The Effect of Carfilzomib and Bortezomib Based Regimes on Cardiotoxicity in Multiple Myeloma Patients at Cooper University Hospital

Introduction Multiple myeloma (MM) is a cancer of plasma cells, which is a white blood cell that normally produces antibodies Treatment in patients younger than 65 years old is typically high dose chemotherapy, usually with bortezomib based regimens or lenalidomide dexamethasone, followed by a stem cell transplant For patients with relapsed myeloma, carfilzomib is usually the treatment of choice Carfilzomib is a highly selective, irreversible proteasome inhibitor that binds to the 20 S proteasome. Several studies have illustrated that carfilzomib has been associated with cardiovascular adverse events (CVAE). Current literature on the role and effect of bortezomib on cardiotoxicity is contradictory Past studies have shown benefits of using carfilzomib in MM patients, leading to improved response rates and overall survival There is scarce research on the risk factors associated with the development of cardiotoxicity with carfilzomib Objective To determine the incidence of cardiovascular adverse events (CVAE) associated with carfilzomib and bortezomib utilization and to assess risk factors for carfilzomib related cardiotoxicit

New interleukin-15 superagonist (IL-15SA) significantly enhances graft-versus-tumor activity.

Interleukin-15 (IL-15) is a potent cytokine that increases CD8+ T and NK cell numbers and function in experimental models. However, obstacles remain in using IL-15 therapeutically, specifically its low potency and short in vivo half-life. To help overcome this, a new IL-15 superagonist complex comprised of an IL-15N72D mutation and IL-15RαSu/Fc fusion (IL-15SA, also known as ALT-803) was developed. IL-15SA exhibits a significantly longer serum half-life and increased in vivo activity against various tumors. Herein, we evaluated the effects of IL-15SA in recipients of allogeneic hematopoietic stem cell transplantation. Weekly administration of IL-15SA to transplant recipients significantly increased the number of CD8+ T cells (specifically CD44+ memory/activated phenotype) and NK cells. Intracellular IFN-γ and TNF-α secretion by CD8+ T cells increased in the IL-15SA-treated group. IL-15SA also upregulated NKG2D expression on CD8+ T cells. Moreover, IL-15SA enhanced proliferation and cytokine secretion of adoptively transferred CFSE-labeled T cells in syngeneic and allogeneic models by specifically stimulating the slowly proliferative and nonproliferative cells into actively proliferating cells.We then evaluated IL-15SA\u27s effects on anti-tumor activity against murine mastocytoma (P815) and murine B cell lymphoma (A20). IL-15SA enhanced graft-versus-tumor (GVT) activity in these tumors following T cell infusion. Interestingly, IL-15 SA administration provided GVT activity against A20 lymphoma cells in the murine donor leukocyte infusion (DLI) model without increasing graft versus host disease. In conclusion, IL-15SA could be a highly potent T- cell lymphoid growth factor and novel immunotherapeutic agent to complement stem cell transplantation and adoptive immunotherapy

IgM Multiple Myeloma: A Rare Clinical Entity and Diagnostic Dilemma

IgM multiple myeloma is a rare disease that shares many common features with Waldenström macroglobulinemia and lymphoplasmacytic lymphoma. It has been described in the literature as having unique diagnostic findings that separate it from the more common IgG and IgA myelomas. It is important for physicians to be able to differentiate between IgM multiple myeloma, Waldenström macroglobulinemia and lymphoplasmacytic lymphoma as their treatments vastly differ. This case report describes the clinical presentation of a patient with IgM lambda multiple myeloma and highlights the pathologic and clinical findings that are specific to this rare entity. We aim to provide further evidence for the previously reported diagnostic criteria for IgM multiple myeloma

