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Multiple myeloma (MM) is a type of B-cell malignancy that remains incurable to date. The bone marrow (BM) microenvironment plays a crucial role in MM progression. The chemokine SDF-1 (CXCL12) is an important actor of the BM microenvironment that has the ability to regulate numerous processes related to its malignant transformation during MM development. The activity of SDF-1 is mainly mediated by its specific receptor CXCR4, which is expressed at the surface of MM cells and various other BM cell types. Current treatments available for MM patients mainly target tumor cells but have limited effects on the BM microenvironment. In this context, SDF-1 and CXCR4 represent ideal targets for the normalization of the MM-supportive BM microenvironment. The present review focuses on the activity of SDF-1 in the MM BM microenvironment and the current efforts carried out to target the SDF-1/CXCR4 axis for treatment of MM. [ABSTRACT FROM AUTHOR]

Graft-versus-tumor (GVT) effects have been thought to mostly result from allogeneic transplants; however, there is a growing body of research that supports a possible autologous GVT effect. In early clinical studies, a positive correlation between lymphocyte count recovery after autologous transplantation and overall survival has been observed. However, mechanistic studies to identify the mediators of autologous GVT responses have been lacking. In this issue of the JCI, Vuckovic et al. observed a T cell-dependent autologous GVT effect in the Vk*MYC myeloma model. Moreover, the authors showed that CD8+ T cells mediate myeloma control through IFN-γ secretion, which could be further augmented with a CD137 agonist, suggesting a therapeutic approach for enhancing autologous GVT. [ABSTRACT FROM AUTHOR]

Smoldering myeloma isa heterogeneous clinical entity where a subset of patients has an indolent course of disease that mimics monoclonal gammopathy of undermined significance, whereas others have a more aggressive course that has been described as "early myeloma." It is defined as either serum M-protein ⩾3 g/L or ⩾10% monoclonal plasma cells in the bone marrow. There are currently no molecular factors to differentiate risks of progression for these patients. Current recommendations of therapy continue to be patient observation or patient enrollment in clinical trials. However, new definitions of active multiple myeloma recently agreed upon by the International Myeloma Working Group may alter the timing of therapy. On the basis of emerging data of therapy in these patients, it seems reasonable to believe that future recommendations for therapy of patients with smoldering myeloma will become an increasingly important topic. In this article, we review the current knowledge of this disease and risk factors associated with progression. We also examine biological insights and alterations that occur in the tumor clone and the surrounding bone marrow niche. Finally, we review clinical trials that have been performed in these patients and provide recommendations for follow-up of patients with this unique disease entity. [ABSTRACT FROM AUTHOR]

The article presents a case study of a patient with MYD88-mutated IgG -lambda lymphoplasmacytic lymphoma (LPL) who underwent salvage therapy with ibrutinib drug . Topics include the patient diagnosed with IgG LPL in August 2000, when experiencing fatigue and night sweats, and the patient stated to have been presented with worsening right-sided preauricular lymphadenopathy.

Extramedullary disease (EMD), defined as a clonal plasmacytic infiltrate at anatomic sites distant from the bone marrow or adjacent soft tissue in a patient with underlying multiple myeloma, is present in a significant percentage of patients with multiple myeloma at some point during the course of their disease. The exact prevalence of EMD, however, has not been reproducibly described, with some series citing EMD in 6% of patients with myeloma, and others up to 20%. EMD is therefore an uncommon, but by no means rare, manifestation of multiple myeloma. Further observational series have suggested that EMD is a highly aggressive disease entity, with clinical behavior distinct from marrow-restricted myeloma. This article summarizes the current research on EMD and examines the opportunity for further research into the pathogenic, immunologic, cytogenetic, clinical, therapeutic and prognostic features of this hitherto poorly understood disease entity. [ABSTRACT FROM AUTHOR]

The present study aimed to determine the safety and activity of the histone deacetylase inhibitor panobinostat in patients with relapsed/refractory Waldenström macroglobuline- mia (WM). Eligibility criteria included patients with relapsed/refractory WM with any number of prior therapies. Patients received panobinostat at 30 mg 3 times a week; 12 of 36 (33%) patients were enrolled at 25 mg dose. A total of 36 patients received therapy. The median age was 62 years (range, 47-80) and the median number of prior therapies was 3 (range, 1-8). All of the patients had received prior rituximab. Minimal response (MA) or better was achieved in 47% of patients (90% confidence interval [Cl], 33-62), with 22% partial remissions and 25% MR. In addition, 18 (50%) patients achieved stable disease and none showed progression while on therapy. The median time to first response was 1.8 months (range, 1.7-3.2). The median progression-free survival was 6.6 months(90% Cl, 5.5-14.8). Grade 3 and 4 toxicities included thrombocytopenia (67%), neutropenia (36%), anemia (28%), leukopenia (22%), and fatigue (11%). We conclude that panobinostat is an active therapeutic agent in patients with relapsed/refractory WM. This study (www.clinicaltrials.gov identifier: NCT00936611) establishes a role for histone deacetylase inhibitors as an active class of therapeutic agents in WM. [ABSTRACT FROM AUTHOR]

The prognosis of patients with multiple myeloma (MM) has radically changed over the past two decades mostly due to the introduction of novel pharmacologic treatments such as thalidomide, bortezomib and lenalidomide. These drugs were the first new anti-myeloma agents since the 1950s, and represented a landmark step in the race for the cure of MM and the paradigm of effectiveness of bench-to-bedside research. Compared to a median overall survival of 2-3 years in the mid- 1950s, patients with MM have nowadays an expected median survival of 7-8 years. Novel agents have not only extended the life expectancy of patients with MM, but also shed light on the necessity of further understanding the biology of MM in order to design more effective, less toxic therapies. Basic research has provided a critical mass of information about the molecular and cellular biology of MM, particularly the pivotal pathogenetic role of the bone marrow niche. Several novel drugs, designed to specifically target MM in the context of its microenvironment, are currently in clinical trials and hold great promise for improving the MM treatment armamentarium and overcoming resistance. In this article we review the biological basis of effectiveness of anti-myeloma agents with an emphasis on experimental drugs. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is a plasma cell dyscrasia characterized by the presence of multiple myelomatous "omas" throughout the skeleton, indicating that there is continuous trafficking of tumor cells to multiple areas in the bone marrow niches. MM may therefore represent one of the best models to study cell trafficking or cell metastasis. The process of cell metastasis is described as a multistep process, the invasion-metastasis cascade. This involves cell invasion, intravasation into nearby blood vessels, passage into the circulation, followed by homing into predetermined distant tissues, the formation of new foci of micrometastases, and finally the growth of micrometastasis into macroscopic tumors. This review discusses the significant advances that have been discovered in the complex process of invasion-metastasis in epithelial carcinomas and cell trafficking in hematopoietic stem cells and how this process relates to progression in MM. This progression is mediated by clonal intrinsic factors that mediate tumor invasiveness as well as factors present in the tumor microenvironment that are permissive to oncogenic proliferation. Therapeutic agents that target the different steps of cell dissemination and progression are discussed. Despite the significant advances in the treatment of MM, better therapeutic agents that target this metastatic cascade are urgently needed. [ABSTRACT FROM AUTHOR]

