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Objective: The objective of the present study was to investigate oral health status, oral health related quality of life, and identify risk factors associated with invasive dental treatment and medication related osteonecrosis of the jaw in patients with multiple myeloma., Material and Methods: Patients newly diagnosed with multiple myeloma (n = 144) referred between January 2015 and September 2022 were retrospectively included. The patients underwent a thorough clinical and radiological oral examination and odontogenic infections were treated before the start of bisphosphonate treatment. The patients were followed annually, including clinical and radiological examinations. The oral health related quality of life was investigated by the OHIP-14 questionnaire., Results: Dental treatment (RR = 7.75), receiving combination antineoplastic therapy≥3 (RR =4.13), periodontitis (RR = 4.21), and reduced number of teeth (RR = 2.87) were associated with an increased risk of medication related osteonecrosis of the jaw. The response rate of the OHIP-14 questionnaire was 70.2%. Oral pain or discomfort in the mouth related to the medical treatment was reported by 30.5%., Conclusion: Dental screening and treatment planning in patients with Multiple Myeloma may result in fewer oral infections and fewer interruptions of the medical treatment of myeloma., (© 2024. The Author(s).)

Background: Air pollution is a growing concern worldwide, with significant impacts on human health. Multiple myeloma is a type of blood cancer with increasing incidence. Studies have linked air pollution exposure to various types of cancer, including leukemia and lymphoma, however, the relationship with multiple myeloma incidence has not been extensively investigated., Methods: We pooled four European cohorts (N = 234,803) and assessed the association between residential exposure to nitrogen dioxide (NO 2 ), fine particles (PM 2.5 ), black carbon (BC), and ozone (O 3 ) and multiple myeloma. We applied Cox proportional hazards models adjusting for potential confounders at the individual and area-level., Results: During 4,415,817 person-years of follow-up (average 18.8 years), we observed 404 cases of multiple myeloma. The results of the fully adjusted linear analyses showed hazard ratios (95% confidence interval) of 0.99 (0.84, 1.16) per 10 μg/m³ NO 2 , 1.04 (0.82, 1.33) per 5 μg/m³ PM 2.5 , 0.99 (0.84, 1.18) per 0.5 10 -5  m -1 BCE, and 1.11 (0.87, 1.41) per 10 μg/m³ O 3 ., Conclusions: We did not observe an association between long-term ambient air pollution exposure and incidence of multiple myeloma., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Bortezomib (BTZ) is a selective and reversible proteasome inhibitor and first line treatment for multiple myeloma (MM). One of the side effects is BTZ-induced peripheral neuropathy (BIPN). Until now there is no biomarker which can predict this side effect and its severity. Neurofilament light chain (NfL) is a neuron specific cytoskeletal protein, of which higher levels can be detected in peripheral blood in case of axon damage. In this study, we aimed to evaluate the relationship between NfL serum levels and characteristics of BIPN., Methods: We performed a first interim analysis of a monocentric, non-randomized, observational clinical trial including 70 patients (DRKS00025422) diagnosed with MM in the inclusion period of June 2021 until March 2022. Two groups of patients-one with ongoing BTZ treatment at the time of recruiting, and one with BTZ treatment in the past-were compared to controls. NfL in serum was analyzed via the ELLA™ device., Results: Both patients with previous and ongoing BTZ treatment had higher serum NfL levels than controls, and patients with ongoing BTZ treatment had higher NfL levels than patients with BTZ treatment in the past. Serum NfL levels correlated with electrophysiological measures of axonal damage in the group with ongoing BTZ treatment., Conclusion: Elevated NfL levels indicate acute axonal damage under BTZ in MM patients., (© 2023. The Author(s).)

With the incorporation of novel agents in earlier lines of therapy, an increasing number of multiple myeloma patients are refractory to traditional classes of drugs. Selinexor in combination with dexamethasone has emerged as a viable option for heavily pretreated triple-class relapsed and refractory multiple myeloma (RRMM). In this systematic review, we analyzed available literature on the role of selinexor in RRMM. The Boston trial demonstrated that selinexor when combined with dexamethasone and bortezomib is associated with a better depth and duration of response without excessive toxicity, compared with bortezomib and dexamethasone alone. Similarly, selinexor in combination with carfilzomib and dexamethasone was found to have a durable response and tolerable safety profile in both carfilzomib-naive and carfilzomib refractory RRMM patients. Selinexor in combination with IMiDs (lenalidomide and pomalidomide) as well as CD38 monoclonal antibodies (daratumumab) also have promising results. Selinexor combination therapy is both safe and effective for patients with pretreated RRMM., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Carfilzomib is a promising anticancer drug for relapsed/refractory multiple myeloma (RRMM). However, real-world evidence has only investigated the cardiovascular safety of carfilzomib, and there is a high demand for thorough safety evaluations. We aimed to comprehensively evaluate the risk of adverse events associated with carfilzomib in Korean patients with RRMM. We followed up with 138 matched patients with RRMM (69 KRd (carfilzomib, lenalidomide, and dexamethasone) and 69 Rd (lenalidomide and dexamethasone) users). A total of 12 adverse events were evaluated. More than 75% of adverse events occurred during the early cycle (1-6 cycles), and the incidence rate showed a tendency to decrease in the later cycle (7-12 and 13-18 cycles). Severities of most adverse events were evaluated as grade 1-2. The KRd regimen were related with significantly increased risks of dyspnea (adjusted HR (aHR) 2.27, 95% confidence interval (CI) 1.24-4.16), muscle spasm (aHR 5.12, 95% CI 1.05-24.9) and thrombocytopenia (aHR 1.84, 95% CI 1.10-3.06). Although the severities were low, carfilzomib has many side effects in treating RRMM; hence, findings on the patterns of its adverse events could lead to both effective and safe use of KRd therapy in real-world settings.

Childhood cancer survivors are confronted with various chronic health conditions like therapy-related malignancies. However, it is unclear how exposure to chemotherapy contributes to the mutation burden and clonal composition of healthy tissues early in life. Here, we studied mutation accumulation in hematopoietic stem and progenitor cells (HSPC) before and after cancer treatment of 24 children. Of these children, 19 developed therapy-related myeloid neoplasms (t-MN). Posttreatment HSPCs had an average mutation burden increase comparable to what treatment-naïve cells accumulate during 16 years of life, with excesses up to 80 years. In most children, these additional mutations were induced by clock-like processes, which are also active during healthy aging. Other patients harbored mutations that could be directly attributed to treatments like platinum-based drugs and thiopurines. Using phylogenetic inference, we demonstrate that most t-MN in children originate after the start of treatment and that leukemic clones become dominant during or directly after chemotherapy exposure., Significance: Our study shows that chemotherapy increases the mutation burden of normal blood cells in cancer survivors. Only few drugs damage the DNA directly, whereas in most patients, chemotherapy-induced mutations are caused by processes similar to those present during normal aging. This article is highlighted in the In This Issue feature, p. 1825., (©2022 The Authors; Published by the American Association for Cancer Research.)

