Direct oral anticoagulants in patients with venous thromboembolism and hematological malignancies.

Data are needed on direct oral anticoagulants (DOACs) for the treatment of venous thromboembolism (VTE) in hematological malignancies (HM). Retrospective studies to date lacked a control group and did not focus on patients with VTE. Out aim was to assess the incidence of VTE recurrence and bleeding in HM patients treated with low molecular weight heparin (LMWH) or DOACs for acute VTE. This is a retrospective cohort study including patients with active HM and newly-diagnosed VTE, indexed on the first day of anticoagulation and followed for 12 months. The outcome was a composite of recurrent VTE, major bleeding or clinically relevant non-major bleeding. Cumulative incidence [95% confidence interval (CI)] was calculated for each anticoagulation group (LMWH, DOAC) and hazard ratios (HR) were calculated using cox-proportional hazards model, with death as a competing risk. 143 HM patients treated with LMWH (96) or DOACs (47) for acute VTE were included. The most common HM types were lymphoma in 83 (58%) and plasma cell dyscrasia in 32 (22.3%). The 12-month cumulative incidence of the composite outcome was 24.2% (95% CI 15.9-33.5%; n = 22) in the LMWH group and 18.5% (8.5-31.5%; n = 8) in the DOAC group (HR 1.51 [0.695-3.297]). Two recurrent VTE occurred (both in the DOAC group while off-treatment). Nine (9.4%) LMWH-treated patients had major bleeding compared to 1 (2.1%) DOAC-treated patient (HR 4.85 [0.64-36.56]). This study generates the hypothesis that DOACs may be a safe and effective alternative to LMWH for VTE in patients with HM types represented in the study.

Multiple myeloma BM-MSCs increase the tumorigenicity of MM cells via transfer of VLA4-enriched microvesicles.

Multiple myeloma (MM) cells accumulate in the bone marrow (BM) where their interactions impede disease therapy. We have shown that microvesicles (MVs) derived from BM mesenchymal stem cells (MSCs) of MM patients promote the malignant traits via modulation of translation initiation (TI), whereas MVs from normal donors (ND) do not. Here, we observed that this phenomenon is contingent on a MVs' protein constituent, and determined correlations between the MVs from the tumor microenvironment, for example, MM BM-MSCs and patients' clinical characteristics. BM-MSCs' MVs (ND/MM) proteomes were assayed (mass spectrometry) and compared. Elevated integrin CD49d (X80) and CD29 (X2) was determined in MM-MSCs' MVs and correlated with patients' staging and treatment response (free light chain, BM plasma cells count, stage, response to treatment). BM-MSCs' MVs uptake into MM cell lines was assayed (flow cytometry) with/without integrin inhibitors (RGD, natalizumab, and anti-CD29 monoclonal antibody) and recipient cells were analyzed for cell count, migration, MAPKs, TI, and drug response (doxorubicin, Velcade). Their inhibition, particularly together, attenuated the uptake of MM-MSCs MVs (but not ND-MSCs MVs) into MM cells and reduced MM cells' signaling, phenotype, and increased drug response. This study exposed a critical novel role for CD49d/CD29 on MM-MSCs MVs and presented a discriminate method to inhibit cancer promoting action of MM-MSCs MVs while retaining the anticancer function of ND-MSCs-MVs. Moreover, these findings demonstrate yet again the intricacy of the microenvironment involvement in the malignant process and highlight new therapeutic avenues to be explored.

Placenta-conditioned extracellular matrix (ECM) activates breast cancer cell survival mechanisms: A key for future distant metastases.

