Presence Of Lytic Bone Lesions Research Articles

Detection of circulating normal and tumor plasma cells in newly diagnosed patients of multiple myeloma and their associations with clinical and laboratory parameters

IntroductionCirculating plasma cells (CPCs) are frequently noted in variable frequencies in the entire spectrum of plasma cells neoplasms. With advent of high sensitivity multi-parametric flow cytometry, it is not only possible to detect CPCs present in very low numbers, but also to categorise them into circulating tumor plasma cells (CTPCs) and circulating normal plasma cells (CNPCs), based on their marker-profile. This study used multi-colour flow cytometry to evaluate the load of both CTPCs & CNPCs at the time of diagnosis and at six months’ time-point of therapy, and evaluated associations of both with clinical and laboratory parameters. MethodsTwenty one newly diagnosed MM patients were enrolled. Six to nine millilitres of EDTA-anticoagulated peripheral blood sample was used for flow cytometry. A ten colour antibody panel was used for analysis of CPCs, which were categorised further into CTPCs and CNPCs. Approximately 4.8 million events were acquired for the analysis. The percentage &absolute numbers of CTPCs and CNPCs were noted and the proportion of CTPCs out of all CPCs (CTPCs + CNPCs) were also calculated for evaluating their statistical associations. ResultsAll 21 patients of newly diagnosed MM showed presence of CPCs (CTPCs and/or CNPCs) at the time of diagnosis. The CTPCs were detected in 76 % of the study population. The median percentage and absolute counts of CTPCs were 0.52 % and 54.9 cells /µL, respectively. CNPCs were found in 95 % and the median percentage and absolute counts of CNPCs were 0.025 % and 2.66 cells/µL. After six months of therapy, CPCs (CTPCs and/or CNPCs) were found in all nine patients evaluated for this assay. CTPCs were found 33 %, with a median of 0.075 % and CNPCs were found in 89 % with a median of 0.01 %. Our study showed that the load of CTPCs was found to be higher in patients with presence of lytic bone lesions, plasmacytoma, presence of PCs on peripheral blood film by light microscopy, presence of Chr 1p32 deletion, expression of CD56 and CD81 on CTPCs, and in patients with absence of very good partial response (VGPR). Conversely, the load of CTPCs was significantly lower in patients with concomitant amyloidosis. Also, percentage of bone marrow plasma cells exhibited a significant positive correlation with the absolute count of CTPCs. We observed that the mean percentage of CNPCs was significantly higher in female patients. The load of CNPCs was lower in patients with thrombocytopenia and with hypoalbuminemia. ConclusionIncreased burden of CTPCs was associated with presence of lytic lesions, plasmacytomas, Chr 1p32 deletion, expression of CD56 and CD81 on tumor cells and with failure to achieve very good partial response. The CNPCs were lower in patients with thrombocytopenia and with hypoalbuminemia. To best ot our knowledge, this is the first study from India on the relevance of circulating tumor plasma cells and the first study in the world to analyse the associations of circulating normal plasma cells in newly diagnosed patients of multiple myeloma. The study also highlights the utility of multi-parametric flow cytometry in identification and enumeration of circulating plasma cells. Micro abstractCirculating plasma cells indicates poorer outcomes in patients of multiple myeloma. Twenty one newly diagnosed multiple myeloma patients were evaluated by flow cytometry to enumerate and characterise circulating tumor plasma cells (CTPCs) and circulating normal plasma cells (CNPCs). Higher load of CTPCs correlated with known poor prognostic markers and poor response to therapy.

Association between Clinical Presentation of Multiple Myeloma, Immunoglobulin Isotypes, and Cytogenetic Risk Groups

Introduction: In multiple myeloma (MM), chromosomal abnormalities (CAs) are valuable in risk stratifying patients and predicting disease free survival. While immunoglobulin isotypes have historically contributed to MM staging, more recently established classifications of CAs have allowed for a revised staging system that better predicts disease behavior. In this retrospective study, we hypothesized that CAs correlate with disease characteristics including immunoglobulin heavy chain isotype, degree of bone marrow infiltration (PC%), and end-organ damage. Methods: MM patients diagnosed between 2013 to 2019 were included in this retrospective chart review using electronic records from two distinct sources: (1) 442 patients from an independent pathology database and (2) a validation cohort composed of 110 patients from our institution. CAs were stratified by Mayo mSMART 2.0 criteria into standard, intermediate, and high-risk groups (Mikhael et al. Mayo Clin Proc 2013). End-organ damage was defined as the presence of lytic bone lesions, anemia, hypercalcemia, or renal failure on clinical presentation. Within each cohort, associations between categorical variables were made using the chi-squared test or Fisher's exact test, as deemed appropriate. The Mann-Whitney test was used to compare between groups for continuous variables. A result was considered statistically significant at the p<0.05 level of significance. All analyses were performed using SAS version 9.4 (SAS Institute Inc., Cary, NC). Results: 552 MM patients were included in the study. Multi-variate analysis revealed that del(13q14), dup(1q21), t(4;14), trisomy (11q13), del(16q23), and hypodiploidy were associated with a significantly higher PC%, whereas kappa light chain only (LCO) disease was associated with a lower PC%. Higher median PC% was found when comparing the intermediate to standard CA risk group. IgA isotype was associated with intermediate risk CAs including del(13q) and standard risk CAs including t(11;14), while IgG isotype was associated with dup(1q21), and kappa LCO disease correlated with a higher rate of higher risk CAs including deletion of p53 at 17p13 and dup(1q21). With regard to clinical presentation, lytic lesions were more frequent in patients with normal cytogenetics and trisomy 11 and less frequent in IgA isotype, whereas the presence of anemia on presentation correlated with IgA isotype. Renal failure was associated with MAF translocations including t(14;16), a high-risk CA. Conclusions: We demonstrate that a relationship exists between specific CAs, immunoglobulin isotypes, and clinical presentations in MM. Our data indicate that IgA isotype is significantly associated with intermediate-risk cytogenetics including del(13q) and anemia on presentation, and that light chain disease and renal failure correlate with high risk CAs including del(17p13). These associations between biological and clinical features further support the concept of divergent cytogenetic evolution in MM as being an underlying factor leading to distinctive disease presentations. Disclosures Braunstein: Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Epizyme: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Verastem: Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Light chain myeloma: A brief report from India.

Light chain myeloma (LCM) has a reported worldwide incidence of approximately 15%-20% among all multiple myeloma (MM) patients. Few western studies have shown strong correlation of LCM with anemia, higher International Staging System scores, proclivity to renal failure, elevated lactate dehydrogenase levels, raised serum-free light chain ratio, higher frequency of extramedullary plasmacytomas, and poorer overall survival, attributable probably to lack of differentiation and skeletal destruction. The primary aim of this retrospective observational study was to define the clinical and hematological characteristics as well as prognostic outcome of Indian LCM patients in comparison with the IgG and IgA subtypes. Patients were defined according to the International Myeloma Working Group diagnostic criteria 2016 and staged as per the International Staging System. Out of 104 patients of newly diagnosed MM in which results of serum immunofixation (IFE) were available, 65 were of IgG isotype (62.5%), 15 had IgA (14.4%), and 24 had light chain myelomas (LCMs) (23.1%). It was observed that LCM patients significantly correlated with hypercalcemia and higher serum-free light chain ratios, whereas IgA patients were strongly associated with anemia and lower serum albumin levels. However, no difference was found among the three subgroups in terms of serum lactate dehydrogenase levels, proclivity to renal failure, presence of lytic bone lesions, prognostic scoring, pretransplant chemosensitivity, and progession-free survival (1 year). Thus, it may be concluded that Indian LCM patients have significantly different clinico-hematological profile in comparison with other published studies worldwide. Also, their prognostic outcomes are not worse when compared with patients of other protein isotypes, probably due to standardized treatment regimens applied.