Diabetes mellitus (DM) has attained the status of a global pandemic. Cardiovascular disease (CV) was the leading cause of morbidity in people with type 2 DM, however, a transition from CV to cancer as the leading contributor to DM related death has been observed lately. Multiple myeloma (MM) is the second most common haematological malignancy. Obesity is a common risk factor for both DM and MM. Although data are limited, studies have shown that DM might be associated with increased risk for the development of MM. The presence of DM might affect the course of patients with MM, since hyperglycemia may have an impact on both the efficacy and the adverse effects of antimyeloma therapy. In parallel, DM and MM share common clinical presentations, such as nephropathy, neuropathy, and CV. In terms of antidiabetic medications, metformin might present a synergistic effect with antimyeloma drugs and also prevent some of the adverse effects of these drugs; pioglitazone might have favourable effects when given as add on treatment in people with relapsed or refractory MM. No clinically important interactions have been observed between antidiabetic agents and the most commonly used antimyeloma drugs. Further data are needed to examine the effect of all classes of antidiabetic medication on MM and its complications. A baseline assessment of risk factors for glucose intolerance and close monitoring of glucose levels during therapy is strongly suggested for patients with MM., (© 2022 John Wiley & Sons Ltd.)

Background: Selinexor 80 mg combined with low-dose dexamethasone (Sd) demonstrated significant clinical benefit in patients with relapsed/refractory multiple myeloma (RRMM) who had disease refractory to a proteasome inhibitor (PI), an immunomodulator (IMiD), and an anti-CD38 monoclonal antibody based on a global phase II STORM study. The present study, MARCH, addresses China regulatory needs to further validate the data from STORM in Chinese patients with RRMM., Methods: The MARCH study was conducted at 17 sites in China, where eligible Chinese RRMM patients who had disease refractory to PI and IMiD were enrolled. Selinexor 80 mg combined with dexamethasone 20 mg was administered orally on day 1 and day 3 of each week in 4-week cycles. The primary endpoint was the overall response rate (ORR) per an independent review committee, with the null hypothesis of ≤15%. Patients who received at least 1 dose of study treatment were included in the safety population. The pharmacokinetic (PK) profile was characterized by parameter and ethnicity sensitivity analyses., Results: A total of 82 patients with RRMM were enrolled in the study, with a median age of 60 years. Of the 82 patients, 55 patients (67.1%) had high-risk cytogenetic abnormalities, defined as one or more of del 17p13, t(4;14), t(14;16), or 1q amplification identified by fluorescence in situ hybridization (FISH); 18 patients (22.0%) had abnormal renal function. Enrolled patients were heavily pre-treated with a median prior regimen number of 5. All 82 patients (100%) were refractory to both PI and IMiD, including 20 patients (24.4%) categorized as triple-class refractory population (refractory to PI, IMiD, and daratumumab). Ten patients (12.2%) had undergone CAR-T therapy. ORR was 29.3% (95% CI 19.7, 40.4) with a median DOR of 4.7 months. The median PFS and OS were 3.7 and 13.2 months, respectively. ORR was 25.0% (95% CI 8.7, 49.1) in the triple-class refractory population. Efficacy was consistent across various subgroups. The most frequent grade 3/4 adverse events (AEs) included anemia (57.3%), thrombocytopenia (51.2%), lymphopenia (42.7%), neutropenia (40.2%), hyponatremia (29.3%), and lung infection (26.8%). Serious AEs were reported in 54.9% of patients. No significant drug accumulation was shown following multiple administrations. No human PK ethnicity difference was identified between Chinese and western patients., Conclusions: With an encouraging ORR, the MARCH study has demonstrated that selinexor combined with low-dose dexamethasone (Sd) delivers meaningful clinical benefit to Chinese patients with RRMM, including triple-class refractory patients. AEs were expected and manageable with supportive care and dose modification., Trial Registration: ClinicalTrials.gov, NCT03944057 (May 09, 2019); Chinadrugtrials.org.cn , CTR20190858 (June 05, 2019)., (© 2022. The Author(s).)

Introduction: Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that takes advantage of increased aminopeptidase activity inside tumor cells to rapidly release alkylating agents therein. Melflufen in combination with dexamethasone has been evaluated in multiple clinical trials in patients with relapsed/refractory multiple myeloma (MM)., Areas Covered: This profile covers the unique mechanism of action of melflufen, the preclinical results supporting its activity in cellular models of resistance to chemotherapy, its activity in animal models of MM, and the clinical pharmacokinetics of melflufen. Findings from clinical trials evaluating melflufen, including the pivotal phase II HORIZON study and the phase III OCEAN study, are discussed., Expert Opinion: Although MM treatment has improved, patients with disease refractory to multiple standard-of-care drug classes face a dismal prognosis. Melflufen demonstrated efficacy and tolerability in select populations, with an initial approval in the United States in patients with ≥ four previous lines of therapy and triple-class-refractory MM. Results from the phase III OCEAN study - currently under discussion with regulatory agencies in the United States and Europe - are more complex and have been put into context herein. Lastly, melflufen provides a proof-of-concept for the utility of the peptide-drug conjugate platform in relapsed/refractory MM.

Purpose: Bortezomib is a neurotoxic drug used in multiple myeloma and responsible for chemotherapy-induced peripheral neuropathy (CIPN). In a previous cross-sectional study, CIPN prevalence was about 26.9% in 67 patients. A second data analysis was performed to explore the relation between CIPN and auditory difficulties., Methods: Based on 66 multiple myeloma patients from a single center, auditory difficulties were assessed with a self-questionnaire and compared to sensory CIPN (QLQ-CIPN20 questionnaire), patients' characteristics and anticancer treatments., Results: The prevalence of auditory difficulties was about 42.4% (95% CI [30.6-55.2]) of the 66 patients analyzed and was higher in patients with CIPN than without (82.4% vs. 28.6%, p < 0.001). Auditory difficulties were not related to the characteristics of patients and treatments. The severity of auditory difficulties were correlated to CIPN severity (spearman's coefficient: 0.49, p = 0.009). Odds-ratio of auditory difficulties (multivariable analysis adjusted for sensory CIPN, recreation or professional noise exposure, gender, age, and treatments) was significantly associated with CIPN (18.7, 95% CI [3.0-117.1], p = 0.002)., Conclusion: This relation between CIPN and auditory difficulties raises concerns about hearing safety in multiple myeloma patients treated by bortezomib., Trial Registration Number: NCT03344328., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Evidence on the association between selenium and cancer risk is inconclusive. We conducted a Mendelian randomization study to examine the associations of selenium levels with 22 site-specific cancers and any cancer. Single nucleotide polymorphisms (SNPs) strongly associated with toenail and blood (TAB) and blood selenium levels in mild linkage disequilibrium (r 2  < .3) were used as instrumental variables. Genetic associations of selenium-associated SNPs with cancer were obtained from the UK Biobank including a total of 59 647 cancer cases and 307 914 controls. Associations with P < .1 in UK Biobank were tested for replication in the FinnGen consortium comprising more than 180 000 individuals. The inverse-variance weighted method accounting for linkage disequilibrium was used to estimate the associations. Genetically predicted TAB selenium levels were not associated with the risk of the 22 site-specific cancers or any cancer (all 22 site-specific cancers). Similarly, we observed no strong association for genetically predicted blood selenium levels. However, genetically predicted blood selenium levels showed suggestive associations with risk of kidney cancer (odds ratio [OR] per one-unit increase in log-transformed levels: 0.83; 95% confidence interval [CI]: 0.67-1.03) and multiple myeloma (OR: 1.40; 95% CI: 1.02-1.93). The same direction of association for kidney cancer but not for multiple myeloma was observed in FinnGen. In the metaanalysis of UK Biobank and FinnGen, the OR of kidney cancer was 0.83 (95% CI: 0.69-1.00). Our study suggests that high selenium status may not prevent cancer development. The associations for kidney cancer and multiple myeloma need to be verified in well-powered studies., (© 2021 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Introduction and Objective: Multiple myeloma (MM) is an incurable condition with variable clinical course. The study included a group of patients with especially poor-prognosis, individuals with relapsed/refractory multiple myeloma (RRMM) and specific cytogenetic disorders. Among the currently used therapies the ixazomib-lenalidomid-dexamethasone (IRd) is considered as a candidate to improve outcomes. The aim of the study was to evaluate the safety and efficacy of IRd regimen in the treatment of patients with RMMM., Material and Methods: Nine patients aged 52-82 years who received ixazomib in the early access programme, were included in the study. All patients met the criteria for recurrent/relapsed MM and had high (t(4:14), t(14:16), del17p or +1q21) risk aberrations. Previous chemotherapy regimens included thalidomide and bortezomib. Median duration of exposure to ixazomib was 12 months., Results: One patient with multiple cytogenetic aberrations and extramedullary plasmocytoma died because of progression after two months of treatment. In the remaining patients, the objective response to treatment was reached, and in four cases it was qualified as a very good partial response (VGPR). Observed adverse effects included neutropenia, infections, and oedema (in three cases Grade 3). Eight patients continue treatment, in two cases the decision was made to reduce lenalidomide doses., Conclusions: Preliminary results suggest potentially high efficacy and good safety profile of IRd therapy in patients with RRMM and unfavourable cytogenetics.