The extracellular matrix (ECM) affects cancer cell characteristics. Inability of normal epithelial cells to attach to the ECM induces apoptosis (anoikis). Cancer cells are often anoikis resistant, a prerequisite for their metastatic spread. Previously we demonstrated that the placenta manipulates its surrounding ECM in a way that prevents breast cancer cells (BCCL) attachment and induces their motility and aggregation. This fits with the fact that although breast cancer during pregnancy is often advanced, metastasis to the placenta is rarely observed. Placental intervillous space provides suitable conditions for cancer cell arrival. Yet, the outcome of the short communication between the placental ECM to the BCCL and its effect on BCCL malignant potential are unknown, and are the focus of our study. In the current study we analyzed the effect of placental ECM on BCCL survival pathways and drug resistance. Microarray analysis suggested activation of the NF-κB and stress response pathways. Indeed, the placenta-conditioned ECM induced autophagy in ERα + BCCL, inactivated the NF-κB inhibitor (IκB) and increased integrin α5 in the BCCL. The autophagy mediated MCF-7 and T47D migration and the placental ECM-BCCL interactions reduced the BCCL sensitivity to Taxol. We also demonstrated by using siRNA that integrin α5 was responsible for the MCF-7 autophagy and suggest this molecule as a suitable target for therapy.

The Muddied Waters of Ibrutinib Therapy.

A 37-year-old male was admitted with an atypical presentation of central nervous system (CNS) aspergillosis while on ibrutinib therapy for a CNS relapse of mantle cell lymphoma. This case highlights the importance of a high clinical suspicion of opportunistic infections in patients receiving small-molecule kinase inhibitors. This report includes a review of reported cases of Aspergillus infections in patients receiving ibrutinib and the shared features of these cases.

Placental supernatants' enhancement of the metastatic potential of breast cancer cells: is estrogen receptor (ERα) essential for this phenomenon?

PURPOSE: Pregnancy-associated breast cancer (PABC) is usually diagnosed at an advanced stage in comparison to non-pregnant women. The placenta secretes hormones and cytokines, which affect breast cancer progression. Previously, we demonstrated that human placental secretome facilitates the survival and migration of ERα+ breast cancer cells (BCCL), but pregnant women have a relatively high frequency of ERα-negative tumors. In the current study, we analyzed the effect of placental secretome on ERα-negative BCCL. METHODS: BCCL [MCF-7(estrogen/progesterone receptor positive (ERα+/PR+), ERα reduced MCF-7 (siRNA, MCF-7 ERα-), HS-578 and BT-549 cells (both ER-/PR-)] were exposed to supernatants (collected from first trimester human placental explants and from control BCCL) or to E2 + P4 (estrogen + progesterone) in placental supernatant concentrations and then tested for cell proliferation (number, cell cycle, PCNA), cell-death, cell migration, STAT3 pathway activation and functionality. RESULTS: Silencing ERα in the MCF-7 cells negated the placental supernatant and E2 + P4 enhancement of cell migration (> 130%, p < 0.05), number (> 120%) and survival (~ 130%). However, it had no such effect on MCF-7-ER- migration, which was still elevated in the presence of placental secretome. ER-/PR- BCCL were unaffected by the hormones, but placental secretome significantly elevated their migration (115%), number (140-170%), STAT3 phosphorylation (~ 180%) and BT-549 STAT3 level. These effects were negated by the STAT3 inhibitor. CONCLUSIONS: Placental supernatant facilitates BCCL malignant characteristics by activating ERα in estrogen responsive cells and STAT3 in ERα- BCCL. This indicates a possible mechanism that may underlie PABC's advanced state and suggests STAT3 pathway as a therapeutic target for PABC.

Microvesicles derived from normal and multiple myeloma bone marrow mesenchymal stem cells differentially modulate myeloma cells' phenotype and translation initiation.

