Introduction

The plasma cell neoplasm multiple myeloma (MM) is characterized by severe dysfunction of the immune system.1–4 Among key immune-related effects of MM are disruption of immune function and increased susceptibility of patients to infections, associated with accumulation of plasma cells in the bone marrow (BM) niche and production of monoclonal protein, development of an immunosuppressive tumor microenvironment enabling immune evasion and proliferation of MM cells and increased plasma cell interactions and signaling in the BM microenvironment resulting in impaired T cell responses, activation of regulatory T cells (Tregs), myeloid-derived suppressor cell (MDSC) activation and decreased tumor antigen presentation.5 As MM progresses, the frequency of mature cytotoxic natural killer (NK) cells decreases, while the proportion of NK cell subsets with poor cytotoxicity and limited effector functions increases.6 In this context, novel immune-related therapies for MM treatment that can positively modulate the immune system represent an important and ongoing clinical need, particularly given the increasing use of immune effector cell therapies and other agents with immune-based mechanisms of action in the newly diagnosed (NDMM) and relapsed/refractory (RRMM) MM treatment algorithm.

The cereblon E3 ligase modulators (CELMoDs) iberdomide and mezigdomide and other protein degraders are next-generation classes of orally administered cereblon-modulating agents that are building upon the mechanism of action of the immunomodulatory drugs (IMiDs), lenalidomide and pomalidomide, in MM. The latest developments with these agents are highlighting their substantial immune effects and related synergy with other standard-of-care immune-based therapies for MM. Recent data have demonstrated enhanced antiproliferative, apoptotic and immune-stimulatory effects with CELMoDs versus IMiDs.7–13 Consequently, the CELMoDs are undergoing widespread investigation in combination with or as an adjunct to current and emerging immune therapies and novel targeted therapies in rational combinations, with findings from these studies suggesting multiple potential roles of relevance for CELMoDs in the evolving MM treatment algorithm. This paper reviews recent updates on CELMoDs and other protein degraders for MM, with a focus on immune effects and treatment approaches in the context of other immune-based therapies and immune exhaustion, including findings reported at the 2025 and 2026 meetings of the American Society of Clinical Oncology (ASCO), European Hematology Association (EHA), International Myeloma Society (IMS) and American Society of Hematology (ASH).

CELMoDs: Overview of mechanisms of action and immune effects

Cereblon modulation and multiple myeloma

The primary mechanism of action of the CELMoDs and the monofunctional degradation activating compound (monoDAC) cemsidomide (CFT7455) is promotion of the selective degradation of the transcription factors IKZF1 and IKZF3, also known as Ikaros and Aiolos.14–17 Iberdomide, mezigdomide and cemsidomide all function by binding to cereblon with the E3 ubiquitin ligase complex CRL4CRBN, altering the structure of cereblon to a ‘closed’ conformation18 and thereby enabling binding of neo-substrate proteins and their subsequent ubiquitination and proteasomal degradation. Importantly, the CELMoDs have each demonstrated superior cereblon-binding properties and targeted protein degradation compared to the IMiDs, plus superior preclinical anti-MM activity, with mezigdomide the most potent at closing the CRL4CRBN complex completely by 100% and iberdomide by 50%.16

This mechanism of action is highly relevant in MM because IKZF1 and IKZF3 have multiple roles in mediating the immune system and immune responses,16 including in innate and adaptive immune cells, as mediators of T-cell exhaustion and in the suppression of interferon-stimulating genes, CD38 expression, T-cell stimulation and gene expression for NK cell activation. Consequently, promoting IKZF1 and IKZF3 degradation results in various beneficial immune effects,14–16,19 including T lymphocyte stimulation, enhanced cytokine expression, stimulation of NK cell activity and cell-mediated immune surveillance,20,21 inhibition of Tregs, resulting in CD4+ and CD8+ T cell responses22 and a reduction in T-cell exhaustion. These effects have been demonstrated in preclinical studies7,8,13 and translational findings are now providing support for this immune-stimulatory activity in patients with NDMM and RRMM.

Translational data on immune effects

Several key immune effects have been reported with iberdomide and mezigdomide. A large-scale immunophenotyping analysis of patients with RRMM who were treated with iberdomide-dexamethasone9,10 demonstrated immunostimulatory effects, with increases in proliferating (Ki67+) T and NK cells and a greater relative abundance of HLA-DR+ and granzyme B+ activated CD8+ T cells. Furthermore, on T cell subset analysis, a shift was seen from a naïve to an activated, effector-memory T cell phenotype, with a decrease in naïve CD8+ T cells and an increase in effector-memory T cells.9 Of note, these effects all appeared more pronounced in patients who achieved a response to iberdomide-dexamethasone therapy. Analysis of paired BM samples revealed that iberdomide treatment resulted in an increased abundance of immune effector cells in the BM microenvironment, with multiple immune cell populations increased during iberdomide treatment, including NK cells, NK T (NKT) cells, CD8+ HLA-DR+ T cells and effector-memory CD8+ T cells; decreased T-cell exhaustion was also noted, with reduced relative abundance of CD8+ TIGIT+ T cells.10 These pharmacodynamic effects of iberdomide were seen regardless of the baseline BM immune microenvironment following prior IMiD, CD38 monoclonal antibody (mAb) or B-cell maturation antigen (BCMA)-targeted therapy10; i.e. iberdomide treatment appears to overcome the adverse immune impacts of prior therapies, such as decreased NK cell levels following CD38 mAb therapy or increased monocyte abundance following BCMA-targeted therapy. More broadly, heavily pretreated patients with RRMM were shown to have an immunosuppressive BM microenvironment, with evidence of T-cell exhaustion, and iberdomide treatment was able to overcome this immunodeficiency.9,10

Similar activation of innate and adaptive immune cell populations has been shown with mezigdomide-dexamethasone in an analysis of the BM microenvironment in patients in the first-in-human CC-92480-MM-001 study.11,12 Demonstrated effects included significant on-treatment changes in CD4+ and CD8+ T-cell populations, with increased proportions of effector-memory cells and reduced proportions of central memory, naïve and terminally differentiated cells. These were coupled with significant increases in HLA-DR CD4+ T, CD8+ T and NKT cells, demonstrating activation and significant decreases in TIGIT+ CD8+ T, NK and NKT cells, indicating a dose-dependent reduction in T-cell exhaustion.11,12 Taken together, these effects indicate the activation of innate and adaptive immunity, with reductions in exhausted T and NK cell populations and a shift to an activated phenotype.12,23 Modulation of T-cell phenotypes with mezigdomide-dexamethasone, including increases in proliferating T cells, activated CD4+ T cells and CD8+ T cells and CD8+ T effector-memory cells, has been seen in patients with RRMM who had received pomalidomide as their last prior line of therapy or who were pomalidomide-refractory, indicating that immune activity was both maintained and restored in the post-IMiD setting.24

These data suggest that iberdomide and mezigdomide could offer immune-enhancing effects in combination with other immune-based therapies such as mAbs, bispecific T-cell engagers and chimeric antigen receptor (CAR) T-cell therapies. Findings presented at ASH 2025 provided a mechanistic rationale for this enhanced antitumor immunity,25 with the CELMoDs shown to significantly decrease monocytic MDSC induction, significantly upregulate inflammatory response genes in MM cells and reduce expression of the key immunosuppressive mediators IL-10 and MIF. These mechanisms contribute to remodeling the tumor microenvironment towards an immune-permissive state.

