‐cell proliferation, and boosts cytotoxic effector responses. Iberdomide and mezigdomide induce more pronounced immune activation than lenalidomide or pomalidomide, supporting strong synergy with monoclonal antibodies, bispecific T‐cell engagers, and other immunotherapies (Figure 2 ) [ 29 ].

The potency of mezigdomide is particularly noteworthy. Its optimized structural design confers even higher affinity for cereblon than iberdomide, enabling more profound and consistent depletion of IKZF1/3. This depth of neosubstrate degradation explains Mezigdomide's efficacy in heavily pretreated, multidrug‐refractory MM, where traditional IMiDs and other agents have limited activity [ 30 ].

Preclinical Evidence

Preclinical investigations provide a strong foundation supporting clinical development of iberdomide and mezigdomide. Iberdomide has demonstrated potent and consistent depletion of IKZF1 and IKZF3 in both IMiD‐sensitive and IMiD‐resistant MM cell lines. Its ability to degrade these transcription factors at lower concentrations and with more rapid kinetics than lenalidomide or pomalidomide leads to more pronounced downregulation of IRF4 and MYC, thereby decreasing cell viability [ 31 ].

Mezigdomide builds on these observations, showing even stronger activity, including in models with markedly reduced CRBN expression or impaired cereblon signaling. Through optimized structural design, it achieves high‐affinity CRBN binding and efficient neosubstrate recruitment despite resistance mechanisms that diminish IMiD efficacy. This enhanced potency correlates with rapid induction of apoptosis, pronounced cell cycle arrest, and broad suppression of transcriptional programs essential for MM cell survival [ 32 ].

Both CELMoDs exhibit synergy with standard myeloma agents. Iberdomide enhances the cytotoxicity of bortezomib and provides additive immunologic stimulation when combined with daratumumab. Preclinical studies indicate that CELMoDs improve NK‐cell activation and thereby enhance daratumumab‐mediated ADCC. The combination with carfilzomib also produces cooperative antimyeloma activity.

Emerging data highlight important interactions with T‐cell–redirecting therapies. CELMoDs increase T‐cell proliferation and cytokine production, suggesting a capacity to enhance responses to bispecific antibody. Ex vivo studies further reveal that iberdomide and mezigdomide can improve CAR‐T cell expansion during manufacturing and may support persistence after infusion. These findings have encouraged exploratory strategies integrating CELMoDs before or after CAR‐T therapy [ 33 ].

In vivo mouse models confirm that CELMoDs reduce tumour burden, prolong survival, and modulate the bone marrow microenvironment in ways that favour immune‐mediated clearance of malignant plasma cells [ 34 ].

Clinical Development of Iberdomide

Iberdomide entered clinical development in heavily pretreated RRMM populations through the phase I/II CC‐220‐MM‐001 ( NCT02773030 ) trial, a large multicenter study conducted across 42 institutions in Europe, Canada, and the United States. The phase I dose‐escalation cohort enrolled 90 patients, with a median age of 65 years and a median of five prior treatment lines.

In the phase I dose‐escalation cohort, 90 patients (median age 65 years, median five prior lines of therapy) received iberdomide in combination with dexamethasone. These patients represent a highly refractory population previously exposed to lenalidomide, pomalidomide, proteasome inhibitors, and CD38‐targeted monoclonal antibodies. In the dose‐escalation phase, iberdomide plus dexamethasone achieved an overall response rate of 32% at a median follow‐up of 5.8 months, including complete, very good partial, and partial responses. This early signal of efficacy was particularly relevant given the degree of refractoriness and the prior IMiD exposure. As expected from a potent cereblon E3 ligase modulator, hematologic toxicity was prominent: neutropenia occurred in nearly half of patients and reached grade > 3 or higher in 42%; while anemia, thrombocytopenia, and infections (~62%) were also frequent. Five deaths occurred during treatment, mostly due to progressive disease, underscoring the clinical frailty of this late‐line population.

The phase II expansion cohort confirmed these findings in an even more heavily pretreated group of 107 triple‐class refractory patients (median age 64; median six prior lines). At a median follow‐up of 7.7 months, the ORR was 26%, with responses observed across sCR, CR, VGPR, and PR categories. Hematologic toxicity remained the dominant adverse event; grade > 3 neutropenia occurred in 45% of patients. Infectious complications—including episodes of sepsis—continued to represent a clinically meaningful safety concern [ 21 , 35 ].