Multiple myeloma (MM) cells' interaction with the bone marrow (BM) microenvironment critically hinders disease therapy. Previously, we showed that MM co-culture with BM-mesenchymal stem cells (MSCs) caused co-modulation of translation initiation (TI) and cell phenotype and implicated secreted components, specifically microvesicles (MVs). Here, we studied the role of the BM-MSCs [normal donors (ND) and MM] secreted MVs in design of MM cells' phenotype, TI and signaling. BM-MSCs' MVs collected from BM-MSCs (MM/ND) cultures were applied to MM cell lines. After MVs uptake confirmation, the MM cells were assayed for viability, cell count and death, proliferation, migration, invasion, autophagy, TI status (factors, regulators, targets) and MAPKs activation. The interdependence of MAPKs, TI and autophagy was determined (inhibitors). ND-MSCs MVs' treated MM cells demonstrated a rapid (5 min) activation of MAPKs followed by a persistent decrease (1-24 h), while MM-MSCs MVs' treated cells demonstrated a rapid and continued (5 min-24 h) activation of MAPKs and TI (↑25-200%, P < 0.05). Within 24 h, BM-MSCs MVs were internalized by MM cells evoking opposite responses according to MVs origin. ND-MSCs' MVs decreased viability, proliferation, migration and TI (↓15-80%; P < 0.05), whereas MM-MSCs' MVs increased them (↑10-250%, P < 0.05). Inhibition of MAPKs in MM-MSCs MVs treated MM cells decreased TI and inhibition of autophagy elevated cell death. These data demonstrate that BM-MSCs MVs have a fundamental effect on MM cells phenotype in accordance with normal or pathological source implemented via TI modulation. Future studies will aim to elucidate the involvement of MVs-MM receptor ligand interactions and cargo transfer in our model.

First trimester human placenta prevents breast cancer cell attachment to the matrix: The role of extracellular matrix.

The extracellular matrix (ECM) affects cancer cell characteristics. Its detachment from the ECM induces cell apoptosis, termed anoikis. Cancer cells can develop anoikis resistance, a necessary step for metastasis, by switching integrins, over-expressing growth factor receptors, and inducing epithelial mesenchymal transition (EMT). The placenta is a non-supportive microenvironment for cancer cells. We showed that breast cancer cells (BCCL) were eliminated from placental implantation sites. During implantation, the placenta manipulates its surrounding matrix, which may induce BCCL elimination. Here, we explored the effect of placenta-induced ECM manipulations on BCCL. During experiments, BCCL (MCF-7/T47D) were cultured on placenta/BCCL-conditioned ECM (Matrigel used for first trimester placenta/BCCL culture and cleared by NH4 OH). After culturing the cells, we analyzed cancer cell phenotype (death, count, aggregation, MMP) and signaling (microarray analysis and pathway validation). We found that the BCCL did not attach to previous placental implantation sites and instead, similarly to anoikis-resistant cells, migrated away, displayed increased MMP levels/activity, and formed aggregates in distant areas. T47D were less affected than the MCF-7 cells, since MCF-7 also showed modest increases in cell death, EMT, and increased proliferation. Microarray analysis of the MCF-7 highlighted changes in the integrin, estrogen, EGFR, and TGFß pathways. Indeed, placental ECM reduced ERα, induced Smad3/JNK phosphorylation and increased integrin-α5 expression (RGD-dependent integrin) in the BCCL. Addition of RGD or TGFßR/JNK inhibitors reversed the phenotypic changes. This study helps explain the absence of metastases to the placenta and why advanced cancer is found in pregnancy, and provides possible therapeutic targets for anoikis-resistant cells. © 2016 Wiley Periodicals, Inc.

The management of hodgkin lymphomas in pregnancies.