Preliminary data on cemsidomide from an ongoing phase I study also show similar immune-stimulating effects.26 Analysis of the pharmacodynamics of cemsidomide-dexamethasone demonstrated CD8+ T-cell activation across all dose levels of cemsidomide studied, with increases in the proportions of HLA-DR CD8+ and CD38+ CD8+ T cells coupled with increased serum IL-2 cytokine expression.26

The current treatment algorithm for MM

Many immune-related therapies have been established or are emerging as standards of care in the NDMM and RRMM settings.27,28 The IMiDs, including lenalidomide and pomalidomide, are established backbones of treatment; similarly the CD38 mAbs daratumumab and isatuximab are in widespread use, with the SLAMF7 mAb elotuzumab an additional option for RRMM.29 Indeed, triplet and quadruplet regimens incorporating an IMiD and a CD38 mAb are among the recommended treatment options for first-line and subsequent lines of therapy.27–29 Furthermore, the BCMA-targeting antibody–drug conjugate (ADC) belantamab mafodotin has recently received approvals in RRMM in triplet combination regimens with bortezomib-dexamethasone (Vd) and pomalidomide-dexamethasone (Pom-dex).27–29 Thus, combinations comprising an IMiD and a mAb or ADC have substantial activity in MM, illustrating the benefit of combining two immune-related agents.

More recently, we have seen the emergence of immune effector cell therapies for RRMM, including the BCMA-targeting CAR T-cell therapies idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) and the bispecific antibodies/T-cell engagers teclistamab, elranatamab and linvoseltamab (each targeting BCMA) and talquetamab (targeting G protein-coupled receptor, class C, group 5, member D; GPRC5D).27,28 Multiple additional CAR T-cell and bispecific antibody therapies are under development for RRMM, while studies are beginning to evaluate the first wave of these therapies in earlier treatment settings, including NDMM. In this context, there are various current challenges and unmet needs in the treatment of MM, including optimizing sequencing of immune therapies,29 identifying active therapies for use in the post-CAR T-cell/bispecific antibody therapy setting that can reactivate or resensitize the immune system in the setting of T-cell exhaustion, as well as determining therapies that can augment the activity of current immune-based therapies and that have activity in heavily pretreated patients with high-risk features. Another important unmet need is for additional accessible treatment options for patients with RRMM, including convenient ‘off-the-shelf’ oral regimens, as well as treatment strategies associated with lower rates of severe infections and other complications.

Clinical efficacy and safety of cereblon modulators, alone or with dexamethasone, alkylators and/or proteasome inhibitors, in RRMM and NDMM

Findings from the first-in-human CC-220-MM-00130,31 and CC-92480-MM-00124,32 phase I/II studies of iberdomide and mezigdomide, respectively, plus dexamethasone in patients with RRMM have been reported and reviewed previously16 and are summarized in Table 1. Both studies demonstrated notable efficacy in heavily pretreated patients in their respective expansion cohorts, with overall response rates (ORRs) of 26% and 41%, including rates of very good partial response or better (≥VGPR) of 8% and 25%, respectively, supporting the greater potency of mezigdomide in this setting. Of particular interest was the efficacy of both iberdomide-dexamethasone (ORR, 34%; ≥VGPR, 17%)33 and mezigdomide-dexamethasone (ORR, 50%; ≥VGPR, 33%)24 in patients with RRMM who had previously received BCMA-targeted therapy (Table 1). Promising early clinical activity has similarly been reported with cemsidomide in patients with RRMM, including those with prior BCMA-targeted therapy (Table 1).26,34 Moreover, preliminary real-world findings are supportive of the activity of mezigdomide-dexamethasone in RRMM, including in triple-class refractory patients and those who had received prior belantamab mafodotin, teclistamab and CAR T cells.35 The first-in-human study also showed the efficacy of mezigdomide-dexamethasone in patients with extramedullary disease (EMD), another hard-to-treat population, with an ORR of 30%, including complete responses (CRs)24; one rationale for this impressive activity may be that mezigdomide is associated with greater tissue penetration and distribution compared with the IMiDs and thereby has greater antitumor activity in the context of EMD. Furthermore, data reported at ASH 2025 demonstrated the pharmacodynamic and clinical activity of mezigdomide-dexamethasone in additional groups of high-risk patients, including pomalidomide-exposed patients, those with high-risk cytogenetics and patients with CRBN defects, with increases in IKZF1 and IKZF3 degradation and reductions in tumor burden markers seen across subgroups.36 Key toxicities associated with iberdomide, mezigdomide and cemsidomide are primarily grade ≥3 hematologic events, including neutropenia and infections, with both proving generally manageable. The rates reported in clinical studies of monotherapy or doublet therapy with dexamethasone are summarized in Table 1.