Racial Differences in Disease Characteristics: Understanding Multiple Myeloma in Hispanics

Background:Racial disparities in multiple myeloma (MM) outcomes are well established. Clinical characteristics and cytogenetic abnormalities dictate outcomes in MM but historically they have been mostly defined in White patients with paucity of information regarding racial-ethnic minorities. Hispanics are the fastest growing racial-ethnic subgroup in United States and have the worst overall survival (OS) in MM but differences in disease presentation among Hispanics compared to Whites, the historical control, are undefined.Methods: MM patients seen at Mayo Clinic in Florida (MCF) and Arizona (MCA) between 1/1/2000-06/15/2017 were included. Patient and disease characteristics including gender, age at diagnosis, bone marrow (BM) plasmacytosis, laboratory data [M spike, creatinine (Cr), beta-2-microglobulin (B2M), Hemoglobin (Hb), calcium (Ca)], MM subtype [IgG, IgA, light chain (LC), other], LC subtype (κ, λ, biclonal), presence of lytic bone lesions, disease stage (DS, ISS, R-ISS), mSMRT cytogenetic risk category, presence of individual cytogenetic mutations (deletions, translocations, gains, trisomy/hyperdiploidy) was collected. Comparisons between Hispanic study cohort characteristics and historical control were made by Chi-square, Fischer's exact and Signed rank tests, where applicable, using data from previous publications [Kyle et al, 2003 (n=1027) and Fonseca et al, 2003 (n=351)]. Patients with missing data on a certain clinical or disease feature were not included in the statistical analysis of that specific characteristic.Results: A total of 1705 MM patients were screened and 266 Hispanic patients seen at either site between the specified dates were identified for the analysis. These included equal number of males and females (n=133 each) with a median age of 58 years (range 25-87). IgG disease was seen in 52% with IgA and LC subtypes in 23% each. LC subtype was κ in 67%, λ in 31% and biclonal in 2% cases. Lytic and extramedullary disease were noted in 71% and 44% patients, respectively. DS and R-ISS stage at the time of MM diagnosis was not available in most patients while ISS stage among 150 patients showed stage 1, 2 and 3 in 48%, 28% and 24% patients, respectively. mSMART risk categories were present in 226 patients and included high, intermediate and standard risk in 12%, 11% and 77% patients, respectively. Of these 226 patients, cytogenetic disease prior to starting any MM treatment was available in 153 patients with similar risk category distribution. Median follow up for the whole Hispanic cohort was 38.6 months with a median OS 10.7 years (Figure 1). Comparison with historical control datasets which were 97% or greater comprised of White patients showed some significant differences for the Hispanic cohort including gender distribution, median age, BM plasmacytosis at the time of diagnosis, median Hb, Cr or M spike at presentation, light chain subtype, presence of lytic bone disease and certain cytogenetic alterations including t(4;14) and del13q/monosomy (Table 1). We did not note differences in high-risk cytogenetics between Hispanics and historical White controls.Conclusions: We report the first description of clinical and cytogenetic characteristics of Hispanic MM patients. The current and historical datasets that we have used are all from Mayo Clinic experience, thus making reasonable comparisons possible. We were able to confirm previous reports of demographic differences in Hispanics e.g., younger age at diagnosis. While some characteristics were significantly different, the clinical and cytogenetic differences we note do not clearly explain the inferior OS noted for Hispanics in population-based studies. Significant differences that we report warrant continued exploration in larger institutional and public databases in addition to a continued look into healthcare access and utilization. An ongoing collaborative analysis with data from Mayo Clinic, University of Miami and University of Southern California, Los Angeles is ongoing. [Display omitted] DisclosuresFonseca:AMGEN: Consultancy; Jansen: Consultancy; Mayo Clinic & Dr Fonseca: Patents & Royalties: Prognostication of myeloma via FISH, ~$2000/year; Celgene Corporation: Consultancy, Research Funding; Merck: Consultancy; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy; Bristol-Myers Squibb: Consultancy; Takeda: Consultancy; Sanofi: Consultancy; Pharmacyclics: Consultancy; Novartis: Consultancy. Kelly:Pharmacyclics: Honoraria; Abbvie: Honoraria; Amgen: Honoraria; Jannsen: Honoraria. Sher:LAM Therapeutics, Inc: Research Funding. Ailawadhi:Pharmacyclics: Research Funding; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria.

Whole-body computed tomography versus conventional skeletal survey in patients with multiple myeloma: a study of the International Myeloma Working Group

For decades, conventional skeletal survey (CSS) has been the standard imaging technique for multiple myeloma (MM). However, recently whole-body computed tomography (WBCT) has been implemented into the diagnostic criteria of MM. This analysis compares sensitivity and prognostic significance of WBCT and CSS in patients with smoldering MM (SMM) and MM. Fifty-four of 212 patients (25.5%) had a negative CSS and a positive WBCT for osteolytic lesions (P<0.0001). Of 66 patients with SMM based on CSS, 12 (22.2%) had osteolytic lesions on WBCT. In comparison, WBCT failed to detect some bone destructions in the appendicular skeleton possibly due to limitations of the field of view. Presence of lytic bone lesions in WBCT was of borderline prognostic significance (P=0.051) for SMM patients, with a median time to progression of 38 versus 82 months for those without bone destructions. In conclusion, WBCT identifies significantly more sites of bone destruction than CSS. More than 20% of patients with SMM according to CSS have in fact active MM detectable with WBCT. On the basis of this and other studies, WBCT (either computed tomography (CT) alone or as part of a positron emission tomography-CT protocol) should be considered the current standard for the detection of osteolytic lesions in MM.