Background: Multiple myeloma is a cancer of plasma cells that often leads to complications including osteolytic bone lesions, nephropathy and neuropathy. Multiple myeloma is only one etiology of many cancer pain conditions that may necessitate interventional pain treatment when refractory to multimodal medications. Notably, local anesthetic systemic toxicity is a rare but life-threatening complication of local anesthetic administered for these interventions., Case Presentation: A 50-60-year-old woman presented with multiple myeloma complicated by chronic bone pain and in an acute pain crisis. A fluoroscopic-guided L4-5 epidural catheter was placed with clinical doses of bupivacaine for comfort to undergo MRI of the spine. Soon after, she became tachycardic, tachypneic and hypoxic requiring non-invasive positive pressure airway support. As this respiratory distress was attributed to a large pleural effusion, a pigtail catheter was inserted in the intensive care unit with submaximally dosed lidocaine infiltration. She then developed a left bundle branch block followed by cardiovascular collapse minimally responsive to high-dose inotrope and vasopressor support. Lipid emulsion was started with dramatic therapeutic response and recovery to baseline. A CT of the thoracolumbar spine showed worsening extensive lytic lesions throughout all vertebral bodies and ribs from diffuse myeloma., Conclusions: Patients with oncologic lesions focal to the thoracolumbar spine may be at higher risk for local anesthetic systemic toxicity from palliative epidurals due to increased cancer-related angiogenesis. Likewise, local anesthetic infiltration for procedures near any malignant sites could have a similar risk and may require lower initial fractionated dosages with increased vigilance., Competing Interests: Competing interests: None declared., (© American Society of Regional Anesthesia & Pain Medicine 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Several commonly used immune-suppressing biologic drugs target proteins and cytokines involved in myeloma pathogenesis. Our objective was to determine whether targeted biologic disease-modifying antirheumatic drugs (DMARDs) are associated with risk of multiple myeloma (MM). We conducted a nested case-control study within a retrospective cohort of 56,886 commercially insured adults undergoing treatment for rheumatoid arthritis, psoriatic arthritis or ankylosing spondylitis between 2009 and 2015 using the Truven Health MarketScan Databases. MM cases (n = 287) were matched to up to 10 controls (n = 2,760) on age, sex and rheumatologic indication using incidence density sampling without replacement. Our exposures of interest were biologic DMARDs targeting tumor necrosis factor-alpha, interleukin 6, cytotoxic t-lymphocyte-associated protein-4 and depletion of B cells. Relative risks were estimated as adjusted odds ratios (OR) and 95% confidence intervals (CI) using conditional logistic regression models. Cases and controls were similar with respect to use of prescription NSAIDs and concurrent conventional-synthetic DMARDs. Cases had slightly fewer etanercept users (4% vs. 7%) and slightly more tocilizumab users (1.4% vs. 0.4%). Compared to patients treated with only conventional-synthetic DMARDs, those receiving concomitant conventional-synthetic plus biologic DMARDs had lower risk of developing MM (OR = 0.48; 95% CI 0.30-0.88; p = 0.02). Risks differed by drug target with an inverse association observed with use of etanercept inhibiting tumor necrosis factor-alpha (OR = 0.55; 95% CI 0.30-1.02; p = 0.06) and a positive association with tocilizumab inhibiting interleukin-6 (OR = 4.33; 95% CI 1.33-14.19; p = 0.02) compared to biologic DMARD-naïve patients. Further investigation is warranted to understand the roles of drugs suppressing tumor necrosis factor-alpha and interleukin-6 in myeloma pathogenesis., (© 2020 UICC.)

Previous studies exploring associations between statin use and risk of multiple myeloma (MM) showed inconsistent results. We searched for articles published in English in databases (PubMed, Web of Science, EMBASE, Medline, and Google Scholar) before October 2019. The multivariate odds ratio (OR)/relative risk (RR) and 95% confidence intervals (CI) were computed to explore associations between statin use and risk of MM. The study indicated that statin users showed significantly lower risks of MM with a random effects model (OR/RR = 0.77, 95% CI 0.63 to 0.95, I 2  = 63.1%, p for Q test = 0.001). Subgroup analyses showed that statin users showed significantly lower risks of MM in Caucasian populations with a fixed effects model (OR/RR = 0.72, 95% CI 0.59 to 0.88, I 2  = 43.5%, p for Q test = 0.060), whereas no significant association was shown between statin use and risks of MM in Asian populations with a random effects model. Additionally, Subgroup analyses showed that statin users showed significantly lower risks of MM in cohort studies with a fixed effects model (RR = 0.83, 95% CI 0.74 to 0.93, I 2  = 0.0%, p for Q test = 0.429), whereas no significant association was shown between statin use and risks of MM in case-control studies with a random effects model. In conclusion, the present study indicated that statin use might be a protective factor for MM incidence. However, the relationship between statin use and MM risk requires repeated and large prospective studies to be verified.

Purpose: Epidemiological studies have found an increased risk of multiple myeloma (MM) in farmers. Few studies have investigated the detailed circumstances of occupational pesticide exposure which could explain these increased risks (pesticide use on crops, seeds or on animals, contact with treated crops) and the role of other exposures. In the Agriculture and Cancer cohort (AGRICAN), we assessed the associations between MM and crop- or animal-related activities, with specific attention to pesticide exposure via use on animals and crops or contact with treated crops and to disinfectant exposure., Methods: Analyses concerned 155,192 participants, including 269 incident MM identified by cancer registries from enrolment (2005-2007) to 2013. Cox models using attained age as time scale were run to calculate hazard ratios (HR) and 95% confidence intervals (CI)., Results: MM risk was increased in farmers (i) who started using pesticides on crops in the 1960s, especially among those applying pesticides on corn (≥ 20 years: HR 1.73, 95% CI 1.08, 2.78, p for trend < 0.01) and (ii) using insecticides on animals (HR 1.48, 95% CI 1.11, 1.98), especially among horse farmers (≥ 10 years: HR 2.77, 95% CI 1.22-6.27, p for trend = 0.01). We also observed significant elevated risks with disinfectant use in animal barns., Conclusions: Findings support the role of pesticide use on crops and animals in the occurrence of MM risk in farmers.