Table 1.Clinical efficacy and safety of iberdomide, mezigdomide and cemsidomide alone or in combination with dexamethasone.
Study Patient population Treatment Key efficacy data Key safety data
Iberdomide
EMN2637,38 NDMM post-ASCT
120 patients, 40 per dose level		 Iber 0.75 / 1.0 / 1.3 mg maintenance ≥CR 78% / 60% / 70%; MRD-pos to MRD-neg 50% / 42% / 53%
2-yr PFS 92% / 82% / 84%		 Grade ≥3 AEs: neutropenia 48% / 58% / 60%; infections 8% / 18% / 18%
Phase II trial NDMM post-ASCT39
38 patients in ≥PR		 Iber 1.0 mg maintenance Post-ASCT: ≥VGPR 100%; ≥CR 58%; MRD-neg 87%
On iber: 50% deepening to sCR; 8% MRD-pos to MRD-neg; post-cycle 12/24 MRD-neg 85% / 100%		 Grade 3/4 neutropenia 50% / 13%
GEM-IBERDARAX 18 elderly/frail NDMM40 Iber 1.6 mg + dex ORR 82%; ≥VGPR 71%; ≥CR 47% Grade 3/4 AEs: neutropenia 67%; infections 39%
All-grade AEs: anemia 33%; thrombocytopenia 28%; rash 44%; diarrhea 33%
Phase II trial 15 RRMM patients41 undergoing salvage ASCT following progression on lenalidomide maintenance and 2 or 3 prior lines Iber 1.0 mg Best response to Iber:
ORR 75%; ≥VGPR 50%; CR/MRD-neg 25%
PFS 9.3 mos		 Grade 3 AEs: infections 20%, maculopapular rash 13%, neutropenia 7%
CC-220-MM-001 Cohort B / D; 90 / 107 RRMM30,31
Median 5/6 prior lines		 Iber 0.3–1.6 mg /
1.6 mg + dex		 ORR 32% / 26%; ≥VGPR 10% / 8%
DoR 10.4 / 7.0 mos; PFS NR / 3.0 mos; OS NR / 10.4 mos		 Grade ≥3 AEs: neutropenia 42% / 45%; anemia 27% / 28%; thrombocytopenia 14% / 22%; infections 26% / 27%
All-grade AEs: infections 62% / 58%
Cohort I; 38 BCMA-exposed RRMM33; median 7 prior lines* Iber 1.6 mg + dex ORR 34%; ≥VGPR 17%; ≥CR 7%
DoR 7.5 mos*; PFS 2.4 mos*		 Grade ≥3 AEs: neutropenia 50%, anemia 29%, thrombocytopenia 21%, infections 24%*
Mezigdomide
CC-92480-MM-001 Escalation/expansion 77/101 RRMM24
Median 6/6 prior lines		 Mezi 0.1–2.0 mg /
1.0 mg + dex		 ORR 25% / 41%; ≥VGPR 13% / 25%; CR 1% / 5%
DoR 6.0 / 7.6 mos; PFS NR / 4.4 mos		 Grade ≥3 AEs: neutropenia 71% / 76%, anemia 38% / 36%, thrombocytopenia 24% / 28%, infections 40% / 35%
All-grade AEs: infections 74% / 65%
BCMA-exposed subgroup24
30 RRMM		 Mezi 1.0 mg + dex ORR 50%; ≥VGPR 33%; CR 3%
DoR 6.9 mos; PFS 5.4 mos		 Not reported separately
Subgroup with EMD24
40 RRMM		 Mezi 1.0 mg + dex ORR 30%; ≥VGPR 23%; CR 5% Not reported separately
Monotherapy cohort
12/5 RRMM32
Median 6.5/3 prior lines		 Mezi 0.6 / 0.4 mg ORR 50% / 0%; ≥VGPR 17% / 0%
PFS 5.7 / 2.8 mos		 Grade ≥3 AEs: neutropenia 80% / 83%; anemia 40% / 42%; thrombocytopenia 20% / 17%; infections 20% / 16%
All-grade AEs: infections 40% / 50%
Real-world EAP EAP – 10 RRMM patients35 Mezi + dex ORR 80%; ≥VGPR 30%; CR 10% Grade 3/4 AEs: neutropenia 60%; thrombocytopenia 40%
All-grade AEs: pneumonia 50%
Cemsidomide (CFT7455)
Phase I Dose-escalation, 72 RRMM26,34
Median 7 prior lines		 Cemsidomide 37.5–100 µg QD, 50 µg TIW + dex ORR 34%; ≥VGPR 9%
DoR 9.3 mos; PFS 3.7 mos		 Grade ≥3 AEs: neutropenia 57%; anemia 24%; thrombocytopenia 11%; infections 25%

AE, adverse event; ASCT, autologous stem cell transplantation; BCMA, B-cell maturation antigen targeted therapy; CR, complete response; dex, dexamethasone; DoR, duration of response; EAP, expanded access protocol; EMD, extramedullary disease; EMN, European Myeloma Network; Iber, iberdomide; Mezi, mezigdomide; mos, months; MRD-pos/neg, minimal residual disease-positive/negative; NDMM, newly diagnosed multiple myeloma; NR, not reported/reached; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PR, partial response; QD, once daily; RRMM, relapsed/refractory multiple myeloma; TIW, three times a week; VGPR, very good partial response; yr, year. *n=38, per abstract.

Clinical evaluation of iberdomide and mezigdomide is also ongoing with the three approved proteasome inhibitors – bortezomib, carfilzomib and ixazomib – and the alkylating agent cyclophosphamide (Table 2). Indeed, positive results have already been reported at ASCO 2026 and EHA 2026 and subsequently published from the SUCCESSOR-2 phase III trial42 of mezigdomide plus carfilzomib-dexamethasone (Kd) versus Kd in patients with RRMM, demonstrating a significant improvement in the primary endpoint, progression-free survival (PFS), as well as higher ORR and rates of ≥VGPR and ≥CR with the triplet regimen (Table 2).43 Previously reported data on iberdomide-Vd/Kd and mezigdomide-Vd/Kd from the CC-220-MM-00144 and CC-92480-MM-00245,46 studies also provided initial evidence of the efficacy of these combinations in RRMM, with high ORRs and rates of ≥VGPR, plus notable durations of response and PFS times (Table 2). These findings are underpinned by preclinical evidence of synergistic activity in cell lines and xenograft models with iberdomide8 and mezigdomide47 plus bortezomib. In addition, more recently published or reported updates from studies in RRMM have similarly shown substantial activity with iberdomide in combination with cyclophosphamide-dexamethasone, in the ICON study,48 and with ixazomib-dexamethasone as an all-oral combination for second-line therapy in elderly patients, in the I2D study,49 with ≥VGPR rates of 49% and 36%, respectively (Table 2).

Multiple studies are investigating iberdomide-based therapy in different treatment settings in patients with NDMM. Updated data were presented at ASH 2025 from the EMN26 study,37,38 which is investigating iberdomide at three different doses as maintenance treatment following high-dose melphalan plus autologous stem cell transplant (ASCT; Table 1); the latest findings demonstrate very high rates of patients converting from minimal residual disease (MRD)-positive to MRD-negative status during iberdomide maintenance, of 42–53%, as well as 2-year PFS rates of up to 92%.38 Data on iberdomide as post-ASCT maintenance were also reported from a phase II study at ASCO 2026.39 Iberdomide-dexamethasone has shown utility in treating elderly and frail patients with NDMM in preliminary results from the GEM-IBERDARAX study reported at EHA 2025, which showed a ≥CR rate of 47% (Table 1),40 while iberdomide-Vd resulted in an ORR of 100%, including 75% ≥CR, in a small cohort of patients in the CC-220-MM-001 study,50 as reported at ASCO 2025 (Table 2). Updated data from the KID study of iberdomide-Kd induction in transplant-eligible patients51 were also reported at ASCO 2025,52 which showed a post-ASCT ORR of 100%, including 26% CR (Table 2).