Summary: Background: Multiple myeloma is the second most prevalent haematological malignancy and is incurable. Our aim was to assess the response and safety of the combination of temsirolimus (an mTOR inhibitor) and bortezomib in patients with relapsed or refractory multiple myeloma. Methods: We did an open-label, dose-escalation study in three centres in the USA. Patients were enrolled from June, 2007, to December, 2009. Eligible patients were aged 18 years or older with relapsed or relapsed and refractory multiple myeloma after one or more treatment (including lenalidomide, bortezomib, or thalidomide), with an Eastern Cooperative Oncology Group performance status of 0–2. Patients were assigned a dose level in the order of their entry into the study. Phase 1 was to assess the safety and establish the maximum tolerated dose (MTD) of the combination and phase 2 was to assess overall response rate at the MTD. Intravenous temsirolimus was given at 15 or 25 mg and intravenous bortezomib at 1·3 or 1·6 mg/m2 once a week, with dose escalation until dose-limiting adverse events were recorded in two of the three people in the dose cohort. Use of steroids were not permitted. The primary endpoint was the proportion of patients with a partial response or better. Analyses were done on an intention-to-treat basis, with all patients who had been enrolled included. The study is registered with ClinicalTrials.gov, number NCT00483262. Findings: 20 patients were enrolled into the phase 1 study and 43 into phase 2. All patients were heavily pretreated (median five lines in the phase 1 cohort, and four lines in the phase 2 cohort). The MTD was determined to be 1·6 mg/m2 bortezomib on days 1, 8, 15, and 22 in combination with 25 mg temsirolimus on days 1, 8, 15, 22, and 29, for a cycle of 35 days. In the phase 2 study, the proportion of patients with a partial response or better was 33% (14 of 43; 90% CI 21–47). Long-term follow-up of patients is ongoing. There were three deaths during treatment in the phase 1 and 2 studies: one patient died of septic shock in the phase 1 study; one patient died with H1N1 influenza infection and one died with cardiac amyloid and ventricular arrhythmia unrelated to treatment in the phase 2 study. In the phase 1 study, the most common treatment-related grade 3–4 adverse events were thrombocytopenia (13 patients), lymphopenia (ten), neutropenia (nine), leucopenia (seven), and anaemia (five). In the phase 2 study, the most common treatment-related grade 3–4 adverse events were thrombocytopenia (25 patients), lymphopenia (24), neutropenia (17), leucopenia (ten), anaemia (seven), and diarrhoea (five). Four patients in the phase 1 study had sensory peripheral neuropathy (grade 2 or less); in the phase 2 study, 11 had sensory peripheral neuropathy (all grade 2 or less) and seven motor peripheral neuropathy (one grade 3, six grade 2 or less). Interpretation: mTOR inhibitors could have a role in combination with weekly bortezomib for the treatment of patients with relapsed and refractory multiple myeloma without the addition of steroids. Funding: Millennium Inc, Pfizer Inc, Multiple Myeloma Research Foundation, and the Leukemia and Lymphoma Society. [Copyright &y& Elsevier]

Objective: In this article we focus on the role that chemokines and chemokine receptors play in the pathogenesis of multiple myeloma and the associated bone destructive process, and consider their utility as novel therapeutic targets for treating this devastating disease. Methods: Current research on the role that chemokine and chemokine receptors play in the pathogenesis of myeloma is reviewed. Results: The chemokines, MIP-1α, MCP-1, IL-8, and SDF-1, and their receptors play important roles in homing of MM cells, tumor growth, and bone destruction in myeloma. They are attractive therapeutic targets for treating myeloma patients. Conclusion: Addition of chemokine antagonists to current treatment regimens for myeloma should result in better therapeutic responses because of the loss of both the protective effect of the marrow microenvironment on the MM cells and the induction of osteoclast activity. [Copyright &y& Elsevier]

We sought to define prognostic factors for survival in Waldenstrom macroglobulinaemia (WM). Of 585 patients diagnosed with WM and seen at Mayo Clinic between 1960 and 2001, 337 symptomatic patients met the inclusion criteria and were analysed for overall and disease-specific survival. The median survival from the time of diagnosis was 6·4 years. The median disease-specific survival was 11·2 years. Univariate analysis for overall survival identified the following adverse prognostic factors: age >65 years ( P < 0·001), organomegaly ( P < 0·001), elevated β2-microglobulin (<0·001), anaemia (Hb < 10·0 g/dl) ( P = 0·01), leucopenia (<4·0 × 109/l) ( P = 0·03), thrombocytopenia (<150 × 109/l) ( P = 0·01), serum albumin <40 g/l ( P = 0·001), and quantitative IgM < 0·4 g/l ( P = 0·04). On multivariate analysis, age >65 years and organomegaly were associated with poor prognosis. A prognostic model was built based on these two variables. Patients at high risk (1–2 risk factors, median survival 4·2 years) experienced worse survival than patients at low risk (0 risk factors, median survival 10·6 years), P < 0·001. The prognostic model was validated in 204 patients who were not included in the analysis cohort. β2-microglobulin ≥4 mg/l was associated with a threefold increase in the risk of death when added to the prognostic model. We describe a simple prognostic model for overall survival for newly diagnosed patients with WM. [ABSTRACT FROM AUTHOR]

Several factors are responsible for the occurrence of cardiac complications after bone marrow transplantation (BMT). These factors include the cardiotoxic effects of radiation therapy, antineoplastic and immunosuppressive drugs, abnormal immunologic reactions associated with graft-vs-host disease, and infectious agents. We report the case of a 45-year-old woman with T-cell prolymphocytic leukemia and no prior risk factors for coronary artery disease in whom sudden cardiac death occurred 2½ years after allogeneic BMT from an unrelated male donor. Autopsy revealed severe 3-vessel coronary disease with grade 4/4 stenosis. This process was primarily nonatherosclerotic, with intimal hyperplasia of undetermined etiology. Furthermore, fluorescence in situ hybridization to identify the donor Y chromosome with simultaneous immunofluorescence labeling of smooth muscle actin suggested the presence of donor cells that transformed into myocytes. Coronary artery disease is an important, albeit tare,complication of BMT. Donor hematopoietic cells may contribute to its pathogenesis. [ABSTRACT FROM AUTHOR]

• Objective: To assess the clinical relevance of chemokine receptor expression on the progression of B-cell chronic lymphocytic leukemia (B-CLL)., • Patients and Methods: Peripheral blood mononuclear cells from 45 patients with B-CLL were purified and compared with lymph node samples collected from 17 of these patients. Also compared were B cells obtained from peripheral blood samples from 5 healthy controls and B cells from reactive lymph nodes from 3 otherwise healthy persons. The patients were treated at the Mayo Clinic in Rochester, Minn, between January 15,1991, and February 7,2003. Mononuclear cells were stained by a 2-color (fluorescein isothiocyanate/phycoerythrin) flow cytometric assay using antibodies to the chemokine receptors (CXCR1, CXCR2, CXCR3, CXCR4, CXCR5 , CCR2, CCR4, CCRS, CCR6, and CCR7) and also to CD19. • Results: Of the 45 patients in this study, 20 had Rai stage 0 disease, 12 had stage I disease, 3 had stage H disease, 2 had stage HI disease, and Shad stage IV disease. The mean fluorescent intensity (MFI) of the chemokine receptor expression on B-CLL cells was compared with normal controls and was not significantly different, except for an increase in the median expression of CXCR3 (P=.003) and CCR7 (P=.001) on B-CLL cells. We also found a significant increase in the expression of CXCR4 and CCR7 in B-CLL cells from patients with stage Pt compared with stage 0 disease (P=.001 and P=.02, respectively). Furthermore, circulating B-CLL cells showed significantly higher expression of CXCR4 and CCR7 when compared with B lymphocytes in lymph nodes (P=.003 and P<001, respectively). • Conclusion: The expression of CXCR4 and CCR7 on B-CLL cells correlates with Rai stage. Also, these chemokine receptors may be down-regulated once malignant B cells enter the lymph nodes. To our knowledge, this is the first published report that shows the strong association of Rai stage with CXCR4 and CCR7 expression levels in B-CLL cells. [ABSTRACT FROM AUTHOR]

