The Treatment of Multiple Myeloma Patients Not Eligible for Asct

Advances in therapies for younger patients with multiple myeloma have resulted in significant improvements in outcome over recent years, on the contrary the progress in treatments for elderly patients has remained more modest. Traditionally, patients who are not eligible for transplantation, like the older patients, have been treated with the combination of melphalan plus prednisone (MP), which leads to responses in approximately 50% of patients; however, patients rarely achieve a complete response (CR) and long-term outcomes are disappointing, with a relapse-free survival of approximately 18 months and an overall survival (OS) of approximately 3 years

The Medical Research Council Myeloma IX trial: the impact on treatment paradigms*

Osteolytic bone disease is a hallmark of symptomatic multiple myeloma. Bisphosphonates have been the mainstay of treatment to preserve skeletal integrity and prevent skeletal-related events in patients with myeloma-related bone disease. Recently, the MRC Myeloma IX trial demonstrated for the first time improved survival and delayed disease progression with the use of an intravenous amino-bisphosphonate, zoledronic acid, vs. an oral agent, clodronate, with intensive and non-intensive anti-myeloma treatment regimens in patients with newly diagnosed multiple myeloma. These results validate a large body of preclinical, translational and other clinical data suggesting anti-myeloma effects of amino-bisphosphonates. In addition, this trial also provided the first head-to-head evidence for superiority of one bisphosphonate over another (zoledronic acid vs. clodronate) for reducing skeletal morbidity in patients with multiple myeloma, as well as a prospective comparison of toxicities. Despite the use of non-bortezomib containing anti-myeloma treatment regimens in the MRC Myeloma IX trial, these results are encouraging and provide an impetus to continue to evaluate current treatment guidelines for myeloma-associated bone disease

Targeting histone deacetylase 3 (HDAC3) in the bone marrow microenvironment inhibits multiple myeloma proliferation by modulating exosomes and IL-6 trans-signaling

Multiple myeloma (MM) is an incurable cancer that derives pro-survival/proliferative signals from the bone marrow (BM) niche. Novel agents targeting not only cancer cells, but also the BM-niche have shown the greatest activity in MM. Histone deacetylases (HDACs) are therapeutic targets in MM and we previously showed that HDAC3 inhibition decreases MM proliferation both alone and in co-culture with bone marrow stromal cells (BMSC). In this study, we investigate the effects of HDAC3 targeting in BMSCs. Using both BMSC lines as well as patient-derived BMSCs, we show that HDAC3 expression in BMSCs can be induced by co-culture with MM cells. Knock-out (KO), knock-down (KD), and pharmacologic inhibition of HDAC3 in BMSCs results in decreased MM cell proliferation; including in autologous cultures of patient MM cells with BMSCs. We identified both quantitative and qualitative changes in exosomes and exosomal miRNA, as well as inhibition of IL-6 trans-signaling, as molecular mechanisms mediating anti-MM activity. Furthermore, we show that HDAC3-KD in BM endothelial cells decreases neoangiogenesis, consistent with a broad effect of HDAC3 targeting in the BM-niche. Our results therefore support the clinical development of HDAC3 inhibitors based not only on their direct anti-MM effects, but also their modulation of the BM microenvironment

Lenalidomide after Stem-Cell Transplantation for Multiple Myeloma

Data are lacking on whether lenalidomide maintenance therapy prolongs the time to disease progression after autologous hematopoietic stem-cell transplantation in patients with multiple myeloma

Distribution of T cell subsets in human lymph nodes

Multiple interactions between T and B lymphocytes are required for generation of the immune response. In large part, these interactions appear to require direct cellcell contact. Therefore, determination of the precise location of T and B ceils within lymphoid structures is of considerable importance. In laboratory animals, approaches utilized to define the anatomic relationship of lymphocyte subpopulations have included determination of the effects of thymectomy on lymphoid architecture (1), study by autoradiography of localization of intravenously injected radiolabeled T and B cell populations (2-4), and immunofluorescence studies of lymphoid tissue employing specific heteroantisera (5). Such studies have provided evidence for a general anatomic compartmentalization of lymphocyte subpopulations. Thus, within lymph nodes, B cells predominate in follicular areas, whereas T cells comprise the predominant cell type in the paracortical areas. In man, immunofluorescence studies of normal lymphoid structures, as well as histologic examination of lymph node tissues from patients with T or B cell deficiency states, have shown similar findings (6-8). These studies have not permitted determination of the location of T cell subsets