Carfilzomib boosted combination therapy for relapsed multiple myeloma

Abstract

Carfilzomib is a proteasome inhibitor that binds selectively and irreversibly to the 20S proteasome, the proteolytic core particle within the 26S proteasome, resulting in the accumulation of proteasome substrates and ultimately growth arrest and apoptosis of tumor cells. The development and ultimate approval of this medication by regulatory agencies has been an important step toward improving clinical outcomes in multiple myeloma. Although initially approved as a single agent for the treatment of multiply relapsed and/or refractory myeloma, in the USA, it is now widely used in the early relapse setting in combination with lenalidomide and dexamethasone. Carfilzomib has also been studied in combination with second-generation immunomodulatory drugs, histone deacetylase inhibitors, alkylating agents and other novel medications. In this review article, we will discuss the efficacy, safety, tolerability and quality of life of carfilzomib-based combination therapies, as well as novel agents, for relapsed multiple myeloma.

Keywords: carfilzomib; multiple myeloma; novel drugs; relapsed and refractory myeloma; salvage chemotherapy.

Figure 1

Depicted mechanisms of action of emerging therapies in the treatment of multiple myeloma. Abbreviations: AG, antigene; AKT, protein kinase B; APRIL, a proliferation-inducing ligand; Bcl-2, B-cell lymphoma 2; BCMA, B-cell maturation antigen; BCR, B-cell receptor; BiTE, bispecific T-cell engager; BTK, Bruton’s tyrosine kinase; CAR, chimeric antigen receptor; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; DM maytansinoid; EZH2, enhancer of zeste homolog 2; Fc, fragment crystallizable; HDAC, histone deacetylase; HDACi, histone deacetylase inhibitor; IL, interleukin; KSP, kinesin spindle protein; MHC, major histocompatibility complex; MEK, mitogen-activated protein kinase; NK, natural killer; PD, programmed cell death; PD-L, programmed death-ligand; PI, proteasome inhibitor; PI3K phosphatidylinositide 3-kinases; PLE, phospholipid ethers; SINE, selective inhibitor of nuclear export; SLAM, signaling lymphocytic activation molecule; SLAMF7, self-ligand receptor of the SLAM family member 7; SP, kinesin spindle protein; SYK, spleen tyrosine kinase; TCR, T-cell receptor; TCRt, T-cell receptor-modified T-cells; XPO-1, exportin 1.