CELMoDs for the treatment of MM: Latest clinical trial data

Cereblon E3 ligase modulators (CELMoDs) are a novel class of therapies that utilize the ubiquitin-proteasome system to selectively degrade key transcription factors such as Ikaros and Aiolos, which are critical to myeloma cell survival.¹ In addition, CELMoDs enhance T-cell activation, cytokine production, and natural killer cell proliferation. This unique mechanism represents an advancement over existing immunomodulatory drugs which are a cornerstone of treatment for multiple myeloma (MM).¹

As of January 2025, there are two novel CELMoDs under development and investigation for the treatment of myeloma, iberdomide and mezigdomide.¹ These agents are being evaluated in several ongoing clinical trials to assess their efficacy and safety in a variety of different settings and patient populations.¹

Iberdomide

CC-220-MM-001²

The CC-220-MM-001 trial (NCT02773030) is a multicenter, open-label, phase Ib/IIa study evaluating the safety and efficacy of iberdomide in different combinations for the treatment of MM, including

• For relapsed/refractory MM (RRMM):
  • As a sole agent
  • In combination with dexamethasone (Dex)
  • In combination with daratumumab and dexamethasone (Dd)
  • In combination with bortezomib and dexamethasone (Vd)
  • In combination with carfilzomib and dexamethasone (Kd)
• For newly diagnosed MM (NDMM):
  • In combination with Dd

Iberdomide-Dex in BCMA-exposed RRMM³

The combination of iberdomide-Dex is being investigated for patients with heavily pretreated MM, particularly for those with triple-class refractory disease. Patients enrolled in Cohort I (n = 38) included those with previous exposure to B-cell maturation antigen (BCMA)-directed therapies, for comparison on the impact of BCMA-exposure compared to the total cohort, Cohort D (N = 107). 

The overall response rate (ORR) observed in Cohort I in patients with prior BCMA-exposure were numerically higher than that of the total cohort at 36.8% compared with 26.2% in Cohort D, highlighting the potential of this combination as a treatment option for patients with prior BCMA exposure, particularly in the context of sequencing therapies for heavily pretreated individuals where therapeutic options are often limited (Figure 1).

CR, complete response; Dex, dexamethasone; ORR, overall response rate; PR, partial response; sCR, stringent complete response; VGPR, very good partial response.
*Data from Lonial² and Lonial et al.³

There were no significant differences between median duration of response (DoR) or progression-free survival (PFS) between patients in Cohort D and Cohort I (Figure 2). 

Dex, dexamethasone; DoR, duration of response; OS, overall survival; PFS, progression-free survival.
*Data from Lonial et al.³

The incidence of treatment-emergent adverse events (TEAEs) were deemed manageable, with the most common adverse event observed being neutropenia, which is anticipated in the heavily pretreated patient population.

Overall, the combination of iberdomide-Dex demonstrated efficacy in patients with heavily pretreated, triple-class exposed RRMM, including in those with previous BCMA-exposure. The regimen was deemed to be generally well tolerated, with TEAEs managed through dose modifications and interruptions. These findings support the continued evaluation of iberdomide combinations for the treatment of MM.

Iberdomide in combination with Dd, Vd, or Kd²

As part of the CC-220-MM-001 trial, additional combinations with iberdomide were evaluated, including Iber-Dd, Iber-Vd, and Iber-Kd. The combination of Iber-Vd observed the highest ORR at 56%, while the highest incidence of stringent complete response (sCR) was observed with the Iber-Kd combination (Figure 3). However, the small sample size in these cohorts necessitates further investigation with larger patient populations to better differentiate response between the triplet regimens. The median duration of response was not reached in either the Iber-Dd or Iber-Kd cohorts, and was 35.7 weeks with Iber-Vd.

CR, complete response; Iber-Dd, iberdomide-daratumumab-dexamethasone; Iber-Vd, iberdomide-bortezomib-dexamethasone; Iber-Kd, iberdomide-carfilzomib-dexamethasone; ORR, overall response rate; PR, partial response; sCR, stringent complete response; VGPR, very good partial response.
*Data from Lonial.²

 Neutropenia was the most frequent Grade 3/4 TEAE across all cohorts, while febrile neutropenia was infrequent, occurring only in the Iber-Dd cohort at 5.1% across all grades (Table 1). Fatigue and diarrhea were the most common non-hematologic TEAE, with the highest incidence observed in the Iber-Kd cohort. Infections were also common across all cohorts, with the numerically highest rate in the Iber-Kd cohort at 77.8% across all grades. The observed TEAEs align with the anticipated safety profiles of the individual agents, with more evaluation required with a larger patient population.

