Pooled study of occupational exposure to aromatic hydrocarbon solvents and risk of multiple myeloma.

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.

Potential pitfalls of serum free light chain analysis to assess treatment response for multiple myeloma.

Response to treatment in patients with a plasma cell disorder is typically measured by evaluating the bone marrow and myeloma markers, including monoclonal protein spike and immunofixation (IFE) in blood and urine, and serum free light chains (sFLCs). Stringent complete response criteria for Multiple Myeloma (MM) patients require a normal FLC ratio and absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence. We performed a retrospective chart review to further evaluate these criteria. A total of 142 patient charts were analysed. Of these, 17 patients were found to have an abnormal sFLC ratio, but no other evidence of disease, including normal flow cytometry and normal fluorescence in situ hybridization (FISH) analysis on highly selected plasma cells. In all patients, the abnormal sFLC ratio was caused by abnormalities in the serum kappa light chains. These results suggest that current definitions may need to be revised to take aberrancies related to abnormal immune recovery into account.

Multiple myeloma and family history of lymphohaematopoietic cancers: Results from the International Multiple Myeloma Consortium.

Family clusters of multiple myeloma (MM) suggest disease heritability. Nevertheless, patterns of inheritance and the importance of genetic versus environmental risk factors in MM aetiology remain unclear. We pooled data from eleven case-control studies from the International Multiple Myeloma Consortium to characterize the association of MM risk with having a first-degree relative with a history of a lympho-haematapoietic cancer. Unconditional logistic regression models, adjusted for study, sex, age and education level, were used to estimate associations between MM risk and having a first-degree relative with a history of non-Hodgkin lymphoma, Hodgkin lymphoma, leukaemia or MM. Sex, African American race/ethnicity and age were explored as effect modifiers. A total of 2843 cases and 11 470 controls were included. MM risk was elevated in association with having a first-degree relative with any lympho-haematapoietic cancer (Odds Ratio (OR) = 1·29, 95% Confidence Interval (CI): 1·08-1·55). The association was particularly strong for having a first-degree relative with MM (OR = 1·90, 95% CI: 1·26-2·87), especially among men (OR = 4·13, 95% CI: 2·17-7·85) and African Americans (OR = 5·52, 95% CI: 1·87-16·27).These results support the hypothesis that genetic inheritance plays a role in MM aetiology. Future studies are warranted to characterize interactions of genetic markers with environmental exposures.

Safety and efficacy of targeted-dose busulfan and bortezomib as a conditioning regimen for patients with relapsed multiple myeloma undergoing a second autologous blood progenitor cell transplantation.

Patients with multiple myeloma (MM) who relapse after autologous transplantation have limited therapeutic options. We conducted a prospective, multicenter, phase IIa study to investigate the safety and efficacy of i.v. busulfan (Bu) in combination with bortezomib as a conditioning regimen for a second autotransplantation. Because a safe Bu exposure was unknown in patients receiving this combination, Bu was initially targeted to a total area under the concentration-time curve (AUC) of 20,000 µM × minute. As no concentration-limiting toxicity was observed in 6 patients, this Bu exposure was utilized in the following treatment cohort (n = 24). Individualized Bu dose, based on test dose .8 mg/kg pharmacokinetics (PK), was administered daily for 4 consecutive days starting 5 days before transplantation, followed by a single dose of bortezomib (1.3 mg/m(2)) 1 day before transplantation. The total mean dose of i.v. Bu (including the test dose and 4-day administration) was 14.2 mg/kg (standard deviation = 2.48; range, 8.7 to 19.2). Confirmatory PK demonstrated that only 2 of 30 patients who underwent transplantation were dosed outside the Bu AUC target and dose adjustments were made for the last 2 doses of i.v. Bu. The median age was 59 years (range, 48 to 73). Median time from first to second transplantation was 28.0 months (range, 12 to 119). Of 26 evaluable patients, 10 patients attained a partial response (PR) or better at 3 months after transplantation, with 2 patients attaining a complete response. At 6 months after transplantation, 5 of 12 evaluable patients had maintained or improved their disease status. Median progression-free survival was 191 days, whereas median overall survival was not reached during the study period. The most common grade 3 and 4 toxicities were febrile neutropenia (50.0%) and stomatitis (43.3%). One transplantation-related death was observed. A combination of dose-targeted i.v. Bu and bortezomib induced PR or better in one third of patients with MM who underwent a second autotransplantation, with acceptable toxicity.