• Objectives: To determine the long-term outcome of patients presenting with synchronous lymphoma and severe liver dysfunction and to describe the outcome of patients treated with initial mechlorethamine-based therapy used as a bridge to more conventional chemotherapy. • Patients and Methods: We reviewed the clinical course of all patients diagnosed as having lymphoma who presented with severe liver dysfunction and received intravenous mechlorethamine between September 1988 and February 2003 at the Mayo Clinic in Rochester, Minn. • Results: Forty-one patients were identified, 33 (80%) of whom had newly diagnosed, previously untreated lymphoma. Thirty-seven (90%) had non-Hodgkin lymphoma, and 4 (10%) had Hodgkin disease. Thirty-four patients (83%) had stage IV disease, and 31 (84%) of 37 had an intermediate-high International Prognostic Index. The median total bilirubin level before therapy was 10.7 mg/dL (range, 2.5-30.2 mg/dL), and the median alkaline phosphatase level was 982 U/L (range, 233-3415 U/L). In addition to mechlorethamine, 34 patients (83%) received concomitant corticosteroids, and 12 (29%) received concomitant rituximab. Twenty-two patients (54%) had sufficient improvement in liver function to receive subsequent standard chemotherapy. Nine patients (22%) are alive and disease-free at a median of 31 months (range, 4 to ≥87 months) after mechlorethamine treatment. Factors associated with improved overall survival included improvement in bilirubin levels (P<.001) and receiving subsequent standard chemotherapy (P=.001). • Conclusion: Mechlorethamine, high-dose corticosteroids, and rituximab are useful therapeutic interventions for this unique group of patients with lymphoma and severe liver dysfunction. Substantial clinical improvement and long-term survival are possible. AST = aspartate aminotransferase; CHOP = cyclophosphamide, hydroxydaunomycin (doxorubicin), Oncovin (vincristine), and prednisone; CT = computed tomography; HD = Hodgkin disease; IPI = International Prognostic Index; LDH = lactate dehydrogenase; NHL = non-Hodgkin lymphoma. [ABSTRACT FROM AUTHOR]

Waldenstro¨m macroglobulinemia (WM) is a lymphoid neoplasm characterised by a monoclonal lymphoplasmacytic expansion accompanied by a serum monoclonal immunoglobulin M (IgM). In some patients, the monoclonal protein will lead to a characteristic hyperviscosity syndrome. Although indolent, WM is incurable and most patients eventually succumb to disease progression. Thus, we need to better understand the natural history and biology of the disease. Recent work has shown that half of patients with WM harbour deletions in the long arm of chromosome 6. Increasing evidence suggests the disease is a defined pathological entity and not purely a clinical syndrome. Current therapeutic modalities include alkylator agents, purine nucleoside analogues, and rituximab. The optimum initial therapeutic strategy is not yet defined, and current clinical trials are addressing the role of combination therapy. In this review, we summarise the current understanding of the pathogenesis, clinical and laboratory features, prognostic factors, and therapeutic options for patients with WM. We also discuss current knowledge of WM and available therapies. [Copyright &y& Elsevier]

A letter to the editor is presented which is concerned with treatment paradigms for multiple myeloma.

The author discusses the retention of the expression of progenitor cell-associated marker CD117 or myeloid-associated marker CD33 in patients with multiple myeloma by plasma cells (PCs). The proliferation of plasma cells with a strong dependence on the bone marrow microenvironment is explained. Down-regulation of CD56 in myelomatous PCs correlated with the likelihood to short progression-free survival in studies is cited.

Multiple myeloma (MM) is the second most common haematological malignancy after non-Hodgkin lymphoma. Despite the improvement in outcomes over the last decade with the introduction of novel therapies, such as immunomodulatory agents (IMiDs) and proteasome inhibitors (PIs), MM remains an incurable disease. Patients who are both refractory to IMiDs and PIs carry a particularly dismal prognosis. The development of targeted therapy in the form of monoclonal antibodies has shifted the treatment paradigm of this disease, resulting in unprecedented response rates, even among the highest-risk patients. In this review, we will summarize the mechanism of action and provide an overview of the clinical trials that have led to the US Food and Drug Administration approval of Daratumumab and Elotuzumab, and their current use in the treatment of MM. [ABSTRACT FROM AUTHOR]

Presents medical images of renal cell carcinoma with acrometastasis and scalp metastasis. Medical history; Radiograph study results; Pathologic specimens.

A letter to the editor about the use of alemtuzumab to treat patients with chronic lymphocytic leukemia is presented.

Background: Multiple myeloma (MM) is an incurable hematologic malignancy requiring long‐term, continuous therapy. Despite its chronic and unrelenting course, studies examining quality of life (QOL), psychological distress, and perceptions of prognosis by line of therapy are lacking. Methods: The authors conducted a cross‐sectional, multisite study of patients undergoing treatment for MM (excluding maintenance) between June 2020 and January 2021. The authors conducted purposeful sampling and recruited patients to 3 cohorts based on lines of therapy: 1) newly diagnosed receiving first‐line therapy; 2) 2 to 3 lines; and 3) 4 or more lines. Patients completed validated questionnaires to assess their QOL, fatigue, psychological distress, and perceptions of prognosis. Results: A total of 180 patients with MM were enrolled (newly diagnosed [n = 60], 2 to 3 lines [n = 60], and ≥4 lines of therapy [n = 60]). QOL, symptom burden, and fatigue scores did not differ by lines of therapy. There were no statistically significant differences in psychological distress by line of therapy. The rates of clinically significant depression, anxiety, and post‐traumatic stress disorder symptoms were 23.9% (43 of 180), 23.9% (43 of 180), and 24.4% (44 of 180), respectively. Most patients (84.7%, 149 of 176) reported that their oncologist told them their cancer was incurable, but only 30.6% (53 of 173) acknowledged that they were terminally ill, and 42.0% (73 of 174) reported that they thought their cancer was incurable. Conclusions: Patients with MM undergoing treatment experience impaired QOL and elevated psychological distress across the disease continuum, regardless of line of therapy. A substantial proportion of patients with MM have significant misperceptions about their prognosis and the curability of their illness despite reporting being informed of the prognosis by their oncologist. Lay Summary: This study discusses 180 patients with MM (newly diagnosed [n = 60], 2‐3 lines [n = 60], and ≥4 lines of therapy [n = 60]). Quality of life, symptom burden, and fatigue scores do not differ by lines of therapy. There are also no statistically significant differences in psychological distress by line of therapy.The rates of clinically significant depression, anxiety, and post‐traumatic stress disorder symptoms are 23.9%, 23.9%, and 24.4%, respectively.Most patients (84.7%) report that their oncologist told them their cancer was incurable, but only 30.6% acknowledge that they are terminally ill, and 42.0% report that they thought their cancer was incurable. Patients with multiple myeloma undergoing treatment experience impaired quality of life and elevated psychological distress across the disease continuum. Although the majority reported that their oncologist had told them that their cancer is incurable, a substantial proportion still reported that they believed their cancer was curable. [ABSTRACT FROM AUTHOR]