Beyond the doublet backbone, iberdomide has also been explored in several rationally designed triplet combinations. In the IberDd cohort—iberdomide, daratumumab, and dexamethasone—an overall response rate of 46% was achieved among 43 patients at a median follow‐up of 4.2 months. Neutropenia remained the most common severe toxicity, occurring in two‐thirds of patients, while anemia was also observed. The IberVd regimen (iberdomide, bortezomib, dexamethasone) produced a response rate of 56% in 25 patients at a median follow‐up of 4.86 months, with neutropenia and thrombocytopenia representing the most frequent grade III–IV adverse events. The IberKd cohort (iberdomide, carfilzomib, dexamethasone), although smaller ( N = 9), demonstrated a response rate of 50% at a median follow‐up of 5 months. Across all triplets, non‐hematologic grade > 3 toxicities were uncommon. Rash, fatigue, or gastrointestinal events were generally mild, suggesting that the enhanced immunomodulatory profile of iberdomide is not accompanied by disproportionate off‐target systemic toxicity [ 36 ].

Iberdomide is also being studied in the post‐transplant maintenance setting. The EMN26 phase II trial ( NCT04564703 ) is investigating iberdomide as maintenance therapy after autologous stem‐cell transplantation in newly diagnosed MM. Interim results analyses of the 1.3 mg and 1.0 mg cohorts show encouraging deepening of responses over successive cycles. Patients entering the study with high‐quality responses—predominantly VGPR or better—yet further conversion to stringent complete responses were documented. After six cycles, the 1.3 mg cohort achieved an overall response rate of 45%, with stringent complete responses rising to 51%; the 1.0 mg cohort showed similarly favorable results. Hematologic toxicity, particularly neutropenia, was dose‐dependent but manageable with standard supportive care. Early 6‐month progression‐free survival exceeded 94% in both cohorts, suggesting a potential role for iberdomide in consolidating deep responses after frontline therapy. A longer follow‐up will clarify durability and long‐term safety [ 37 ].

Table 1 summarizes the main characteristics of clinical studies on iberdomide in Multiple Myeloma.

Clinical Development of Mezigdomide

The development of mezigdomide has generated compelling evidence supporting the capacity of next‐generation cereblon E3 ligase modulators to induce meaningful responses even in profoundly refractory multiple myeloma. The pivotal first‐in‐human study, CC‐92480‐MM‐001 ( NCT03374085 ), evaluated mezigdomide in combination with dexamethasone in a relapsed/refractory population. The phase I component enrolled 77 patients with a median age of 65 years and extensive prior therapy exposure—median six previous lines (with 78%) having undergone autologous stem‐cell transplantation.

At a median follow‐up of 6.3 months, mezigdomide produced an overall response rate of 25%, a noteworthy outcome given the deep refractoriness of the cohort. The potency of mezigdomide was mirrored by an incidence of hematologic toxicity: neutropenia occurred in 81% of patients and reached grade > 3 severity in 71%, while febrile neutropenia appeared in nearly 10%. Anemia, thrombocytopenia, infectious complications, nausea, and fatigue were also frequent, reflecting the profound cereblon‐mediated IKZF1/IKZF3 degradation characteristic of this agent. Nevertheless, toxicity was considered manageable with dose adjustments and supportive care, and the recommended phase II dose was established as 1.0 mg once daily for 21 days of each 28‐day cycle.

The phase II expansion cohort included 101 patients (median age of 67 years), all with triple‐class refractory MM, and included a sizeable proportion previously treated with BCMA‐directed therapy (30%). Notably, 40% presented with plasmacytomas, underscoring the aggressive biology typical of late‐stage disease. At a median follow‐up of 7.5 months, the ORR reached 41%, including complete and stringent complete responses. Responses were observed in patients with plasmacytomas or prior BCMA‐targeted therapy, supporting the capacity of mezigdomide to overcome biological resistance and target difficult‐to‐eradicate clonal populations that frequently evade other therapeutic modalities.

As anticipated, grade III‐IV neutropenia (77%) remained the most prominent adverse event, with febrile neutropenia occurring in 15%. Most patients required G‐CSF support, but overall, the safety profile was considered acceptable for such a heavily pretreated cohort. The median progression‐free survival was 4.4 months, extending to 5.4 months in patients previously exposed to BCMA‐targeted agents, an encouraging signal in a population with very limited therapeutic alternatives [ 30 , 38 ].