What is the significance of molecular remission in multiple myeloma?

The present definition of complete remission (CR) in myeloma is not adequate. The definition is mainly based on measuring the secreted product of myeloma cells (M protein), which has a high interpatient and intrapatient variability, rather than on direct measurement of the remaining tumor load. Polymerase chain reaction (PCR) techniques are very sensitive to measure minimal residual disease, but in myeloma such a technique is very costly and labor intensive because a specific probe needs to be generated for each patient. There is preliminary evidence, based on a limited number of patients analyzed, that specific PCRs are better predictors of outcome in myeloma than the presently used definition of hematologic CR. Our limited experience indicates that with intensive therapy, including tandem transplants, a high percentage of patients in hematologic CR also achieve a molecular CR. The time to disease progression of such patients appears to be significantly longer compared to that of patients not achieving a molecular CR.

New insights into role of microenvironment in multiple myeloma.

Multiple Myeloma (MM) is a malignant disease of terminally differentiated B cells. It most likely originates in a B cell which has traversed the germinal center and has been exposed there extensively to antigens based on the high number of somatic mutations in the complementarity determining regions. The cell of origin is either a plasmablast, or more likely, a memory B-cell. Typically MM goes through different phases from indolent (MGUS, smoldering myeloma) to overt myeloma and then to a fulminant phase, characterized by extramedullary manifestations, high LDH, immature morphology and increased proliferation rate. In the indolent phase, the disease already has acquired major cytogenetic abnormalities as demonstrated by FISH and DNA flow cytometry. It has a gene pattern very similar to myeloma cells on gene array analysis. In the early stages of overt MM, the myeloma cells are completely dependent upon the micro-environment for their growth and survival. The interaction between myeloma cells and micro-environment causes bone disease, genetic instability and more importantly, drug-resistance, which is caused by upregulation of anti-apoptotic factors, resistance to apoptosis induced by FAS and TRAIL activation, and by cell adhesion-induced growth arrest. In this phase of the disease, MM is susceptible to chemotherapy, if delivered with adequate intensity. In the fulminant phase of MM, myeloma cells have acquired sufficient genetic alternations to become completely independent of the micro-environment which allows them to grow at extramedullary sites. Because of the many DNA breaks necessary for immature B cells to become mature plasma cells, B cells already have inherent genetic instability. DNA breaks are necessary for VDJ recombinations, somatic mutations and isotype switching and it is therefore not surprising that genetic alternations frequently occur at the Ig heavy chain site at 14q32, which is abnormal in three quarters of myeloma patients. Some of the translocations with 14q32 involve terminal fragments of chromosomes and can not be diagnosed with standard cytogenetics. Cytogenetic abnormalities are found in 30-35% of newly diagnosed patients and require sufficient proliferation of MM cells to find enough analyzable mitoses. The cytogenetic abnormalities are typically complex, involving > or = 3 chromosomes in 80% of patients. Almost all chromosomes can be involved in deletions, additions or translocations of genetic material. Our group has repeatedly stressed the prognostic significance of chromosome 13 deletion by conventional cytogenetics. The role of chromosome 13 deletion by FISH. is less clear. In addition to chromosome 13 deletion, the presence of a hypodiploid or hypotetraploid karyotye also carries a poor prognosis. Frequently, deletions of chromosome 13 and hypodiploidy go hand in hand. It remains unclear what specific gene confers the poor prognosis to patients with deletion 13. The issues of bone disease, drug resistance and cytogenetics will be addressed in detail during this presentation.

Hypercoagulable states in patients with multiple myeloma can affect the thalidomide-associated venous thromboembolism.

The therapeutic use of thalidomide in patients with multiple myeloma is often complicated by the development of venous thromboembolism. The objective of the present study was to identify hypercoagulable states associated with development of venous thromboembolism in thalidomide-treated multiple myeloma patients. We screened 49 consecutive multiple myeloma patients treated with thalidomide at baseline for hypercoagulability. With a median follow-up of 11 months, 10 of 49 multiple myeloma patients developed a thrombotic episode. Laboratory assays revealed an underlying abnormality in nine of the 10 patients; hypercoagulable screenings were normal in 36 of the 39 patients who did not develop venous thromboembolism (P < 0.0001). Our retrospective study results suggest that the multiple myeloma patients with thromboembolic complications during treatment with thalidomide have a frequent concomitant underlying thrombophilic state.