Table 1. TEAEs of interest observed with Iber-Dd, Iber-Kd, and Iber-Vd*

Dd, daratumumab-dexamethasone; Iber, iberdomide; Kd, carfilzomib-dexamethasone; NR, not reported; TEAE, treatment-emergent adverse events; URTI, upper respiratory tract infection; Vd, bortezomib-dexamethasone. *Data from Lonial.2
TEAEs of interest, %	Iber-Dd (n = 39)		Iber-Vd (n = 25)		Iber-Kd (n = 9)
	All grades	Grade 3/4	All grades	Grade 3/4	All grades	Grade 3/4
Neutropenia	69.2	12.8/53.8	36	20/8	33.3	22.2/11.1
Febrile neutropenia	5.1	2.6/2.6	0	0/0	0	0/0
Thrombocytopenia	33.3	7.7/5.1	36	4/20	22.2	0/11.1
Anemia	30.8	20.5/0	24	12/0	22.2	0/0
Fatigue	28.2	2.6/0	32	0/0	33.3	11.1/0
Diarrhea	17.9	2.6/0	24	4/0	33.3	0/0
Constipation	12.8	0/0	20	0/0	NR	NR
Peripheral neuropathy	7.7	0/0	32	0/0	22.2	0/0
Rash	7.7	0/0	16	4/0	NR	NR
Thrombotic event	0	0/0	0	0/0	0	0/0
Infection	59	10.3/5.1	68	16/4	77.8	22.2/11.1
URTI	28.2	0/0	36	8/0	22.2	0/0

The recommended phase II dose for the Iber-Dd cohort was established at 1.6 mg, with ongoing dose evaluation in the Iber-Vd and Iber-Kd cohorts. These findings support the continued development of iberdomide-based regimens.²

Iber-Dd for NDMM

Cohort K (n = 75) evaluated Iber-Dd as a treatment for patients with NDMM who are either transplant-ineligible or not receiving autologous hematopoietic stem cell transplant (auto-HSCT) as their first therapy. The results from Cohort K of this trial are presented on the Multiple Myeloma Hub here.

EXCALIBER-RRMM⁴

The EXCALIBER-RRMM trial (NCT04975997) is a phase III, randomized, multicenter, open-label study evaluating the efficacy and safety of Iber-Dd compared to daratumumab, bortezomib, and dexamethasone (DVd) in patients with RRMM who have received 1–2 prior lines of therapy. As of January 2025, EXCALIBER-RRMM is still recruiting patients, with an estimated initial completion date of March 2026. The primary endpoint is PFS with secondary endpoints including ORR, measurable residual disease (MRD) negativity, overall survival (OS), health-related quality of life (HRQoL), and safety.

EXCALIBER-Maintenance⁵

The EXCALIBER-Maintenance trial (NCT05827016) is a phase III, randomized, multicenter, open-label study evaluating iberdomide as maintenance therapy following auto-HSCT compared with lenalidomide maintenance for patients with NDMM. The primary endpoint is PFS, with secondary endpoints including safety, HRQoL, MRD negativity in patients with CR at 12 months of maintenance treatment, time to progression, and OS.

Mezigdomide

CA057-003⁶

The CA057-003 trial (NCT05372354) is an ongoing phase I/II, multicenter study investigating the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of mezigdomide in combination with dexamethasone and other agents in patients with RRMM. This study includes patients who have received ≥2 prior lines of therapy, including an immunomodulatory drug and a proteasome inhibitor. 

