TY  - JOUR
A1  - Dimopoulos, Meletios A.
A1  - Weisel, Katja C.
A1  - Song, Kevin W.
A1  - Delforge, Michel
A1  - Karlin, Lionel
A1  - Goldschmidt, Hartmut
A1  - Moreau, Philippe
A1  - Banos, Anne
A1  - Oriol, Albert
A1  - Garderet, Laurent
A1  - Cavo, Michele
A1  - Ivanova, Valentina
A1  - Alegre, Adrian
A1  - Martinez-Lopez, Joaquin
A1  - Chen, Christine
A1  - Spencer, Andrew
A1  - Knop, Stefan
A1  - Bahlis, Nizar J.
A1  - Renner, Christoph
A1  - Yu, Xin
A1  - Hong, Kevin
A1  - Sternas, Lars
A1  - Jacques, Christian
A1  - Zaki, Mohamed H.
A1  - San Miguel, Jesus F.
T1  - Cytogenetics and long-term survival of patients with refractory or relapsed and refractory multiple myeloma treated with pomalidomide and low-dose dexamethasone
JF  - Haematologica
N2  - Patients with refractory or relapsed and refractory multiple myeloma who no longer receive benefit from novel agents have limited treatment options and short expected survival. del(17p) and t(4;14) are correlated with shortened survival. The phase 3 MM-003 trial demonstrated significant progression-free and overall survival benefits from treatment with pomalidomide plus low-dose dexamethasone compared to high-dose dexamethasone among patients in whom bortezomib and lenalidomide treatment had failed. At an updated median follow-up of 15.4 months, the progression-free survival was 4.0 versus 1.9 months (HR, 0.50; P<0.001), and median overall survival was 13.1 versus 8.1 months (HR, 0.72; P=0.009). Pomalidomide plus low-dose dexamethasone, compared with high-dose dexamethasone, improved progression-free survival in patients with del(17p) (4.6 versus 1.1 months; HR, 0.34; P < 0.001), t(4;14) (2.8 versus 1.9 months; HR, 0.49; P=0.028), and in standard-risk patients (4.2 versus 2.3 months; HR, 0.55; P<0.001). Although the majority of patients treated with high-dose dexamethasone took pomalidomide after discontinuation, the overall survival of patients treated with pomalidomide plus low-dose dexamethasone or highdose dexamethasone was 12.6 versus 7.7 months (HR, 0.45; P=0.008) in patients with del(17p), 7.5 versus 4.9 months (HR, 1.12; P=0.761) in those with t(4;14), and 14.0 versus 9.0 months (HR, 0.85; P=0.380) in standard-risk subjects. The overall response rate was higher in patients treated with pomalidomide plus low-dose dexamethasone than in those treated with high-dose dexamethasone both among standard-risk patients (35.2% versus 9.7%) and those with del(17p) (31.8% versus 4.3%), whereas it was similar in patients with t(4; 14) (15.9% versus 13.3%). The safety of pomalidomide plus low-dose dexamethasone was consistent with initial reports. In conclusion, pomalidomide plus low-dose dexamethasone is efficacious in patients with relapsed/refractory multiple myeloma and del(17p) and/or t(4;14).
KW  - translocation
KW  - plus dexamethasone
KW  - deletion 17P
KW  - bortezomib
KW  - therapy
KW  - abnormalities
KW  - stem-cell transplantation
KW  - growth-factor receptor 3
KW  - high-risk cytogenetics
KW  - intergroupe francophone
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-140349
VL  - 100
IS  - 10
SP  - 1327
EP  - 1333
ER  - 
TY  - JOUR
A1  - Ruiz-Heredia, Yanira
A1  - Sánchez-Vega, Beatriz
A1  - Onecha, Esther
A1  - Barrio, Santiago
A1  - Alonso, Rafael
A1  - Carlos Martínez-Avila, Jose
A1  - Cuenca, Isabel
A1  - Agirre, Xabier
A1  - Braggio, Esteban
A1  - Hernández, Miguel-T.