Many novel therapeutic agents are being tested in clinical trials for Waldenstrom macroglobulinemia (WM). However, given the paucity of large clinical trials in WM, the establishment of a standard treatment regimen that can be used for comparison of response has become challenging. We therefore performed a review of published clinical trials in WM. Systematic searches of the PubMed and Medline databases, including The Cochrane Library, were performed for the search terms: clinical trials, Waldenstrom, macroglobulinemia, and lymphoplasmacytic lymphoma. Studies of transplant in WM are beyond the scope of this review and were excluded. A total of 44 clinical trials were found in this search (38 full articles, six abstracts). Of these, 11 were performed in patients with untreated WM, 14 in patients with relapsed or refractory WM, 17 in both upfront and relapsed or refractory WM, and two studies did not provide this information. Based on this review, we recommend new response criteria and definitions of time to event analysis to be used in future clinical trials of WM. This review of the published literature would serve as a reference for comparison of response and survival analysis in current clinical trials. [ABSTRACT FROM AUTHOR]

Waldenström Macroglobulinemia (WM) is a low-grade B-cell lymphoma characterized by disease progression from IgM MGUS to asymptomatic and then symptomatic disease states. We profiled exosomes from the peripheral blood of patients with WM at different stages (30 smoldering/asymptomatic WM, 44 symptomatic WM samples and 10 healthy controls) to define their role as potential biomarkers of disease progression. In this study, we showed that circulating exosomes and their miRNA content represent unique markers of the tumor and its microenvironment. We observed similar levels of miRNAs in exosomes from patients with asymptomatic (smoldering) and symptomatic WM, suggesting that environmental and clonal changes occur in patients at early stages of disease progression before symptoms occur. Moreover, we identified a small group of miRNAs whose expression correlated directly or inversely with the disease status of patients, notably the known tumor suppressor miRNAs let-7d and the oncogene miR-21 as well as miR-192 and miR-320b. The study of these miRNAs’ specific effect in WM cells could help us gain further insights on the mechanisms underlying WM pathogenesis and reveal their potential as novel therapeutic targets for this disease. [ABSTRACT FROM AUTHOR]

Abstract: We sought a regimen that incorporates optimal novel agents and balances efficacy with toxicity in transplant‐ineligible multiple myeloma (MM) patients. Our study evaluated modified lenalidomide‐bortezomib‐dexamethasone (RVD lite) in this population and was administered over a 35‐day cycle. Lenalidomide 15 mg was given orally on days 1–21; bortezomib 1·3 mg/m2 weekly subcutaneously on days 1, 8, 15 and 22; and dexamethasone 20 mg orally was given on the day of and day after bortezomib for 9 cycles followed by 6 cycles of consolidation with lenalidomide and bortezomib. The primary objective was to evaluate the overall response rate (ORR); secondary objectives included safety, progression‐free survival (PFS) and overall survival (OS). Fifty‐three eligible patients were screened between April 2013 and May 2015; 50 received at least one dose of therapy. Median age at study entry was 73 years (range 65–91). The ORR was 86% and 66% of patients achieved a very good partial response or better. Median PFS was 35·1 months (95% confidence interval 30·9–not reached) and median OS was not reached at a median follow‐up of 30 months. Peripheral neuropathy was reported in 31 (62%) patients with only 1 patient experiencing grade 3 symptoms. RVD lite is a well‐tolerated and highly effective regimen, with robust PFS and OS, in the transplant‐ineligible MM population. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is a plasma cell cancer that develops in the skeleton causing profound bone destruction and fractures. The bone disease is mediated by increased osteoclastic bone resorption and suppressed bone formation. Bisphosphonates used for treatment inhibit bone resorption and prevent bone loss but fail to influence bone formation and do not replace lost bone, so patients continue to fracture. Stimulating bone formation to increase bone mass and fracture resistance is a priority; however, targeting tumor-derived modulators of bone formation has had limited success. Sclerostin is an osteocyte-specific Wnt antagonist that inhibits bone formation. We hypothesized that inhibiting sclerostin would prevent development of bone disease and increase resistance to fracture in MM. Sclerostin was expressed in osteocytes from bones from naive and myeloma-bearing mice. In contrast, sclerostin was not expressed by plasma cells from 630 patients with myeloma or 54 myeloma cell lines. Mice injected with 5TGM1-eGFP, 5T2MM, or MM1.S myeloma cells demonstrated significant bone loss, which was associated with a decrease in fracture resistance in the vertebrae. Treatment with anti-sclerostin antibody increased osteoblast numbers and bone formation rate but did not inhibit bone resorption or reduce tumor burden. Treatment with anti-sclerostin antibody prevented myeloma-induced bone loss, reduced osteolytic bone lesions, and increased fracture resistance. Treatment with anti-sclerostin antibody and zoledronic acid combined increased bone mass and fracture resistance when compared with treatment with zoledronic acid alone. This study defines a therapeuticstrategysuperior tothecurrent standardof care that will reducefractures forpatients withMM. [ABSTRACT FROM AUTHOR]

Symptomatic hyperviscosity is a common clinical manifestation in patients with Waldenström macroglobulinaemia ( WM) and high serum IgM levels. Prompt intervention is required to prevent catastrophic events, such as retinal or central nervous system bleeding. Identifying patients at high risk of symptomatic hyperviscosity might support the decision to treat asymptomatic patients before irreversible damage occurs. We carried out a large retrospective study in 825 newly diagnosed WM patients, of who 113 (14%) developed symptomatic hyperviscosity. The median serum IgM level at the time of symptomatic hyperviscosity was 61·8 g/l (range 31-124 g/l). Forty-four patients (36%) had symptomatic hyperviscosity at the time of WM diagnosis. A serum IgM level >60 g/l at diagnosis was associated with a median time to symptomatic hyperviscosity of 3 months, whereas the median time for patients with serum IgM level of 50·01-60 g/l was approximately 3 years. Adjusting for other clinical factors, the odds of developing symptomatic hyperviscosity were 370-fold higher with serum IgM levels >60 g/l, and showed an association with CXCR4 mutational status. Symptomatic hyperviscosity did not impact overall survival ( P = 0·12). The findings support the use of serum IgM level >60 g/l as a criterion for initiation of therapy in an otherwise asymptomatic WM patient. [ABSTRACT FROM AUTHOR]

Exosomes, secreted by several cell types, including cancer cells, can be isolated from the peripheral blood and have been shown to be powerful markers of disease progression in cancer. In this study, we examined the prognostic significance of circulating exosomal microRNAs (miRNAs) in multiple myeloma (MM). A cohort of 156 patients with newly diagnosed MM, uniformly treated and followed, was studied. Circulating exosomal miRNAs were isolated and used to perform a small RNA sequencing analysis on 10 samples and a quantitative reverse transcription polymerase chain reaction (qRT-PCR) array on 156 samples. We studied the relationship between miRNA levels and patient outcomes, including progression-free survival (PFS) and overall survival (OS). We identified miRNAs as the most predominant small RNAs present in exosomes isolated from the serum of patients with MM and healthy controls by small RNA sequencing of circulating exosomes. We then analyzed exosomes isolated from serum samples of 156 patients using a qRT-PCR array for 22 miRNAs. Two of these miRNAs, let-7b and miR-18a, were significantly associated with both PFS and OS in the univariate analysis and were still statistically significant after adjusting for the International Staging System and adverse cytogenetics in the multivariate analysis. Our findings support the use of circulating exosomal miRNAs to improve the identification of patients with newly diagnosed MM with poor outcomes. The results require further validation in other independent prospective MM cohorts. [ABSTRACT FROM AUTHOR]

