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Panminerva Medica 2020 Sep 22

DOI: 10.23736/S0031-0808.20.04148-8


lingua: Inglese

Old and new generation proteasome inhibitors in multiple myeloma

Vittorio MONTEFUSCO 1 , Alberto MUSSETTI 2, 3, Maria Rosa SALA 2, 3, Giovanni MARTINELLI 4, Claudio CERCHIONE 4

1 Onco-Hematology, ASST Santi Paolo e Carlo, Milan, Italy; 2 Clinical Hematology Department, Institut Català d'Oncologia-Hospitalet, Barcelona, Spain; 3 Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Barcelona, Spain; 4 Hematology Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Forlì-Cesena, Italy


Proteasome inhibitors (PIs) represent a recently developed drug class that inhibit the ubiquitinproteasome system, thus interfering with the intracellular machinery who has the duty of misfolded proteins disposal. Myeloma plasma cells are structurally aimed at the production of large quantities of immunoglobulins. This explains their vulnerability to any perturbation of intracellular protein homeostasis. Bortezomib is the first-in-class PI and nowadays, in combination with other compounds, is the cornerstone of multiple myeloma (MM) treatment in several settings. Bortezomib has several attractive features for its inclusion in the induction phase of therapy: high efficacy, rapid cytoreduction, absence of nephrotoxicity, fast reduction of plasmacytomas, and fast pain control. However, the safety profile of bortezomib is characterized by a not negligible peripheral neuropathy. Newer PIs, such as carfilzomib and ixazomib, have been developed and each offers specific advantages. Carfilzomib is extremely efficient in proteasome inhibition. This results in high efficacy but suffers from a significant cardiotoxicity. Ixazomib is the first oral PI with a proteasome inhibition profile similar to bortezomib, with lower neurotoxicity. PIs mechanism of action is complementary with other drug classes, and this explains the synergism between PIs and other drugs, in particular steroids and immunomodulators. PIs are frequently used in doublets and triplets. Also, they can be associated with anti-CD38 monoclonal antibodies. This review summarizes the principal biological and clinical features of PIs in the MM treatment.

KEY WORDS: Proteasome inhibitors;Myeloma; Bortezomib

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