Mezigdomide has also been assessed in combination regimens in the CC‐92480‐MM‐002 phase I/II study ( NCT03989414 ). The MeziDd cohort—mezigdomide, daratumumab, and dexamethasone—enrolled 56 patients (median age 67 years; median two prior lines). Although less heavily pretreated than those in the monotherapy study, the majority were refractory to both IMiDs and proteasome inhibitors. The ORR reached 75%, with stringent complete, complete, and deep partial responses. Hematologic toxicity remained common but manageable, with grade III–IV neutropenia in just over half of patients and low rates of febrile neutropenia. Infectious complications were present but occurred at lower frequencies than in monotherapy cohorts.

The MeziEd cohort (mezigdomide, elotuzumab, dexamethasone) enrolled 20 patients and achieved an ORR of 45%. Hematologic toxicities followed a similar pattern, with high‐grade neutropenia in 40% and manageable rates of febrile neutropenia and infection.

Collectively, these findings demonstrate that mezigdomide has significant clinical activity both as a doublet with dexamethasone in deeply refractory MM and in combination with monoclonal antibodies in less heavily pretreated settings. Importantly, its activity in individuals previously exposed to BCMA‐directed therapies represents a meaningful advance, given the growing prevalence of immunotherapy resistance. The primary limitation across studies remains the high incidence of severe neutropenia, emphasizing the need for optimized dosing strategies, proactive supportive care, and infection prophylaxis [ 39 ].

Table 2 summarizes the main characteristics of the studies on Mezigdomide in Multiple Myeloma.

CELMoDs Versus IMiDs

CELMoDs represent a structural evolution of IMiDs, specifically designed to overcome cereblon‐mediated resistance observed with lenalidomide and pomalidomide. The enhanced cereblon affinity of iberdomide and mezigdomide facilitates more efficient formation of the CRBN–CUL4A–RBX1–DDB1 complex in its active configuration. As a result, target substrate degradation is deeper and more sustained, resulting in more robust inhibition of IRF4 and MYC and more extensive immunologic activation [ 40 ].

These pharmacologic properties translate into clinically meaningful differences. Whereas lenalidomide and pomalidomide frequently lose efficacy in early relapses—post‐lenalidomide maintenance—CELMoDs retain activity despite prior IMiD exposure and refractoriness. This distinction is particularly relevant in the current therapeutic landscape, where patients commonly receive lenalidomide during induction, consolidation, and prolonged maintenance [ 41 ].

Regarding toxicity, CELMoDs and IMiDs share broadly similar profiles, with hematologic suppression being the predominant adverse effect. CELMoDs generally induce more pronounced neutropenia, reflecting their higher potency. Importantly, the increased incidence and severity of cytopenias associated with CELMoDs—particularly neutropenia—should be regarded as an on‐target consequence of their enhanced biological activity rather than an off‐target toxicity. Hematopoietic progenitor cells rely on tightly regulated transcriptional programs involving IKZF family members and related pathways. More potent and sustained cereblon‐mediated substrate degradation can therefore disrupt normal hematopoiesis, resulting in dose‐limiting cytopenias. This mechanistic linkage underscores the narrow therapeutic window of CELMoDs and highlights the need for careful dose optimization, intermittent scheduling, and proactive supportive care. Taken together, the superior efficacy and increased hematologic toxicity of CELMoDs represent two sides of the same biological coin, both driven by intensified cereblon engagement and amplified downstream effects [ 42 ].

Effective management of neutropenia is therefore essential to maintain treatment intensity while minimizing infectious complications. In clinical trials, neutropenia has been commonly managed through a combination of dose interruptions, dose reductions, and supportive care with granulocyte colony‐stimulating factor (G‐CSF), enabling most patients to resume therapy without permanent discontinuation. Reactive use of short‐acting G‐CSF is appropriate for the management of grade ≥ 3 neutropenia or febrile neutropenia, especially in heavily pretreated or clinically vulnerable patients [ 36 , 39 ].

Prophylactic strategies may be considered in selected settings, such as patients with baseline cytopenias, extensive prior therapy, or recurrent neutropenia during early treatment cycles. In this context, the use of pegylated G‐CSF (peg‐G‐CSF) may offer practical advantages by providing sustained neutrophil support with reduced injection frequency, particularly for patients treated with intermittent dosing schedules. Although prospective data directly comparing prophylactic and reactive growth factor strategies in CELMoD‐treated patients are limited, available clinical trial experience suggests that early and proactive hematologic support can reduce treatment interruptions and improve overall tolerability [ 43 ].