Triplet regimens being evaluated include:

• Mezigomide and dexamethasone in combination with:
  • Tazemetostat (Taz)  
  • BMS-986158
  • Trametinib (TRAM)

The primary objective of the CA057-003 trial is to assess the safety and tolerability of mezigdomide in combination with dexamethasone and each additional agent to determine the recommended phase II dose. The secondary objectives are to evaluate the preliminary efficacy, including ORR, DoR, PFS, and OS. The latest efficacy data were presented by Costa at the 66th American Society of Hematology (ASH) Annual Meeting and Exposition.⁶

Mezigomide and dexamethasone in combination with Taz

Overall, the 1.0 mg dose of mezigdomide showed the highest rates of very good partial response or better, at 50%. However, the highest overall response rate was observed with the 0.3 mg dose, although all responses were limited to very good partial responses, with no higher responses observed (Figure 4). The number of patients at each dose level was limited, and further studies with a larger cohort are necessary to determine the optimal dosing of mezigdomide in combination with Taz. The median PFS across all dose levels was 6.7 months, with a time to first response of 1 month.

CR, complete response; MEZI, mezigdomide; MEZId, mezigdomide-dexamethasone; ORR, overall response rate; PR, partial response; sCR, stringent complete response; TAZ, tazemetostat; VGPR, very good partial response.
*Adapted from Costa et al.⁶

Mezigdomide in combination with dexamethasone and BMS-986158

The 1.0 mg dose of mezigdomide achieved the highest ORR at 60%, as well as the highest rate of very good partial response at 20% (Figure 5). The median PFS across all dose levels was 4.6 months, with a median time to first response of 1 month. Although patient numbers were limited, these results offer insights toward dosing for further studies of this combination for the treatment of MM. 

CR, complete response; MEZI, mezigdomide; MEZId, mezigdomide-dexamethasone; ORR, overall response rate; PR, partial response; VGPR, very good partial response.
*Data from Costa et al.⁶

Mezigdomide in combination with dexamethasone and TRAM

An ORR of 100% was observed at the 0.6 mg mezigdomide with 1.5 mg TRAM dosing, indicating promising efficacy at this dose level, although based on a very small patient cohort (n = 4). Notably, this dosing level observed the sole incidence of stringent complete response across all cohorts (Figure 6).

CR, complete response; MEZI, mezigdomide; MEZId, mezigdomide-dexamethasone; ORR, overall response rate; PR, partial response; sCR, stringent complete response; TRAM, trametinib; VGPR, very good partial response.
*Data from Costa et al.⁶

Overall, these data provide a rationale for the further investigation of all-oral triplet combinations with mezigdomide and dexamethasone for the treatment of RRMM.

CC-92480-MM-001⁷

The CC-92480-MM-001 trial (NCT03374085) is an ongoing phase I/II, open-label, multicenter study evaluating the safety, pharmacokinetics, and efficacy of mezigdomide, alone and in combination with dexamethasone for the treatment of RRMM.

The efficacy data demonstrate encouraging response rates in patients with prior BCMA exposure, particularly significant given the challenges of treatment sequencing and the limited options available for patients following targeted immunotherapies, including BCMA-directed therapies (Figure 7).

In the dose expansion cohort, the median DoR across all patients was 7.6 months, with a median PFS of 4.4 months. For the subgroup of patients who had previous exposure to BCMA-directed therapies, the median DoR was slightly shorter at 6.9 months, but the median PFS was longer at 5.4 months. These findings further highlight the potential for the regimen in patients with prior BCMA-exposure.

BCMA, B-cell maturation antigen; CR, complete response; ORR, overall response rate; PR, partial response; Pts, patients; sCR, stringent complete response; VGPR, very good partial response.
*Data from Richardson et al.⁷

CC-92480-MM-002⁸

The CC-92480-MM-002 trial (NCT03989414) is a phase I/II, multicenter study evaluating the optimal dosing, safety, and efficacy of mezigdomide in combination with dexamethasone and either bortezomib or carfilzomib in patients with relapsed or RRMM. During the 66th American Society of Hematology (ASH) Annual Meeting and Exposition, Sandhu reported the latest data from:

• Cohort A (dose escalation): Patients treated with mezidomide received in combination with bortezomib and dexamethasone (MeziVd)
• Cohort D (dose expansion): Patients treated with MeziVd with a 1.0 mg dose of mezigdomide
• Cohort C: Patients treated with mezigdomide in combination with carfilzomib and dexamethasone (MeziKd) 

At all dose levels, the highest ORR was observed in Cohort D (MeziVd) at 85.7%, followed by Cohort C (MeziKd) at 85.2%. Cohort A (MeziVd) had the lowest ORR at 75% (Figure 8). There were no statistically significant differences between these response data; however, the median PFS and DoR were also higher in Cohort D (MeziVd). The data from Cohorts A (MeziVd) and C (MeziKd) showed comparable median PFS and DoR, though lower than those observed in Cohort D (MeziVd) (Figure 9).

