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.

Terns' CML drug is an allosteric inhibitor, targeting a different site on the target protein than older drugs. This mechanism provides greater selectivity, avoiding off-target effects like arterial blockages common with active-site inhibitors. This technical advantage creates a compelling safety and tolerability profile, a key differentiator in a market with established therapies.

Step Pharma's synthetic lethality approach targets two redundant enzymes in the same pathway. Deleting one makes cancer cells entirely dependent on the other. This direct dependency is harder for biology to circumvent compared to approaches targeting different, interconnected pathways, creating a "cleaner" kill mechanism.

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.

Pirtobrutinib's reduced side effects, like atrial fibrillation, stem from its precise targeting of BTK with minimal 'binding promiscuity' to other kinases. This makes it a safer option for patients who have already been on a less-targeted BTK inhibitor.

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.

During the pandemic, a multicenter mezigdomide trial had zero COVID-19 deaths. This contrasts sharply with bispecific antibody trials in similar populations, which reported significant COVID mortality. This suggests CELMoDs have a more favorable immune profile for managing viral infections in immunocompromised patients.

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.