IgM Myeloma: A Multicenter Retrospective Study of 159 Patients

Introduction: IgM-secreting myeloma is rare, encompassing about 1% of all the myeloma cases. Given its rarity, the characteristics and survival of these patients have not been extensively studied. Therefore, we carried out a multicenter retrospective study in patients with IgM myeloma.Methods: The study protocol was reviewed and approved by the Institutional Review Board of each participating institution. Clinical data were gathered and included age, sex, hemoglobin, calcium, LDH, estimated glomerular filtration rate (GFR), presence of lytic bone lesions, International Staging System score, cytogenetic abnormalities, final outcome and overall survival (OS) time. OS was defined as the time in months from diagnosis to last follow-up or death. The Chi-square and the rank-sum tests were used to compare categorical and continuous variables, respectively. The Kaplan-Meier method was used to estimate OS and the log-rank waas used to compare groups. The Cox proportional-hazard regression method was used to fit univariate and multivariate survival models, reported as hazard ratio (HR) with 95% confidence intervals (CI). All reported p-values are two-sided, and were considered significant if less than 0.05.Results: A total of 159 patients with IgM myeloma from 20 centers from Europe, USA and Latin America were included in this analysis. Patients were diagnosed between 1996 and 2015. The median age at diagnosis was 65 years (range 37-86 years) with a male predominance (68%). The median serum IgM level was 2510 mg/dl (range 27-12,100 mg/dl) with 25% of patients having a serum IgM within normal limits but an IgM monoclonal spike detectable in serum electrophoresis. Hemoglobin levels <10 g/dl were seen in 49 patients (32%), serum calcium was elevated in 24 (16%), estimated GFR of 60 ml/min or less in 56 (37%), lytic lesions were detected in 86 (58%), and serum LDH was elevated in 28 (24%). ISS scores of 1, 2 and 3 were seen in 53 (36%), 63 (43%) and 31 (21%) of patients, respectively. Although immunohistochemistry and/or flow cytometry data were limited, CD20 expression was seen in 15/26 (58%) and cyclin D1 in 10/15 (67%) patients. The most common cytogenetic abnormalities were t(11;14) in 26/67 (39%), del13q in 25/76 (33%) and del17p in 6/76 (8%) patients. 149 patients (94%) received at least one line of systemic therapy for myeloma of which 13 (9%) received rituximab as part of initial therapy. After a median follow-up of 47 months, 74 patients (47%) have died. The median OS was 62 months (95% CI 51-79 months). Cause of death was known in 38 patients, and the most common was myeloma progression (74%). IN the univariate analysis, prognostic factors associated with a worse OS were age (HR 1.03, 95% CI 1.01-1.06; p=0.01) and ISS score (ISS 2: HR 1.43, 95% CI 0.83-2.48; p=0.2, and ISS 3: HR 3.03, 95% CI 1.54-5.98; p=0.001, using ISS 1 as reference group), while male sex was associated with a better OS (HR 0.56, 95% CI 0.34-0.90; p=0.02). Hemoglobin, calcium, estimated GFR and lytic lesions were not associated with OS. In the multivariate analysis, male sex was associated with a better OS (HR 0.57, 95% CI 0.35-0.95; p=0.03) and ISS with worse OS (ISS 2: HR 1.57, 95% CI 0.89-2.74; p=0.12, and ISS 3: HR 2.76, 95% CI 1.38-5.55; p=0.004, using ISS 1 as reference group).Conclusion: Patients with IgM myeloma apparently present with similar clinical characteristics as patients with non-IgM myeloma. Pathologically, CD20 and cyclin D1 expression is common. The most common cytogenetic abnormalities identified were t(11;14) and del13q. Survival does not appear shorter than non-IgM myeloma patients, and the ISS appears to have similar prognostic value. DisclosuresCastillo:Millennium: Research Funding; Janssen: Honoraria; Otsuka: Consultancy; Biogen: Consultancy; Abbvie: Research Funding; Pharmacyclics: Honoraria. Ghobrial:Celgene: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Novartis: Honoraria; Takeda: Honoraria; Noxxon: Honoraria; Amgen: Honoraria. Hájek:Celgene: Consultancy, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Honoraria; BMS: Honoraria; Takeda: Consultancy. Hungria:International Myeloma Foundation Latin America: Membership on an entity’s Board of Directors or advisory committees; Takeda: Consultancy; Amgen: Consultancy; Roche: Consultancy; Bristol: Consultancy; Janssen: Consultancy, Speakers Bureau. Niesvizky:Celgene: Consultancy, Research Funding, Speakers Bureau; Takeda: Consultancy, Research Funding, Speakers Bureau; Onyx: Consultancy, Research Funding, Speakers Bureau. Reagan:Alexion: Honoraria; Seattle Genetics: Membership on an entity’s Board of Directors or advisory committees. Richardson:Celgene: Membership on an entity’s Board of Directors or advisory committees. Spicka:Janssen Cilag: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Millenium: Honoraria. Gertz:Celgene: Honoraria; Med Learning Group: Honoraria, Speakers Bureau; Research to Practice: Honoraria, Speakers Bureau; Alnylam Pharmaceuticals: Research Funding; Novartis: Research Funding; Prothena Therapeutics: Research Funding; Ionis: Research Funding; NCI Frederick: Honoraria; Sandoz Inc: Honoraria; GSK: Honoraria; Annexon Biosciences: Research Funding.

Immunoglobulin Heavy/Light Chain Ratio and Suppression of the Myeloma Non-Involved Heavy/Light Chain Pair Isotype Correlate with Poor Survival in Multiple Myeloma at Diagnosis and after Autologous Stem Cell Transplant

The outcome for patients with Multiple Myeloma (MM) is highly variable. Understanding the prognosis for a particular patient can help when selecting the intensity of treatment to be used and the frequency of reviews. The quantification of heavy/light chains pairs by the immunoassay Hevylite (HLC) allows us a precise measurement of monoclonal and non-monoclonal immunoglobulins of the same isotype. In this study we evaluate i) the impact of the "HLC ratio" defined as monoclonal immunoglobulin over isotype matched non-monoclonal immunoglobulin (involved/uninvolved HLC ratio or i/u HLC ratio), ii) the suppression of non-monoclonal pair denominated "HLC-matched pair suppression" and iii) the effect of "systemic immunoparesis", at diagnosis and at +100 days after autologous stem cell transplant (ASCT).Methods: 85 patients (50 M:35 F) with a median age of 70 years (56-78) were followed (35 IgGK, 18 IgGl, 17 IgAK and 15 IgAl) for a median of 19 (5-30) months. Sixteen patients (18%) presented ISS stage I, 15 (28%) stage II and 54 (64%) stage III. Thirty transplanted patients were evaluated at day +100 of ASCT. Serum free light chains (FLC) and immunoglobulin heavy/light chain pairs (HLC) were assessed by Freelite and Hevylite assays, respectively (The Binding Site, UK). FLC, HLC, b2-microglobulin, albumin, creatinine, hemogloblin, calcium, LDH, bone marrow plasma cell infiltration, presence of lytic bone lesions and ISS stage were evaluated for their impact on patient´s outcome. Statistical analysis with SPSS 23. Overall survival (OS) and progression-free survival (PFS) were evaluated by Kaplan-Meier method and Cox Regression.Results: The median OS of the 85 patients was 54% and 26 patients deceased during the study due to MM. The median value of i/u HLC ratio at diagnosis was 80 (31.5-319.71) and values >80 were significantly associated with worse OS (48 vs. 61%, p=0,005, fig.1A and Table 1) and shorter PFS (23% vs. 42%, p=0,006, fig.1B). Severe HLC-matched pair suppression (i.e. more than 50% below the lower reference range) was identified in 68% of the newly diagnosed patients and was associated with shorter OS (35% vs. 81%, p=0,004, fig. 1C) and PFS (21% vs. 50%, p=0,013, fig.1D). Severe (>50%) systemic immunoparesis was identified in 64% of the patients and was also significantly associated with shorter OS (32% vs. 81%, p=0,030, fig.1E) but not with shorter PFS (26% vs. 44%, p=0,306, fig. 1F). In a multivariate analysis, severe HLC-matched pair suppression and albumin were found as independent risk factors for OS whereas creatinine and i/u HLC ratio >80 were independent risk factors for PFS.In the post-ASCT evaluation of the patients (n=30), normalization of HLC Ig´k/Ig´l ratio was observed in 8 patients (27%). An altered HLC ratio was predictive of shorter PFS after ASCT (25% vs. 70%, HR: 3,42, 95%CI 1,12-11,97, p=0,039, fig. 2B) and with a trend towards a worse OS (p=0,072, fig. 2A). Severe HLC-matched pair suppression was found in 12 patients (40%) and was predictive of worse OS (0% vs 70%, HR: 10,63, 95%CI: 1,11-114,11, p=0,023, fig.2C) and shorter PFS (35% vs. 71%, HR: 8,87, 95%CI: 1,72-45,92, p=0,002, fig. 2D). The severe systemic immunoparesis observed in 17 patients (57%) was not associated with OS (p=0,644, fig.2E) or PFS (p=0,750, fig. 2F).Conclusions: Severe HLC-matched pair suppression and i/u HLC>80 are associated with worse OS and shorter PFS in MM patients suggesting a potential use of these parameters as prognostic biomarkers in newly diagnosed patients. Severe HLC-matched pair suppression is an independent risk factor for OS whereas i/u HLC>80 is independently associated with shorter PFS. In patients after ASCT, severe HLC-matched pair suppression reflects the persistence of clonal cells that is not associated with severe systemic immunoparesis. [Display omitted] [Display omitted] [Display omitted] DisclosuresBarbosa:The Binding Site: Employment. Pais:The Binding Site: Employment.