A1  - Martínez, Rafael
A1  - Rosiñol, Laura
A1  - Gutierrez, Norma
A1  - Martin-Ramos, Marisa
A1  - Ocio, Enrique M.
A1  - Echeveste, María-Asunción
A1  - Pérez de Oteyza, Jaime
A1  - Oriol, Albert
A1  - Bargay, Joan
A1  - Gironella, Mercedes
A1  - Ayala, Rosa
A1  - Bladé, Joan
A1  - Mateos, María-Victoria
A1  - Kortum, Klaus M.
A1  - Stewart, Keith
A1  - García-Sanz, Ramón
A1  - San Miguel, Jesús
A1  - José Lahuerta, Juan
A1  - Martinez-Lopez, Joaquín
T1  - Mutational screening of newly diagnosed multiple myeloma patients by deep targeted sequencing
JF  - Haematologica
N2  - no abstract available
KW  - Copy number changes
KW  - Survival
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227151
VL  - 103
IS  - 11
ER  - 
TY  - JOUR
A1  - Haertle, Larissa
A1  - Buenache, Natalia
A1  - Cuesta Hernández, Hipólito Nicolás
A1  - Simicek, Michal
A1  - Snaurova, Renata
A1  - Rapado, Inmaculada
A1  - Martinez, Nerea
A1  - López-Muñoz, Nieves
A1  - Sánchez-Pina, José María
A1  - Munawar, Umair
A1  - Han, Seungbin
A1  - Ruiz-Heredia, Yanira
A1  - Colmenares, Rafael
A1  - Gallardo, Miguel
A1  - Sanchez-Beato, Margarita
A1  - Piris, Miguel Angel
A1  - Samur, Mehmet Kemal
A1  - Munshi, Nikhil C.
A1  - Ayala, Rosa
A1  - Kortüm, Klaus Martin
A1  - Barrio, Santiago
A1  - Martínez-López, Joaquín
T1  - Genetic alterations in members of the proteasome 26S subunit, AAA-ATPase (PSMC) gene family in the light of proteasome inhibitor resistance in multiple myeloma
JF  - Cancers
N2  - For the treatment of Multiple Myeloma, proteasome inhibitors are highly efficient and widely used, but resistance is a major obstacle to successful therapy. Several underlying mechanisms have been proposed but were only reported for a minority of resistant patients. The proteasome is a large and complex machinery. Here, we focus on the AAA ATPases of the 19S proteasome regulator (PSMC1-6) and their implication in PI resistance. As an example of cancer evolution and the acquisition of resistance, we conducted an in-depth analysis of an index patient by applying FISH, WES, and immunoglobulin-rearrangement sequencing in serial samples, starting from MGUS to newly diagnosed Multiple Myeloma to a PI-resistant relapse. The WES analysis uncovered an acquired PSMC2 Y429S mutation at the relapse after intensive bortezomib-containing therapy, which was functionally confirmed to mediate PI resistance. A meta-analysis comprising 1499 newly diagnosed and 447 progressed patients revealed a total of 36 SNVs over all six PSMC genes that were structurally accumulated in regulatory sites for activity such as the ADP/ATP binding pocket. Other alterations impact the interaction between different PSMC subunits or the intrinsic conformation of an individual subunit, consequently affecting the folding and function of the complex. Interestingly, several mutations were clustered in the central channel of the ATPase ring, where the unfolded substrates enter the 20S core. Our results indicate that PSMC SNVs play a role in PI resistance in MM.
KW  - Multiple Myeloma
KW  - drug resistance
KW  - proteasome inhibitors
KW  - immunoglobulin rearrangement
KW  - ATPase activity
KW  - PSMC2
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-305013
SN  - 2072-6694
VL  - 15
IS  - 2
ER  -