Alexandra J. Greenberg

Racial disparities in the prevalence of monoclonal gammopathies: a population-based study of 12 482 persons from the National Health and Nutritional Examination Survey

Multiple myeloma (MM) incidence is markedly higher in blacks compared with whites, which may be related to a higher prevalence of monoclonal gammopathy of undetermined significance (MGUS). Our objective was to define the prevalence and risk factors of MGUS in a large cohort representative of the US population. Stored serum samples from the National Health and Nutritional Examination Survey (NHANES) III or NHANES 1999–2004 were available for 12 482 individuals of age ⩾50 years (2331 ‘blacks’, 2475 Hispanics, 7051 ‘whites’ and 625 ‘others’) on which agarose-gel electrophoresis, serum protein immunofixation, serum-free light-chain assay and M-protein typing were performed. MGUS was identified in 365 participants (2.4%). Adjusted prevalence of MGUS was significantly higher (P<0.001) in blacks (3.7%) compared with whites (2.3%) (P=0.001) or Hispanics (1.8%), as were characteristics that posed a greater risk of progression to MM. The adjusted prevalence of MGUS was 3.1% and 2.1% for the North/Midwest versus South/West regions of the United States, respectively (P=0.052). MGUS is significantly more common in blacks, and more often has features associated with higher risk of progression to MM. A strong geographic disparity in the prevalence of MGUS between the North/Midwest versus the South/West regions of the United States was found, which has etiologic implications.

Disparities in the prevalence, pathogenesis and progression of monoclonal gammopathy of undetermined significance and multiple myeloma between blacks and whites.

There is marked racial disparity in the incidence of monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma, with a two to threefold increased risk in blacks compared with whites. The increased risk has been seen both in Africans and African Americans. Similarly, an increased risk of monoclonal gammopathies in blacks compared with whites has been noted after adjusting for socioeconomic and other risk factors, suggesting a genetic predisposition. The higher risk of multiple myeloma in blacks is likely a result of the higher prevalence of the premalignant MGUS stage; there are no data to suggest that blacks have a higher progression rate of MGUS to myeloma. Studies are emerging that suggest the baseline cytogenetic characteristics, and progression may differ by race. In contrast, to the increased risk noted in blacks, studies suggest that the risk may be lower in certain racial and ethnic groups, notably persons from Japan and Mexico. We review the literature on racial disparity in the prevalence, pathogenesis and progression of MGUS and multiple myeloma between blacks and whites. We also discuss future directions for research that could inform management of these conditions and positively influence patient outcomes.

Familial monoclonal gammopathy of undetermined significance and multiple myeloma: epidemiology, risk factors, and biological characteristics.

Monoclonal gammopathy of undetermined significance (MGUS), a precursor to multiple myeloma (MM), is one of the most common premalignant conditions in the general population. The cause of MGUS is largely unknown. Recent studies show that there is an increased prevalence of MGUS in blood relatives of persons with lymphoproliferative and plasma cell proliferative disorders, suggesting presence of shared underlying genetic influences. In the past few years, additional studies have examined risk factors and biologic characteristics that may contribute to the increased prevalence of MGUS among relatives of probands with MGUS, MM, and other blood malignancies. This article reviews the known epidemiology and risk factors for familial MGUS and myeloma, the risk of lymphoproliferative disorders and other malignancies among blood-relatives of patients with MGUS and MM, and discusses future directions for research.

Relationship between initial clinical presentation and the molecular cytogenetic classification of myeloma

Multiple myeloma (MM) consists of several distinct cytogenetic subtypes, and we hypothesized that each subtype may have a unique mode of initial presentation and end-organ damage. We studied 484 patients with newly diagnosed MM to determine the relationship between specific myeloma-defining event (MDE) and the cytogenetic subtype. Patients were divided into four non-overlapping groups based on the MDE at diagnosis: isolated renal failure, isolated anemia, isolated lytic bone disease or a combination (mixed). MM with translocations without trisomies accounted for 30% of all patients, but accounted for 50% of patients with renal failure. Specifically, the t(14;16) translocation accounted for only 5% of all MM patients, but was present in 13.5% of patients with renal failure as MDE. Among patients with t(14;16), 25% presented with renal failure only as MDE. Patients with isolated renal failure as MDE had significantly poorer survival compared with all other groups, whereas patients with bone disease as MDE had the best outcome (P<0.001). Our findings support the hypothesis that in addition to prognostic differences, there is significant heterogeneity in clinical presentation associated with the cytogenetic subtype, suggesting that MM encompasses a group of cytogenetically and phenotypically distinct disorders rather than a single entity.

Linking expression of FOXM1, CEP55 and HELLS to tumorigenesis in oropharyngeal squamous cell carcinoma†‡

To investigate the relationship between the expression of FOXM1, CEP55, and HELLS in oropharyngeal squamous cell carcinoma to human papillomavirus (HPV), smoking, and tumor stage.

Genome-wide association study identifies variants at 16p13 associated with survival in multiple myeloma patients

Here we perform the first genome-wide association study (GWAS) of multiple myeloma (MM) survival. In a meta-analysis of 306 MM patients treated at UCSF and 239 patients treated at the Mayo clinic, we find a significant association between SNPs near the gene FOPNL on chromosome 16p13 and survival (rs72773978; P=6 × 10(-10)). Patients with the minor allele are at increased risk for mortality (HR: 2.65; 95% CI: 1.94-3.58) relative to patients homozygous for the major allele. We replicate the association in the IMMEnSE cohort including 772 patients, and a University of Utah cohort including 318 patients (rs72773978 P=0.044). Using publicly available data, we find that the minor allele was associated with increased expression of FOPNL and increased expression of FOPNL was associated with higher expression of centrosomal genes and with shorter survival. Polymorphisms at the FOPNL locus are associated with survival among MM patients.