The broader immunologic effects of CELMoDs extend their utility beyond the antimyeloma effects observed with IMiDs alone. The capacity to potentiate ADCC, improve T‐cell activation, and enhance NK‐cell function positions CELMoDs as highly valuable partners for combination therapy with monoclonal antibodies and T‐cell–redirecting agents [ 44 ].

Compared with classical IMiDs, CELMoDs were rationally designed to overcome key mechanisms of resistance to lenalidomide and pomalidomide, most notably impaired cereblon (CRBN) function. Reduced CRBN expression or suboptimal assembly of the CRL4^CRBN E3 ubiquitin ligase complex can limit IMiD efficacy by preventing efficient ubiquitination and degradation of critical neosubstrates, including IKZF1 and IKZF3. Iberdomide and mezigdomide exhibit substantially higher CRBN‐binding affinity, resulting in more stable and productive E3 ligase complex formation and deeper, more sustained degradation of Ikaros and Aiolos, even in the context of partial CRBN deficiency. This enhanced target engagement leads to more pronounced suppression of the IRF4–MYC transcriptional axis, collapse of myeloma‐specific survival programs, and restoration of antitumor activity in IMiD‐refractory disease, while concurrently amplifying T‐ and NK‐cell–mediated immune effects [ 33 ].

Despite this increased potency, resistance to CELMoDs can still emerge. Similar to IMiDs, CRBN remains a central resistance mechanism, although more profound disruptions appear to be required to fully abrogate CELMoD activity. Additional resistance pathways likely include adaptive transcriptional reprogramming downstream of IKZF1/3 loss, activation of alternative survival signaling pathways that bypass IRF4–MYC dependence, and microenvironmental or immune escape mechanisms that attenuate immunomodulatory effects. Further elucidation of these processes will be essential for optimizing treatment sequencing, rational combination strategies, and patient selection as CELMoDs are increasingly integrated into clinical practice [ 44 ].

Table 3 summarizes key pharmacologic and clinical differences between CELMoDs and IMiDs.

Future Directions

The structural and mechanistic attributes of iberdomide and mezigdomide make them attractive candidates for a wide array of therapeutic combinations. Enhanced NK‐cell activation observed with CELMoDs provides a compelling rationale for combining them with CD38 monoclonal antibodies such as daratumumab or isatuximab. The EXCALIBER‐RRMM trial exemplifies this approach by evaluating iberdomide in combination with daratumumab and dexamethasone in early‐relapsed MM [ 37 ].

The rationale for combination with proteasome inhibitors is equally compelling. Proteasome inhibitors disrupt protein homeostasis and induce apoptosis in MM cells, while CELMoDs weaken survival pathways through transcription factor degradation. Preclinical models consistently demonstrate synergy, and ongoing clinical trials will determine whether this translates into improved outcomes.

Integration with T‐cell–redirecting therapies represents one of the most promising avenues for CELMoD development. Bispecific antibodies targeting BCMA or GPRC5D rely on T‐cell activation and proliferation. CELMoDs enhance these processes, potentially producing deeper and more durable responses. This combination may also mitigate T‐cell exhaustion and support persistence during therapy [ 45 ].

CELMoDs also play a role in CAR‐T cell therapy. Both iberdomide and mezigdomide enhance T‐cell expansion ex vivo, suggesting that their incorporation into CAR‐T cell manufacturing could yield more potent cell products. Additionally, their immune‐stimulatory effects post CAR‐T infusion may sustain T‐cell persistence and contribute to long‐term disease control.

In the post‐ASCT maintenance setting, CELMoDs may offer advantages over lenalidomide, providing deeper immunomodulation and enhanced minimal residual disease (MRD) clearance. Ongoing studies are evaluating this potential [ 46 ].

Despite promising mechanistic and early clinical data, several questions remain. Long‐term toxicities—particularly cumulative cytopenias and infection risk—require further characterization. The mechanisms of acquired resistance to CELMoDs have not been fully understood, and it remains unclear whether prolonged exposure will select for CRBN‐independent survival pathways analogous to those observed with long‐term IMiD therapy.