Hodgkin lymphoma is the most common hematological malignancy in pregnancy. Its management presents several unique challenges, as decisions have to take both maternal and fetal risks into consideration. Using three hypothetical cases, we review current evidence and guidelines and suggest our recommendations for managing pregnant Hodgkin lymphoma patients. The opportunity for a prompt and accurate diagnosis should not be missed; this may be achieved by vigilance to suggestive symptoms, performance of biopsy which is not contraindicated during pregnancy and use of MRI for staging. Most patients should receive treatment with doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) after completion of the first trimester. Bridging therapy with corticosteroids or vinblastine should be considered during the first trimester. In most cases of early disease, the addition of chemotherapy cycles to the treatment plan seems preferable to radiation therapy. Diagnosis at relapse raises unique dilemmas regarding second-line chemotherapeutic regimens and timing of consolidation with high-dose therapy and autologous stem cell transplantation, an approach which is contraindicated during pregnancy. Considering the excellent outcomes of Hodgkin lymphoma outside pregnancy, every effort should be made to strive toward a curative treatment plan while balancing the multiple issues and dilemmas which arise when treating this malignancy in a pregnant patient.

Multiple myeloma and bone marrow mesenchymal stem cells' crosstalk: Effect on translation initiation.

Multiple myeloma (MM) malignant plasma cells reside in the bone marrow (BM) and convert it into a specialized pre-neoplastic niche that promotes the proliferation and survival of the cancer cells. BM resident mesenchymal stem cells (BM-MSCs) are altered in MM and in vitro studies indicate their transformation by MM proximity is within hours. The response time frame suggested that protein translation may be implicated. Thus, we assembled a co-culture model of MM cell lines with MSCs from normal donors (ND) and MM patients to test our hypothesis. The cell lines (U266, ARP-1) and BM-MSCs (ND, MM) were harvested separately after 72 h of co-culture and assayed for proliferation, death, levels of major translation initiation factors (eIF4E, eIF4GI), their targets, and regulators. Significant changes were observed: BM-MSCs (ND and MM) co-cultured with MM cell lines displayed elevated proliferation and death as well as increased expression/activity of eIF4E/eIF4GI; MM cell lines co-cultured with MM-MSCs also displayed higher proliferation and death rates coupled with augmented translation initiation factors; in contrast, MM cell lines co-cultured with ND-MSCs did not display elevated proliferation only death and had no changes in eIF4GI levels/activity. eIF4E expression was increased in one of the cell lines. Our study demonstrates that there is direct dialogue between the MM and BM-MSCs populations that includes translation initiation manipulation and critically affects cell fate. Future research should be aimed at identifying therapeutic targets that may be used to minimize the collateral damage to the cancer microenvironment and limit its recruitment into the malignant process. © 2015 Wiley Periodicals, Inc.

Can flow cytometry of bone marrow aspirate predict outcome of patients with diffuse large B cell lymphoma? A retrospective single centre study.

Bone marrow (BM) trephine biopsy is a part of routine staging of patients with newly diagnosed diffuse large B cell lymphoma (DLBCL). The significance of lymphoid monoclonal population on flow cytometry (FC) of the BM aspirate in the presence of negative BM histology has not been clarified. In this study, we assessed the clinical role of positive FC in predicting outcome of patients with DLBCL and a negative BM histology. We retrospectively analysed 101 patients diagnosed with DLBCL at a single institution between years 1994-2003. Three groups of patients were compared: patients with histologic involvement of the BM (BM+), patients with no histologic involvement of the BM but with positive FC (BM-FC+) and patients with neither histologic or FC evidence of BM involvement (BM-FC-). The BM+ group included 13 patients (13%). The BM-FC+ group 16 patients (16%), and the BM-FC-included 72 patients (71%). Median age of the cohort was 67 years. Disease stage and International Prognostic Index score were significantly higher in the BM+ and BM-FC+ groups compared with the BM-FC- group. Median overall survival (OS) for the BM-FC-, BM-FC+ and BM + groups were 4.6, 2.2 and 0.9 years, respectively. Median progression free survival (PFS) for the BM-FC-, BM-FC+ and BM+ groups were 3.2, 1.4 and 0.6 years, respectively (p=0.01 for both analysis). In multivariable Cox regression models adjusting for age, sex, stage and International Prognostic Index, there was no significant differences in OS or PFS between the BM-FC+ and BM-FC- groups. In conclusion, positive FC in the setting of negative BM histology at diagnosis did not significantly affect OS or PFS.

