Old and new generation immunomodulatory drugs in multiple myeloma

Over the last two decades, the outcomes of patients with multiple myeloma (MM), a malignant plasma cells dyscrasia, have dramatically improved. The development and the introduction of the immunomodulatory drugs (IMiDs) which include thalidomide, lenalidomide, and pomalidomide, have contributed significantly to these improvements.

The IMiDs have been shown a multitude of mechanisms of action, including antiangiogenic, cytotoxic and immunomodulatory. The more recent discoveries that the IMiDs bind to cereblon and thus regulate the ubiquitination of key transcription factors including IKZF1 and IKZF3, have provided new insight about their activities.

The IMIDs are widely used in the treatment of the different setting of MM patients and particularly lenalidomide represents the backbone in the therapy of newly diagnosed transplant eligible and transplant ineligible patients, in the maintenance setting post-transplant and in the relapsed/refractory setting, while pomalidomide is currently utilized in the relapsed/refractory setting.

Here the mechanisms of action, the clinical efficacy and the management of side effects are reviewed as well as the new classes of cereblon E3 ligase modulator (CELMoD) and their promising clinical data are described.