The absence of mature Phase III results limits the precise placement of CELMoDs within the MM treatment algorithm. Optimal sequencing relative to CAR‐T cells, bispecific antibodies, and proteasome inhibitors remains to be defined. Data on newly diagnosed MM are also limited, though ongoing trials clarify potential roles in induction or maintenance [ 47 ].

The impact of CELMoDs on T‐cell exhaustion in combination with immunotherapies remains incompletely understood. Finally, the heterogeneity of MM and its dynamic evolution under therapeutic pressure highlight the need for long‐term clinical and translational investigation [ 48 ].

Conclusions

Iberdomide and mezigdomide represent a significant advance in cereblon‐targeting therapeutics for multiple myeloma. By enhancing substrate degradation, increasing cereblon affinity, and exerting a potent immunomodulatory effect, CELMoDs effectively overcome many resistance mechanisms that limit IMiD efficacy.

Early clinical responses observed in heavily pretreated RRMM—including triple‐ and penta‐refractory populations—highlight their therapeutic potential. Iberdomide appears particularly suitable for early‐relapse settings and for integration into combination regimens with monoclonal antibodies or proteasome inhibitors. Mezigdomide, with its more robust pharmacodynamic profile, may address an urgent need in deeply refractory disease.

The complementary profiles of iberdomide and mezigdomide (Figure 3 )—where iberdomide provides flexibility for combination therapy in early‐relapse MM and mezigdomide delivers potent activity in heavily pretreated, penta‐refractory populations—suggest that drug selection may be guided by disease stage, prior therapy exposure, and patient tolerance to hematologic adverse events. Mezigdomide's increased potency, however, is associated with higher rates of hematologic toxicity, primarily neutropenia, emphasizing the need for careful monitoring and supportive care.

As the MM treatment landscape increasingly emphasizes immunotherapy‐based approaches, CELMoDs offer a unique opportunity to strengthen immune effector function, enhance cytotoxicity, and synergize with CAR‐T and bispecific therapies. Ongoing Phase III trials will be crucial in defining their ultimate therapeutic positioning.

Overall, CELMoDs hold the potential of reshaping the MM treatment continuum, deepening responses, extending remission durations, and overcoming resistance barriers inherent to traditional IMiDs.

Author Contributions

Enrica Antonia Martino, Santino Caserta, Mamdouh Skafi, Fortunato Morabito, Massimo Gentile: Conceptualization. Enrica Antonia Martino, Francesco Mendicino, Ernesto Vigna, Antonella Bruzzese, and Fortunato Morabito: Methodology. Enrica Antonia Martino, Santino Caserta, Fortunato Morabito, Massimo Gentile Writing – Original Draft Preparation. Enrica Antonia Martino, Santino Caserta, Mamdouh Skafi, Fortunato Morabito, Massimo Gentile: Writing, review, and editing. All authors have read and agreed to the published version of the manuscript.

Funding

The authors have nothing to report.

Ethics Statement

The authors have nothing to report.

Conflicts of Interest

The authors declare no conflicts of interest.

Acknowledgments

Open access publishing facilitated by Universita della Calabria, as part of the Wiley ‐ CRUI‐CARE agreement.

Data Availability Statement

Data sharing does not apply to this article, as no new data were generated or analyzed in this study.

References

1. Rajkumar S. V., “Multiple Myeloma: 2024 Update on Diagnosis, Risk‐Stratification, and Management,” American Journal of Hematology 99, no. 9 (2024): 1802–1824, 10.1002/ajh.27422.

2. Eisfeld C., Kajúter H., Möller L., Wellmann I., Shumilov E., and Stang A., “Time Trends in Survival and Causes of Death in Multiple Myeloma: A Population‐Based Study From Germany,” BMC Cancer 23, no. 1 (2023): 317, 10.1186/s12885-023-10787-5.

3. Giordano L., Cacciola R., Barone P., et al., “Autoimmune Diseases and Plasma Cells Dyscrasias: Pathogenetic, Molecular and Prognostic Correlations,” Diagnostics (Basel) 14, no. 11 (2024): 1135.

4. Malek E., de Lima M., Letterio J. J., et al., “Myeloid‐Derived Suppressor Cells: The Green Light for Myeloma Immune Escape,” Blood Reviews 30, no. 5 (2016): 341–348, 10.1016/j.blre.2016.04.002.