As seen in doublet therapy studies of iberdomide-dexamethasone and mezigdomide-dexamethasone in RRMM, common toxicities with these proteasome inhibitor-based combinations and in studies in NDMM were again reversible hematologic toxicities and infections (Table 1, Table 2). Of note, rates of grade ≥3 nonhematologic toxicities other than infections have been generally low to date and the triplet regimens appear generally well tolerated, with low rates of discontinuations due to adverse events (AEs).

Table 2.Clinical efficacy and safety of iberdomide and mezigdomide in combination with alkylators or proteasome inhibitors.
Study Patient population Treatment Key efficacy data Key safety data
Iberdomide
CC-220-MM-001 Cohort F; 25 RRMM44
Median 5 prior lines		 Iber 1.0–1.6 mg + Vd ORR 56%; ≥VGPR 28%; CR 4%
DoR 36 weeks		 Grade ≥3 AEs: neutropenia 28%; thrombocytopenia 24%; anemia 12%; infections 20%
All-grade AEs: infections 68%
Cohort J1; 18 NDMM50 Iber 1.6 mg + Vd ORR 100%; ≥VGPR 94%; ≥CR 75% Grade ≥3 AEs: neutropenia 29%; infections 47%, peripheral neuropathy 12%
Cohort G; 9 RRMM44
Median 6 prior lines		 Iber 1.1–1.3 mg + Kd ORR 50%; ≥VGPR 38%; CR 13% Grade ≥3 AEs: neutropenia 33%; thrombocytopenia 11%; infections 33%
All-grade AEs: infections 78%
KID 31 transplant-eligible NDMM51,52 Iber 1.0–1.6 mg + Kd Post-induction: ORR 96%; ≥VGPR 46%; CR 4%
Post-ASCT: ORR 100%; ≥VGPR 79%; CR 26%		 Grade 3 AEs: neutropenia 26%, thrombocytopenia 6%, rash 6%
I2D 70 elderly RRMM49
2nd-line therapy		 Iber 1.6 mg + Ixa-dex ORR 64%; ≥VGPR 36%
12-mo DoR 76%; PFS 13 mos; 12-mo OS 86%		 Grade ≥3 AEs: neutropenia 46%; thrombocytopenia 9%; infections 8%
All-grade AEs: infections 30%; peripheral neuropathy 22%
ICON 61 RRMM48
Median 3 prior lines		 Iber 1.6 mg + Cy-dex ORR 82%; ≥VGPR 49%; ≥CR 15%
PFS 17.6 mos		 Grade ≥3 AEs: neutropenia 56%; infections 34%
Mezigdomide
SUCCESSOR-2 288 vs 191 RRMM43
Median 2 prior lines		 Mezi 1.0 mg + Kd vs Kd ORR 80% vs 53%; ≥VGPR 60% vs 31%; ≥CR 27% vs 9%
12-mo DoR 72% vs 54%
PFS 18.0 vs 8.3 mos; HR 0.48 (95% CI: 0.36–0.63); p<0.0001
PFS2 23.6 vs 13.0 mos; HR 0.53 (95% CI: 0.39–0.72)		 Grade ≥3 AEs: neutropenia 61% vs 9%; thrombocytopenia 39% vs 23%; anemia 26% vs 15%; pneumonia 16% vs 6%
All-grade (grade 3/4) infections: 73% (28/6%) vs 54% (15/1%); grade 5 infections: 2.4% vs 1.1%
Discontinuation due to AEs: 9.7% vs 5.8%
CC-92480-MM-002 Escalation / expansion (1.0 / 0.6 mg dose) cohorts: 28 / 49 (38 / 11) RRMM45,46
Median 3 / 1 prior lines		 Mezi 0.3–1.0 mg / 1.0 mg / 0.6 mg + Vd ORR 75% / 84% / 91%; ≥VGPR 39% / 63% / 82%; ≥CR 18% / 18% / 27%
DoR 10.9 (escalation) / 19.4 (expansion) mos
PFS 11.2–13.4 / 16.6 / 20.8 mos		 Grade ≥3 AEs (escalation / expansion): neutropenia 36% / 63%; thrombocytopenia 21% / 27%; anemia 14% / 6%; infections 18% / 33%
All-grade AEs: infections 71% / 80%
Escalation cohort; 27 RRMM45,46
Median 2 prior lines		 Mezi 0.3–1.0 mg + Kd ORR 85%; ≥VGPR 44%; ≥CR 15%
DoR 11.9 mos		 Grade ≥3 AEs: neutropenia 44%; thrombocytopenia 15%; anemia 15%; infections 33%
All-grade AEs: infections 70%

AE, adverse event; ASCT, autologous stem cell transplantation; CI, confidence interval; CR, complete response; Cy, cyclophosphamide; d/dex, dexamethasone; DoR, duration of response; Iber, iberdomide; Ixa, ixazomib; K, carfilzomib; Mezi, mezigdomide; mo(s), month(s); NDMM, newly diagnosed multiple myeloma; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; RRMM, relapsed/refractory multiple myeloma; V, bortezomib; VGPR, very good partial response.

Cereblon modulators with monoclonal antibodies in MM

Mechanistic and immune effects

Preclinical and translational studies have demonstrated synergistic activity of iberdomide and mezigdomide with mAbs, supporting the rationale for their use in combination in RRMM and NDMM. In MM cell lines, the CELMoDs resulted in enhanced complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) in combination with daratumumab through stimulation and activation of T cells and NK cells,8,53–55 with mezigdomide-daratumumab-dexamethasone resulting in increased levels of Ki67+ proliferative NK cells and CD3+ T cells, effector-memory CD4+ T cells and HLA-DR CD4+ T-cell activation, along with reduced levels of naïve CD4+ T cells.55 Similarly, iberdomide-daratumumab-dexamethasone in patients with NDMM resulted in substantial increases in proliferating T and NK cells and activated/effector-memory T cells, along with substantial reductions in absolute B cell levels and naïve T cells.56 Additionally, as noted earlier, iberdomide and mezigdomide increase CD38 cell surface expression through degradation of IKZF1 and IKZF3.