Rituximab for Non-Hodgkin's Lymphoma: A Story of Rapid Success in Translation

Translational stories range from straightforward to complex. In this commentary, the story of the rapid and successful translation of rituximab therapy for the treatment of non‐Hodgkins lymphoma (NHL) is examined. Development of this monoclonal antibody therapy began in the late 1980s. In 1994, rituximab received its first approval for the treatment of NHL by the United States Food and Drug Administration (FDA). Rituximab has since been approved for additional indications and has transformed medical practice. However, the social and political implications of these rapid successes are only beginning to become clear. In this commentary, key events in the rapid translation of rituximab from the bench to bedside are highlighted and placed into this historical framework. To accomplish this, the story of rituximab is divided into the following six topics, which we believe to be widely applicable to case studies of translation: (1) underlying disease, (2) key basic science, (3) key clinical studies in translation, (4) FDA approval process, (5) changes to medical practice, and (6) the social and political influences on translation.

Single-nucleotide polymorphism rs1052501 associated with monoclonal gammopathy of undetermined significance and multiple myeloma

Monoclonal gammopathy of undetermined significance (MGUS) is the most prevalent clonal plasma cell proliferative disorder, present in over 3% of the population aged 50 years and older, with a rate of progression to malignancy of 1% per year. (Kyle, et al 2006, Kyle, et al 2002) MGUS has been shown to precede MM in almost all cases. (Landgren, et al 2009b) We, and others, have shown evidence for a familial component to MGUS, with first-degree relatives of MM or MGUS probands having a 2.5 fold increased risk of MGUS, indicative of an underlying genetic predisposition. (Landgren, et al 2009a, Vachon, et al 2009) While several genetic variants have been identified for MM, none have been identified that are associated with MGUS. (Greenberg, et al 2012) Broderick et al. (Broderick, et al 2011) recently conducted the first genome-wide association study (GWAS) of MM using case-control studies from the United Kingdom and Germany and identified three novel loci at 3p22.1 (rs1052501 in ULK4), 7p15.3 (rs4487645) and 2p23.3 (rs6746082) associated with risk of MM, although the latter did not reach genome wide significance (p<5×10−8). Here, we investigate whether these three loci for MM risk are also associated with risk of MGUS in order to provide evidence that genetic variation influences MM through MGUS. We also attempt to replicate the association of these loci with MM within a case-control study of MM.

Differences in Access to and Use of Electronic Personal Health Information Between Rural and Urban Residents in the United States

PURPOSE The increase in use of health information technologies (HIT) presents new opportunities for patient engagement and self-management. Patients in rural areas stand to benefit especially from increased access to health care tools and electronic communication with providers. We assessed the adoption of 4 HIT tools over time by rural or urban residency. METHODS Analyses were conducted using data from 7 iterations of the National Cancer Institutes Health Information National Trends Survey (HINTS; 2003-2014). Rural/urban residency was based on the USDAs 2003 Rural-Urban Continuum Codes. Outcomes of interest included managing personal health information online; whether providers maintain electronic health records (EHRs); e-mailing health care providers; and purchasing medicine online. Bivariate analyses and logistic regression were used to assess relationships between geography and outcomes, controlling for sociodemographic characteristics. FINDINGS In total, 6,043 (17.6%, weighted) of the 33,749 respondents across the 7 administrations of HINTS lived in rural areas. Rural participants were less likely to report regular access to Internet (OR = 0.70, 95% CI = 0.61-0.80). Rural respondents were neither more nor less likely to report that their health care providers maintained EHRs than were urban respondents; however, they had decreased odds of managing personal health information online (OR = 0.59, 95% CI = 0.40-0.78) and e-mailing health care providers (OR = 0.62, 95% CI = 0.49-0.77). CONCLUSIONS The digital divide between rural and urban residents extends to HIT. Additional investigation is needed to determine whether the decreased use of HIT may be due to lack of Internet connectivity or awareness of these tools.

Racial differences in primary cytogenetic abnormalities in multiple myeloma: A multi-center study

We examined four clinically assessed cytogenetic subtypes (t(11;14), t(4;14), monosomy 13/del13q and monosomy 17/del17p in 292 black patients with newly diagnosed multiple myeloma (MM) from four medical centers, who had fluorescent in situ hybridization testing results available in their medical records. We then compared the prevalence of these abnormalities with a previously characterized Mayo Clinic cohort of 471 patients with MM. We found a significant difference in the prevalence of the t(11;14) immunoglobulin heavy chain (IgH) translocation between blacks and whites, 6.5% versus 17.6%, respectively, P<0.0001. Blacks also had lower rates of the t(4;14) IgH translocation, (5.5% versus 10%); monosomy 13/del13q (29.1 versus 49.3%); and monosomy 17/del17p (7.9% versus 13%). Consequently, 63.4% of blacks versus 34.6% of whites did not have any of the four abnormalities that we studied, P<0.001. As almost all MM is associated with either an IgH translocation or trisomies, we hypothesize that MM in blacks is associated with either excess prevalence of either the trisomic (hyperdiploid) form of MM or an IgH translocation besides t(11;14) or t(4;14). We conclude that there are significant differences in the cytogenetic subtypes of MM that occur in blacks and whites.