[THE EFFECT OF PREGNANCY ON BREAST CANCER].

Cancer and pregnancy coincide in about one in 1,000 pregnancies. One of the most common malignancies associated with pregnancy is breast cancer. Women with pregnancy-associated breast cancer (PABC) have a higher likelihood of being diagnosed with metastatic disease and estrogen receptor (ER) negative tumors than do non-pregnant women. Controversies exist regarding the effect of pregnancy on breast cancer prognosis. Some researchers suggest that pregnancy does not affect breast cancer prognosis, whereas others claim the opposite. Although PABC is usually discovered in an advanced stage, breast cancer metastasis on the placenta is a rare event. During cancer progression, the surrounding microenvironment co-evolves into an activated state through continuous communication with the malignant cells, thereby promoting tumor growth. The effect of pregnancy and placental environment on breast cancer biology is the issue of this review. Placental and cancer cells implantation processes share similar molecular pathways. This suggests that placental factors may affect breast cancer cells biology. Previously, we analyzed the effect of first trimester human placenta on breast cancer cells. Breast cancer cells were co-cultured with placental explants during their implantation on matrigel substrate. We found that the placenta reduced ER expression on the cancer cells and induced their migration and invasion abilities. As a result of it, breast cancer cells migrated away from the placental implantation sites. Hormonal pathways were involved in these phenomena. These results may explain the high incidence of metastases during pregnancy in on the one hand and the rarity of metastases on the placenta on the other hand.

[SECONDARY PREVENTION IN PATIENTS WITH ACUTE CORONARY SYNDROME HOSPITALIZED IN INTERNAL MEDICINE DEPARTMENTS].

BACKGROUND: Secondary prevention treatment with aspirin/ clopidogrel, beta blockers, inhibitors of the rennin-angiotensin-aldosterone converting system and statins reduces the morbidity and mortality of patients after acute coronary syndrome (ACS). However, clinical experience suggests that prescription rates in patients hospitalized in internal medicine departments may be low. AIM: To determine the rate of administration of secondary prevention in ACS patients hospitalized in internal medicine departments; identify predictors for full regimen use and evaluate reasons for non-prescription of the medications. METHODS: Retrospective review of the files of 399 patients with ACS hospitalized in the 5 departments of internal medicine in a university affiliated medical center in 2010. Data were collected on demographic and clinical parameters, findings on current admission, medications at admission and at discharge, and reasons for nonprescription of secondary preventive medications. RESULTS: Overall, 62% of patients were discharged with full secondary preventive treatment. In the remainder, the reason for not prescribing the medications was usually not specified. Factors associated with prescription of the "full regimen" were patient receipt of full secondary prevention treatment prior to admission, hypertension, history of myocardial infarction and revascularization, non-ST elevation myocardial infarction as the reason for the current admission, and performance of percutaneous coronary intervention during the current hospitalization. Atrial fibrillation was a negative predictor. CONCLUSIONS: The prescription of full secondary prevention treatment in ACS patients hospitalized in internal medicine departments is suboptimal. Further efforts are needed to implement comprehensive guideline-based management.

[THE EFFECT OF PLACENTAL SOLUBLE FACTORS AND STEROID HORMONES ON OVARIAN CANCER PHENOTYPE].