Clinical efficacy and safety in RRMM and NDMM

The latest updates from clinical studies on regimens incorporating iberdomide or mezigdomide and a mAb are demonstrating substantial efficacy (Table 3). Indeed, the US Food and Drug Administration (FDA) has accepted a new drug application for iberdomide plus daratumumab-dexamethasone based on data from a planned analysis of MRD rates in the phase III EXCALIBER-RRMM trial of iberdomide-daratumumab-dexamethasone versus daratumumab-Vd.57 These positive findings are supported by data from earlier-phase studies of iberdomide-daratumumab-dexamethasone in both the non-transplant NDMM56,58 and RRMM44 settings in two cohorts of the CC-220-MM-001 study (Table 3); importantly, in the context of improving long-term outcomes, the regimen resulted in high rates of MRD-negative responses of up to 59% in patients with NDMM, with approximately two-thirds remaining MRD-negative at 12 months, as reported at ASH 2025.56,58 In a presentation at IMS 2025, iberdomide-daratumumab-dexamethasone was also shown to be feasible and active in elderly/frail patients with NDMM in the GEM-IBERDARAX study,59 resulting in a ≥CR rate of 34%, while data previously reported from the COMMANDER study highlighted the regimen as effective for MRD burden reduction as post-ASCT therapy.60 Building on the triplet regimen, the IDEAL study of iberdomide-daratumumab-Vd in patients with NDMM demonstrated a 52% ≥CR rate and a 48% MRD-negative rate, with promising preliminary outcomes, in findings reported at ASCO 2026.61 Similarly, iberdomide-daratumumab-Kd resulted in high response rates, including 38% ≥CR and a 67% MRD-negative rate, in patients receiving second-line therapy in the ReKInDLE study reported at ASH 2025,62 while the IMIS AMaRC 20-01 study,63 also reported at ASH 2025, demonstrated the benefit of iberdomide plus isatuximab-dexamethasone as second-line therapy in functional high-risk patients with RRMM (Table 3).

Table 3.Clinical efficacy and safety of iberdomide and mezigdomide in combination with monoclonal antibodies, bispecific antibodies or novel agents.
Study Patient population Treatment Key efficacy data Key safety data
Iberdomide
CC-220-MM-001 Cohort E; 43 RRMM44
Median 4 prior lines		 Iber 1.0–1.6 mg + Dara-dex ORR 46%; ≥VGPR 24%; CR 8% Grade ≥3 AEs: neutropenia 67%; anemia 21%; thrombocytopenia 13%; infections 15%
All-grade AEs: infections 59%
Cohort K; 75 non-transplant NDMM, 25 per dose level56,58 Iber 1.0 / 1.3 / 1.6 mg + Dara-dex MRD-neg ≥VGPR 59% / 59% / 44%
72% MRD-neg ≥VGPR at 12 mos		 Not reported
GEM-IBERDARAX 77 elderly/frail NDMM59 Iber 1.0–1.6 mg + Dara-dex ORR 93%; ≥VGPR 83%; ≥CR 34%
12-mo PFS 81%; 12-mo OS 81%		 Grade 3/4 AEs: neutropenia 68%; thrombocytopenia 7%; anemia 5%; febrile neutropenia 5%; infections 17%
All-grade AEs: infections 48%; rash 23%; diarrhea 17%
IDEAL 44 transplant-eligible/ineligible NDMM at RP2D61 Iber 0.75 mg + Dara-Vd ORR 100%; ≥CR 36% (induction), 52% (overall); MRD-neg 30% (induction), 48% (overall)
18-mo PFS 88%; 18-mo OS 94%		 Most common toxicities: neutropenia, rash, peripheral neuropathy, diarrhea, infections
COMMANDER 12 NDMM post-ASCT60 Iber 1.0–1.6 mg + Dara-dex (n=9) + K (n=3) MRD burden reduction: 7/9 and 3/3
MRD <10-5 4/9 and 3/3
MRD <10-6 4/9 and 2/3		 Most common AEs were neutropenia, thrombocytopenia and infection
ReKInDLE 30 RRMM62
Median 1 prior line		 Iber 1.0 mg + Dara-Kd ORR 92%; ≥VGPR 73%; ≥CR 38%
67% MRD-neg CR and PET-neg		 Grade ≥3 hematologic AEs: neutropenia 50%; thrombocytopenia 10%; anemia 3%
IBIS AMaRC 20-01 29 functional high-risk RRMM63
2nd-line therapy		 Iber 1.6 mg + Isa-dex ORR 69%
9-mo PFS 51%; 9-mo OS 82%		 Grade 3/4 AEs: neutropenia 52%; insomnia 8%; infusion-related reaction 2%; upper respiratory tract infection 4%
ALLG MM25 (Viber-M) 20 t(11;14) RRMM64
75% 1 prior line, 25% 2 prior lines		 Iber 1.3–1.6 mg + Venetoclax-dex ORR 80%; 25% ≥VGPR Grade ≥3 AEs: neutropenia 45%, thrombocytopenia 10%, infections 20%
MagnetisMM-30 22 RRMM65
Median 2.5 prior lines		 Iber 1.0–1.3 mg + Elranatamab Unconfirmed ORR 91%; ≥VGPR 68%; ≥CR 46% Grade 3/4 AEs: neutropenia 59%; anemia 14%; thrombocytopenia 14%; infections 5%
All-grade AEs: CRS 68%; ICANS 9%; infections 41%
Mezigdomide
CC-92480-MM-002 Escalation cohort; 56 RRMM54
Median 2 prior lines		 Mezi 0.3–0.6 mg + Dara-dex ORR 75%; ≥VGPR 46%; ≥CR 18% Grade ≥3 AEs: neutropenia 54%; anemia 11%; thrombocytopenia 7%; infections 20%
Escalation cohort; 20 RRMM54
Median 3 prior lines		 Mezi 0.3–0.6 mg + Elo-dex ORR 45%; ≥VGPR 10%; ≥CR 5% Grade ≥3 AEs: neutropenia 40%; anemia 20%; thrombocytopenia 10%; infections 35%
CA057-00366 16 RRMM patients
Median 5 prior lines		 Mezi 0.3–1.0 mg + Tazemetostat + dex ORR 50%; ≥VGPR 31%; sCR 10% Grade ≥3 AEs: neutropenia 50%; anemia 13%; thrombocytopenia 6%; infections 25%
All-grade AEs: infections 69%
20 RRMM patients
Median 5 prior lines		 Mezi 0.3–1.0 mg + BMS-986158 + dex ORR 35%; ≥VGPR 5%; sCR 5% Grade ≥3 AEs: neutropenia 65%; thrombocytopenia 40%; anemia 35%; infections 15%
All-grade AEs: infections 50%
20 RRMM patients
Median 4 prior lines		 Mezi 0.3–1.0 mg + trametinib + dex ORR 75%; ≥VGPR 45%; sCR 5% Grade ≥3 AEs: neutropenia 80%; thrombocytopenia 15%; anemia 15%; infections 25%
All-grade AEs: infections 85%
STOMP Arm 12 13 RRMM patients67
Median 5 prior lines		 Mezi 0.6–1.0 mg + Selinexor
40–60 mg + dex		 ORR 50%; ≥VGPR 50% Grade ≥3 AEs: neutropenia 54%
MELT-MM 11 RRMM patients68
Median 4 prior lines		 Mezi 0.3–1.0 mg + Elranatamab ORR 90%; ≥VGPR 60%; ≥CR 50% Grade 1 CRS 55%