Background: Glyphosate is the most widely used herbicide in the USA and worldwide. There has been considerable debate about its carcinogenicity. Epidemiological studies suggest that multiple myeloma (MM) and non-Hodgkin lymphoma (NHL) have a positive and statistically significant association with glyphosate exposure. As a B cell genome mutator, activation-induced cytidine deaminase (AID) is a key pathogenic player in both MM and B cell NHL., Methods: Vk*MYC is a mouse line with sporadic MYC activation in germinal center B cells and considered as the best available MM animal model. We treated Vk*MYC mice and wild-type mice with drinking water containing 1000 mg/L of glyphosate and examined animals after 72 weeks., Results: Vk*MYC mice under glyphosate exposure developed progressive hematological abnormalities and plasma cell neoplasms such as splenomegaly, anemia, and high serum IgG. Moreover, glyphosate caused multiple organ dysfunction, including lytic bone lesions and renal damage in Vk*MYC mice. Glyphosate-treated wild-type mice developed benign monoclonal gammopathy with increased serum IgG, anemia, and plasma cell presence in the spleen and bone marrow. Finally, glyphosate upregulated AID in the spleen and bone marrow of both wild-type and Vk*MYC mice., Conclusions: These data support glyphosate as an environmental risk factor for MM and potentially NHL and implicate a mechanism underlying the B cell-specificity of glyphosate-induced carcinogenesis observed epidemiologically.

Patients with rheumatoid arthritis occasionally develop lymphoproliferative disorders. Methotrexate-associated lymphoproliferative disorders is a lymphoproliferative disease or lymphoma in patients treated with methotrexate for autoimmune diseases, such as rheumatoid arthritis. Here we report two rare cases of highly aggressive plasmablastic lymphoproliferative disorders in rheumatoid arthritis treated with methotrexate. Case 1 is a 68-year-old female patient with leukemic transformation of malignant lymphoma. She received methotrexate therapy for rheumatoid arthritis for >6 years. The patient showed rapid progressive course and died on the 2nd hospital day. After the death, we diagnosed the patient as plasmablastic lymphoma. Case 2 is an 80-year-old female patient with plasmablastic plasma cell myeloma, with a history of methotrexate treatment for rheumatoid arthritis for >5 years. Although M-protein was decreased by chemotherapy, bone marrow examination revealed the further increase of plasmablastic cells and she died 2 months later. The present cases were difficult to diagnose because proliferation of malignant plasmablasts was hardly predicted because neither lymph node enlargement nor an evident M-protein was observed. Both cases showed aggressive features and extremely poor prognosis. Clinicians should be aware of the underlying malignant plasmablastic proliferation when inexplicable inflammatory findings are observed in inactive rheumatoid arthritis patients., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Although epidemiologic studies have suggested a possible association between occupational exposures to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and the risk of development of multiple myeloma, definitive evidence in support of this association is lacking. In the present study, we employed the Vk*Myc mouse model of multiple myeloma to assess the impact of TCDD exposure on multiple myeloma pathogenesis. TCDD induced splenomegaly and multiple peripheral blood abnormalities, including anemia and high serum IgG levels. In addition, TCDD triggered bone lytic lesions, as well as renal tubular casts, a phenomenon associated with human myeloma kidney disease. Even in wild-type C57BL/6 mice, TCDD increased serum IgG levels, induced anemia, and increased plasma cell presence in the spleen and bone marrow, hallmarks of benign monoclonal gammopathy. Lastly, TCDD induced AKT activation and the DNA damage response, key pathogenic events in myeloma pathogenesis, in animal spleen and/or bone marrow. These data indicate that TCDD accelerates monoclonal gammopathy development and promotes progression to multiple myeloma in genetically-predisposed mice. This work offers the first direct experimental evidence establishing TCDD as an environmental risk factor for monoclonal gammopathy of undetermined significance and multiple myeloma., (Copyright © 2018. Published by Elsevier B.V.)

Objectives: To investigate the association between occupational exposure to aromatic hydrocarbon solvents and risk of multiple myeloma (MM) in a large, consortium-based study., Methods: We pooled data on 2854 cases and 10 743 controls from nine studies participating in the InterLymph consortium. Occupational exposures to benzene, toluene and xylene were assigned by a job-exposure matrix, coupled with 'correction' of exposure probability by self-reported or expert-assessed exposure from the individual studies. Cumulative intensity was calculated as the job-specific exposure intensity multiplied by job duration, summed across jobs. Associations were estimated using logistic regression, with inclusion of covariates for study matching factors and other potential confounders. We repeated our main analysis using random-effects meta-analysis to evaluate heterogeneity of effect., Results: Benzene, toluene and xylene were each associated with MM. For the three solvents, the highest quartile of high-probability cumulative intensity exposure (vs unexposed) was associated with 42% to 63% increased risks of MM. Associations with toluene and xylene exposures were fairly consistent and robust to sensitivity analyses. The estimated effect for benzene was moderately heterogeneous between the studies. Each solvent's association with MM was stronger for exposure occurring within 20 years of diagnosis than with exposure lagged by more than 20 years., Conclusions: Our study adds important evidence for a role of aromatic hydrocarbon solvents in causation of MM. The difficulty in disentangling individual compounds in this group and a lack of data on potential carcinogenicity of toluene and xylene, in widespread current use, underscore a need for further epidemiological evaluation., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2018. No commercial re-use. See rights and permissions. Published by BMJ.)

The production of the oncometabolite 2-hydroxyglutarate (2-HG) has been associated with c-MYC overexpression. c-MYC also regulates glutamine metabolism and drives progression of asymptomatic precursor plasma cell (PC) malignancies to symptomatic multiple myeloma (MM). However, the presence of 2-HG and its clinical significance in PC malignancies is unknown. By performing 13C stable isotope resolved metabolomics (SIRM) using U[13C6]Glucose and U[13C5]Glutamine in human myeloma cell lines (HMCLs), we show that 2-HG is produced in clonal PCs and is derived predominantly from glutamine anaplerosis into the TCA cycle. Furthermore, the 13C SIRM studies in HMCLs also demonstrate that glutamine is preferentially utilized by the TCA cycle compared with glucose. Finally, measuring the levels of 2-HG in the BM supernatant and peripheral blood plasma from patients with precursor PC malignancies such as smoldering MM (SMM) demonstrates that relatively elevated levels of 2-HG are associated with higher levels of c-MYC expression in the BM clonal PCs and with a subsequent shorter time to progression (TTP) to MM. Thus, measuring 2-HG levels in BM supernatant or peripheral blood plasma of SMM patients offers potential early identification of those patients at high risk of progression to MM, who could benefit from early therapeutic intervention.