Mcl-1 Inhibition Modulates ERK-Mediated Resistance in Multiple Myeloma

Novel multiple myeloma (MM) treatments have significantly improved over the previous several decades, primarily on account of targeting bone marrow microenvironment (BMM) pathways. However, drug resistance and patient relapse remain major clinical problems. The role of BMM in the upregulation of anti-apoptotic protein Mcl-1 is well documented. The Mcl-1 protein plays a critical role in the progression and acquired drug resistance in MM. The regulation of Mcl-1, a protein characterized by a short half-life, from transcription to degradation is crucial for understanding its role in cell survival. The GSK3β and Erk play important role in the stability of Mcl-1. Also, overexpression of phospho Erk is associated with the acquired resistance. In this study, we investigated Mcl-1 regulation, focusing on transcriptional and post-translational modifications and their impact on protein stability in Mcl-1 inhibitor ( KS18) treated cells. The small molecule inhibitor KS18 induces Mcl-1Ser159/Thr163 phosphorylation and ubiquitination resulting in a sharp decline in Mcl-1 protein levels. Furthermore, we assessed the effects of the KS18 in a combination with ERK inhibitors on cell viability and found that blocking the Mcl-1 stabilization mechanism improves the effectiveness and potency of KS18. Furthermore, we compared KS18 to different classes of chemotherapeutic agents, such as GSK3β/α inhibitor (LY209031), ERK inhibitor (SEH77272), MEK inhibitor (PD18435), and Akt inhibitor (AZD5363). Interestingly, we found KS18 more potent than other agents. Combined, our results propose a strong rationale for novel combination therapies using selective KS18 and ERK inhibitors, which have the potential to markedly improve the outcome of MM treatment. This may also address one of the major clinical problems, drug resistance, and enhance the use of existing drugs

Development of Novel Dual Inhibitor of Chemokine Receptor 4 and Mcl-1 Against Multiple Myeloma

Multiple myeloma (MM) is a neoplastic plasma-cell disorder. This is characterized by clonal proliferation of malignant plasma cells in the bone-marrow (BM) microenvironment, monoclonal protein in blood or urine, and associated organ dysfunction. The treatment options approved by FDA are immune-modulatory agents, proteasome inhibitors, and autologous stem cell transplantation (ASCT). Unfortunately, MM remains uniformly fatal owing to intrinsic or acquired drug resistance and the median survival time is 3 to 5 years. Thus, there is a great need for novel strategies to combat MM. The intimate relationship of myeloma cells to BM microenvironment is “hallmark of myeloma”. The homing of MM cells to the BM, mediated by the chemokine stromal cell-derived factor-1α (SDF-1α) and its receptor CXCR4 has important functional sequelae. The BM microenvironment constituting cells secrete chemokines, cytokines, and growth factors such as interleukin 6 (IL6), vascular endothelial growth factor (VEGF), SDF-1α, and tumor necrosis factor α (TNFα) etc. These growth factors either secreted by MM or BM microenvironment cells (e.g. stromal cells) contribute in activation of several signaling pathways including nuclear factor-κB (NF-κB); phosphatidylinositol 3-kinase (PI3K)-Akt; Ras-Raf-MAPK kinase (MEK)-extracellular signal regulated kinase (ERK); and the Janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3). Activation of these pathways has been associated with increased expression of several anti-apoptotic proteins such as Bcl-2, Bcl-xL, Mcl-1, and XIAP. Collectively, these discoveries highlight that interaction of MM cells to BM microenvironment not only promote growth, survival and migration of MM cells, but also confer resistance to conventional chemotherapy. We hypothesized that an agent capable of inhibiting the migration of myeloma cells to bone marrow and suppressing the expression of survival protein Mcl-1 would be a better option for MM treatment.We have synthesized a novel dual inhibitor of CXCR4 and Mcl-1. Our data suggests that this molecule inhibits the expression of CXCR4 and Mcl-1 and survival of MM cells

Double Haploidentical Hematopoietic Stem Cell Transplantation Results in Successful Engraftment of Bone Marrow from Both Donors without Graft-versus-Host or Graft-versus-Graft Effects