5. Mafra A., Laversanne M., Marcos‐Gragera R., et al., “The Global Multiple Myeloma Incidence and Mortality Burden in 2022 and Predictions for 2045,” Journal of the National Cancer Institute 117, no. 5 (2025): 907–914.

6. Martino E. A., Vigna E., Bruzzese A., et al., “Vaccination in Multiple Myeloma: Challenges and Strategies,” European Journal of Haematology 115 (2025): 334–343, 10.1111/ejh.70013.

7. Avivi I., Vesole D. H., Davila‐Valls J., et al., “Outcome of Second Primary Malignancies Developing in Multiple Myeloma Patients,” Cancers (Basel) 15, no. 17 (2023): 4359, 10.3390/cancers15174359.

8. Ramasamy K., Gay F., Weisel K., Zweegman S., Mateos M. V., and Richardson P., “Improving Outcomes for Patients With Relapsed Multiple Myeloma: Challenges and Consid Erations of Current and Emerging Treatment Options,” Blood Reviews 49 (2021): 100808, 10.1016/j.blre.2021.100808.

9. Alati C., Pitea M., Porto G., et al., “SLAMF7: A Potential Target for CAR T‐Cell Therapy in Multiple Myeloma,” Cancers (Basel) 17, no. 21 (2025): 3471.

10. Martino E. A., Pitino A., Offidani M., et al., “Comparison of Isatuximab‐Pomalidomide‐Dexamethasone Versus Elotuzumab‐Pomalidomidedexamethasone in Relapsed/Refractory Multiple Myeloma Patients: A Target Trial Emulation Using Real‐World Data,” Haematologica 110, no. 8 (2025), 10.3324/haematol.2025.287325.

11. Martino E. A., Derudas D., Rossi E., et al., “Efficacy and Prognostic Indicators of Isatuximab, Pomalidomide, and Dexamethasone (IsaPd) in Daratumumab‐Refractory Multiple Myeloma Patients: A Multicenter Real‐World Study,” Hematological Oncology 43, no. 2 (2025): e70042, 10.1002/hon.70042.

12. Martino E. A., Palmieri S., Galli M., et al., “Outcomes and Prognostic Indicators in Daratumumab‐Refractory Multiple Myeloma: A Multicenter Real‐World Study of Elotuzumab, Pomalidomide, and Dexamethasone in 247 Patients,” ESMO Open 10, no. 2 (2025): 104084, 10.1016/j.esmoop.2024.104084.

13. Labanca C., Martino E. A., Vigna E., et al., “Talquetamab in Multiple Myeloma: Efficacy, Safety, and Future Directions,” European Journal of Haematology 114, no. 3 (2025): 386–399, 10.1111/ejh.14353.

14. Martino E. A., Bruzzese A., Iaccino E., et al., “Belantamab Mafodotin in Multiple Myeloma,” Expert Opinion on Biological Therapy 23, no. 11 (2023): 1043–1047, 10.1080/14712598.2023.2218543.

15. Martino E. A., Bruzzese A., Iaccino E., et al., “Isatuximab in Multiple Myeloma,” Expert Opinion on Biological Therapy 23, no. 4 (2023): 315–318, 10.1080/14712598.2023.2193289.

16. Bruzzese A., Martino E. A., Vigna E., et al., “Elotuzumab in Multiple Myeloma,” Expert Opinion on Biological Therapy 23, no. 1 (2023): 7–10, 10.1080/14712598.2022.2145882.

17. Martino E. A., Vigna E., Bruzzese A., et al., “Selinexor in Multiple Myeloma,” Expert Opinion on Pharmacotherapy 25, no. 4 (2024): 421–434, 10.1080/14656566.2024.2333376.

18. Martino E. A., Bruzzese A., Labanca C., et al., “Teclistamab‐cqyv in Multiple Myeloma,” European Journal of Haematology 112, no. 3 (2024): 320–327, 10.1111/ejh.14121.

19. Martino E. A., Caridà G., Lofaro D., et al., “A Network Meta‐Analysis of Randomized Clinical Trials in Lenalidomide‐Exposed or ‐Refractory Multiple Myeloma Patients,” ESMO Open 10, no. 8 (2025): 105514, 10.1016/j.esmoop.2025.105514.

20. Portuguese A. J., Banerjee R., Chen G., Reddi S., and Cowan A. J., “Novel Treatment Options for Multiple Myeloma,” JCO Oncology Practice 21 (2025): 950–961, 10.1200/OP-24-00752.