AE, adverse event; ASCT, autologous stem cell transplantation; CR, complete response; CRS, cytokine release syndrome; d/dex, dexamethasone; Dara, daratumumab; Elo, elotuzumab; Iber, iberdomide; ICANS, immune effector cell-associated neurotoxicity syndrome; Isa, isatuximab; K, carfilzomib; Mezi, mezigdomide; mo(s), month(s); MRD(-neg), minimal residual disease(-negative); NDMM, newly diagnosed multiple myeloma; ORR, overall response rate; OS, overall survival; PET, positron emission tomography; PFS, progression-free survival; RP2D, recommended phase 2 dose; RRMM, relapsed/refractory multiple myeloma; sCR, stringent CR; VGPR, very good partial response.

Previously reported findings have highlighted the substantial activity of mezigdomide plus daratumumab-dexamethasone and elotuzumab-dexamethasone in patients with RRMM, with the ORR exceeding 75% with daratumumab-based therapy.54 Reflecting other combination regimens and the known safety profile of mAbs, the key toxicities with these CELMoD-mAb-based regimens are grade ≥3 hematologic AEs and infections, with overall rates of infections of up to 59% reported, but all proving manageable (Table 3).

Cereblon modulators with novel targeted agents in MM

Mezigdomide is being/has been evaluated in rational combinations with targeted agents including selinexor, an exportin-1 inhibitor, and tazemetostat, an EZH2 inhibitor, with potential complementary immune-based mechanisms of action. Key elements of the mechanism of action of selinexor are mediated through inhibition of nuclear export, including reduced NF-κB activation, increased MM cell immunogenicity and NK cell cytotoxic activity, increased CD8 and granzyme B expression and reduced proinflammatory cytokine signaling and myeloid-derived suppressor cell immunosuppressive activity.69 As reported at ASH 2025, in combination with mezigdomide-dexamethasone, this has been shown to result in CD8+ T cell proliferation and activation, decreased CD57 expression (a marker of senescence) and upregulation of T-cell activation-related cytokines and suppression of pro-inflammatory cytokines inversely associated with poor MM prognosis.67 Clinical data from Arm 12 of the STOMP study showed a remarkable 50% ≥VGPR rate in heavily pretreated patients with RRMM (Table 3).67

Tazemetostat results in dysregulation of the chromatin remodelling complex polycomb repressive complex 2 (PRC2), which, in addition to being associated with MM tumorigenesis, may deactivate immune response genes in MM cells.70 Synergistic activity has been reported recently with mezigdomide plus tazemetostat – higher than that seen with iberdomide and lenalidomide – that was mediated by the combination suppressing IRF4 expression to inhibit MM cell growth.71 Research presented at ASH 2025 showed synergistic mechanisms including upregulation of apoptotic gene clusters and downregulation of cell cycle gene clusters with the combination, which also resulted in significantly reduced IKZF1 and IKZF3 binding and increased chromatin accessibility.72 The CA057-003 study of mezigdomide plus novel targeted agents in RRMM66 has reported notable preliminary activity with mezigdomide plus tazemetostat-dexamethasone, as well as with the BET inhibitor BMS-986158 and the MEK inhibitor trametinib, plus dexamethasone, in heavily pretreated patients (Table 3). However, due to emerging evidence from the ongoing SYMPHONY-1 trial in follicular lymphoma of a secondary hematologic malignancies risk with tazemetostat and its subsequent voluntary withdrawal from all indications in 2026, further development of the mezigdomide-tazemetostat-dexamethasone combination is not planned.

Cereblon modulators with immune effector cell therapies in MM

Mechanistic effects and rationale

Through immune-based mechanistic effects CELMoDs are demonstrating specific utility in combination with immune effector cell therapies in preclinical studies. Indeed, iberdomide and mezigdomide appear to offer a potential strategy for overcoming immune exhaustion as T-cell ‘energizing’ agents in combination with or after T-cell-exhausting agents. For example, in vitro evaluation of iberdomide and mezigdomide with CAR T cells showed a significant increase in CAR T-cell viability after CELMoD treatment, a doubling (iberdomide) or tripling (mezigdomide) of activation markers HLA-DR and CD69 and a doubling of the production of effector-memory phenotype CAR T cells with use of CELMoDs during transduction, potentially promoting survival and function, as well as increased production of antigen-specific cytokines by CD8+ and CD4+ CAR T cells against BCMA-expressing MM cells and increased antigen-specific toxicity.73,74

In addition to these beneficial immune effects, iberdomide-dexamethasone has demonstrated positive impacts on CAR T cells or on immune activation following CAR T-cell therapy.75 Increases in CD4+ T cells, central memory and effector-memory T cells and T-cell-expressing activation markers were seen in iberdomide-treated samples obtained for CAR T-cell therapy production, along with higher proliferation rates and decreased proportions of exhausted cells in manufactured CAR T cells. Moreover, ex vivo treatment with iberdomide resulted in enhanced CAR T-cell expansion and functionality, and iberdomide in patients with prior CAR T-cell therapy stimulated increased T/NK-cell proliferation and a shift to an activated effector-memory phenotype.