UNLABELLED: Estrogen is involved in ovarian cancer etiology. Crosstalk exists between estrogen and progesterone ending with the inhibition of estrogen effects. While estrogen induces ovarian cancer cell proliferation, progesterone protects women from ovarian cancer. The placenta facilitates estrogen and progesterone production. Moreover, during pregnancy epithelial ovarian cancer is more common than in young non-pregnant women and borderline ovarian tumors exhibit aggressive behavior These data suggest that pregnancy changes ovarian cancer characteristics. AIM: Analyzing the effect of placental soluble factors and estrogen+progesterone [E+P, in placental supernatant level) on epithelial ovarian cancer cell phenotype. METHODS: Ovarian epithelial cancer cells (OVCAR-3, SKOV-3) were exposed to 1) supernatants collected from first trimester human placental explant culture; 2) E+P in levels equivalent to those measured in the placental supernatants. As a control OVCAR-3 and SKOV-3 were exposed to their supernatants or to the hormones solvent. Then we tested ovarian cancer cells proliferation, death, cell-cycle and migration. RESULTS: Placental supernatants facilitated cancer cells migration and SKOV-3 proliferation. E+P facilitated SKOV-3 migration and elevated OVCAR-3 cell-number and apoptotic rate. CONCLUSION: Placental soluble factors and E+P affect ovarian cancer cells phenotype. Discussion: The elevated aggressiveness observed following exposure of ovarian cancer cells to placental supernatant and to E+P may contribute to the special phenomena observed in ovarian cancer during pregnancy. During pregnancy, ovarian cancer is usually discovered at an early stage, which improves patients' prognosis. Nevertheless, our results suggest that physicians should closely follow ovarian tumors during pregnancy as they might be affected by pregnancy-related factors.

Gynecologic cancers in pregnancy: guidelines of a second international consensus meeting.

OBJECTIVES: This study aimed to provide timely and effective guidance for pregnant women and health care providers to optimize maternal treatment and fetal protection and to promote effective management of the mother, fetus, and neonate when administering potentially teratogenic medications. New insights and more experience were gained since the first consensus meeting 5 years ago. METHODS: Members of the European Society of Gynecological Oncology task force "Cancer in Pregnancy" in concert with other international experts reviewed the existing literature on their respective areas of expertise. The summaries were subsequently merged into a complete article that served as a basis for discussion during the consensus meeting. All participants approved the final article. RESULTS: In the experts' view, cancer can be successfully treated during pregnancy in collaboration with a multidisciplinary team, optimizing maternal treatment while considering fetal safety. To maximize the maternal outcome, cancer treatment should follow a standard treatment protocol as for nonpregnant patients. Iatrogenic prematurity should be avoided. Individualization of treatment and effective psychologic support is imperative to provide throughout the pregnancy period. Diagnostic procedures, including staging examinations and imaging, such as magnetic resonance imaging and sonography, are preferable. Pelvic surgery, either open or laparoscopic, as part of a treatment protocol, may reveal beneficial outcomes and is preferably performed by experts. Most standard regimens of chemotherapy can be administered from 14 weeks gestational age onward. Apart from cervical and vulvar cancer, as well as important vulvar scarring, the mode of delivery is determined by the obstetrician. Term delivery is aimed for. Breast-feeding should be considered based on individual drug safety and neonatologist-breast-feeding expert's consult. CONCLUSIONS: Despite limited evidence-based information, cancer treatment during pregnancy can succeed. State-of-the-art treatment should be provided for this vulnerable population to preserve maternal and fetal prognosis. SUPPLEMENTARY INFORMATION: Supplementary data on teratogenic effects, ionizing examinations, sentinel lymph node biopsy, tumor markers during pregnancy, as well as additional references and tables are available at the extended online version of this consensus article, go to http://links.lww.com/IGC/A197.

Haematological cancers in pregnancy.

Haematological cancer in pregnancy, although rare, poses a substantial risk to both mother and fetus. Hodgkin's lymphoma is the most common, followed by non-Hodgkin lymphoma and acute leukaemia. Diagnosis of haematological cancers is challenged by an overlap of the disease and gestation-related symptoms and limitations of imaging studies in pregnancy. Data for safety and effectiveness of therapy are scarce and mostly retrospective. This report provides updated guidance for management, focusing on chemotherapy and biological agents. The primary goal of treatment is to preserve the mother's health; hence, pregnancy termination is often advisable at early stages, allowing delivery of adequate therapy. However, at later gestational stages treatment is often feasible. Pregnancy-related hypercoagulability, augmented by cancer, often necessitates thromboprophylaxis. The consequences and complex management of haematological cancer during pregnancy emphasise the need for collaborative research, focusing on basic mechanisms of disease and prospective epidemiological studies.

