Abstract
In the past few years, multiple targeted therapies and immunotherapies including second generation immunomodulatory drugs (pomalidomide) and proteasome inhibitors (carfilzomib, ixazomib), monoclonal antibodies and checkpoint inhibitors were approved for the treatment of myeloma or entered advanced phases of clinical testing. These agents showed significant activity in advanced myeloma and increased the available treatment strategies.Pomalidomide is well-tolerated and effective in patients with relapsed/refractory multiple myeloma who have exhausted any possible treatment with lenalidomide and bortezomib. Carfilzomib, a second-generation proteasome inhibitor, is active as a single agent and in combination with other anti-myeloma agents. Ixazomib is the first oral proteasome inhibitor to be evaluated in myeloma and is associated with a good safety profile and anti-myeloma activity in relapsed/refractory patients, even in those refractory to bortezomib. Monoclonal antibodies and immune checkpoint inhibitors are likely to play a major role in the treatment of myeloma over the next decade.In phase 3 studies, triplet regimens based on these agents combined with a backbone therapy (including lenalidomide, pomalidomide or bortezomib) were more efficacious than doublet regimens in patients with relapsed/refractory multiple myeloma, with limited additional toxic effects.This paper aims to provide an overview of the recent use of these agents for the treatment of myeloma, in particular focusing on the role of multi-agent combinations.
Highlights
INTRODUCTIONMultiple myeloma (MM) is a neoplastic disease characterized by the proliferation of abnormal bone marrow plasma cells and immunoglobulin or light chain overproduction, which can cause end-organ damage
Multiple myeloma (MM) is a neoplastic disease characterized by the proliferation of abnormal bone marrow plasma cells and immunoglobulin or light chain overproduction, which can cause end-organ damage.Before 2000, the median survival of patients with newly diagnosed MM was approximately 2.5 years
No differences in terms of overall response rate (ORR) and outcomes were reported but patients receiving pomalidomide continuously reported a higher rate of infections (19% in the 21/28 arm vs 27% in the 28/28 arm) and pneumonia (7% in the 21/28 arm 19.5% in the 28/28 arm)
Summary
Multiple myeloma (MM) is a neoplastic disease characterized by the proliferation of abnormal bone marrow plasma cells and immunoglobulin or light chain overproduction, which can cause end-organ damage. Firstgeneration novel agents, namely bortezomib, thalidomide, and lenalidomide, and the introduction of autologous stem cell transplantation (ASCT) have substantially improved overall survival (OS), which currently ranges from 5 to 7 years [1]. Patients with disease refractory to both immunomodulatory drugs (IMiDs) and bortezomib have a median event-free-survival (EFS) and OS of only 5 and 9 months, respectively [2]. The search for newer agents with different mechanisms of action to overcome drug-resistance has led to the development of second-generation IMiDs and proteasome inhibitors (PIs), histone deacetylase inhibitors (HDACs), Akt and mTOR inhibitors. We will review the clinical activity of the newer generation IMiDs and PIs, HDACs and MoAbs, giving an in-depth insight of their possible application and their role when used in combination
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