Similar findings have been reported with iberdomide and mezigdomide in the context of bispecific antibodies/T-cell redirecting therapies. In a mouse model, pretreatment with CELMoD-dexamethasone prior to T-cell engager therapy resulted in higher response rates, improved survival and more favorable T-cell profiling over time.76 Furthermore, mezigdomide has been shown to result in increased proliferation levels, enhanced CD4+/CD8+ T-cell and NK/NKT-cell activation and a shift to an effector-memory phenotype, regardless of prior T-cell redirecting therapy treatment, thereby reactivating the immune system response.77 Additionally, increased bispecific-mediated antitumor activity, cytokine levels, T-cell activation and tumor tissue T-cell infiltration have been seen with CELMoDs in combination with the BCMA-targeted bispecific antibody alnuctamab78 and the GPRC5D-targeted agent forimtamig.79 Preliminary data also show that cemsidomide results in enhanced immune cell lysis in combination with daratumumab in an ADCC cytotoxicity assay and with teclistamab in a T-cell-dependent cellular cytotoxicity assay.80,81

Clinical efficacy and safety in RRMM

While limited clinical data were reported at ASH 2025, including on iberdomide or mezigdomide in combination with elranatamab in the MagnetisMM-3065 and MELT-MM68 studies, respectively (Table 3), trial-in-progress abstracts highlighted the numerous studies that are ongoing with CELMoDs and CAR T cell or bispecific antibody therapies (Table 4). These include the CADMIUM study of iberdomide as maintenance therapy post-ide-cel,82 the CA088-1005 study evaluating iberdomide or mezigdomide in combination with arlocabtagene autoleucel83 and the CA057-1040 study of mezigdomide plus elranatamab.84 Numerous other similar studies are currently ongoing, as well as studies of iberdomide and mezigdomide with mAbs and the ADC belantamab mafodotin (Table 4).

Discussion

The latest clinical data on iberdomide- and mezigdomide-based therapies in NDMM and RRMM, including recently reported findings from the SUCCESSOR-2 phase III trial,43 provide increasing evidence to support the substantial activity of these agents and regimens across multiple treatment settings. Furthermore, research is showing that the efficacy of these combinations is underpinned by significant effects of the CELMoDs on the BM immune microenvironment in RRMM patients, as seen in recent preclinical and translational/pharmacodynamic data reported from clinical studies. Additionally, multiple studies are highlighting the immunostimulatory findings seen with iberdomide, mezigdomide and cemsidomide, with effects being seen regardless of prior treatment with immune-based therapies including CD38 mAbs and BCMA-targeted therapies. Thus, in this context, CELMoDs represent a potentially important approach for overcoming immune exhaustion in RRMM and for enhancing the activity of immune cell effector therapies such as CAR T cells and bispecific antibodies. These roles will be of increasing value in the near-future, with the ongoing evolution of the MM treatment algorithm and the expanding range of immune-based therapies being employed. In addition to the ongoing importance of the CD38 mAbs in NDMM and RRMM, the BCMA-targeted ADC belantamab mafodotin has re-emerged in highly active regimens for RRMM and multiple CAR T-cell therapies and bispecific antibodies are established or emerging for early-relapse and later-relapse MM, as well as being evaluated in NDMM settings. These changes are giving rise to various challenges in RRMM treatment selection due to the broadening range of immune-based therapies used earlier in the disease course, including treatment sequencing and immune exhaustion following progression.

Table 4.Phase III trials of iberdomide and mezigdomide in NDMM and RRMM, ongoing clinical studies of immune-based combination approaches, and studies of monotherapy and other combination regimens in MM and smoldering MM (ClinicalTrials.gov, April 2, 2026).
Regimen Study Phase Setting Population N Estimated initial / final
study completion
Phase III trials
Iber vs R EXCALIBER-Maintenance
(NCT05827016)		 III NDMM Post-ASCT maintenance ~1,216 Mar 2029 / Jan 2036
Iber-Isa-Vd vs Isa-RVd vs RVd GEM21menos65 (NCT05558319) III NDMM Pre-ASCT induction ~480 Apr 2027 / Apr 2029
Iber-Isa MIDAS / IFM 2020-02
(NCT04934475)		 III NDMM Post-ASCT maintenance for MRD-pos post-induction 791 Sept 2024 / Sept 2028
Iber-Isa vs Iber GMMG-HD9 / DSMM XVIII, post GMMG-HD8 / DSMM XIX
(NCT06216158)		 III NDMM Post-ASCT maintenance ~411 Dec 2028 / Jun 2029
Iber-Dara-dex vs Dara-Vd EXCALIBER-RRMM (NCT04975997) III RRMM 1–2 prior lines, no prior CD38 mAb ~864 Nov 2027 / Jun 2032
Mezi-Vd vs Pom-Vd SUCCESSOR-1 (NCT05519085) III RRMM 1–3 prior lines, prior R exposure ~810 Jan 2027 / Nov 2033
Mezi-Kd vs Kd^43^ SUCCESSOR-2 (NCT05552976) III RRMM ≥1 prior line, prior R, mAb exposure 606 Jul 2026 / Jul 2029
mAb/ADC combinations
Iber-Dara IBEX (NCT06107738) II NDMM Post-ASCT maintenance ~60 Dec 2025 / Dec 2026
Iber-Isa-Vd BOREALIS (NCT05272826) II NDMM Non-transplant-eligible ~75 Mar 2028 / Mar 2031
Iber-Elo-dex NCT05560399 I RRMM 1–3 prior lines ~7 Nov 2026 / Dec 2026
Iber-Elo-dex DFCI 24-189 (NCT06518551) I/II RRMM ≥4 prior lines, post-ide-cel ~49 Dec 2029 / Dec 2034
Mezi-Elo-dex NCI-2023-05518 (NCT05981209) I RRMM ≥2 prior therapies including CD38- and BCMA-targeted therapies ~27 Dec 2026 / Dec 2026
Iber-Dara-Elo-dex MC230812 (NCT06785415) I/II RRMM 1–3 prior lines, incl PI, IMiD, CD38 mAb ~37 Apr 2031 / Apr 2031
Iber-Belamaf-dex A062101 (NCT06232044) I/II RRMM ≥2 prior lines, TCE ~88 May 2028 / Aug 2030
Bispecific antibody combinations
Iber + teclistamab NCI-2024-04754 (NCT06465316) Ib RRMM ≥4 prior lines ~26 Sep 2026 / Sep 2026
Mezi + teclistamab MSKCC 24-393 (NCT07105059) I RRMM ≥2 prior lines ~18 Aug 2028 / Aug 2028
Iber + talquetamab + dex NCI-2024-01992 (NCT06348108) I RRMM ≥3 prior lines, TCE ~32 Jul 2027 / Jul 2029
Mezi + talquetamab + dex MAGENTA (NCT07032714) I RRMM ≥3 prior lines ~25 Jul 2027 / Jul 2028
Mezi + elranatamab + dex^84^ CA057-1040 (NCT06988488) Ib/IIa RRMM 2–4/1–3 prior lines ~62 May 2027 / Jun 2027
Iber + cevostamab PLYCOM, CHAWLA substudy (NCT05583617) I/II RRMM ≥3 prior lines, TCE ~200 Jul 2028 / Jul 2028
Iber + etantamig M24-555 (NCT06896916) I RRMM No prior BCMA-targeted therapy ~135 Mar 2036 / Mar 2036
Mezi + alnuctamab + dex CA058-002 (NCT06163898) I RRMM ≥3/1–3 prior lines ~156 May 2025 / May 2025
With/post CAR T-cell therapies
Iber post ide-cel^82^ CADMIUM (NCT06179888) II RRMM ≥4 lines; post-ide-cel maintenance ~78 Oct 2027 / Oct 2027
Iber / mezi + arlo-cel^83^ CA088-1005 (NCT06121843) I RRMM 1–3 prior lines ~147 Aug 2028 / Aug 2028
Mezi NCI-2023-06771 (NCT06048250) I RRMM ≥4 lines, post-ide-cel maintenance ~15 Sep 2026 / Sep 2026
Other studies
Iber ± dex WINSHIP5157-20 (NCT04776395) II SMM Intermediate- and high-risk SMM ~68 Sep 2027 / Sep 2029
Iber + Isa-dex MODIFY (NCT06762769) II SMM Intermediate- and high-risk SMM ~63 Nov 2032 / Nov 2032
Iber NCT05177536 II NDMM Post-ASCT maintenance 40 Jan 2026 / Jan 2031
Mezi + Kd APHP241725 (NCT07348393) II RRMM 1/2 prior lines incl R, CD38 mAb ~70 Feb 2029 / Feb 2029
Mezi + Kd I-3576824 (NCT06627751) II RRMM Patients with EMD ~28 May 2027 / May 2030
Mezi + KTX-1001 (MMSETi) KTX-MMSET-001 (Cohort B1, B2; NCT05651932) I RRMM ≥3 prior lines ~125 Dec 2027 / Jun 2028