21. Richardson P. G., Mateos M. V., Vangsted A. J., et al., “The Role of E3 Ubiquitin Ligase in Multiple Myeloma: Potential for Cereblon E3 Ligase Modulators in the Treatment of Relapsed/Refractory Disease,” Expert Review of Proteomics 19, no. 4‐6 (2022): 235–246.

22. Botta C., Mendicino F., Martino E. A., et al., “Mechanisms of Immune Evasion in Multiple Myeloma: Open Questions and Therapeutic Opportunities,” Cancers (Basel) 13, no. 13 (2021): 3213, 10.3390/cancers13133213.

23. Botta C., Martino E. A., Conticello C., et al., “Treatment of Lenalidomide Exposed or Refractory Multiple Myeloma: Network Meta‐Analysis of Lenalidomide‐Sparing Regimens,” Frontiers in Oncology 11 (2021): 643490, 10.3389/fonc.2021.643490.

24. Cippitelli M., Stabile H., Kosta A., et al., “Role of Aiolos and Ikaros in the Antitumor and Immunomodulatory Activity of IMiDs in Multiple Myeloma: Better to Lose Than to Find Them,” International Journal of Molecular Sciences 22, no. 3 (2021): 1103, 10.3390/ijms22031103.

25. Van Rhee F., Al Hadidi S., and Patel T., “Cereblon E3 Ligase Modulators Mezigdomide and Iberdomide in Multiple Myeloma Clinical Lymphoma, Myeloma & Leukemia,” 24, no. 11 (2024): 762–769, 10.1016/j.clml.2024.06.004.

26. Zhu Y. X., Braggio E., Shi C. X., et al., “Identification of Cereblon‐Binding Proteins and Relationship With Response and Survival After IMiDs in Multiple Myeloma,” Blood 124, no. 4 (2014): 536–545, 10.1182/blood-2014-02-557819.

27. Chrisochoidou Y., Scarpino A., Morales S., et al., “Evaluating the Impact of CRBN Mutations on Response to Immunomodulatory Drugs and Novel Cereblon E3 Ligase Modulators in Myeloma,” Blood 145, no. 22 (2025): 2630–2644.

28. Bjorklund C. C., Lu L., Kang J., et al., “Rate of CRL4(CRBN) Substrate Ikaros and Aiolos Degradation Underlies Differential Activity of Lenalidomide and Pomalidomide in Multiple Myeloma Cells by Regulation of c‐Myc and IRF4,” Blood Cancer Journal 5, no. 10 (2015): e354.

29. Meermeier E. W., Pfeffer K., Stein C. K., et al., “An Immunostimulatory CELMoD Combination Overcomes Resistance to T‐Cell Engagers Caused by a High Multiple Myeloma Burden,” Blood 146, no. 25 (2025): 3072–3085.

30. Richardson P. G., Trudel S., Popat R., et al., “Mezigdomide Plus Dexamethasone in Relapsed and Refractory Multiple Myeloma,” New England Journal of Medicine 389, no. 11 (2023): 1009–1022.

31. Sagar L., Michael A., Rakesh P., et al., “Translational and Clinical Evidence of a Differentiated Profile for the Novel CELMoD, Iberdomide (CC‐220),” Blood 134, no. Supplement_1 (2019): 3119, 10.1182/blood-2019-124298.

32. Hartley‐Brown M. A., Mo C. C., Nadeem O., Midha S., Laubach J. P., and Richardson P. G., “Mezigdomide—A Novel Cereblon E3 Ligase Modulator Under Investigation in Relapsed/Refractory Multiple Myeloma,” Cancers 16 (2024): 1166, 10.3390/cancers16061166.

33. van de Donk N. W. C. J., Bahlis N. J., Pawlyn C., et al., “The Role of CELMoD Agents in Multiple Myeloma,” Oncotargets and Therapy 18 (2025): 921–933, 10.2147/OTT.S398118.

34. Ocio E. M., Fernández‐Lázaro D., San‐Segundo L., et al., “In Vivo Murine Model of Acquired Resistance in Myeloma Reveals Differential Mechanisms for Lenalidomide and Pomalidomide in Combination With Dexamethasone,” Leukemia 29 (2015): 705–714, 10.1038/leu.2014.238.

