Myeloma is a malignant proliferation of monoclonal plasma cells. Although morphologically similar, several subtypes of the disease have been identified at the genetic and molecular level. These genetic subtypes are associated with unique clinicopathological features and dissimilar outcome. At the top hierarchical level, myeloma can be divided into hyperdiploid and non-hyperdiploid subtypes. The latter is mainly composed of cases harboring IgH translocations, generally associated with more aggressive clinical features and shorter survival. The three main IgH translocations in myeloma are the t(11;14)(q13;q32), t(4;14)(p16;q32) and t(14;16)(q32;q23). Trisomies and a more indolent form of the disease characterize hyperdiploid myeloma. A number of genetic progression factors have been identified including deletions of chromosomes 13 and 17 and abnormalities of chromosome 1 (1p deletion and 1q amplification). Other key drivers of cell survival and proliferation have also been identified such as nuclear factor-B-activating mutations and other deregulation factors for the cyclin-dependent pathways regulators. Further understanding of the biological subtypes of the disease has come from the application of novel techniques such as gene expression profiling and array-based comparative genomic hybridization. The combination of data arising from these studies and that previously elucidated through other mechanisms allows for most myeloma cases to be classified under one of several genetic subtypes. This paper proposes a framework for the classification of myeloma subtypes and provides recommendations for genetic testing. This group proposes that genetic testing needs to be incorporated into daily clinical practice and also as an essential component of all ongoing and future clinical trials.

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Promising new drugs are being evaluated for treatment of multiple myeloma (MM), but their impact should be measured against the expected outcome in patients failing current therapies. However, the natural history of relapsed disease in the current era remains unclear. We studied 286 patients with relapsed MM, who were refractory to bortezomib and were relapsed, refractory, or ineligible, to an IMiD (Immunomodulatory Drug), with measurable disease and ECOG PS of 0, 1 or 2. The date patients satisfied the entry criteria was defined as time zero (T0). The median age at diagnosis was 58 years and time from diagnosis to T0 was 3.3 years. Following T0, 213 (74%) patients had a treatment recorded with one or more regimens (median=1; range 0-8). The first regimen contained bortezomib in 55 (26%) patients and an IMiD in 70 (33%). A minor response or better was seen to at least one therapy after T0 in 94 patients (51%) including >=partial response in 69 (38%). The median overall survival and event free survival from T0 were 9 and 5 months respectively. This study confirms the poor outcome once patients become refractory to current treatments. The results provide context for interpreting ongoing trials of new drugs.

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The receptor for hyaluronan-mediated motility (RHAMM), an acidic coiled coil protein, has previously been characterized as a cell surface receptor for hyaluronan, and a microtubule-associated intracellular hyaluronan binding protein. In this study, we demonstrate that a subset of cellular RHAMM localizes to the centrosome and functions in the maintenance of spindle integrity. We confirm a previous study showing that the amino terminus of RHAMM interacts with microtubules and further demonstrate that a separate carboxy-terminal domain is required for centrosomal targeting. This motif overlaps the defined hyaluronan binding domain and bears 72% identity to the dynein interaction domain of Xklp2. RHAMM antibodies coimmunprecipitate dynein IC from Xenopus and HeLa extracts. Deregulation of RHAMM expression inhibits mitotic progression and affects spindle architecture. Structure, localization, and function, along with phylogenetic analysis, suggests that RHAMM may be a new member of the TACC family. Thus, we demonstrate a novel centrosomal localization and mitotic spindle-stabilizing function for RHAMM. Moreover, we provide a potential mechanism for this function in that RHAMM may cross-link centrosomal microtubules, through a direct interaction with microtubules and an association with dynein.

The prognosis for patients multiple myeloma (MM) has improved substantially over the past decade with the development of new, more effective chemotherapeutic agents and regimens that possess a high level of anti-tumor activity. In spite of this important progress, however, nearly all MM patients ultimately relapse, even those who experience a complete response to initial therapy. Management of relapsed MM thus represents a vital aspect of the overall care for patients with MM and a critical area of ongoing scientific and clinical research. This comprehensive manuscript from the International Myeloma Working Group provides detailed recommendations on management of relapsed disease, with sections dedicated to diagnostic evaluation, determinants of therapy, and general approach to patients with specific disease characteristics. In addition, the manuscript provides a summary of evidence from clinical trials that have significantly impacted the field, including those evaluating conventional dose therapies, as well as both autologous and allogeneic stem cell transplantation. Specific recommendations are offered for management of first and second relapse, relapsed and refractory disease, and both autologous and allogeneic transplant. Finally, perspective is provided regarding new agents and promising directions in management of relapsed MM.

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IntroductionHematopoiesis in bone marrow (BM) occurs in distinct microenvironmental niches. Discrete extracellular matrix (ECM) microenvironments within the BM help to separate endosteum, an interface between bone and BM, from the central marrow. Methods for studying hematopoiesis include clonal culture systems in semisolid media, 1 short-term 2 and long-term 3,4 liquid cultures, and tissue culture systems where hematopoietic cells grow on feeder layers of BM stromal cells. 5,6 However, cell culture systems involving growth on the surface of tissue culture plastic do not accurately represent tissue architecture 7 or the complex interactions between cells and their micro-environment. Recently, a stromal spheroid coculture model 8 and various scaffolds 9,10 have been developed to recreate the three-dimensional (3-D) environment of the BM, but these models fail to recapitulate the physiologic conditions of the BM. To adequately study B-cell development, 11 pathogenesis, 12,13 and neoplasia, 14 a culture system that places BM cells within their physiologic environment is required. For BM-localized malignancies, more effective culture systems must incorporate all compartments of the malignant clone, including cancer stem and progenitor cells, to identify their therapeutic vulnerabilities.Multiple myeloma (MM), an incurable cancer with 3-to 5-year survival despite the development of potent new therapies, 15 is characterized by monoclonal immunoglobulin (Ig), lytic bone lesions, 16 Here we present a robust 3-D tissue culture model in which the human BM microenvironment is reconstructed in vitro. In 3-D, the MM clone expands within its native microenvironment providing a valuable preclinical model within which conventional (melphalan) and novel (bortezomib) therapeutics selectively kill their target cells. In 3-D cultures, nonproliferating cells from MM BM concentrate at a reconstructed endosteummarrow junction (rEnd). Purified nonproliferating MM BM cells include MM-CSCs, as defined by their ability in a secondary culture to generate B/PC progeny harboring the unique MM clonotypic signature. Three-dimensional cultures of BM or mobilized blood autografts (MBAs) offer a preclinical model within which new therapies can be tested for their impact on all compartments of the MM clone, as well as providing access to the MM-CSC that underlie disease progression. An Inside Blood analysis of this article appears at the front of this issue.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. For personal use only. on May 8, 2018. by guest www.bloodjournal.org From Methods MaterialsAfter approval from the Health Research Board (University of Alberta) and the Alberta Cancer Board, and after informed consent was obtained in accordance with the Declaration of Helsinki, BM samples (n ϭ 48) were provided from patients undergoing BM biopsies at the Cross Cancer Institute. Al...