ADC, antibody–drug conjugate; arlo-cel, arlocabtagene autoleucel; ASCT, autologous stem cell transplantation; BCMA, B-cell maturation antigen targeted therapy; Belamaf, belantamab mafodotin; CAR, chimeric antigen receptor; d/dex, dexamethasone; Dara, daratumumab; Elo, elotuzumab; EMD, extramedullary disease; GPRC5D, G protein-coupled receptor, class C, group 5, member D; ide-cel, idecabtagene vicleucel; Iber, iberdomide; IMiD, immunomodulatory drug; Isa, isatuximab; K, carfilzomib; mAb, monoclonal antibody; Mezi, mezigdomide; MMSETi, MMSET inhibitor; MRD-pos, minimal residual disease-positive; NDMM, newly diagnosed multiple myeloma; PI, proteasome inhibitor; pom, pomalidomide; R, lenalidomide; RRMM, relapsed/refractory multiple myeloma; SMM, smoldering multiple myeloma; TCE, triple-class-exposed; V, bortezomib.

In this context, data on the immune effects of iberdomide and mezigdomide suggest that these agents represent ideal combination partners for immune-based therapies, given their immune-activating properties. It is therefore not surprising that, in addition to ongoing pivotal phase III studies in NDMM and RRMM, from which data are recently available43 or anticipated soon, potentially followed by regulatory approvals, there are multiple studies of both iberdomide and mezigdomide in immune-based combination approaches underway (Table 4). As reviewed earlier, numerous CELMoD-mAb-based regimens are being studied, including iberdomide plus daratumumab-dexamethasone in the EXCALIBER-RRMM phase III trial, which may result in the approval of this iberdomide-based triplet later in 2026. Additionally, multiple studies are investigating the CELMoDs with various bispecific antibodies in heavily pretreated patients and both iberdomide and mezigdomide are being evaluated as maintenance treatment following CAR T-cell therapy. The potential for immune priming with CELMoD agents prior to or in combination with immune effector cell therapies may result in enhanced activity and also overcome the adverse impact of prior immune-based therapy on outcomes. Thus, the results of these studies will be important in defining the future potential roles of the CELMoDs in the treatment of MM, including as part of novel, active combination regimens, as a means of boosting the potential activity of existing immune-based therapies and as a way of overcoming immune exhaustion following prior immune-based therapies.

With respect to the current regulatory status, as of July 2026, iberdomide and mezigdomide remain investigational but have entered regulatory review. The FDA has accepted the New Drug Application (NDA) for iberdomide-daratumumab-dexamethasone in RRMM, granted Breakthrough Therapy designation and Priority Review and assigned a target action date of August 17, 2026.85 Iberdomide is also under Swissmedic review for temporary authorization.86 The FDA has accepted the NDA for mezigdomide-Kd in RRMM with assigned target action date of May 13, 2027.87 Mezigdomide is currently under evaluation by the European Medicines Agency,88 while no corresponding Swissmedic application is listed as of June 30, 2026.86 Cemsidomide remains investigational, with no regulatory applications publicly reported to date.

Conclusions

The CELMoDs represent potentially valuable additions to the NDMM and RRMM treatment algorithm. In 2026, positive data from the SUCCESSOR-2 trial of mezigdomide-Kd43 and the positive report regarding the findings of the EXCALIBER-RRMM trial of iberdomide-daratumumab-dexamethasone57 have raised the possibility that these CELMoD-based combinations may soon become part of the treatment armamentarium for RRMM. Results from these and other phase III trials, as well as ongoing studies of novel combinations and in novel settings, particularly in the context of immune effector cell therapies, are eagerly anticipated for elucidating the value of these agents and their range of future roles in MM treatment, for the overall goal of further improving patient outcomes.

Conflict of interest

Y.L. declared participation in an advisory board for Opna Bio. O.N. declared participation in advisory boards for AstraZeneca, BMS, Janssen, Kite, Sanofi and GPCR Therapeutics; research funding from Janssen and BMS/Celgene. C.C.M. declared participation in advisory boards for AbbVie, BMS, GSK, Janssen, Karyopharm, Sanofi and Takeda; consultancy for AbbVie, Janssen, Karyopharm and Sanofi. P.G.R. declared institutional grants for clinical trials from Karyopharm and Oncopeptides; advisory committees for Bristol Myers Squibb/Celgene, GSK, Karyopharm, Oncopeptides, Regeneron and Sanofi. These funding entities did not play a role in the development of the manuscript and did not influence its content in any way. P.T., M.M., I.R., K.B., B.F., T.J.S., E.S. and M.H. declared that the manuscript was written in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Funding

This review received no external funding.

Author contributions

PGR developed the scope of the manuscript and the first draft. All authors reviewed and revised the manuscript outline and/or first draft, and final draft, and approved the manuscript for submission.

Acknowledgments

The authors gratefully acknowledge Steve Hill, PhD, of Ashfield MedComms, an Inizio company, for medical writing and editing support, funded by Dana-Farber Cancer Institute and the RJ Corman Multiple Myeloma Research Fund.