35. Lonial S., Popat R., Hulin C., et al., “Iberdomide Plus Dexamethasone in Heavily Pretreated Late‐Line Relapsed or Refractory Multiple Myeloma (CC‐220‐MM‐001): A Multicentre, Multicohort, Open‐Label, Phase 1/2 Trial,” Lancet Haematology 9, no. 11 (2022): e822–e832.

36. White D., Lipe B., Mesa M. G., et al., “Iberdomide, Bortezomib, and Dexamethasone (IberVd) in Transplant‐Ineligible (TNE) Newly Diagnosed Multiple Myeloma (NDMM): Updated Results From the CC‐220‐MM‐001 Trial,” Journal of Clinical Oncology 43 (2025): 7532.

37. Lonial S., Dimopoulos M. A., Berdeja J. G., et al., “EXCALIBER‐RRMM: A Phase III Trial of Iberdomide, Daratumumab, and Dexamethasone in Relapsed/Refractory Multiple Myeloma,” Future Oncology 21, no. 14 (2025): 1761–1769.

38. Chow T. T., Stong N., Tamim S., et al., “Biomarker Analyses of the CC‐92480‐MM‐001 Trial to Guide Combinatorial Strategies for Mezigdomide,” Blood 144, no. Supplement 1 (2024): 3261, 10.1182/blood-2024-199019.

39. Sandhu I., Richardson P. G., Oriol A., et al., “Mezigdomide (MEZI) Plus Dexamethasone (DEX) and Bortezomib (BORT) or Carfilzomib (CFZ) in Patients (Pts) With Relapsed/Refractory Multiple Myeloma (RRMM): Updated Results From the CC‐92480‐MM‐002 Trial,” Blood 144, no. supplement 1 (2024): 1025.

40. Liu Y., Mo C. C., Hartley‐Brown M. A., et al., “Targeting Ikaros and Aiolos: Reviewing Novel Protein Degraders for the Treatment of Multiple Myeloma, With a Focus on Iberdomide and Mezigdomide,” Expert Review of Hematology 17, no. 8 (2024): 445–465.

41. Zhang Q., Song Y., Zhou K., and Lin Q., “Emerging Therapeutic Agents in Multiple Myeloma: Highlights From the 2024 ASH Annual Meeting,” Biomarker Research 13, no. 1 (2025): 90.

42. Morè S., Corvatta L., Manieri V. M., Morsia E., Poloni A., and Offidani M., “Novelties on Multiple Myeloma From the Main 2024 Hematology Conferences,” Mediterranean Journal of Hematology and Infectious Diseases 17, no. 1 (2025): e2025027, 10.4084/MJHID.2025.027.

43. Li S., Fu J., Wang H., et al., “IMiD Compounds Affect CD34 + Cell Fate and Maturation via CRBN‐Induced IKZF1 Degradation,” Blood Advances 2, no. 5 (2018): 492–504, 10.1182/bloodadvances.2017010348.

44. Meermeier E. W., Pfeffer K., Stein C. K., et al., “An Immunostimulatory CELMoD Combination Overcomes Resistance to T‐Cell Engagers Caused by a High Multiple Myeloma Burden,” Blood 146, no. 25 (2025): 3072–3085, 10.1182/blood.2025029215.

45. Richardson P. G., San Miguel J. F., Moreau P., et al., “Interpreting Clinical Trial Data in Multiple Myeloma: Translating Findings to the Real‐World Setting,” Blood Cancer Journal 8, no. 11 (2018): 109.

46. Kegyes D., Bancos A., Tigu A. B., et al., “Targeting Degradation of IKZF1 and IKZF3 Through Modulation of the E3 Ligase Substrates in the Context of Cellular Therapies for Multiple Myeloma,” Biomarker Research 13, no. 1 (2025): 105.

47. Aleman A., Grossman L., Zajdman A. K., et al., “Improving Anti‐BCMA CAR‐T Functionality With Novel Celmods in Multiple Myeloma,” Blood 144, no. Supplement 1 (2024): e3259, 10.1182/blood-2024-201186.

48. Meermeier E. W., Sharik M., Du M., et al., “Celmod‐Dexamethasone Combination Overcomes Primary Resistance to T Cell Engagers Caused by High Tumor Burden in a Human CRBN+ Preclinical Model of Multiple Myeloma,” Blood 144, no. Supplement 1 (2024): e356, 10.1182/blood-2024-212225.

Associated Data

Data Availability Statement

Data sharing does not apply to this article, as no new data were generated or analyzed in this study.