Currently, two CELMoDs, iberdomide (CC220) and mezigdomide (CC92480), are under investigation for Multiple Myeloma in late-stage. Mezigdomide is significantly more potent pre-clinically than iberdomide, which itself is up to 20 to 40 times more potent than pomalidomide or lenalidomide in similar model systems. While still in clinical trials, mezigdomide has shown promising results. 

The combination of mezigdomide and dexamethasone has proven very effective in patients who have undergone at least three prior lines of therapy, including those treated with B-cell maturation antigen (BCMA)-directed therapy, with overall response rates (ORRs) typically ranging from 40% to 50%. Mezigdomide has also been tested in combination with other agents earlier in the disease course, particularly with proteasome inhibitors in patients with at least one prior line of therapy, yielding encouraging ORRs of 60%–80%. Additionally, the CC-92480-MM-002 clinical trial of mezigdomide and dexamethasone combined with either DARZALEX or EMPLICITI demonstrated promising efficacy and a manageable safety profile in patients with relapsed or refractory myeloma.

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In the CA057-003 trial (NCT05372354), at the data cutoff date of April 5, 2024, 13 patients had received Mezigdomide (MEZI) + Tazemetostat (TAZ) + Dexamethasone (DEX). In this study, median prior lines of therapy was 5 (3-14); 13 (100%) patients had been exposed to an IMID agent (10 [76.9% ] to Pomalidomide]), proteasome inhibitor (PI), and anti-CD38 monoclonal antibody (mAb), and 9 (69.2%) patients had received prior T cell-redirecting therapy, including anti-B-cell maturation antigen (BCMA).

In the efficacy-evaluable population (n = 13), ORR was 53.8% (25.1-80.8) with 1 stringent complete response (SCR), 2 very good partial responses (VGPRS), and 4 partial responses (PRS). More and deeper responses were observed with the highest Mezigdomide dose (5/7 patients; ORR 71.4% [29.0-96.3]), with 3/7 patients achieving VGPR or better. The Median time to response was 0.95 (0.9-3.0) months.

Coming to the safety part, grade 3/4 TEAEs occurred in 9 (69.2%) patients. The most frequent hematologic grade 3/4 TEAEs were neutropenia (46.2%) and anemia (15.4%); 5 patients received granulocyte-colony stimulating factor (G-CSF). Grade 3/4 infections occurred in 15.4% of patients. No patient had Mezigdomide dose reductions or discontinuation due to TEAE. Also, no DLTs were reported. One patient discontinued study due to pulmonary sepsis followed by death. 

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KOL insights

“As the most potent CELMoD, mezigdomide quickly degrades Ikaros and Aiolos substrate proteins and induces apoptosis in multiple myeloma cells, while also strongly stimulating the immune system. This gives mezigdomide a distinct preclinical profile compared to IMiD compounds.” – MD, United States.

Conclusion: 

Multiple myeloma market is expected to grow in the upcoming years, owing to rise in incident cases, label expansion and penetration of current therapies in earlier lines, high adoption of newer therapies, and expected increase in investment in the R&D activities. CELMoDs are now one of the most anticipated classes of treatments for multiple myeloma. BMS is developing potential successors to REVLIMID, and POMALYST to become the future cornerstone for multiple myeloma treatment. It is notable that there are two primary CELMoDs, iberdomide and mezigdomide. CELMoDs have shown impressive activity in preclinical models and are 20–40 times more potent than pomalidomide and lenalidomide. 

Pre-clinically, these drugs effectively overcome resistance to pomalidomide and lenalidomide and show high synergy with traditional partners like dexamethasone, daratumumab, and proteasome inhibitors such as bortezomib and carfilzomib. Combining mezigdomide with other therapies has yielded impressive response rates exceeding 70%, especially when paired with proteasome inhibitors and monoclonal antibodies. Iberdomide is being introduced into frontline settings and studied for maintenance strategies and small disease applications, while mezigdomide is entering the relapsed/refractory treatment space. An intriguing aspect is how these drugs will interact with CAR-T therapies and bispecifics, potentially serving as optimal partners to enhance the benefits of these advanced treatments. 

The future of CELMoDs looks promising in enhancing both existing and new treatments, with further studies underway to confirm these results.