TY  - JOUR
A1  - Weißbach, Susann
A1  - Heredia-Guerrero, Sofia Catalina
A1  - Barnsteiner, Stefanie
A1  - Großhans, Lukas
A1  - Bodem, Jochen
A1  - Starz, Hanna
A1  - Langer, Christian
A1  - Appenzeller, Silke
A1  - Knop, Stefan
A1  - Steinbrunn, Torsten
A1  - Rost, Simone
A1  - Einsele, Hermann
A1  - Bargou, Ralf Christian
A1  - Rosenwald, Andreas
A1  - Stühmer, Thorsten
A1  - Leich, Ellen
T1  - Exon-4 Mutations in KRAS Affect MEK/ERK and PI3K/AKT Signaling in Human Multiple Myeloma Cell Lines
JF  - Cancers
N2  - Approximately 20% of multiple myeloma (MM) cases harbor a point mutation in KRAS. However, there is still no final consent on whether KRAS-mutations are associated with disease outcome. Specifically, no data exist on whether KRAS-mutations have an impact on survival of MM patients at diagnosis in the era of novel agents. Direct blockade of KRAS for therapeutic purposes is mostly impossible, but recently a mutation-specific covalent inhibitor targeting KRAS\(^{p.G12C}\) entered into clinical trials. However, other KRAS hotspot-mutations exist in MM patients, including the less common exon-4 mutations. For the current study, the coding regions of KRAS were deep-sequenced in 80 newly diagnosed MM patients, uniformely treated with three cycles of bortezomib plus dexamethasone and cyclophosphamide (VCD)-induction, followed by high-dose chemotherapy and autologous stem cell transplantation. Moreover, the functional impact of KRAS\(^{p.G12A}\) and the exon-4 mutations p.A146T and p.A146V on different survival pathways was investigated. Specifically, KRAS\(^{WT}\), KRAS\(^{p.G12A}\), KRAS\(^{p.A146T}\), and KRAS\(^{p.A146V}\) were overexpressed in HEK293 cells and the KRAS\(^{WT}\) MM cell lines JJN3 and OPM2 using lentiviral transduction and the Sleeping Beauty vector system. Even though KRAS-mutations were not correlated with survival, all KRAS-mutants were found capable of potentially activating MEK/ERK- and sustaining PI3K/AKT-signaling in MM cells.
KW  - multiple myeloma
KW  - KRAS
KW  - MEK/ERK-signaling
KW  - AKT-signaling
KW  - amplicon sequencing
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-200617
SN  - 2072-6694
VL  - 12
IS  - 2
ER  - 
TY  - JOUR
A1  - Merz, Maximilian
A1  - Dechow, Tobias
A1  - Scheyt, Mithun
A1  - Schmidt, Christian
A1  - Knop, Stefan
T1  - The clinical management of lenalidomide-based therapy in patients with newly diagnosed multiple myeloma
JF  - Annals of Hematology
N2  - Lenalidomide is an integral, yet evolving, part of current treatment pathways for both transplant-eligible and transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM). It is approved in combination with dexamethasone as first-line therapy for transplant-ineligible patients with NDMM, and as maintenance treatment following autologous stem cell transplantation (ASCT). Although strong clinical trial evidence has supported the integration of lenalidomide into current treatment paradigms for NDMM, applying those paradigms to individual patients and determining which patients are most likely to benefit from lenalidomide treatment are more complex. In this paper, we utilize the available clinical trial evidence to provide recommendations for patient selection and lenalidomide dosing in both the first-line setting in patients ineligible for ASCT and the maintenance setting in patients who have undergone ASCT. In addition, we provide guidance on management of those adverse events that are most commonly associated with lenalidomide treatment, and consider the optimal selection and sequencing of next-line agents following long-term frontline or maintenance treatment with lenalidomide.
KW  - adverse events
KW  - lenalidomide
KW  - multiple myeloma
KW  - newly diagnosed
KW  - safety
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-231862
SN  - 0939-5555
VL  - 99
ER  -