MeziKd, mezigdomide-carfilzomib-dexamethasone; MeziVd, mezigdomide-bortezomib-dexamethasone; ORR, overall response rate.
*Data from Sandhu.⁸

DoR, duration of response; MeziKd, mezigdomide-carfilzomib-dexamethasone; MeziVd, mezigdomide-bortezomib-dexamethasone; PFS, progression-free survival.
*Data from Sandhu.⁸

Neutropenia was the most commonly occuring Grade 3/4 TEAE, with the highest rates observed in Cohort D (MeziVd) at the 0.6 mg dose level. Thrombocytopenia and anemia were also common hematologic TEAEs. The most common non-hematologic TEAEs were infections, occuring most frequently in Cohort D (MeziVd) at the 1.0 mg dose level.

Table 2. Most common Grade 3/4 TEAEs and TEAEs of interest by cohort*

MeziKd, mezigdomide-carfilzomib-dexamethasone; MeziVd, mezigdomide-bortezomib-dexamethasone;TEAE, treatment-emergent adverse events. *Data from Sandhu.8
Grade 3/4 TEAEs of interest, %	Cohort A (MeziVd) (n = 28)		Cohort D (MeziVd) (n = 49)		Cohort C (MeziKd) (n = 27)
	0.3 mg + 0.6 mg (n = 18)	1.0 mg (n = 10)	0.6 mg (n = 11)	1.0 mg (n = 38)	0.3 mg + 0.6 mg (n = 18)	1.0 mg (n = 9)
Neutropenia	16.7	70	72.7	60.5	33.3	66.7
Thrombocytopenia	27.8	10	18.2	28.9	5.6	33.3
Anemia	16.7	10	0	7.9	11.1	22.2
Infections	27.8	0	18.2	36.8	33.3	33.3
COVID-19	0	0	9.1	7.9	22.2	11.1
Pneumonia	16.7	0	9.1	23.7	0	11.1
Any neutropenia + Grade 3/4 infection	5.6	0	9.1	7.9	0	11.1
Grade 3/4 neutropenia + any infection	5.6	10	36.4	31.6	0	22.2

SUCCESSOR-1⁹

The SUCCESSOR-1 trial (NCT05519085) is a phase III, randomized, study assessing the efficacy and safety of mezigdomide in combination with bortezomib and dexamethasone compared to pomalidomide in combination with bortezomib and dexamethasone in patients with RRMM who have been treated with 1–3 prior therapies, including lenalidomide. The primary endpoint is PFS, with secondary endpoints including ORR, CR rate, OS, MRD negativity, safety, and quality of life. As of January 2025, this trial is currently recruiting, with an expected enrollment of 810 patients across multiple centers.

SUCCESSOR-2¹⁰

The SUCCESSOR-2 trial (NCT05552976) is a phase III, randomized study evaluating the efficacy and safety of mezigdomide in combination with carfilzomib and dexamethasone compared to carfilzomib and dexamethasone in patients with RRMM who have received ≥1 prior therapy. The primary endpoint is PFS, with secondary endpoints including ORR, CR rate, OS, MRD negativity, safety, and quality of life. The trial is currently recruiting participants as of January 2025.

Conclusion

CELMoDs, including iberdomide and mezigdomide, offer a novel approach for the treatment of MM, particularly in patients with heavily pretreated disease or those with limited options following BCMA-directed therapies. Both agents have demonstrated promising early response rates in combination regimens, with oral administration and manageable safety profiles. Ongoing phase III trials aim to optimize dosing and establish the role of CELMods in the MM treatment paradigm.

This educational resource is independently supported by Bristol Myers Squibb. All content was developed by SES in collaboration with an expert steering committee. Funders were allowed no influence on the content of this resource.