Arterial Thromboembolism in Patients With AF and CHA2DS2-VASc Score 0-2 With and Without Cancer.

Background: It is unclear whether newly diagnosed cancer adds to the risk of arterial thromboembolism (ATE) in patients with atrial fibrillation/flutter (AF). This is especially relevant for AF patients with low to intermediate CHA2DS2-VASc scores in whom the risk-benefit ratios between ATE and bleeding are delicately balanced. Objectives: The objectives were to evaluate the ATE risk in AF patients with a CHA2DS2-VASc score of 0 to 2 with and without cancer. Methods: A population-based retrospective cohort study was performed. Patients with a CHA2DS2-VASc score of 0 to 2 not receiving anticoagulation at cancer diagnosis (or the matched index date) were included. Patients with embolic ATE or cancer before study index were excluded. AF patients were categorized into AF and cancer and AF and no cancer cohorts. Cohorts were matched for multinomial distribution of age, sex, index year, AF duration, CHA2DS2-VASc score, and low/high/undefined ATE risk cancer. Patients were followed from study index until the primary outcome or death. The primary outcome was acute ATE (ischemic stroke, transient ischemic attack, or systemic ATE) at 12 months using International Classification of Diseases-Ninth Revision codes from hospitalization. The Fine-Gray competing risk model was used to estimate the HR for ATE with death as a competing risk. Results: The 12-month cumulative incidence of ATE was 2.13% (95% CI: 1.47-2.99) in 1,411 AF patients with cancer and 0.8% (95% CI: 0.56-1.10) in 4,233 AF patients without cancer (HR: 2.70; 95% CI: 1.65-4.41). The risk was highest in men with CHA2DS2-VASc = 1 and women with CHA2DS2-VASc = 2 (HR: 6.07; 95% CI: 2.45-15.01). Conclusions: In AF patients with CHA2DS2-VASc scores of 0 to 2, newly diagnosed cancer is associated with an increased incidence of stroke, transient ischemic attack, or systemic ATE compared with matched controls without cancer.

Tetraspanins stimulate protein synthesis in myeloma cell lines.

Intensive protein synthesis is a unique and differential trait of multiple myeloma (MM) cells. Previously we showed that tetraspanin (CD81, CD82) overexpression in MM cell lines attenuated Akt/mTOR cascades, activated UPR, and caused autophagic death, suggesting breach of protein homeostasis. Here, we explored the role of protein synthesis in the tetraspanin-induced MM cell death. Contrary to attenuation of the major metabolic regulator, mTOR we determined elevated steady-state levels of protein in CD81N1/CD82N1 transfected MM lines (RPMI-8226, CAG). Elevated levels of immunoglobulins supported increased protein production in RPMI-8226. Changes in cell morphology consistent with elevated protein synthesis were also determined (cell, nuclei, and nucleoli sizes and ratios). Increased levels of phospho-rpS6 and decreased levels of phospho-AMPK were consistent with increased translation but independent of mTOR. Involvement of p38 and its role in tetraspanin induced translation and cell death were demonstrated. Microarray analyses of tetraspanin transfected MM cell lines revealed activation of protein synthesis signaling cascades and signals implicated in ribosome biogenesis (snoRNAs). Finally, we showed tetraspanins elevated protein synthesis was instrumental to MM cells' death. This work explores and demonstrates that excessive protein translation can be detrimental to MM cell lines and therefore may present a therapeutic target. Proteostasis is particularly important in MM because it integrates the high levels of protein production unique to myeloma cells with critically important microenvironmental cues. We suggest that increasing translation may be the path of least resistance in MM and thus may afford a novel platform for strategically designed therapy.