Will the therapeutic effect of ixazomib gradually diminish after long-term use?

As the world's first oral proteasome inhibitor, Ixazomib has been widely used in the maintenance treatment and relapsed and refractory stages of multiple myeloma (MM) patients since its launch. The trade name is Enleri, which is approved in China for use in combination with lenalidomide and dexamethasone. It is of great significance in prolonging the progression-free survival of patients. However, a common problem with long-term use of such targeted drugs is whether the efficacy will decrease over time, that is, the emergence of drug resistance. In current research and clinical practice, some patients do show signs of slow disease progression after receiving ixazomib treatment for 6-12 months or even longer, manifested as increased M protein, increased proportion of bone marrow plasma cells, new lesions on imaging, etc. This is usually considered to be a clinical manifestation of weakened drug effect.

The reason for this phenomenon is not the failure of the drug itself, but the extremely strong adaptability of myeloma cells. They can evade the killing effect of ixazomib by remodeling the proteasome structure, upregulating cellular defense pathways such asNF-κB, and even activating multidrug resistance pumps (such as P-gp). In addition, although some patients are effective in the early stages of treatment, the efficacy of the drug may also be affected due to physical changes, decreased immune function, interference from concomitant medications, etc.

Overseas clinical guidelines emphasize that patients taking long-term medication should be monitored on an individualized basis, including periodic testing of indicators such as M protein, light chain ratio, and bone marrow residual disease (MRD). Once the efficacy is found to be weakened, program adjustments should be considered, such as adding immunomodulatory drugs, alternate use of other proteasome inhibitors (such as bortezomib or carfilzomib), etc. It is worth mentioning that compared with injectable targeted drugs, although the oral properties of ixazomib are convenient, fluctuations in patient compliance may also indirectly lead to diminishing efficacy.

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