Lenalidomide in Multiple Myeloma: Review of Resistance Mechanisms, Current Treatment Strategies and Future Perspectives

SIMPLE SUMMARY: Multiple myeloma (MM) is the second most common hematological malignancy. Initially, prognosis for MM patients was poor. However, due to the development of novel treatment regimens, their clinical outcomes have significantly improved. One of the milestones in the treatment of MM was the implementation of immunomodulatory drugs (IMiDs). Lenalidomide (LEN) is probably the most commonly used IMiD worldwide. However, despite its potent anti-MM activity, the vast majority of patients become LEN-resistant. In this review, we focus on LEN-resistance mechanisms as well as on strategies for the treatment of LEN-refractory disease. ABSTRACT: Multiple myeloma (MM) is the second most common hematologic malignancy, accounting for approximately 1% of all cancers. Despite the initial poor prognosis for MM patients, their life expectancy has improved significantly with the development of novel agents. Immunomodulatory drugs (IMiDs) are widely used in MM therapy. Their implementation has been a milestone in improving the clinical outcomes of patients. The first molecule belonging to the IMiDs was thalidomide. Subsequently, its novel derivatives, lenalidomide (LEN) and pomalidomide (POM), were implemented. Almost all MM patients are exposed to LEN, which is the most commonly used IMiD. Despite the potent anti-MM activity of LEN, some patients eventually relapse and become LEN-resistant. Drug resistance is one of the greatest challenges of modern oncology and has become the main cause of cancer treatment failures. The number of patients receiving LEN is increasing, hence the problem of LEN resistance has become a great obstacle for hematologists worldwide. In this review, we intended to shed more light on the pathophysiology of LEN resistance in MM, with particular emphasis on the molecular background. Moreover, we have briefly summarized strategies to overcome LEN resistance and we have outlined future directions.