MRI in multiple myeloma: a pictorial review of diagnostic and post-treatment findings.

Magnetic resonance imaging (MRI) is increasingly being used in the diagnostic work-up of patients with multiple myeloma. Since 2014, MRI findings are included in the new diagnostic criteria proposed by the International Myeloma Working Group. Patients with smouldering myeloma presenting with more than one unequivocal focal lesion in the bone marrow on MRI are considered having symptomatic myeloma requiring treatment, regardless of the presence of lytic bone lesions. However, bone marrow evaluation with MRI offers more than only morphological information regarding the detection of focal lesions in patients with MM. The overall performance of MRI is enhanced by applying dynamic contrast-enhanced MRI and diffusion weighted imaging sequences, providing additional functional information on bone marrow vascularization and cellularity.This pictorial review provides an overview of the most important imaging findings in patients with monoclonal gammopathy of undetermined significance, smouldering myeloma and multiple myeloma, by performing a ‘total’ MRI investigation with implications for the diagnosis, staging and response assessment.Main message• Conventional MRI diagnoses multiple myeloma by assessing the infiltration pattern.• Dynamic contrast-enhanced MRI diagnoses multiple myeloma by assessing vascularization and perfusion.• Diffusion weighted imaging evaluates bone marrow composition and cellularity in multiple myeloma.• Combined morphological and functional MRI provides optimal bone marrow assessment for staging.• Combined morphological and functional MRI is of considerable value in treatment follow-up.

A New Model for Risk Stratification in Patients with Newly Diagnosed Multiple Myeloma: Impact of Serum Free Light Chains in Prognosis

Background: The outcome for patients with Multiple Myeloma (MM) is highly variable. Understanding the prognosis for a particular patient can help when selecting the intensity of treatment to be used and the frequency of reviews. The International Staging System (ISS) is the current standard used for risk stratification of patients with MM. Recent studies have evaluated the relationship between serum free light chains (sFLC) at diagnosis and the prognosis of these patients. The aim of this study is to evaluate the prognostic value of sFLC ratio (sFLCR) at baseline in newly diagnosed MM in a Southern Spanish population.Materials and Methods: 180 patients (82 Male:98 Female) with a median age of 69 years (range 61-76) were recruited and followed for up to 7 years. The median follow up of the patients was 35 (18-61) months. sFLC concentrations were measured nephelometrically (Freelite, The Binding Site, Birmingham, UK) and the sFLCR was calculated using the monoclonal sFLC as the numerator. Patients were stratified into two groups according to the median value of sFLCR: group "low" with sFLCR<50 (90 patients) and group "high" with sFLCR≥50 (90 patients). Clinical and laboratory variables (including sFLC, Albumin, Beta-2-microglobulin (B2M), creatinine, hemoglobin, calcium, LDH, M-protein size, plasma cell infiltration and presence of lytic bone lesions) were recorded and evaluated for their impact on patient's outcome. Statistical analysis was performed using SPSS 23. Overall survival (OS) was analyzed by Kaplan-Meier method and significant variables were further analyzed by Cox Regression analysis.Results: During follow-up there were 72 disease-related deaths: 23 in group "low" and 49 in group "high". The 7-years OS of all patients was 38%, whereas it was 57% and 10% in groups "low" and "high" respectively (HR=5.07 IC95% 3.01-8.55, p<0.0001). Univariate analysis identified age>65 years old, creatinine>2 mg/dL, hemoglobin<10 g/dL, B2M>3.5 mg/L, albumin<3.5 g/dL, involved sFLC≥100 mg/L and ISS stages 2 & 3 as being significantly associated with adverse outcome (Table 1). There was no significant correlation with the others variables. Multivariate Cox regression identified sFLCR (HR=4.65, IC95% 2.71-7.98, p<0.0001) and B2M (HR=2.92, IC95% 1.67-5.11, p<0.0001) as independent risk factors for adverse outcome. The combination of sFLCR≥50 and B2M>3.5 mg/L allows us to include patients in a new model with three risk groups more accurate compared with ISS model (Table 2 and Figure 1).Conclusions: sFLCR value at diagnosis is an important independent risk factor for poor prognosis in patients with newly diagnosed MM. Our new staging system model based on sFLCR and B2M allow us an accurate risk stratification of patients with MM in our population.Table 1Univariate and multivariate analysis of prognostic factors for patients with newly diagnosed MM.VariablesUnivariate analysisMultivariate analysisHR (95%IC)p-valueHR (95%IC)p-valueAge>65 years1.99 (1.17-3.41)0.01-sFLC ratio≥50(involved/uninvolved)5.07 (3.01-8.55)<0.00014.65 (2.71-7.98)<0.0001Involved sFLC≥100 mg/L2.19 (1.24-3.90)0.007-Total protein (g/dL)1.45 (0.91-2.31)0.2-Calcium>11 mg/dL1.75 (0.87-3.53)0.2-Hemoglobin<10 g/dL1.95 (1.22-3.12)0.005-Creatinine>2 mg/dL2.15 (1.25-3.70)0.005-Lytic bone lesions1.21 (0.74-1.97)0.4-B2M>3.5 mg/L3.66 (2.16-6.21)<0.00012.92 (1.67-5.11)<0.0001Albumin<3.5 g/dL1.84 (1.14-2.96)0.01-M-protein>3 g/dL1.86 (1.07-3.21)0.03-Plasma cell>10%1.57 (0.92-2.71)0.1-ISS-2 (vs. ISS-1)3.02 (1.56-5.73)0.001-ISS-3 (vs. ISS-3)4.88 (2.50-9,52)<0.0001-Table 2Prognostic value of International Staging System (ISS) and New Staging System based on sFLCR and B2M. NR=not reached. (1)p-value=0.09 between ISS-2 and ISS-3. (2)p-value<0.0001 between stages 2 and 3.Risk groupsNNumber of deceasesn (%)7-years OS (%)Median survival(months)HR (95% CI)p-valueInternational Staging System (ISS)Stage 15614 (25)56NR1.00-Stage 26530 (46)33513.02 (1.59-5.73)0.001Stage 35928 (47)0444.88 (2.50-9.52<0.0001 (1)New Staging System based on sFLCR and B2MStage 1(B2M<3.5 mg/L and sFLCR<50)5312 (23)63NR1.00-Stage 2(B2M>3.5 mg/L or sFLCR≥50)6223 (37)33673.02 (1.49-6.13)0.002Stage 3(B2M>3.5 mg/L and sFLCR≥50)6537 (57)03511.60 (5.53-24.33)<0.0001 (2) [Display omitted] DisclosuresHarding:The Binding Site Group Ltd: Employment, Membership on an entity's Board of Directors or advisory committees. Campos:The Binding Site Spain: Employment.