Thrombotic events in patients with cancer receiving antiangiogenesis agents.

Tumor-associated neoangiogenesis has recently become a suitable target for antineoplastic drug development. In this overview, we discuss specific drug-associated hemostatic complications, the already known pathogenetic mechanisms involved, and the effect of varying antithrombotic strategies. Multiple agents with angiogenic inhibitory capacity (thalidomide, lenalidomide, bevacizumab, sunitinib, sorafenib, and sirolimus) have obtained US Food and Drug Administration approval, and many others have entered clinical trials. Arterial and venous thromboembolism and hemorrhage have emerged as significant toxicities associated with the use of angiogenesis inhibitors. We present a detailed analysis of the literature on thrombotic complication of antiangiogenic drugs. Close attention to hemostatic complications during antiangiogenic treatment is warranted. Further studies are required to better understand the pathophysiologic mechanisms involved and to define a safe prophylactic strategy.

Composite patient reports: a laboratory informatics perspective and pilot project for personalized medicine and translational research.

Clinical laboratories are a strong and integral partner in personalized health care. Laboratory information systems hold a vast amount of data representing human phenotypes, genotypes, biomarkers, progression of disease and response to therapy. These structured and unstructured free text data are critical for patient care and a resource for personalized medicine and translational research. Laboratory data are integrated into many electronic medical records that provide "summary reports" and "trending" to visualize longitudinal patient data. However, these generic reports are not sufficient to manage complex sub-specialty patients. There is an urgent need for end-user driven composite reports for the care of such patients. Using multiple myeloma as a model, this pilot was performed to assess the needs of stakeholders and create a customized report. This laboratory informatics solution is delivered at the point of care through the hospital EMR. Future work will involve further integration with hospital systems to promote clinical decision support and translational research.

Bortezomib down-regulates the cell-surface expression of HLA class I and enhances natural killer cell-mediated lysis of myeloma.

Human leukocyte antigen class I molecules expressed by tumor cells play a central role in the regulation of natural killer (NK) cell-mediated immune responses. The proteasome inhibitor bortezomib has demonstrated significant activity in multiple myeloma (MM). We hypothesized that treatment of MM with bortezomib results in the reduction of cell-surface expression of class I and thereby sensitizes MM to NK cell-mediated lysis. Here we report that bortezomib down-regulates class I in a time- and dose-dependent fashion on all MM cell lines and patient MM cells tested. Downregulation of class I can also be induced in vivo after a single dose of 1.0 mg/m(2) bortezomib. Bortezomib significantly enhances the sensitivity of patient myeloma to allogeneic and autologous NK cell-mediated lysis. Further, the level of decrease in class I expression correlates with increased susceptibility to lysis by NK cells. Clinically relevant bortezomib concentrations do not affect NK-cell function. Our findings have clear therapeutic implications for MM and other NK cell-sensitive malignancies in the context of both allogeneic and autologous adoptively transferred NK cells.

Long-term outcome results of the first tandem autotransplant trial for multiple myeloma.

Total Therapy 1, the first tandem autotransplant trial for newly diagnosed patients with multiple myeloma, was designed to increase the frequency of complete response (CR) and thereby extend survival. With a median follow-up of 12 years, 62 of 231 initially enrolled patients are alive (17% at 15 years); 31 remain event free (7% at 15 years) including 16 of 94 (41%) that initially achieved CR. Currently alive patients less frequently had cytogenetic abnormalities (CAs) at baseline (P = 0.002), postenrolment (P < 0.001) and at relapse (P = 0.004); elevations of serum C-reactive protein (CRP) (P = 0.003) and lactate dehydrogenase (P = 0.029), anaemia (P = 0.029) and they more often completed two transplants within 12 months (P = 0.019). Postenrolment overall survival (OS) and event-free survival (EFS) were superior in the absence of CA of the hypodiploidy or deletion 13 variety (P < 0.001 and 0.037 respectively) and in the presence of low CRP at baseline (P = 0.001 and 0.017 respectively). Postrelapse survival was longer in the absence of CA at relapse (P < 0.001), IgA isotype (P = 0.002), International Staging System stage 3 (P = 0.014), and when patients had two protocol transplants prior to relapse (P = 0.038). Ten-year EFS and OS could be accomplished in 15% and 33% of patients, respectively, when all agents available in 1989, especially high-dose melphalan, were applied together upfront for the management of myeloma.