Mechanisms of action and resistance for multiple myeloma novel drug treatments

Excerpt

Multiple myeloma (MM) is an incurable plasma cell malignancy that develops as a result of multistep tumorigenic events [1]. The median overall survival of patients with newly diagnosed MM was approximately 2.5–3 years when melphalan and prednisone (MP) therapy was the standard of care. However, since the end of the 20th century, genetic and epigenetic alterations associated with the pathogenesis of MM and tumor cell biology of the bone marrow microenvironment have been gradually unraveled [2, 3]. In parallel, the discovery of thalidomide as an active agent for MM in 1999 ushered in a new era in the treatment of this intractable disease [4]. This was followed by the clinical application of bortezomib, a first-generation proteasome inhibitor (PI), based on the results of pre-clinical translational studies [3, 5]. Novel thalidomide derivatives called immunomodulatory drugs (IMiDs), such as lenalidomide and pomalidomide, were also developed [6, 7]. Second-generation PIs, such as carfilzomib and ixazomib, have recently been approved by the FDA [8]. Currently, PIs and IMiDs, as well as corticosteroid and alkylating agents, are the key novel drugs for MM treatment which have resulted in the achievement of a median survival of approximately 5–6 years [9]. Moreover, additional agents with different mechanisms of action have been incorporated into the treatment of MM, including the deacetylase inhibitor panobinostat and monoclonal antibodies, targeting SLAMF7, CD38, and PD-1 represented by elotuzumab, daratumumab/isatuximab, and pembrolizumab/nivolumab, respectively [10, 11]. Thus, the prognosis of patients with MM is expected to continue to improve. …