Abstract 3852: Obesity is associated with clinical characteristics in African American multiple myeloma patients

Abstract African-American ethnicity, male sex, older age and obesity are accepted risk factors for multiple myeloma (MM). Obesity early in life is a risk factor for many cancers, including MM; most studies have focused on populations of European origin. African-Americans have a higher prevalence of obesity than other populations, and may have a distinct genetic contribution to this condition. We established a multi-center study to investigate possible explanations for the excess risk of MM among African-Americans. The aim of the present case-case analysis was to determine whether body mass index (BMI) was associated with clinical characteristics at presentation in African-American MM patients. 1,065 patients diagnosed with active MM from January 1, 2009 through September 30, 2013 were recruited through nine outpatient centers at academic medical centers and 3 SEER population-based cancer registries. Information on weight and height at 20 years of age and at 5 years prior to diagnosis was obtained from questionnaires. Clinical information collected from the medical records and interviews included age at diagnosis, stage, percent plasmacytosis on bone marrow biopsy, B2 microglobulin level, immunoglobulin class and presence of lytic bone lesions. Molecular profiling abstracted from pathology reports included chromosomal gain/deletions (1P-, 1Q+, +3, +5, +7, +9, +11, 12P-, Del(13), +15, Del(17P), Del(17P13)), translocations (4;14), (11;14), and (14;16 ). Analysis of Variance (ANOVA) was used to test the null hypothesis that age at diagnosis was similar across BMI categories. A T-test was used to test the null hypothesis that the mean age at diagnosis in underweight/normal patients was not different than that for overweight and obese patients. The Mantel-Haenszel Chi square test for trend was used to test the null hypothesis that the proportion of cytogenetic and molecular abnormalities was similar across BMI categories. The study population consists of 306 African American male and 396 African American female MM patients. In both, obesity at 20 years of age was associated with younger age at diagnosis, compared to a normal/underweight (p=0.0015). Among males only, obesity at 5 years prior to diagnosis was also associated with younger age at diagnosis (p=0.03). A trend between increasing BMI and molecular characteristics associated with a poor prognosis was suggested. We observed a strong association between obesity at age 20 and younger age at diagnosis among males and females, and in males only at 5 years prior to diagnosis. Obesity is one of the few known potentially modifiable risk factors for MM. Younger age at diagnosis reflects an earlier accumulation of either or both genetic and environmental risk factors. We also observed a link between obesity at each of the two time points and specific molecular markers of poor prognosis. Additional studies are needed to determine biological significance of the results. Citation Format: Amie E. Hwang, Sikander Ailwadhi, Carol Ann Huff, Leon Bernal-Mizrachi, Christopher A. Haiman, Edward Peters, Seema Singhal, Karen Pawlish, Cathryn Bock, Todd Zimmerman, David J. Van Den Berg, David V. Conti, Brenda B. Birmann, Jayesh Mehta, John J. Graff, Daniel O. Stram, Niquelle Brown, Yang Yu, Moosa Azadian, Laurence Kolonel, Brian E. Henderson, Ann Mohrbacher, Graham Colditz, Brian-C Chiu, Michael Tomasson, Jeffrey Zonder, Robert Z. Orlowski, Sagar Lonial, Wendy Cozen. Obesity is associated with clinical characteristics in African American multiple myeloma patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3852. doi:10.1158/1538-7445.AM2014-3852

Obesity In Young Adulthood Is Associated With Early Onset Multiple Myeloma In African Americans