Multiple myeloma ( MM) is a lethal haematological malignancy that arises in the context of a tumour microenvironment that promotes resistance to apoptosis and immune escape. In the present study, we demonstrate that co-culture of MM cells with stromal cells results in increased resistance to cytotoxic and biological agents as manifested by decreased rates of cell death following exposure to alkylating agents and the proteosome inhibitor, bortezomib. To identify the mechanism of increased resistance, we examined the effect of the co-culture of MM cells with stroma cells, on expression of the MUC1 oncogene, known to confer tumour cells with resistance to apoptosis and necrosis. Co-culture of stroma with MM cells resulted in increased MUC1 expression by tumour cells. The effect of stromal cell co-culture on MUC1 expression was not dependent on cell contact and was therefore thought to be due to soluble factors secreted by the stromal cells into the microenvironment. We demonstrated that MUC1 expression was mediated by interleukin-6 and subsequent up-regulation of the JAK- STAT pathway. Interestingly, the effect of stromal cell co-culture on tumour resistance was partially reversed by silencing of MUC1 in MM cells, consistent with the potential role of MUC1 in mediating resistance to cytotoxic-based therapies. [ABSTRACT FROM AUTHOR]

Bing-Neel syndrome ( BNS) is a rare complication seen in patients with Waldenström macroglobulinaemia ( WM), in which lymphoplasmacytic lymphoma cells colonize the central nervous system. In this retrospective multi-centre study, we present the clinicopathological features, imaging findings, therapy, response and outcomes of 34 patients with BNS. The median time from WM diagnosis to BNS diagnosis was 3 years, 15% of patients were diagnosed with BNS at the time of WM diagnosis, and 22% of patients developed BNS when responding to active treatment for WM. Patients with BNS presented with variable clinical features including limb motor deficits, change in mental status and cranial nerve palsies. The diagnosis was made using a combination of cerebrospinal fluid cytology, flow cytometry and detection of the MYD88 L265 mutation, and magnetic resonance imaging. The estimated 3-year overall survival rate was 59%. Of the survivors, 40% have evidence of pathological and/or radiological persistence of disease. Age older than 65 years, platelet count lower than 100 × 109/l, and treatment for WM prior to BNS diagnosis were associated with worse outcome. Exposure to rituximab for treatment of BNS was associated with a better outcome. Multi-institutional collaboration is warranted to improve treatment and outcomes in patients with BNS. [ABSTRACT FROM AUTHOR]

Advancement of many solid tumors and hematologic malignancies is frequently characterized by dissemination and homing of cancer cells to the bone marrow (BM). Methods to quantitatively characterize these key steps of the metastatic cascade in mammalian models are currently limited and do not offer opportunities to perform rapid, large-scale genomic, or drug screening. Because of their optical clarity, we used zebrafish to develop an in vivo model of cancer cell dissemination and homing to the BM.We performed intracardiac injection of multiple myeloma (MM) cells derived from human BM or cell lines and monitored their migration to the caudal hematopoietic tissue (CHT), the region where hematopoiesis occurs in the zebrafish embryo, which recapitulates a BM-like niche. Transcriptomic analyses confirmed thatMM cells homing to the CHT displayed gene-expression differences compared with MM cells outside of the CHT, including significant enrichment for genes known to regulate interleukin-6 (IL6) signaling, cell adhesion, and angiogenesis. Collectively, our findings point to the zebrafish as a valuable model in which to study cancer cell homing to the hematopoietic niche and to establish a screening platform for the identification of factors and mechanisms contributing to the early steps of bone metastasis. [ABSTRACT FROM AUTHOR]

Proteasome inhibitors ( PI) and immunomodulatory agents ( IMIDs) have improved the overall survival (OS) of patients with multiple myeloma ( MM), but concerns have been raised about increased incidence of extramedullary disease ( EMD) after the combined use of PIs and IMIDs for upfront therapy. We evaluated whether the addition of lenalidomide to bortezomib-based front-line regimens precipitated earlier development of EMD. We reviewed the charts of 117 MM patients (median follow-up from diagnosis 6·1 years; range 0·1-10·2 years) enrolled in eight clinical trials of first-line treatment with bortezomib-based regimens, with or without lenalidomide. We assessed development of EMD as extraosseous (distant from bone) or osseous (originating from bone) plasmacytomas. The primary endpoint was time from diagnosis until development of EMD, based on imaging, biopsy and/or physical examination. Any form of EMD at progression was observed in 40 (34·2%) patients, including 21 (18%) osseous, 8 (7%) extraosseous and 11 (9%) both osseous and extraosseous. Median OS was 0·9 years (range 0·1-4·8 years) after extraosseous EMD development. Sensitivity analyses with follow-up times truncated at 5 years detected no statistically significant difference in rates of any EMD form between the two groups ( P > 0·2 for each comparison). Therefore, we observed no evidence that bortezomib-lenalidomide-based front-line therapy precipitates earlier EMD. [ABSTRACT FROM AUTHOR]

Extramedullary disease ( EMD), defined as an infiltrate of clonal plasma cells at an anatomic site distant from the bone marrow, is an uncommon manifestation of multiple myeloma. Six hundred and sixty-three consecutive patients with multiple myeloma who underwent stem cell transplantation between January 2005 and December 2011 were assessed for the presence of EMD. A cohort of 55 patients with biopsy-proven EMD was identified, comprising 8·3% of the total study population. EMD was present at the time of diagnosis in 14·5% of cases and at the time of relapse in 76% of patients. The most common EMD presentations at relapse were liver involvement and pleural effusions. EMD specimens had high expression of CD44 (92%) and moderate expression of CXCR4. The median overall survival from time of myeloma diagnosis was 4·1 years (95% CI: 3·1, 5·1) and the median overall survival from time of EMD diagnosis was 1·3 years (95% CI: 0·8, 2·3). This report demonstrates that the incidence of EMD has not increased with the introduction of novel agents and stem cell transplantation. The most common EMD presentations in the relapsed setting were liver and pleural fluid. The presence of CD44 and CXCR4 expression may represent new markers of EMD that warrant further investigation. [ABSTRACT FROM AUTHOR]

Multiple myeloma is a B-cell malignancy characterized by the unrelenting proliferation of plasma cells. Multiple myeloma causes osteolytic lesions and fractures that do not heal due to decreased osteoblastic and increased osteoclastic activity. However, the exact relationship between osteoblasts and myeloma cells remains elusive. Understanding the interactions between these dynamic bone-forming cells and myeloma cells is crucial to understanding how osteolytic lesions form and persist and how tumors grow within the bone marrow. This review provides a comprehensive overview of basic and translational research focused on the role of osteoblasts in multiple myeloma progression and their relationship to osteolytic lesions. Importantly, current challenges for in vitro studies exploring direct osteoblastic effects on myeloma cells, and gaps in understanding the role of the osteoblast in myeloma progression are delineated. Finally, successes and challenges in myeloma treatment with osteoanabolic therapy (i.e., any treatment that induces increased osteoblastic number or activity) are enumerated. Our goal is to illuminate novel mechanisms by which osteoblasts may contribute to multiple myeloma disease progression and osteolysis to better direct research efforts. Ultimately, we hope this may provide a roadmap for new approaches to the pathogenesis and treatment of multiple myeloma with a particular focus on the osteoblast. [ABSTRACT FROM AUTHOR]

