While CELMoDs frequently cause neutropenia, this effect is most pronounced in early cycles and manageable with growth factors. This contrasts sharply with the persistent, quality-of-life-impairing non-hematologic side effects of lenalidomide, such as rash and severe fatigue. This trade-off results in a significantly better long-term tolerability profile for patients.

Prophylactically administering tocilizumab before bispecific antibody treatment can slash the incidence of cytokine release syndrome (CRS) from ~75% down to 20%. This simple intervention, analogous to using G-CSF for neutropenia, mitigates side effects and makes outpatient administration a much safer and more feasible option for patients.

CELMoDs are being actively trialed as a maintenance therapy after CAR T-cell treatment. The strategy is to leverage the CELMoDs' ability to enhance T-cell function and upregulate effector T-cells to boost the activity and persistence of the CAR-T product, potentially leading to more durable responses and preventing relapse.

Lenalidomide has a unique off-target effect on C1K alpha which clonally selects for p53 mutated cells, increasing second cancer risk. Preclinical data clearly show that CELMoDs like iberdomide and mezigdomide do not share this mechanism, offering a significant potential safety advantage over the older IMiD.

Unlike T-cell engaging therapies, the bispecific antibody zanidatumab does not cause cytokine release syndrome (CRS). This unique safety feature is because it binds to two distinct sites on the HER2 receptor itself, rather than engaging T-cells, providing a key toxicity advantage.

Unlike older IMiDs where T-cell effects are secondary, CELMoDs have a powerful, independent pro-T-cell mechanism. This dual action is so significant that in the future, CELMoDs will be prescribed not just for their direct anti-myeloma effects, but specifically to enhance the efficacy of T-cell therapies like CAR-T and bispecific antibodies.

An expert who initially viewed CELMoDs as incremental improvements now considers them fundamentally different. The new litmus test for future myeloma trials will be tracking prior patient exposure to CELMoDs like iberdomide, just as they track prior IMiD exposure today, cementing their status as a distinct therapeutic category.

Unlike IMiDs, which only partially engage the target, CELMoDs like iberdomide are larger molecules that fully close the cereblon E3 ligase pocket. This maximizes degradation of target proteins Ikaros and Aiolos, leading to greater potency and what is described as "hitting the death star" of the myeloma cell.

Mezigdomide is considered one of the most active oral agents against extramedullary disease (EMD). Its molecular structure was specifically engineered to optimize tissue penetration, addressing a significant clinical challenge where myeloma grows outside the bone marrow in heavily pretreated patients.