Elevated NF-kB levels have been identified in primitive bone marrow cells from patients with MDS/AML, suggesting NF-kB as a therapeutic target in MDS/AML. We herein describe an MDS patient ineligible for SCT who, following treatment with azacitidine and bortezomib, transformed to leukemia, but maintained complete remission after monotherapy with ixazomib.
Osteolytic bone disease is present in about 80% of patients with multiple myeloma at the time of diagnosis. Managing bone disease in patients with multiple myeloma is a challenge and requires a multi-faceted treatment approach with medication, surgery, and radiation. The established treatments with intravenous or subcutaneous antiresorptives can cause debilitating adverse events for patients, mainly osteonecrosis of the jaw, which, traditionally, has been difficult to manage.
Primary plasma cell leukemia (pPCL) is a rare and aggressive form of plasma cell disorder, which accounts for ~70% of all PCL. Survival of pPCL remains poor, and is related with early mortality. There is no standard therapy for patients with pPCL.
Proteasome inhibitors (PIs) have long been used in myeloma therapy but also for Waldenström macroglobulinemia. Their use has been successful and has also been investigated for the frontline management of the disease. Bortezomib was effective either as a single agent or in combination with other regimens with high response rates observed in most studies, despite its adverse effects, especially neurotoxicity, which remains a major concern.
With the development and approval of new proteasome inhibitors, proteasome inhibition is increasingly recognized in cancer therapy. Besides successful anti-cancer effects in hematological cancers, side effects such as cardiotoxicity are limiting effective treatment. In this study, we used a cardiomyocyte model to investigate the molecular cardiotoxic mechanisms of carfilzomib (CFZ) and ixazomib (IXZ) alone or in combination with the immunomodulatory drug dexamethasone (DEX) which is frequently used in combination therapies in the clinic.
Ever since the ubiquitin proteasome system was characterized, efforts have been made to manipulate its function to abrogate the progression of cancer. As a result, the anti-cancer drugs bortezomib, carfilzomib, and ixazomib targeting the 26S proteasome were developed to treat multiple myeloma, mantle cell lymphoma, and diffuse large B-cell lymphoma, among others. Despite success, adverse side effects and drug resistance are prominent, raising the need for alternative therapeutic options.