Animal and human data suggest statins may be protective against developing multiple myeloma; however, findings may be biased by the interrelationship with lipid levels. We investigated the association between statin use and risk of multiple myeloma in a large US population, with an emphasis on accounting for this potential bias. We conducted a case-control study nested within 6 US integrated healthcare systems participating in the National Cancer Institute-funded Cancer Research Network. Adults aged ≥40 years who were diagnosed with multiple myeloma from 1998-2008 were identified through cancer registries (N = 2,532). For each case, five controls were matched on age, sex, health plan, and membership duration prior to diagnosis/index date. Statin prescriptions were ascertained from electronic pharmacy records. To address potential biases related to lipid levels and medication prescribing practices, multivariable marginal structural models were used to model statin use (≥6 cumulative months) and risk of multiple myeloma, with examination of multiple latency periods. Statin use 48-72 months prior to diagnosis/index date was associated with a suggestive 20-28% reduced risk of developing multiple myeloma, compared to non-users. Recent initiation of statins was not associated with myeloma risk (risk ratio range 0.90-0.99 with 0-36 months latency). Older patients had more consistent protective associations across all latency periods (risk ratio range 0.67-0.87). Our results suggest that the association between statin use and multiple myeloma risk may vary by exposure window and age. Future research is warranted to investigate the timing of statin use in relation to myeloma diagnosis., (© 2017 UICC.)

Data on the risk of lymphatic and hematopoietic neoplasms among workers whose jobs entail high exposure to polycyclic aromatic hydrocarbons (PAH) are sparse, and mainly based on small-size studies. We carried out a systematic review of occupational cohort studies that reported results on incidence or mortality from Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL), leukemia or multiple myeloma (MM) among workers exposed to PAH. We computed meta-analytic estimates using a random effect model. Meta-relative risk (meta-RR) was computed separately by each type of neoplasm, job or industry. We identified 41 studies (12 in iron and steel foundries, 11 in aluminum plant, 6 in cokeries, 6 in carbon electrode manufacturing, 2 on asphalt workers, 2 on creosote-exposed workers, 1 on tar distillery workers and 1 evaluating both tar distillery workers and roofers). No significant excess risk of any lymphatic and hematopoietic neoplasms was found among workers employed in jobs or industries entailing high PAH exposure. Among 18 meta-analytic estimates by job or industry and type of neoplasm, 16 were close to unit, i.e., between 0.72 and 1.27, whereas the meta-RR was 1.38 [95 % confidence interval (CI) 0.95-2.01] for HL in foundry workers and 2.01 (95 % CI 0.96-4.22) for NHL in workers exposed to creosote. There was no association between occupation entailing high PAH exposure and risk of MM or leukemia.

Multiple myeloma (MM) has been consistently linked with agricultural activities, including farming and pesticide exposures. Three case-control studies in the United States and Canada were pooled to create the North American Pooled Project (NAPP) to investigate associations between pesticide use and haematological cancer risk. This analysis used data from 547 MM cases and 2700 controls. Pesticide use was evaluated as follows: ever/never use; duration of use (years); and cumulative lifetime-days (LD) (days/year handled × years of use). Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression adjusted for age, province/state of residence, use of proxy respondents and selected medical conditions. Increased MM risk was observed for ever use of carbaryl (OR = 2.02, 95% CI = 1.28-3.21), captan (OR = 1.98, 95% CI = 1.04-3.77) and DDT (OR = 1.44, 95% CI = 1.05-1.97). Using the Canadian subset of NAPP data, we observed a more than threefold increase in MM risk (OR = 3.18, 95% CI = 1.40-7.23) for ≤10 cumulative LD of carbaryl use. The association was attenuated but remained significant for >10 LD of carbaryl use (OR = 2.44; 95% CI = 1.05-5.64; ptrend  = 0.01). For captan, ≤17.5 LD of exposure was also associated with a more than threefold increase in risk (OR = 3.52, 95% CI = 1.32-9.34), but this association was attenuated in the highest exposure category of >17.5 LD (OR = 2.29, 95% CI = 0.81-6.43; ptrend  = 0.01). An increasing trend (ptrend  = 0.04) was observed for LD of DDT use (LD > 22; OR = 1.92, 95% CI = 0.95-3.88). In this large North American study of MM and pesticide use, we observed significant increases in MM risk for use of carbaryl, captan and DDT., (© 2016 UICC.)

Cardiac amyloidosis is an infiltrative disorder of the myocardium. It is the result of one of 4 types of amyloidosis: primary systemic (immunoglobulin light chain), secondary, familial (hereditary), or senile. Cardiac amyloidosis ultimately causes congestive heart failure due to irreversible restrictive cardiomyopathy. Because of the rapid progression of the disease, early recognition and determination of underlying etiology are important for tailored therapy. Current interventions range from conservative heart failure management to autologous stem cell and heart transplantation. We present a case of cardiac amyloidosis accompanying undiagnosed multiple myeloma to illustrate the rapid progression of the disease and the complexities of diagnosing and treating this disorder.

Multiple myeloma (MM) is a plasma cell malignancy without effective therapeutics. Thromboxane A2 (TxA2)/TxA2 receptor (T prostanoid receptor (TP)) modulates the progression of some carcinomas; however, its effects on MM cell proliferation remain unclear. In this study, we evaluated cyclooxygenase (COX) enzymes and downstream prostaglandin profiles in human myeloma cell lines RPMI-8226 and U-266 and analyzed the effects of COX-1/-2 inhibitors SC-560 and NS-398 on MM cell proliferation. Our observations implicate COX-2 as being involved in modulating cell proliferation. We further incubated MM cells with prostaglandin receptor antagonists or agonists and found that only the TP antagonist, SQ29548, suppressed MM cell proliferation. TP silencing and the TP agonist, U46619, further confirmed this finding. Moreover, SQ29548 and TP silencing promoted MM cell G2/M phase delay accompanied by reducing cyclin B1/cyclin-dependent kinase-1 (CDK1) mRNA and protein expression. Notably, cyclin B1 overexpression rescued MM cells from G2/M arrest. We also found that the TP agonist activated JNK and p38 MAPK phosphorylation, and inhibitors of JNK and p38 MAPK depressed U46619-induced proliferation and cyclin B1/CDK1 protein expression. In addition, SQ29548 and TP silencing led to the MM cell apoptotic rate increasing with improving caspase 3 activity. The knockdown of caspase 3 reversed the apoptotic rate. Taken together, our results suggest that TxA2/TP promotes MM cell proliferation by reducing cell delay at G2/M phase via elevating p38 MAPK/JNK-mediated cyclin B1/CDK1 expression and hindering cell apoptosis. The TP inhibitor has potential as a novel agent to target kinase cascades for MM therapy., (© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.)

This systematic review and meta-analysis rigorously examines the relationship between glyphosate exposure and risk of lymphohematopoietic cancer (LHC) including NHL, Hodgkin lymphoma (HL), multiple myeloma (MM), and leukemia. Meta-relative risks (meta-RRs) were positive and marginally statistically significant for the association between any versus no use of glyphosate and risk of NHL (meta-RR = 1.3, 95% confidence interval (CI) = 1.0-1.6, based on six studies) and MM (meta-RR = 1.4, 95% CI = 1.0-1.9; four studies). Associations were statistically null for HL (meta-RR = 1.1, 95% CI = 0.7-1.6; two studies), leukemia (meta-RR = 1.0, 95% CI = 0.6-1.5; three studies), and NHL subtypes except B-cell lymphoma (two studies each). Bias and confounding may account for observed associations. Meta-analysis is constrained by few studies and a crude exposure metric, while the overall body of literature is methodologically limited and findings are not strong or consistent. Thus, a causal relationship has not been established between glyphosate exposure and risk of any type of LHC.