IntroductionAfrican-American ethnicity, male sex, older age and obesity are accepted risk factors for multiple myeloma (MM). Obesity early in life is a risk factor for many cancers, including MM; most studies have focused on populations of European origin. African-Americans have a higher prevalence of obesity than other populations, and may have a distinct genetic contribution to this condition. We established a multi-center collaborative study to investigate possible explanations for the excess risk of MM among African-Americans. The aim of the present case-case analysis was to determine whether body mass index (BMI) was associated with risk factors and clinical characteristics at presentation in African-American MM patients. MethodsPatients diagnosed with active MM since January 1, 2009 were recruited from nine outpatient centers and three Surveillance, Epidemiology, End-Results Program (SEER) population-based cancer registries. Information on weight and height at 20 years of age and at 5 years prior to diagnosis was obtained from questionnaires. Clinical information collected included age at diagnosis, stage, percent plasmacytosis on bone marrow biopsy, β2 microglobulin level, Ig serotype, light vs. heavy chain disease, and presence of lytic bone lesions. BMI (ht/wt2) was categorized into 3 levels (normal <25, overweight 25-29, obese >30) according to World Health Organization standard. The Pearson chi-square test was used to test the association between BMI category, and risk factors and clinical characteristics. Mean ages at diagnosis across BMI categories were compared using linear regression and a t-test for trend calculated. ResultsTo date, 1,044 African-American MM patients have been enrolled and of those, 1,014 provided a DNA sample. At present, 970 patients have completed a questionnaire, clinical records have been abstracted for 823 patients, and 509 patients have some information on gender, age at diagnosis, weight, height and clinical characteristics.The mean age at diagnosis was 59. Increasing BMI at age 20 was associated with younger age at diagnosis (p= 0.0004), whereas BMI at 5 years prior to diagnosis was not associated with age at diagnosis (p=0.9477). Among men, mean age at diagnosis decreased with increasing BMI at age 20 (p= 0.0125) (Table 1a) and at 5 years prior to diagnosis (p=0.0252) (Table 1b). Among women, the trend was signficant at age 20 (p=0.0018) (Table 1a) but not at 5 years prior to diagnosis (p= 0.7094) (Table 1b). Increasing BMI was not significantly associated with any other clinical characteristics.Table 1aAssociation of body mass index (BMI) at age 20 with age at diagnosis among African-American multiple myeloma patients.MenWomenTotalBody Mass Index (ht/wt2)NMean Age at DiagnosisNMean Age At DiagnosisNMean Age At Diagnosis< 2512160.723160.135260.425-306457.93257.49657.7> 301855.22352.944153.9Total203286489P for trendP= 0.0125P= 0.0018P<0.0001Table 1bAssociation of body mass index (BMI) at 5 years prior to age at diagnosis among African-American multiple myeloma patients.MenWomenTotalBody Mass Index (ht/wt2)NMean Age at DiagnosisNMean Age At DiagnosisNMean Age At Diagnosis< 254661.77859.312460.225-308859.79859.018659.3> 307757.412259.819958.9Total211298509P for trendP= 0.0252P= 0.7094P= 0.3063 Conclusion/DiscussionIn a large collection of African-American MM patients, we observed a strong association between increasing BMI at age 20 and younger age at diagnosis. A similar trend was observed in men only at 5 years prior to diagnosis, consistent with previous reports. Obesity is one of the few known potentially modifiable risk factors for MM. Younger age at diagnosis reflects an earlier accumulation of either or both genetic and environmental risk factors. Obesity at an early age may influence MM risk through shared biological pathways such as interleukin-6 and insulin-like growth factor, by contributing to chronic B-cell activation, thereby increasing susceptibilty for MM later in life. The significance of the gender difference for the association closer to diagnosis is unclear and requires additional study. Disclosures:Terebelo:Amgen: Honoraria; Millennium: Honoraria. Mehta:Celgene: Speakers Bureau; Millennium: Speakers Bureau. Zonder:Skyline: Consultancy. Orlowski:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: The Takeda Oncology Company: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Resverlogix: Research Funding; Array Biopharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees. Lonial:Celgene Corporation: Consultancy; Millennium: Consultancy; Novartis: Consultancy; Bristol Myers Squibb: Consultancy; Sanofi: Consultancy; Onyx: Consultancy.

Value Of Serum Free Light Chains Ratio As New Biomarker Of High Prognostic Value In Patients With Newly Diagnosed Multiple Myeloma

BackgroundThe International Staging System (ISS) is the current standard used for risk stratification of patients with newly diagnosed Multiple Myeloma (MM). Patients are stratified into three categories using the values ​​of serum albumin and beta2-microglobulin (B2M). Recent studies have evaluated the relationship between serum free light chains (sFLC) at diagnosis and the prognosis of these patients. The aim of this study is to evaluate the prognostic value of sFLC ratio at baseline in newly diagnosed multiple myeloma (MM) in a Spanish population. Materials and Methods79 patients (35 Male : 44 Female) with a median age of 69 years (range 41-91) were recruited and followed for up to 5years. sFLC concentrations were measured nephelometrically (Freelite, The Binding Site, Birmingham, UK) and the sFLC ratio (sFLCr) was calculated using the monoclonal sFLC as the numerator. Patients were stratified into two groups according to the median value of sFLCR: group “low” with sFLCR <26 (39 patients) and group “high” with sFLCR >26 (40 patients). Clinical and laboratory variables (including Albumin, B2M, Creatinine, hemoglobin, calcium, LDH, M-protein size, plasma cell infiltration and presence of lytic bone lesions) were recorded and evaluated for their impact on patient's outcome. Statistical analysis were performed using (SPSS version 20.0) and significant variable were further analyzed by Cox Regression analysis. ResultsDuring follow-up there were 25 disease-related deaths: 5 in group “low” and 20 in group “high”. The 5-years OS of all patients was 63.7%, whereas it was 86.4% and 38.1% in groups “low” and “high” respectively (hazard ratio (HR): 5.51, p<0.0001) (Figure). Univariate analysis identified age>65 years old (OR: 3.61, p=0.030), creatinine>2 mg/dL (OR: 4.50, p=0.009), hemoglobin <10 g/dL (OR: 3.87, p=0.006), and ISS stage (p=0.001) as being significantly associated with adverse outcome. There was no significant correlation with the other variables. Multivariate Cox regression identified sFLCR (sFLCR>26, HR: 4.39, p=0.004) and B2M (B2M>3.5 mg/L, HR: 3.42, p=0.008) as independent risk factors for adverse outcome. A combination of ISS stage with high or low sFLCR to check correlation between sFLCR and OS (Table). The sFLCR separated every ISS stages in two subsets; one with low sFLCR and another with high sFLCR. Within ISS stage 2, the presence of high sFLCR was associated with a worse OS (p = 0.003). The OS was 86.5% versus 17.5% for the low and high sFLCR subsets, respectively. In stage 3, the OS of patients with high sFLCR was 0% while the OS of those with low sFLCR was 75%. In ISS stage 1, the two subsets defined by low and high sFLCR had a similar OS. ConclusionsThe sFLCR value at diagnosis is an important independent risk factor for poor prognosis in patients with newly diagnosed MM. Our results suggest that sFLCR should be included in the ISS System or a new risk model stratification in patients with newly diagnosed MM. [Display omitted] Disclosures:Harding:Binding Site: Employment.TablePrognostic value of International Stage System stratified by sFLCR. P-value within groups defined by low (sFLCR < 26) and high sFLCR (sFLCR ≥ 26).Risk groupNNumber of deceases n (%)Overall survival at 5 years (%)Median survival (months)Hazard ratio (95% CI)p-valueISS stage 1303 (10%)89.4%Not reatched--sFLCR < 26192 (10%)89.2%Not reatched1.00 (reference)-sFLCR ≥ 26111(9%)90.9%Not reatched1.03 (0.09-11.43)0.983ISS stage 23111 (36%)56.6%Not reatched--sFLCR < 26162 (12%)86.5%Not reatched1.00 (reference)-sFLCR ≥ 26159 (60%)17.5%457.01 (2.09-23.52)0.003ISS stage 31811 (61%)19.9%34--sFLCR < 2641 (26%)75.0%Not reatched1.00 (reference)-sFLCR ≥ 261410 (71%)0%344.89 (1.39-17.20)0.080

A Novel Sequestosome-1/p62 ZZ Domain Inhibitor Induces New Bone Formation In The Presence Of Myeloma In Vivo

