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Multiple myeloma (MM) is an incurable plasma cell malignancy with dose-limiting toxicities and inter-individual variation in response/resistance to the standard-of-care/primary drugs, proteasome inhibitors (PIs), and immunomodulatory derivatives (IMiDs). Although newer therapeutic options are potentially highly efficacious, their costs outweigh the effectiveness. Previously, we have established that clofazimine (CLF) activates peroxisome proliferator-activated receptor-γ, synergizes with primary therapies, and targets cancer stem-like cells (CSCs) in drug-resistant chronic myeloid leukemia (CML) patients. In this study, we used a panel of human myeloma cell lines as in vitro model systems representing drug-sensitive, innate/refractory, and clonally-derived acquired/relapsed PI- and cereblon (CRBN)-negative IMiD-resistant myeloma and bone marrow-derived CD138+ primary myeloma cells obtained from patients as ex vivo models to demonstrate that CLF shows significant cytotoxicity against drug-resistant myeloma as single-agent and in combination with PIs and IMiDs. Next, using genome-wide transcriptome analysis (RNA-sequencing), single-cell proteomics (CyTOF; Cytometry by time-of-flight), and ingenuity pathway analysis (IPA), we identified novel pathways associated with CLF efficacy, including induction of ER stress, autophagy, mitochondrial dysfunction, oxidative phosphorylation, enhancement of downstream cascade of p65-NFkB-IRF4-Myc downregulation, and ROS-dependent apoptotic cell death in myeloma. Further, we also showed that CLF is effective in killing rare refractory subclones like side populations that have been referred to as myeloma stem-like cells. Since CLF is an FDA-approved drug and also on WHO's list of safe and effective essential medicines, it has strong potential to be rapidly re-purposed as a safe and cost-effective anti-myeloma drug. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented related to the revealing of novel mutations in cereblon, proteasome subunit G2 and the glucocorticoid receptor in multi drug resistant disease by extramedullary myeloma whole genome sequencing.

Although several mechanisms have been proposed to explain the activity of thalidomide, lenalidomide and pomalidomide in multiple myeloma (MM), including demonstrable anti-angiogenic, anti-proliferative and immunomodulatory effects, the precise cellular targets and molecular mechanisms have only recently become clear. A landmark study recently identified cereblon (CRBN) as a primary target of thalidomide teratogenicity. Subsequently it was demonstrated that CRBN is also required for the anti-myeloma activity of thalidomide and related drugs, the so-called immune-modulatory drugs (IMiDs). Low CRBN expression was found to correlate with drug resistance in MM cell lines and primary MM cells. One of the downstream targets of CRBN identified is interferon regulatory factor 4 (IRF4), which is critical for myeloma cell survival and is down-regulated by IMiD treatment. CRBN is also implicated in several effects of IMiDs, such as down-regulation of tumor necrosis factor-α (TNF-α) and T cell immunomodulatory activity, demonstrating that the pleotropic actions of the IMiDs are initiated by binding to CRBN. Future dissection of CRBN downstream signaling will help to delineate the underlying mechanisms for IMiD action and eventually lead to development of new drugs with more specific anti-myeloma activities. It may also provide a biomarker to predict IMiD response and resistance. [ABSTRACT FROM AUTHOR]

Most myeloma patients still experience recurrent relapse and eventually become resistant and/or intolerant of effective agents such as corticosteroids, alkylating agents, immune modulators (lenalidomide and thalidomide) or proteasome inhibitors such as bortezomib. Once this happens average survivals are less than one year. Progress has been made for such patients, however, with the demonstration of clinical benefit of novel proteasome inhibitors (carfilzomib) and immune modulators (pomalidomide). Pomalidomide when used with dexamethasone has activity in 30-60% of patients depending on disease stage. Carfilzomib is an irreversible proteasome inhibitor with favorable toxicity profile (minimal neuropathy) and response rates of 17-54% depending on the disease stage treated. Novel targets are also being explored. Histone deacetylase inhibitors such as vorinostat and panobinostat are in phase II testing although results from a randomized trial combining vorinostat with bortezomib were disappointing. Other small molecules or monoclonal antibodies with novel targets such as kinase inhibitors(AKT, CDK5) and cell surface receptors (e.g. elotuzumab) are undergoing active investigation. [ABSTRACT FROM AUTHOR]