Drug resistance remains a major clinical challenge for cancer treatment. Multiple myeloma is an incurable plasma cell cancer selectively localized in the bone marrow. The main cause of resistance in myeloma is the minimal residual disease cells that are resistant to the original therapy, including bortezomib treatment and high-dose melphalan in stem cell transplant. In this study, we demonstrate that altered tumor cell metabolism is essential for the regulation of drug resistance in multiple myeloma cells. We show the unprecedented role of the metabolic phenotype in inducing drug resistance through LDHA and HIF1A in multiple myeloma, and that specific inhibition of LDHA and HIF1A can restore sensitivity to therapeutic agents such as bortezomib and can also inhibit tumor growth induced by altered metabolism. Knockdown of LDHA can restore sensitivity of bortezomib resistance cell lines while gain-of-function studies using LDHA or HIF1A induced resistance in bortezomib- sensitive cell lines. Taken together, these data suggest that HIF1A and LDHA are important targets for hypoxia-driven drug resistance. Novel drugs that regulate metabolic pathways in multiple myeloma, specifically targeting LDHA, can be beneficial to inhibit tumor growth and overcome drug resistance. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is characterized by clonal expansion of malignant plasma cells in the bone marrow (BM). Despite the significant advances in treatment, MM is still a fatal malignancy. This is mainly due to the supportive role of the BM microenvironment in differentiation, migration, proliferation, survival, and drug resistance of the malignant plasma cells. The BM microenvironment is composed of a cellular compartment (stromal cells, osteoblasts, osteoclasts, endothelial cells, and immune cells) and a non-cellular compartment. In this review, we discuss the interaction between the malignant plasma cell and the BM microenvironment and the strategy to target them. [ABSTRACT FROM AUTHOR]

In the past decade, extracellular vesicles (EVs) have been recognized as potent vehicles of intercellular communication, both in prokaryotes and eukaryotes. This is due to their capacity to transfer proteins, lipids and nucleic acids, thereby influencing various physiological and pathological functions of both recipient and parent cells. While intensive investigation has targeted the role of EVs in different pathological processes, for example, in cancer and autoimmune diseases, the EV-mediated maintenance of homeostasis and the regulation of physiological functions have remained less explored. Here, we provide a comprehensive overview of the current understanding of the physiological roles of EVs, which has been written by crowd-sourcing, drawing on the unique EV expertise of academia-based scientists, clinicians and industry based in 27 European countries, the United States and Australia. This review is intended to be of relevance to both researchers already working on EV biology and to newcomers who will encounter this universal cell biological system. Therefore, here we address the molecular contents and functions of EVs in various tissues and body fluids from cell systems to organs. We also review the physiological mechanisms of EVs in bacteria, lower eukaryotes and plants to highlight the functional uniformity of this emerging communication system. [ABSTRACT FROM AUTHOR]

Clonal proliferation of plasma cells within the bone marrow (BM) affects local cells, such as mesenchymal stromal cells (MSCs), leading to osteolysis and fatality in multiple myeloma (MM). Consequently, there is an urgent need to find better mechanisms of inhibiting myeloma growth and osteolytic lesion development. To meet this need and accelerate clinical translation, better models of myeloma within the BM are required. Herein we have developed a clinically relevant, three-dimensional (3D) myeloma BM coculture model that mimics bone cell/cancer cell interactions within the bone microenvironment. The coculture model and clinical samples were used to investigate myeloma growth, osteogenesis inhibition, and myeloma-induced abnormalities in MM-MSCs. This platform demonstrated myeloma support of capillarylike assembly of endothelial cells and cell adhesion-mediated drug resistance (CAM-DR). Also, distinct normal donor (ND)- and MM-MSC miRNA (miR) signatures were identified and used to uncover osteogenic miRs of interest for osteoblast differentiation. More broadly, our 3D platform provides a simple, clinically relevant tool to model cancer growth within the bone-useful for investigating skeletal cancer biology, screening compounds, and exploring osteogenesis. Our identification and efficacy validation of novel bone anabolic miRs in MM opens more opportunities for novel approaches to cancer therapy via stromal miR modulation. [ABSTRACT FROM AUTHOR]

Currently, no reliable biomarkers are available to predict transformation from smoldering myeloma (SMM) to multiple myeloma (MM). Using an ultrasensitive enzyme-linked immunosorbent assay (ELISA) we assessed the levels of a broad range of cytokines and chemokines in the peripheral blood (PB) and bone marrow (BM) supernatant collected from 14 SMM and 38 MM patients and compared to healthy donors. We found significantly increased levels of key cytokines, in particular CXCL8 (IL-8), associated with progressive disease state (controls→SMM→MM). Cytokine profiles were found similar in PB and BM. Five of fourteen SMM patients (36%) progressed to MM. Our findings, although based on a limited number of patients, suggest that serum-based cytokines may have a future role as biomarkers for disease progression and could potentially be assessed as novel targets for treatment. [ABSTRACT FROM AUTHOR]

Epigenetic changes frequently occur during tumorigenesis and DNA hypermethylation may account for the inactivation of tumor suppressor genes in cancer cells. Studies in Multiple Myeloma (MM) have shown variable DNA methylation patterns with focal hypermethylation changes in clinically aggressive subtypes. We studied global methylation patterns in patients with relapsed/refractory MM and found that the majority of methylation peaks were located in the intronic and intragenic regions in MM samples. Therefore, we investigated the effect of methylation on miRNA regulation in MM. To date, the mechanism by which global miRNA suppression occurs in MM has not been fully described. In this study, we report hypermethylation of miRNAs in MM and perform confirmation in MM cell lines using bisulfite sequencing and methylation-specific PCR (MSP) in the presence or absence of the DNA demethylating agent 5-aza-2′-deoxycytidine. We further characterized the hypermethylation-dependent inhibition of miR-152, -10b-5p and -34c-3p which was shown to exert a putative tumor suppressive role in MM. These findings were corroborated by the demonstration that the same miRNAs were down-regulated in MM patients compared to healthy individuals, alongside enrichment of miR-152-, -10b-5p, and miR-34c-3p-predicted targets, as shown at the mRNA level in primary MM cells. Demethylation or gain of function studies of these specific miRNAs led to induction of apoptosis and inhibition of proliferation as well as down-regulation of putative oncogene targets of these miRNAs such as DNMT1, E2F3, BTRC and MYCBP. These findings provide the rationale for epigenetic therapeutic approaches in subgroups of MM. [ABSTRACT FROM AUTHOR]