Multiple myeloma (MM) cells activate multiple signaling pathways in bone marrow stromal cells (BMSC), which results in enhanced tumor growth, increased osteoclast (OCL) formation and activity, and profound inhibition of bone formation by osteoblasts (OBL). We recently showed that sequestosome-1 (p62) acts as a signaling hub for these pathways, including MM-cell induced NFκβ, p38MAPK, and PI3K activation in MM patient BMSC, and that the p62 ZZ domain is required for BMSC enhancement of MM cell growth, IL-6 production, VCAM-1 expression and OCL formation. To target the ZZ domain we developed a small molecule inhibitor (CMPD3) that specifically blocked p62-ZZ domain mediated protein interactions required for BMSC support of tumor / OCL formation, but had no effect on CFU-blasts. We now report characterization of CMPD3 in an in vivomodel of MM.Murine MM cells (5TGM1-tk-gfp) were implanted intra-tibially in female SCID mice and male C57BL/KaLwRij mice and allowed to engraft for 2 weeks. Pilot PK studies using a multiple dose MTD of 60mg/kg IV in female SCID mice bearing MM cells demonstrated a terminal t1/2 of CMPD3 in plasma of greater than 5 hours (h), and extratibial tumor CMPD3 concentrations ranging between 5 and 10-fold higher than plasma. A pilot efficacy study in male C57BL/KaLwRij mice based on the multiple dose MTD demonstrated that mice treated with CMPD3 lost weight compared with vehicle treated mice. CMPD3 treatment did not alter activity scores of the mice or plasma IgG2b levels, a marker of tumor burden. Both compartmental and non-compartmental pharmacokinetic analysis of plasma concentrations of CMPD3 in the male C57BL/KaLwRij mice on the multiple dosing regime after doses of 27 mg/kg/day or 40 mg/kg/day ip resulted in a plasma terminal t1/2 of 10 -12 h and a clearance of 1188 ml/h/kg. An expanded efficacy study using CMPD3 doses of 27mg/kg/day or 40mg/kg/day, or vehicle ip for 5 days/week for 2 weeks demonstrated no change in body weights, tumor scores, or plasma IgG2b levels in any animals.Radiographic analysis of tibiae confirmed the presence of lytic bone lesions in all animals, and of 27 evaluable animals at the end of treatment, 6 CMPD3 treated and 2 vehicle treated mice developed grade 4 tumors (defined as tumor expanding outside the tibia and impairing the use of the limb). 4 of the 6 CMPD3 treated mice with grade 4 tumors and 1 of the 2 vehicle treated animals had radiographic evidence of new bone formation on the anterior tibial surface. µCT analysis of the tibiae from all CMPD3 vs. vehicle treated mice showed that the ratio of new bone volume to total bone volume (NBV/TBV) was increased in CMPD3 treated mice regardless of tumor score (1 - 4) (p=0.015). Stratification of NBV/TBV based on tumor score showed that CMPD3 treated animals with a tumor score of 4 had significantly more new bone formation than animals with tumor scores of 1 - 3 (p<0.01). NBV/TBV was not increased in the non-injected tibiae, indicating a lack of systemic effect on non tumor-bearing bone.Thus, CMPD3 induces new bone formation in bones bearing MM and suggest that p62 ZZ inhibition modulates tumor induced OBL suppression. Non-compartmental analysis of the maximal plasma concentration of CMPD3 at the 40mg/kg dose was 5.7µM, while the in vitro IC50 of CMPD3 for 5TGM1 cells was 4.35µM. This difference may explain why IgG2b levels did not change with CMPD3 treatment. In contrast, the IC50 in OCL formation assays was 0.1µM, suggesting that CMPD3's inhibition of OCL formation in vivo may also contribute to increased bone. These findings demonstrate that CMPD3 can modulate tumor cell – bone cell interactions in MM in vivo, and support development of CMPD3 as a potential anabolic bone agent for MM. Disclosures:Roodman:Amgen: Consultancy; Eli Lilly and Co.: Research Funding.

Adult T-cell leukemia cells overexpress Wnt5a and promote osteoclast differentiation

AbstractAdult T-cell leukemia/lymphoma (ATL) is etiologically linked to infection with the human T-cell leukemia/lymphoma virus type 1 (HTLV-I). ATL is classified into 4 distinct clinical diseases: acute, lymphoma, chronic, and smoldering. Acute ATL is the most aggressive form, representing 60% of cases and has a 4-year survival of <5%. A frequent complication and cause of death in acute ATL patients is the presence of lytic bone lesions and hypercalcemia. We analyzed the Wnt/β-catenin pathway because of its common role in cancer and bone remodeling. Our study demonstrated that ATL cells do not express high levels of β-catenin but displayed high levels of LEF-1/TCF genes along with elevated levels of β-catenin (LEF-1/TCF target genes) responsive genes. By profiling Wnt gene expression, we discovered that ATL patient leukemia cells shifted expression toward the noncanonical Wnt pathway. Interestingly, ATL cells overexpressed the osteolytic-associated genes—Wnt5a, PTHLH, and RANKL. We further show that Wnt5a secreted by ATL cells favors osteoclast differentiation and expression of RANK. Our results suggest that Wnt5a is a major contributing factor to the increase in osteolytic bone lesions and hypercalcemia found in ATL patients. Anti-Wnt5a therapy may prevent or reduce osteolytic lesions found in ATL patients and improve therapy outcome.

Extramedullary Relapse in a Case of Multiple Myeloma Involving the Thyroid Cartilage: Case Report and Review of Literature

Multiple myeloma (MM) is a B-cell malignancy occurring due to monoclonal expansion of plasma cells. It accounts for 10% of all hematopoietic malignancies. The classic triad in the diagnosis of MM is detection of serum or urine monoclonal or M protein, greater than 10% plasmacytosis on bone marrow examination and the presence of lytic bone lesions on radiological evaluation [1]. In rare instances, the plasma cell neoplasm may arise within the soft tissues, termed as extramedullary plasmacytomas (EMP) [2]. The EMP can occur as a de novo disease (primary or true EMP) or as a manifestation of MM (secondary EMP). .Although, over 80% of these EMP occurs in the head and neck region, but the involvement of the thyroid cartilage is a rare phenomenon. Only few cases have been reported in the English literature so far [3–6]. We report a 63- year- old patient with multiple myeloma, who developed plasmacytoma involving the thyroid cartilage 4 years after treatment with chemotherapy and autologous stem cell transplantation (ASCT).

IgM multiple myeloma: Disease definition, prognosis, and differentiation from Waldenstrom's macroglobulinemia

IgM multiple myeloma (MM) and Waldenstrom's macroglobulinemia (WM) are two distinct hematologic entities with the common finding of an IgM monoclonal gammopathy. Distinguishing these two diagnoses is critical as the approach to therapy is different. A priori, we defined IgM MM as a symptomatic clonal plasma cell proliferative disorder characterized by an IgM monoclonal protein (regardless of size), 10% or more plasma cells on bone marrow biopsy, plus the presence of lytic bone lesions and/or translocation t(11;14). Twenty-one patients met this definition of IgM MM. All 21 patients had lytic bone lesions. Of the 16 evaluated with FISH, 6 (38%) demonstrated t(11;14). Median overall survival was 30 months, which is similar to non-IgM myeloma patients treated during this period and shorter than what would be expected for WM. In this, the largest series of patients with IgM MM, we describe the clinical features and prognosis of patient with IgM MM using a strict definition for the disease. The subset of patients without lytic lesions or t(11;14) but with immunophenotypic features suggestive of MM need further study.