We established double-haploidentical (DH) hematopoietic stem cell transplantation (HSCT) murine models to explore competitive engraftment, graft-versus-graft effect and graft-versus-host disease (GVHD). T cell–depleted (TCD) bone marrow (BM) cells from B6SJF1 (donor 1 [D1]) and B6D2F1 (donor 2 [D2]) mice achieved >90% donor engraftment when transplanted into B6CBAF1 mice. B6CBAF1 recipients survived without evidence of GVHD when undergoing HSCT with TCD-BM from 2 haploidentical donors, D1 and D2. DH-HSCT recipients had significantly higher leukocyte and neutrophil counts than single-haploidentical HSCT recipients from either D1 or D2. DH recipients consistently showed successful mixed chimerism in both BM and spleen. Two other DH-HSCT models, B6D2F1 + C3D2F1→B6C3F1 and B6CBAF1 + B6SJLF1→B6D2F1, showed similar engraftment patterns. Low-dose T cell infusion from both D1 and D2 increased the degree of early engraftment of the respective donors in BM and spleen; however, this early engraftment pattern did not determine long-term engraftment dominance. In the long term, minimally engrafted D1 BM recovered and comprised >50% of all donor- derived B, T, and natural killer cells. We conclude that early BM engraftment is determined by donor T cell immunodominance, but long-term engraftment is related to the engraftment potential of stem cells after DH-HSCT

Ocular surface epithelia contain ABCG2-dependent side population cells exhibiting features associated with stem cells.

When cell populations are incubated with the DNA-binding dye Hoechst 33342 and subjected to flow cytometry analysis for Hoechst 33342 emissions, active efflux of the dye by the ABCG2/BCRP1 transporter causes certain cells to appear as a segregated cohort, known as a side population (SP). Stem cells from several tissues have been shown to possess the SP phenotype. As the lack of specific surface markers has hindered the isolation and subsequent biochemical characterization of epithelial stem cells this study sought to determine the existence of SP cells and expression of ABCG2 in the epithelia of the ocular surface and evaluate whether such SP cells had features associated with epithelial stem cells. Human and rabbit limbal-corneal and conjunctival epithelial cells were incubated with Hoechst 33342, and analyzed and sorted by flow cytometry. Sorted cells were subjected to several tests to determine whether the isolated SP cells displayed features consistent with the stem cell phenotype. Side populations amounting to \u3c1% of total cells, which were sensitive to the ABCG2-inhibitor fumitremorgin C, were found in the conjunctival and limbal epithelia, but were absent from the stem cell-free corneal epithelium. Immunohistochemistry was used to establish the spatial expression pattern of ABCG2. The antigen was detected in clusters of conjunctival and limbal epithelia basal cells but was not present in the corneal epithelium. SP cells were characterized by extremely low light side scattering and contained a high percentage of cells that: showed slow cycling prior to tissue collection; exhibited an initial delay in proliferation after culturing; and displayed clonogenic capacity and resistance to phorbol-induced differentiation; all features that are consistent with a stem cell phenotype

Bruton\u27s Tyrosine Kinase Targeting in Multiple Myeloma.

Multiple myeloma (MM), a clonal plasma cell disorder, disrupts the bones\u27 hematopoiesis and microenvironment homeostasis and ability to mediate an immune response against malignant clones. Despite prominent survival improvement with newer treatment modalities since the 2000s, MM is still considered a non-curable disease. Patients experience disease recurrence episodes with clonal evolution, and with each relapse disease comes back with a more aggressive phenotype. Bruton\u27s Tyrosine Kinase (BTK) has been a major target for B cell clonal disorders and its role in clonal plasma cell disorders is under active investigation. BTK is a cytosolic kinase which plays a major role in the immune system and its related malignancies. The BTK pathway has been shown to provide survival for malignant clone and multiple myeloma stem cells (MMSCs). BTK also regulates the malignant clones\u27 interaction with the bone marrow microenvironment. Hence, BTK inhibition is a promising therapeutic strategy for MM patients. In this review, the role of BTK and its signal transduction pathways are outlined in the context of MM