The CXCR4/stromal cell-derived factor-1 (SDF-1) axis is essential for cell trafficking and has been shown to regulate tumor progression and metastasis in many tumors including multiple myeloma (MM). A second chemokine receptor for SDF-1, CXCR7 was discovered recently and found on activated endothelial cells. We examined the role of CXCR7 in angiogenic mononuclear cells (AMCs) trafficking in MM. Our data demonstrate that AMCs are circulating in patients with MM and in vivo studies show that they specifically home to areas of MM tumor growth. CXCR7 expression is important for regulating trafficking and homing of AMCs into areas of MM tumor growth and neoangiogenesis. We demonstrate that the CXCR7 inhibitor, POL6926, abrogated trafficking of AMCs to areas of MM tumor progression leading to a significant inhibition of tumor progression. These effects were through regulation of endothelial cells and not through a direct tumor effect, indicating that targeting a bone marrow microenvironmental cell can lead to a delay in MM tumor progression. In conclusion, our studies demonstrate that CXCR7 may play an important role in the regulation of tumor progression in MM through an indirect effect on the recruitment of AMCs to areas of MM tumor growth in the bone marrow niche. [ABSTRACT FROM AUTHOR]

Glycosylation is a stepwise procedure of covalent attachment of oligosaccharide chains to proteins or lipids, and alterations in this process, especially increased sialylation, have been associated with malignant transformation and metastasis. The role of altered sialylation in multiple myeloma (MM) cell trafficking has not been previously investigated. In the present study we identified high expression of β-galactoside α-2,3-sialyltransferase, ST3GAL6, in MM cell lines and patients. This gene plays a key role in selectin ligand synthesis in humans through the generation of functional sialyl Lewis X. In MRC IX patients, high expression of this gene is associated with inferior overall survival. In this study we demonstrate that knockdown of ST3GAL6 results in a significant reduction in levels of α-2,3-linked sialic acid on the surface of MM cells with an associated significant reduction in adhesion to MM bone marrow stromal cells and fibronectin along with reduced transendothelial migration in vitro. In support of our in vitro findings, we demonstrate significantly reduced homing and engraftment of ST3GAL6 knockdown MM cells to the bone marrow niche in vivo, along with decreased tumor burden and prolonged survival. This study points to the importance of altered glycosylation, particularly sialylation, in MM cell adhesion and migration. [ABSTRACT FROM AUTHOR]

Waldenström macroglobulinemia (WM) is a distinct B-cell lymphoproliferative disorder for which clearly defined criteria for the diagnosis, initiation of therapy, and treatment strategy have been proposed as part of the consensus panels of International Workshops on WM (IWWM). As part of the IWWM-7 and based on recently published and ongoing clinical trials, the panels updated treatment recommendations. Therapeutic strategy in WM should be based on individual patient and disease characteristics (age, comorbidities, need for rapid disease control, candidacy for autologous transplantation, cytopenias, IgM-related complications, hyperviscosity, and neuropathy). Mature data show that rituximab combinations with cyclophosphamide/dexamethasone, bendamustine, or bortezomib/dexamethasone provided durable responses and are indicated for most patients. New monoclonal antibodies (ofatumumab), second-generation proteasome inhibitors (carfilzomib), mammalian target of rapamycin inhibitors, and Bruton's tyrosine kinase inhibitors are promising and may expand future treatment options. A different regimen is typically recommended for relapsed or refractory disease. In selected patients with relapsed disease after long-lasting remission, reuse of a prior effective regimen may be appropriate. Autologous stem cell transplantation may be considered in young patients with chemosensitive disease and in newly diagnosed patients with very-high-risk features. Active enrollment of patients with WM in clinical trials is encouraged. [ABSTRACT FROM AUTHOR]

Tumor-associated neovasculature is a critical therapeutic target; however, despite significant progress made in the clinical efficacy of anti-vessel drugs, the effect of these agents remains transient: over time, most patients develop resistance, which inevitably leads to tumor progression. To develop more effective treatments, it is imperative that we better understand the mechanisms involved in tumor vessel formation, how they participate to the tumor progression and metastasis, and the best way to target them. Several mechanisms contribute to the formation of tumor-associated vasculature: i) neoangiogenesis; ii) vascular co-option; iii) mosaicism; iv) vasculogenic mimicry, and v) postnatal vasculogenesis. These mechanisms can also play a role in the development of resistance to anti-angiogenic drugs, and could serve as targets for designing new anti-vascular molecules to treat solid as well as hematological malignancies. Bone marrow-derived endothelial progenitor cell (EPC)-mediated vasculogenesis represents an important new target, especially at the early stage of tumor growth (when EPCs are critical for promoting the "angiogenic switch"), and during metastasis, when EPCs promote the transition from micro- to macro-metastases. In hematologic malignancies, the EPC population could be related to the neoplastic clone, and both may share a common ontogeny. Thus, characterization of tumor-associated EPCs in blood cancers may provide clues for more specific anti-vascular therapy that has both direct and indirect anti-tumor effects. Here, we review the role of vasculogenesis, mediated by bone marrow-derived EPCs, in the progression of cancer, with a particular focus on the role of these cells in promoting progression of hematological malignancies. [ABSTRACT FROM AUTHOR]

Everolimus, an oral mammalian target of rapamycin ( mTOR) inhibitor, has been studied in multiple myeloma (MM) but lacks significant single agent activity. Based on preclinical studies showing synergistic activity of mTOR inhibitors with lenalidomide, we studied the combination of lenalidomide and everolimus in relapsed or refractory MM in a phase I clinical trial. We assessed patient samples using gene expression, Western blotting and immunohistochemistry to probe the mTOR pathway. Twenty-six patients were evaluable for toxicity. Dose-limiting toxicities included grade 4 neutropenia and thrombocytopenia. The maximum tolerated dose was lenalidomide 15 mg and everolimus 5 mg for 21 d with a 7 d rest period. Grade 3/4 adverse events included thrombocytopenia (35%) and neutropenia (42%). The overall response rate was 65% (1 complete response + 4 partial response + 10 minimal response). The median progression-free survival was 5·5 months and median overall survival was 29·5 months. Biomarker data demonstrated downregulation of phosphorylated p70S6K. Gene expression profiling suggested activation of mTOR in responders versus non-responders. The combination of lenalidomide and everolimus was well tolerated with predictable toxicities and showed responses in a heavily pretreated population. When confirmed with larger patient numbers, this analysis may guide patient selection for future clinical trials of mTOR inhibition in MM. [ABSTRACT FROM AUTHOR]

Bortezomib frequently produces severe treatment-related peripheral neuropathy (PN) in Waldenström's macroglobulinemia (WM). Carfilzomib is a neuropathy-sparing proteasome inhibitor. We examined carfilzomib, rituximab, and dexamethasone (CaRD) in symptomatic WM patients naïve to bortezomib and rituximab. Protocol therapy consisted of intravenous carfilzomib, 20 mg/m2 (cycle 1) and 36 mg/m2 (cycles 2-6), with intravenous dexamethasone, 20 mg, on days 1, 2, 8, and 9, and rituximab, 375 mg/m2, on days 2 and 9 every 21 days. Maintenance therapy followed 8 weeks later with intravenous carfilzomib, 36 mg/m2, and intravenous dexamethasone, 20 mg, on days 1 and 2, and rituximab, 375 mg/m2, on day 2 every 8 weeks for 8 cycles. Overall response rate was 87.1 % (1 complete response, 10 very good partial responses, 10 partial responses, and 6 minimal responses) and was not impacted by MYD88L265P or CXCR4WHIM mutation status. With a median follow-up of 15.4 months, 20 patients remain progression free. Grade >2 toxicities included asymptomatic hyperlipasemia (41.9%), reversible neutropenia (12.9%), and cardiomyopathy in 1 patient (3.2%) with multiple risk factors, and PN in 1 patient (3.2%) which was grade 2. Declines in serum IgA and IgG were common. CaRD offers a neuropathy-sparing approach for proteasome inhibitor-based therapy in WM. This trial is registered at www.clinicaltrials.gov as #NCT01470196. [ABSTRACT FROM AUTHOR]