Background: The effect of artificial sweetener consumption on cancer risk has been debated in animal models for over four decades. To further investigate this relationship, this study aims to synthesise results from several of the most recent studies in humans., Methods: An online literature search was performed in MEDLINE from 2003 to 2014 using Ovid, PubMed, Web of Science, and Scopus using keywords 'artificial', 'sweetener' and 'cancer'. Ninety-two results were then manually assessed for eligibility. Studies were included if the relationship between artificial sweeteners and cancer was their central hypothesis, and if they adjusted for age, gender, smoking status and body mass index. Extracted data included study design, patient characteristics, outcome measure and results., Results: In the five publications that satisfied the inclusion criteria, significant direct associations with artificial consumption were found for laryngeal (odds ratio, OR 2.34, 95% CI: 1.20-4.55), urinary tract tumours (OR 2.12, 95% CI: 1.22-3.89), non-Hodgkin lymphoma in men (RR 1.31, 95% CI: 1.01-1.72), multiple myeloma in men (RR 2.02, 95% CI: 1.20-3.40) and leukaemia (RR 1.42, 95% CI: 1.00-2.02). Inverse relationships were found in breast (OR 0.70, 95% CI: 0.54-0.91, p trend = 0.015) and ovarian (OR 0.56, 95% CI: 0.38-0.81, p trend < 0.001) cancers., Conclusion: The statistical value of this review is limited by the heterogeneity and observational designs of the included studies. Although there is limited evidence to suggest that heavy consumption may increase the risk of certain cancers, overall the data presented are inconclusive as to any relationship between artificial sweeteners and cancer., (© 2015 John Wiley & Sons Ltd.)

Importance: Multiple myeloma has been classified as exhibiting "limited or suggestive evidence" of an association with exposure to herbicides in Vietnam War veterans. Occupational studies have shown that other pesticides (ie, insecticides, herbicides, fungicides) are associated with excess risk of multiple myeloma and its precursor state, monoclonal gammopathy of undetermined significance (MGUS); however, to our knowledge, no studies have uncovered such an association in Vietnam War veterans., Objective: To examine the relationship between MGUS and exposure to Agent Orange, including its contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), in Vietnam War veterans., Design, Setting, and Participants: This was a prospective cohort study conducted in 2013 to 2014, testing for MGUS in serum specimens collected and stored in 2002 by the Air Force Health Study (AFHS). The relevant exposure data collected by the AFHS was also used. We tested all specimens in 2013 without knowledge of the exposure status. The AFHS included former US Air Force personnel who participated in Operation Ranch Hand (Ranch Hand veterans) and other US Air Force personnel who had similar duties in Southeast Asia during the same time period (1962 to 1971) but were not involved in herbicide spray missions (comparison veterans). Agent Orange was used by the US Air Force personnel who conducted aerial spray missions of herbicides (Operation Ranch Hand) in Vietnam from 1962 to 1971. We included 479 Ranch Hand veterans and 479 comparison veterans who participated in the 2002 follow-up examination of AFHS., Exposures: Agent Orange and TCDD. Serum TCDD levels were measured in 1987, 1992, 1997, and 2002., Main Outcomes and Measures: Risk of MGUS measured by prevalence, odds ratios (ORs), and 95% CIs., Results: The 479 Ranch Hand veterans and 479 comparison veterans had similar demographic and lifestyle characteristics and medical histories. The crude prevalence of overall MGUS was 7.1% (34 of 479) in Ranch Hand veterans and 3.1% (15 of 479) in comparison veterans. This translated into a 2.4-fold increased risk for MGUS in Ranch Hand veterans than comparison veterans after adjusting for age, race, BMI in 2002, and the change in BMI between 2002 and the time of blood draw for TCDD measurement (adjusted OR, 2.37; 95% CI, 1.27-4.44; P=.007)., Conclusions and Relevance: Operation Ranch Hand veterans have a significantly increased risk of MGUS, supporting an association between Agent Orange exposure and multiple myeloma.

Purpose: Establishing a causal relationship between 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and risk of specific lymphoid cancers, including non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), and multiple myeloma (MM), would be useful for risk assessment., Methods: This article systematically and critically reviews epidemiologic studies of the association between exposure to TCDD or TCDD-contaminated herbicides and risk of lymphoid malignancies. These include studies of military, industrial, accidental environmental, and general environmental exposure to Agent Orange or TCDD., Results: Collectively, the epidemiologic evidence from industrial cohorts suggests a positive association with NHL mortality, but results are not consistent across other studies, a clear exposure-response gradient is not evident, and data are insufficient to conclude that the association is causal. Furthermore, available studies provide little information on NHL incidence or specific NHL subtypes. Epidemiologic studies do not show an association of TCDD exposure with HL, whereas the indication of a positive association with MM in a limited number of studies, but not others, remains to be confirmed in additional research. Exposure classification error and small numbers are important limitations of the available epidemiologic studies., Conclusions: Overall, a causal effect of TCDD on NHL, HL, MM, or subtypes of these lymphoid malignancies has not been established., (Copyright © 2015 Elsevier Inc. All rights reserved.)

A previous publication of 57,311 pesticide applicators enrolled in the US Agricultural Health Study (AHS) produced disparate findings in relation to multiple myeloma risks in the period 1993-2001 and ever-use of glyphosate (32 cases of multiple myeloma in the full dataset of 54,315 applicators without adjustment for other variables: rate ratio (RR) 1.1, 95% confidence interval (CI) 0.5 to 2.4; 22 cases of multiple myeloma in restricted dataset of 40,719 applicators with adjustment for other variables: RR 2.6, 95% CI 0.7 to 9.4). It seemed important to determine which result should be preferred. RRs for exposed and non-exposed subjects were calculated using Poisson regression; subjects with missing data were not excluded from the main analyses. Using the full dataset adjusted for age and gender the analysis produced a RR of 1.12 (95% CI 0.50 to 2.49) for ever-use of glyphosate. Additional adjustment for lifestyle factors and use of ten other pesticides had little effect (RR 1.24, 95% CI 0.52 to 2.94). There were no statistically significant trends for multiple myeloma risks in relation to reported cumulative days (or intensity weighted days) of glyphosate use. The doubling of risk reported previously arose from the use of an unrepresentative restricted dataset and analyses of the full dataset provides no convincing evidence in the AHS for a link between multiple myeloma risk and glyphosate use.

Farming and pesticide use have previously been linked to non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL) and multiple myeloma (MM). We evaluated agricultural use of specific insecticides, fungicides, and fumigants and risk of NHL and NHL-subtypes (including CLL and MM) in a U.S.-based prospective cohort of farmers and commercial pesticide applicators. A total of 523 cases occurred among 54,306 pesticide applicators from enrollment (1993-97) through December 31, 2011 in Iowa, and December 31, 2010 in North Carolina. Information on pesticide use, other agricultural exposures and other factors was obtained from questionnaires at enrollment and at follow-up approximately five years later (1999-2005). Information from questionnaires, monitoring, and the literature were used to create lifetime-days and intensity-weighted lifetime days of pesticide use, taking into account exposure-modifying factors. Poisson and polytomous models were used to calculate relative risks (RR) and 95% confidence intervals (CI) to evaluate associations between 26 pesticides and NHL and five NHL-subtypes, while adjusting for potential confounding factors. For total NHL, statistically significant positive exposure-response trends were seen with lindane and DDT. Terbufos was associated with total NHL in ever/never comparisons only. In subtype analyses, terbufos and DDT were associated with small cell lymphoma/chronic lymphocytic leukemia/marginal cell lymphoma, lindane and diazinon with follicular lymphoma, and permethrin with MM. However, tests of homogeneity did not show significant differences in exposure-response among NHL-subtypes for any pesticide. Because 26 pesticides were evaluated for their association with NHL and its subtypes, some chance finding could have occurred. Our results showed pesticides from different chemical and functional classes were associated with an excess risk of NHL and NHL subtypes, but not all members of any single class of pesticides were associated with an elevated risk of NHL or NHL subtypes. These findings are among the first to suggest links between DDT, lindane, permethrin, diazinon and terbufos with NHL subtypes.