Clinical Features of Bone Complications and Prognostic Value of Bone Lesions Detected by X-ray Skeletal Survey in Previously Untreated Patients with Multiple Myeloma

Multiple myeloma is usually associated with the presence of lytic bone lesions. We reviewed the clinical and laboratory features of patients with newly diagnosed myeloma bone disease and evaluated the prognostic significance of different X-ray image patterns in symptomatic MM patients. We retrospectively reviewed 260 patients with newly diagnosed MM. X-ray image patterns of patients were correlated with hematologic parameters, therapeutic reaction and patient survival. Patients with the X-ray imaging pattern of grade 2-4 had significantly higher marrow plasma cells levels, marrow CD138(+) D38(+) cell percentage, ECOG performance score, and serum IL-6 level than grade 0-1. Univariate analysis demonstrated that skeletal lytic changes associated with rapid progression. There is a high incidence of myeloma bone disease (MBD) in patients of MM in China. Patients of extensive bone lesions have more severe alterations in hematologic parameters than do those without bone lesions and severe bone lesions is an important adverse prognostic factor associated with a short TTP.

Detecting methylation patterns of p16, MGMT, DAPK and E‐cadherin genes in multiple myeloma patients

Multiple myeloma (MM) is a B-cell neoplasia characterized by the clonal proliferation of plasma cells. Besides known genetic abnormalities, epigenetic changes are also known to effect MM pathogenesis. DNA methylation is an epigenetic mechanism that silences genes by adding methyl groups to cytosine-guanine dinucleotides at the promoter regions. In this study, the methylation status of four genes; p16, O6-methyl guanine DNA methyl transferase (MGMT), death-associated protein kinase (DAPK) and E-cadherin (ECAD); at the time of diagnosis was investigated using methylation-specific polymerase chain reaction (MS-PCR). In the 20 cases studied; methylation of the promoter regions of p16, MGMT, DAPK and ECAD genes was detected in 10%, 40%, 10% and 45% of the cases, respectively. In 65% (13/20) of cases, at least one of the genes studied had promoter methylation; while 35% of cases (7/20) had methylated promoters of more than one gene. There was a significant correlation between promoter hypermethylation of MGMT and the presence of extramedullary involvement; but for the other genes no correlation was found regarding disease properties like age, disease stage, clinical course and the presence of lytic bone lesions. Determining the methylation profiles of genes in MM, could lead to a new understanding of the disease pathogenesis and guide the assessment of treatment options.

Serum Levels of Total-RANKL in Multiple Myeloma

BackgroundReceptor activator of nuclear factor-κB ligand (RANKL) plays a key role in osteoclast activation in myeloma bone disease. The increased expression of RANKL in the bone marrow microenvironment was demonstrated in several studies, but there are only rare data on circulating RANKL levels in patients with multiple myeloma (MM). Patients and MethodsIn the current study, we investigated the clinical significance of serum RANKL levels, using an enzyme-linked immunosorbent assay test that detects both free and osteoprotegerin (OPG)-bound RANKL (total-RANKL, tRANKL) in patients with newly diagnosed MM (n = 93) and monoclonal gammopathy of undetermined significance (MGUS; n = 20) compared with healthy controls (n = 20). ResultsCirculating serum tRANKL was significantly elevated in patients with MM compared with controls (P < .001) or MGUS (P < .001). Furthermore, tRANKL levels were higher in smoldering MM versus MGUS (P = .031) and in symptomatic versus smoldering MM (P < .001). Serum tRANKL increased parallel to International Staging System stages I to III (P = .004) and correlated with the presence of lytic bone lesions (P < .001). Total-RANKL was a prognostic factor for overall survival in symptomatic MM (P = .043). A significantly longer progression-free survival was observed in patients with a > 50% decrease in tRANKL levels after 3 months of combined chemotherapy and bisphosphonate treatment. ConclusionOur study demonstrates for the first time that serum tRANKL reflects advanced disease, lytic bone destruction, and poor prognosis in MM.

Geographical Variation Shows Differences in Disease Characteristics Among Patients with Multiple Myeloma.

Abstract 4895 BackgroundMultiple myeloma (MM) remains an incurable cancer. Several biological and environmental factors have been considered to contribute to its pathogenesis, but so far no clear etiology is known. It remains undetermined if geographical differences and variability in environmental factors influences biological behavior and clinical presentation of MM patients. In depth research into the regional and demographic variation of these characteristics has not yet been done. To evaluate the impact of environmental influences we compared MM disease characteristics in two distinct geographical regions. MethodsPatients with plasma cell disorders seen in the malignant hematology clinics of the University of Southern California (USC), Los Angeles, CA and the Multiple Myeloma Program Clinic at the Roswell Park Cancer Institute (RPCI), Buffalo, NY were included in this analysis. Demographic and disease-related clinical characteristics at the time of diagnosis of active MM were evaluated. Chi-square test or Mann-Whitney U test were used where appropriate. A 0.05 nominal significance level was used in all hypothesis testing. ResultsOne hundred and sixty patients at USC and 170 patients at RPCI were studied. Among these, 140 and 144 had active MM at the time of diagnosis, respectively. The median age at diagnosis was 58 years (range 20-85) and 60 years (range 35-83), and males represented 48% and 52 % of the patients, respectively in the two geographic locations. Predominant patient race was Hispanic at USC (54%) and Caucasian at RPCI (92%). Advanced stage disease (>stage 1) was present in 87% and 85% patients, respectively as per the Durie Salmon (DS) staging and 53% and 48%, respectively as per the International Staging System (ISS). IgG MM was the most common subtype in both locations, but there were a higher number of patients on the West coast with LCO disease (22% vs. 10%). Lytic lesions were noted at the time of diagnosis in 59% of the patients at USC and 78% of the patients at RPCI while non-secretory MM was noted in 9% and 10% of the patients, respectively. There was a statistically significant difference between the patient populations in the two geographical regions with respect to median age at diagnosis (p=0.048), patient race (p<0.001), disease subtype (p=0.018), and presence of lytic bone disease at diagnosis (p<0.001). The difference in median age at diagnosis remained statistically significant even when patients were divided into age cohorts of <50 yrs, <60 yrs, <70 yrs and ≥70 yrs (p=0.03). There was no statistically significant difference between the two groups of patients for gender (p=0.48), DS stage (p=0.22), renal dysfunction (p=0.77), ISS stage (p=0.62), light chain subtype (p=0.72), or secretor status (p=0.75). To ensure that these variations were not just due to ethnic differences, the Caucasian population at USC (n=30) was compared with the Caucasian population at RPCI (n=133). Disease subtype and presence of lytic bone lesions were still significantly different between these groups (p=0.04, and p=0.02, respectively). ConclusionsDespite widespread heterogeneity amongst MM patients, variations in disease characteristics amongst geographically distinct regions have not been studied systematically. Our investigation represents the first attempt to compare patient characteristics from the West and East coasts of USA. We observe several demographic and clinical characteristics that were significantly different between the two populations that could not be explained based on ethnic influences of the study population. These differences in clinical characteristics may represent undefined environmental influences that are unique to geographic location of the patient(s) and can potentially influence disease biology. Our pilot observation will need validation in a larger patient population to better understand the influences mediated by environmental factors and geographic diversity on clinical and biological behavior of the disease. DisclosuresNo relevant conflicts of interest to declare.