The C-X-C chemokine receptor type 4 (CXCR4) plays a crucial role in modulating cell trafficking in hematopoietic stem cells and clonal B cells. We screened 418 patients with B-cell lymphoproliferative disorders and described the presence of the C1013G/CXCR4 warts, hypogammaglobulinemia, infections, and myelokathexis-associated mutation in 28.2% (37/131) of patients with lymphoplasmacytic lymphoma (Waldenström macroglobulinemia [WM]), being either absent or present in only 7% of other B-cell lymphomas. In vivo functional characterization demonstrates its activating role in WM cells, as demonstrated by significant tumor proliferation and dissemination to extramedullar organs, leading to disease progression and decreased survival. The use of a monoclonal antibody anti-CXCR4 led to significant tumor reduction in a C1013G/CXCR4 WM model, whereas drug resistance was observed in mutated WM cells exposed to Bruton's tyrosine kinase, mammalian target of rapamycin, and phosphatidylinositol 3-kinase inhibitors, but not protea-some inhibitors. These findings demonstrate that C1013G/CXCR4 is an activating mutation in WM and support its role as a critical regulator of WM molecular pathogenesis and as an important therapeutic target. [ABSTRACT FROM AUTHOR]

Abstract: Metastasis is a phenomenon of crucial importance in defining prognosis in patients with cancer and is often responsible for cancer-related mortality. It is known that several steps are necessary for clonal cells to disseminate from their primary tumor site and colonize distant tissues, thus originating metastatic lesions. Therefore, investigating the molecular actors regulating this process may provide helpful insights in the development of efficient therapeutic responses. Recent evidences have indicated the role of microRNAs (miRNAs) in modulating the metastatic process in solid tumors. miRNAs are small regulatory non-coding RNAs that bind to specific target mRNAs, leading to translational repression. miRNAs are known to act as negative regulators of gene expression and are involved in the regulation of biological processes, including cell growth, differentiation and apoptosis, both in physiological conditions and during diseases, such as tumors. In the specific field of tumorigenesis, miRNAs play an important role in mediating oncogenesis and favoring tumor progression, as a result of their ability to modulate epithelial-to-mesenchymal transition (EMT) and other series of events facilitating the formation of metastasis. The role of miRNAs in cancer development has been widely studied and has helped elucidate events such as the change in expression of oncogenes, tumor-suppressors and cancer-related proteins. This review focuses on the mechanisms underlying the role of miRNAs as part of the metastatic process. [Copyright &y& Elsevier]

In this prospective, multicenter, phase 2 study, 64 patients with relapsed or relapsed and refractory multiple myeloma (MM) received up to 8 21-day cycles of bortezomib 1.0 mg/m2 (days 1,4,8, and 11), lenalidomide 15 mg/day (days 1 -14), and dexamethasone 40/20 mg/day (cycles 1-4) and 20/10 mg/day (cycles 5-8) (days of/after bortezomib dosing). Responding patients could receive maintenance therapy. Median age was 65 years; 66% were male, 58% had relapsed and 42% had relapsed and refractory MM, and 53%, 75%, and 6% had received prior bortezomib, thalidomide, and lenalidomide, respectively. Forty-eight of 64 patients (75%; 90% confidence interval, 65-84) were alive without progressive disease at 6 months (primary end point). The rate of partial response or better was 64%; median duration of response was 8.7 months. Median progression-free and overall survivals were 9.5 and 30 months, respectively (median follow-up: 44 months). Common treatment-related toxicities included sensory neuropathy (53%), fatigue (50%), and neutropenia (42%); common grade 3/4 treatment-related toxicities included neutropenia (30%), thrombocytopenia (22%), and lymphopenia (11%). Grade 3 motor neuropathy was reported in 2 patients. Lenalidomide-bortezomib-dexamethasone appears effective and tolerable in patients with relapsed or relapsed and refractory MM, demonstrating substantial activity among patients with diverse prior therapies and adverse prognostic characteristics. [ABSTRACT FROM AUTHOR]

Background: While the treatment of HER2 over-expressing breast cancer with recent HER-targeted drugs has been highly effective for some patients, primary (also known as innate) or acquired resistance limits the success of these drugs. microRNAs have potential as diagnostic, prognostic and predictive biomarkers, as well as replacement therapies. Here we investigated the role of microRNA-630 (miR-630) in breast cancer progression and as a predictive biomarker for response to HER-targeting drugs, ultimately yielding potential as a therapeutic approach to add value to these drugs. Methods: We investigated the levels of intra- and extracellular miR-630 in cells and conditioned media from breast cancer cell lines with either innate- or acquired- resistance to HER-targeting lapatinib and neratinib, compared to their corresponding drug sensitive cell lines, using qPCR. To support the role of miR-630 in breast cancer, we examined the clinical relevance of this miRNA in breast cancer tumours versus matched peritumours. Transfection of miR-630 mimics and inhibitors was used to manipulate the expression of miR-630 to assess effects on response to HER-targeting drugs (lapatinib, neratinib and afatinib). Other phenotypic changes associated with cellular aggressiveness were evaluated by motility, invasion and anoikis assays. TargetScan prediction software, qPCR, immunoblotting and ELISAs, were used to assess miR-630’s regulation of mRNA, proteins and their phosphorylated forms. Results: We established that introducing miR-630 into cells with innate- or acquired- resistance to HER-drugs significantly restored the efficacy of lapatinib, neratinib and afatinib; through a mechanism which we have determined to, at least partly, involve miR-630’s regulation of IGF1R. Conversely, we demonstrated that blocking miR-630 induced resistance/insensitivity to these drugs. Cellular motility, invasion, and anoikis were also observed as significantly altered by miR-630 manipulation, whereby introducing miR-630 into cells reduced cellular aggression while inhibition of miR-630 induced a more aggressive cellular phenotype. Conclusions: Taken together, our findings suggest miR-630 as a key regulator of cancer cell progression in HER2 over-expressing breast cancer, through targeting of IGF1R. This study supports miR-630 as a diagnostic and a predictive biomarker for response to HER-targeted drugs and indicates that the therapeutic addition of miR-630 may enhance and improve patients’ response to HER-targeting drugs. [ABSTRACT FROM AUTHOR]

BM mesenchymal stromal cells (BM-MSCs) support multiple myeloma (MM) cell growth, but little is known about the putative mechanisms by which the BM microenvironment plays an oncogenic role in this disease. Cell-cell communication is mediated by exosomes. In this study, we showed that MM BM-MSCs release exosomes that are transferred to MM cells, thereby resulting in modulation of tumor growth in vivo. Exosomal microRNA (miR) content differed between MM and normal BM-MSCs, with a lower content of the tumor suppressor miR-15a. In addition, MM BM-MSC-derived exosomes had higher levels of oncogenic proteins, cytokines, and adhesion molecules compared with exosomes from the cells of origin. Importantly, whereas MM BM-MSC-derived exosomes promoted MM tumor growth, normal BM-MSC exosomes inhibited the growth of MM cells. In summary, these in vitro and in vivo studies demonstrated that exosome transfer from BM-MSCs to clonal plasma cells represents a previously undescribed and unique mechanism that highlights the contribution of BM-MSCs to MM disease progression. [ABSTRACT FROM AUTHOR]