Background: The U.S. Environmental Protection Agency (EPA) completed a toxicological review of tetrachloroethylene (perchloroethylene, PCE) in February 2012 in support of the Integrated Risk Information System (IRIS)., Objectives: We reviewed key findings and scientific issues regarding the human health effects of PCE described in the U.S. EPA's Toxicological Review of Tetrachloroethylene (Perchloroethylene)., Methods: The updated assessment of PCE synthesized and characterized a substantial database of epidemiological, experimental animal, and mechanistic studies. Key scientific issues were addressed through modeling of PCE toxicokinetics, synthesis of evidence from neurological studies, and analyses of toxicokinetic, mechanistic, and other factors (tumor latency, severity, and background rate) in interpreting experimental animal cancer findings. Considerations in evaluating epidemiological studies included the quality (e.g., specificity) of the exposure assessment methods and other essential design features, and the potential for alternative explanations for observed associations (e.g., bias or confounding)., Discussion: Toxicokinetic modeling aided in characterizing the complex metabolism and multiple metabolites that contribute to PCE toxicity. The exposure assessment approach-a key evaluation factor for epidemiological studies of bladder cancer, non-Hodgkin lymphoma, and multiple myeloma-provided suggestive evidence of carcinogenicity. Bioassay data provided conclusive evidence of carcinogenicity in experimental animals. Neurotoxicity was identified as a sensitive noncancer health effect, occurring at low exposures: a conclusion supported by multiple studies. Evidence was integrated from human, experimental animal, and mechanistic data sets in assessing adverse health effects of PCE., Conclusions: PCE is likely to be carcinogenic to humans. Neurotoxicity is a sensitive adverse health effect of PCE.

Multiple myeloma (MM) has been linked to certain agricultural exposures, including pesticides. This analysis aimed to investigate the association between lifetime use of multiple pesticides and MM risk using two exposure metrics: number of pesticides used and days per year of pesticide use. A frequency-matched, population-based case-control study was conducted among men in six Canadian provinces between 1991 and 1994. Data from 342 MM cases and 1,357 controls were analyzed using logistic regression to calculate odds ratios (OR) and 95% confidence intervals. Pesticides were grouped by type, chemical class and carcinogenic potential, using a composite carcinogenic probability score. Selected individual pesticides were also examined. Regression models were adjusted for age, province of residence, use of proxy respondents, smoking and selected medical history variables. The overall pattern of results was complex. Positive trends in risk were observed for fungicides (ptrend=0.04) and pesticides classified as probably carcinogenic or higher (ptrend=0.03). Excess risks of MM were observed among men who reported using at least one carbamate pesticide (OR=1.94, 1.16-3.25), one phenoxy herbicide (OR=1.56, 1.09-2.25) and ≥3 organochlorines (OR=2.21, 1.05-4.66). Significantly higher odds of MM were seen for exposure to carbaryl (OR=2.71, 1.47-5.00) and captan (OR=2.96, 1.40-6.24). Use of mecoprop for >2 days per year was also significantly associated with MM (OR=2.15, 1.03-4.48). Focusing on multiple pesticide exposures is important because this more accurately reflects how exposures occur in occupational settings. Significant associations observed for certain chemical classes and individual pesticides suggest that these may be MM risk factors., (Copyright © 2013 UICC.)

Antithyroid drugs as thionamides are largely used in the treatment of the thyrotoxicosis. Side effects were reported in less than 10% of the cases, especially hematological, hepatic or skin allergies. One of the most severe manifestations is agranulocytosis, probably based on an immune mechanism that is exacerbated by the presence of the thyroid autoimmune disease itself. If the presence of the severe leucopenia is actually an epiphenomenon of a preexisting hematological disturbance as multiple myeloma is debated. The myeloma may also be correlated with an autoimmune predisposition. We present the case of a 56 years old female patient diagnosed with Graves' disease, who developed agranulocytosis after 8 months of therapy with thiamazole. Two months after antithyroid drug's withdrawal, the granulocytes number increased and she received therapy with radioiodine. Two years later she came back for diffuse bone pain that turned out to be caused by a multiple myeloma, confirmed by bone marrow biopsy. It might be a connection between the severe form of leucopenia that the patient developed and the medullar malignancy.

Lenalidomide, an immunomodulatory drug used in myeloma therapy, has been claimed to be less neurotoxic than thalidomide, but evidence is still weak. We prospectively assessed lenalidomide safety in myeloma patients to evaluate whether it would induce or modify a previously ensued chemotherapy-induced peripheral neuropathy (CIPN). Thirty consecutive patients (17 men, mean age 63.7 ± 9.4) previously treated with bortezomib and/or thalidomide and starting on lenalidomide (25 mg/day for 21-day cycles) for relapsed or refractory myeloma were assessed at baseline, 6, and 12 months from the beginning of lenalidomide with Total Neuropathy Score clinical version (TNSc), Eastern Cooperative Oncology Group (ECOG) performance status, and numeric rating scale (NRS) for pain. TNSc >2 was considered significant for CIPN. TNSc changes of at least 4 points from baseline value were considered clinically relevant. At baseline 16 of the 30 patients (53.3%) had CIPN (mean TNSc 5.8, range 3-15). After 6 months, 13 patients were unchanged, 1 improved, and 2 worsened. After 12 months the patient who had improved persisted stable, and the two who had worsened returned to TNSc baseline value. The 14 patients without CIPN at baseline did not develop neuropathy. NRS and ECOG performance status persisted unchanged. Our results demonstrate lenalidomide safety and very low neurotoxicity also in patients with pre-existing CIPN treated for 1 year., (© 2013 Peripheral Nerve Society.)

Pyoderma gangrenosum (PG) may be associated with inflammatory disorders and haematological conditions such as monoclonal gammopathy of uncertain significance (MGUS). We report the case of a 53-year old man who had PG and MGUS. After treatment with infliximab for the PG, he developed myeloma. The course of events in this case suggests that infliximab facilitated the progression from MGUS to myeloma., (© The Author(s). CED © 2011 British Association of Dermatologists.)

