Unlike therapies that can deplete the immune system, mezigdomide enhances T-cell number and function. This unique immune-enhancing property makes it a promising agent to use before, or in combination with, immunotherapies like CAR-T to overcome resistance and improve outcomes in highly refractory patients.

In combination with bispecifics like teclistamab, daratumumab not only targets myeloma cells but also enhances the partner drug's efficacy by reducing immunosuppressive T-regulatory (Tregs) and B-regulatory (Bregs) cells, making the primary therapy more effective.

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.

Unlike IMiDs (lenalidomide) which only close the Cereblon E3 ligase complex by 15-20%, mezigdemide achieves 100% closure. This leads to more robust degradation of key proteins, causing powerful direct myeloma cell destruction and enhanced immune activation, earning it the nickname 'CAR T in a pill.'

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.

Using a BCMA bispecific antibody first can exhaust a patient's T-cells or cause tumors to lose the BCMA target, rendering a subsequent BCMA-targeted CAR-T therapy ineffective. The optimal sequence is CAR-T first, which preserves T-cell function and BCMA expression, leaving bispecifics as a viable later-line option.

In a heavily pretreated population, mezigdemide plus dexamethasone achieved a 50% response rate in patients refractory to prior BCMA-based approaches, including antibody-drug conjugates, bispecifics, and CAR T-cell therapy. This demonstrates a distinct mechanism that can overcome resistance to the latest immunotherapies.

Belantamab's primary mechanism, immunogenic cell death, does not exhaust T-cells. This unique quality allows clinicians to use it as a first BCMA-targeted agent without compromising the efficacy of subsequent T-cell redirecting therapies like CAR T or bispecifics.

Clinicians report significant and durable responses using Belantamab in patients who have relapsed after BCMA-targeted CAR-T. This success may be due to Belantamab's immunogenic mechanism, which doesn't rely on endogenous T-cells and may favorably interact with the post-CAR immune environment.