Multiple myeloma evolves clinically from monoclonal gammopathy of undetermined significance through smoldering disease, active myeloma with end organ damage to a preterminal phase of extramedullary disease and marrow collapse. The molecular equivalents of such clinical observation can now be defined as genetically dormant, genetic crisis and genetic chaos (popularly termed malignant myeloma). Patients may present for the first time in any one of these stages. Not surprisingly, clinical outcomes for multiple myeloma are variable and the prospects for therapeutic responsiveness are defined by the stage at presentation. We describe here a genetically driven definition of high- and low-risk myeloma and offer guidelines for the adoption of routine diagnostic testing. We define high-risk disease as the presence of t(4;14), t(14;16), deletion 17p13 by FISH or the presence of hypodiploidy or deletion of chromosome 13 by conventional cytogenetics. By default, other patients are not considered high risk. Thus, as a minimum, we recommend routine testing for t(4;14) and 17p13 deletion by FISH and conventional cytogenetics. This classification will identify multiple myeloma patients at high genetic risk for early progression after conventional therapies. [ABSTRACT FROM AUTHOR]

The frequency and prognostic relevance of translocations t(11;14) and t(4;14), the most common translocations involving the immunoglobulin heavy chain (IgH) gene in multiple myeloma (MM), were investigated in 128 patients treated with intensive chemotherapy and autologous stem cell transplant. Myeloma cells were identified by cytoplasmic light chain immunofluorescence combined with fluorescence in situ hybridization (cIg-FISH) for detection of translocations t(11;14) and t(4;14). Overall, t(11;14) was detected in 16 of 125 (12·8%) and t(4;14) in 15 of 120 (12·5%) patients. Progression-free and overall survivals were similar for patients with or without t(11;14). However, patients with t(4;14) had significantly shorter progression-free (median 9·9 months vs. 25·8 months; P = 0·0003) and overall survivals (median 18·3 months vs. 48·1 months; P < 0·0001) than patients without t(4;14). The t(4;14) was associated with IgA and t(11;14) with light chain MM. There was no association between the t(11;14) or t(4;14) and other biological parameters including age, gender, haemoglobin, β-2 microglobulin, C-reactive protein, calcium, creatinine, albumin, or the percentage of bone marrow plasma cells. Multivariate analysis identified t(4;14) as the only adverse prognostic factor for both progression-free survival and overall survival. Our results indicate that the t(4;14) detected by cIg-FISH is associated with a poor prognosis in MM patients receiving intensive chemotherapy and autotransplant. [ABSTRACT FROM AUTHOR]

The article presents a study on cyclophosphamide, bortezomib and dexamethasone induction therapy for newly diagnosed patients with multiple myeloma (MM). It discusses the development of new therapies for MM, method used to calculate the patients' survival, and the overall response for all patients in the study.

The antiapoptotic protein bcl-xL is upregulated in a variety of solid tumors and in primary hematologic malignancies such as multiple myeloma. Activated caspase-3 cleaves proteins essential for cell survival, including bcl-xL. To explore the potential of caspase-3 as a cytotoxic and immunostimulatory molecule in the treatment of malignancy, an RU486-inducible caspase-3 retrovirus was constructed, validated, and used to transduce first 3T3 and subsequently murine myeloma B9BM1 cells (creating the cell line B9BM-C3). After induction, apoptotic cell death of 3T3 and B9BM-C3 cells began by 4 h and was complete by 48 h postinduction, while nontransduced cells remained viable. Annexin V staining demonstrated 43, 76, and 98% apoptotic cell death at 12, 18, and 24 h postinduction. Activation of caspase-3 was evident in induced cells and cell death could be inhibited by the addition of a caspase-3-specific inhibitor. Overexpression of the myeloma-associated oncogene FGFR3, which upregulates bcl-xL, delayed but did not prevent caspase-3-mediated killing. B9BM-C3 cells formed tumors after subcutaneous injection in mice. Early treatment with RU486 eradicated tumors; however, rechallenge of treated mice failed to demonstrate evidence of immunoprotection. These results indicate that therapeutic attempts to induce caspase-3 in malignant cells may prove useful in the treatment of bcl-xL-expressing tumors. [Copyright &y& Elsevier]