Multiple myeloma (MM) is a lethal human cancer characterized by a clonal expansion of malignant plasma cells in bone marrow. Mouse models of human MM are technically challenging and do not always recapitulate human disease. Therefore, new mouse models for MM are needed. Mineral-oil induced plasmacytomas (MOPC) develop in the peritoneal cavity of oil-injected BALB/c mice. However, MOPC typically grow extramedullary and are considered poor models of human MM. Here we describe an in vivo-selected MOPC315 variant, called MOPC315.BM, which can be maintained in vitro. When injected i.v. into BALB/c mice, MOPC315.BM cells exhibit tropism for bone marrow. As few as 10(4) MOPC315.BM cells injected i.v. induced paraplegia, a sign of spinal cord compression, in all mice within 3-4 weeks. MOPC315.BM cells were stably transfected with either firefly luciferase (MOPC315.BM.Luc) or DsRed (MOPC315.BM.DsRed) for studies using noninvasive imaging. MOPC315.BM.Luc cells were detected in the tibiofemoral region already 1 hour after i.v. injection. Bone foci developed progressively, and as of day 5, MM cells were detected in multiple sites in the axial skeleton. Additionally, the spleen (a hematopoietic organ in the mouse) was invariably affected. Luminescent signals correlated with serum myeloma protein concentration, allowing for easy tracking of tumor load with noninvasive imaging. Affected mice developed osteolytic lesions. The MOPC315.BM model employs a common strain of immunocompetent mice (BALB/c) and replicates many characteristics of human MM. The model should be suitable for studies of bone marrow tropism, development of osteolytic lesions, drug testing, and immunotherapy in MM.

Background: Although the acute effects of pesticides in humans are well known, uncertainty still exists about the health effects of chronic low-level exposure to pesticides., Aims: To compare mortality and cancer incidence experienced by a cohort of British pesticide users to that of the Great Britain (GB) population., Methods: The Pesticide Users Health Study (PUHS) comprises users of agricultural pesticides who have Certificates of Competence under the Control of Pesticides Regulations 1986. Participants were followed up between 1987 and 2004 (cancer incidence) or 2005 (mortality). Standardized mortality ratios (SMRs) and Standardized incidence ratios (SIRs) were estimated for outcomes of interest identified from the literature., Results: Altogether, 62,960 pesticide users were followed up for 829,709 person-years (to 31 December 2005). Most participants were male (94%) and based in England (86%). All-cause mortality was lower for both men [SMR 0.58, 95% confidence interval (CI) 0.55-0.60] and women (SMR 0.71, 95% CI 0.52-0.98) compared to the GB population. Mortality and incidence were below those expected for all cancers combined among men (SMR 0.71, 95% CI 0.66-0.77; SIR 0.85, 95% CI 0.81-0.90), particularly for cancers of the lip, oral cavity and pharynx, digestive organs and respiratory system. The incidence of testicular cancer, non-melanoma skin cancer and multiple myeloma were above expected. Mortality from injury by machinery was significantly above expected for men (SMR 4.21, 95% CI 2.11-8.42)., Conclusions: This study suggests that pesticide users in the PUHS are generally healthier than the national population but may have excesses of non-melanoma skin cancer, testicular cancer and multiple myeloma.

Objectives: Few studies have examined whether exposure to chlorinated solvents is associated with multiple myeloma. We evaluated associations between multiple myeloma and occupational exposure to six chlorinated solvents: 1,1,1-trichloroethane, trichloroethylene (TCE), methylene chloride (DCM), perchloroethylene, carbon tetrachloride and chloroform., Methods: In-person interviews obtained occupational histories and information on jobs with likely solvent exposure. We assigned exposure metrics of probability, frequency, intensity and confidence using job-exposure matrices modified by job-specific questionnaire information. We used logistic regression to estimate ORs and 95% CIs for associations between multiple myeloma and ever exposure to each, and any, chlorinated solvent and analysed whether associations varied by duration and cumulative exposure. We also considered all occupations that were given the lowest confidence scores as unexposed and repeated all analyses., Results: Risk of multiple myeloma was elevated for subjects ever exposed to 1,1,1-trichloroethane (OR (95% CI): 1.8 (1.1 to 2.9)). Ever exposure to TCE or DCM also entailed elevated, but not statistically significant, risks of multiple myeloma; these became statistically significant when occupations with low confidence scores were considered unexposed (TCE: 1.7 (1.0 to 2.7); DCM: 2.0 (1.2 to 3.2)). Increasing cumulative exposure to perchloroethylene was also associated with increasing multiple myeloma risk. We observed non-significantly increased multiple myeloma risks with exposure to chloroform; however, few subjects were exposed., Conclusions: Evidence from this relatively large case-control study suggests that exposures to certain chlorinated solvents may be associated with increased incidence of multiple myeloma; however, the study is limited by relatively low participation (52%) among controls.

Background: The use of occupational cohort studies to assess the association of benzene and lymphoma is complicated by problems with exposure misclassification, outcome classification, and low statistical power., Objective: We performed meta-analyses of occupational cohort studies for five different lymphoma categories: Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL), multiple myeloma (MM), acute lymphocytic leukemia (ALL), and chronic lymphocytic leukemia (CLL)., Data Extraction: We assessed three study quality dimensions to evaluate the impact of study quality variations on meta-relative risks (mRRs): stratification by the year of start of follow-up, stratification by the strength of the reported acute myelogenous leukemia association, and stratification by the quality of benzene exposure assessment., Data Synthesis: mRRs for MM, ALL, and CLL increased with increasing study quality, regardless of the study quality dimension. mRRs for NHL also increased with increasing study quality, although this effect was less pronounced. We observed no association between occupational benzene exposure and HL., Conclusions: Our meta-analysis provides support for an association between occupational benzene exposure and risk of MM, ALL, and CLL. The evidence for an association with NHL is less clear, but this is likely complicated by the etiologic heterogeneity of this group of diseases. Further consideration of the association between benzene and NHL will require delineation of risks by NHL subtype.

Recombinant human parathyroid hormone (1-34) (rhPTH 1-34), teriparatide (Forsteo in Europe), is a new compound that has been introduced and shown to be successful in the treatment of osteoporosis. The mechanisms of action include a pulsative influence on the RANKL/OPG system resulting in osteoblast activation and increased bone formation by teriparatide. In malignant myeloma there is an imbalance between osteoclast and osteoblast activity with involvement of the RANKL/OPG system among others. We report a case with monoclonal gammopathy of uncertain significance (MGUS) who developed malignant myeloma after teriparatide treatment and we suggest that in addition to malignant myeloma and smouldering myeloma, MGUS should also be considered contraindicated for teriparatide treatment.

Background: Hairdressers and allied occupations represent a large and fast growing group of professionals. The fact that these professionals are chronically exposed to a large number of chemicals present in their work environment, including potential carcinogens contained in hair dyes, makes it necessary to carry out a systematic evaluation of the risk of cancer in this group., Methods: We retrieved studies by systematically searching Medline and other computerized databases, and by manually examining the references of the original articles and monographs retrieved. We also contacted international researchers working on this or similar topics to complete our search. We included 247 studies reporting relative risk (RR) estimates of hairdresser occupation and cancer of different sites., Results: Study-specific RRs were weighted by the inverse of their variance to obtain fixed and random effects pooled estimates. The pooled RR of occupational exposure as a hairdresser was 1.27 (95% CI 1.15-1.41) for lung cancer, 1.52 [95% confidence interval (CI) 1.11-2.08] for larynx cancer, 1.30 (95% CI 1.20-1.42) for bladder cancer and 1.62 (95% CI 1.22-2.14) for multiple myeloma. Data for other anatomic sites showed increases of smaller magnitude. The results restricted to those studies carried out before the ban of two major carcinogens from hair dyes in the mid-1970s were similar to the general results., Conclusions: Hairdressers have a higher risk of cancer than the general population. Improvement of the ventilation system in the hairdresser salons and implementation of hygiene measures aimed at mitigating exposure to potential carcinogens at work may reduce the risk.