Page 10 - Haematologica May 2022

LANDMARK PAPER IN HEMATOLOGY
Proteasome inhibition: the dawn of novel therapies in multiple myeloma
Monika Engelhardt, Johannes Moritz Waldschmidt and Ralph Wäsch
Department of Internal Medicine I, Faculty of Medicine and Medical Center, University of Freiburg, Hugstetterstr. Freiburg, Germany.
E-mail: monika.engelhardt@uniklinik-freiburg.de doi:10.3324/haematol.2022.280857
TITLE AUTHORS JOURNAL
Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. Richardson PG, Sonneveld P, Schuster MW, et al.
New England Journal of Medicine 2005;352(24):2487-2498. PMID: 15958804
Nowadays for multiple myeloma (MM) experts it is well established that the prognosis of this often evil disease has improved. Numerous novel anti-MM agents have shown impressive activity, inducing longevity or chronic disease courses. The currently available anti-MM drug options include proteasome inhibitors (PI), immunomodulatory agents (IMiD), immunotherapies, such as monoclonal antibodies (mAb), antibody drug conjugates, bispecific antibodies, chimeric antigen receptor T cells, chemotherapy (CTx) and others. Moreover, MM biology and genomic heterogeneity are better understood, suggesting that it is important to enumerate the extent of clonal hetero- geneity and to interpret the results of subsequent therapy in light of this heterogeneity. Effective targeted therapy requires drug combinations which target distinct subclones, and the employment of targeted therapies only in patients for whom the drug target is entirely clonal,1 the former being
common and the latter scarce. This provides the rationale for
doublet, triplet and quadruplet therapies.
2
At the time of the APEX study, the inhibition of the protea-
some was a completely novel therapeutic approach, with remarkable preclinical activity in MM.3 The drug bortezomib was the first in class for clinical application (Figure 1A).2 This large randomized open-label phase III study compared borte- zomib/dexamethasone (VD) versus single agent dexametha- sone (D) in 669 patients with relapsed/refractory MM (RRMM), who had one to three prior lines of therapy. It was also the first major international phase III study in RRMM that brought together the MM community in Europe and North America. Notably, after the interim analysis deter- mined superiority of VD over D, patients in the D arm were permitted to cross over to receive bortezomib (Bz) after dis- ease progression. This study illustrated higher responses, longer time to progression and extended overall survival in
AC
B
Figure 1. Proteosome inhibition. (A) Mechanism of proteasome inhibition. (B) APEX trial randomizing 669 patients (pts) 1:1 to bortezomib (Bz)/dexamethasone (D) (VD) vs. D alone and the achievements evolving from this pivotal trial. (C) Key clinical trials that led to Food and Drug Adminstration (FDA) and European Medicines Agency (EMA) approval of various novel agents (NA). The proteosome inhibitor (PI) Bz in the APEX trial was established as one fundamental NA and was the clinical study that led others to follow and likewise achieve clinical significance in multiple myeloma (MM). Dex: dexamethasone; RRMM: relapsed/refractory MM (RRMM).
1018
haematologica | 2022; 107(5)