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Chinese Americans are a fast‐growing immigrant group with worse rheumatic disease outcomes compared to white populations and frequently use traditional Chinese medicine (TCM). Whether TCM use is associated with lower adherence to Western rheumatic medications is unknown. The present study was undertaken to examine adherence to Western medications for systemic rheumatic diseases in the Chinese American immigrant population and its association with TCM use. Chinese Americans actively treated for a systemic rheumatic disease were recruited from 2 Chinatown clinics. Sociodemographic, TCM use, and clinical data were gathered. Self‐reported health status was assessed using Patient‐Reported Outcome Measurement Information System short forms. Adherence was stratified using the 8‐item Morisky Medication Adherence Scale. Factors independently associated with high adherence were identified using multivariable logistic regression. Of 230 subjects, the median age was 55 years (range 20–97 years), 65% were female, 71% had a high school education or less, 70% were enrolled in Medicaid, and 22% reported fluency in English. The most common rheumatic diagnoses were rheumatoid arthritis (41%), systemic lupus erythematosus (17%), and seronegative spondyloarthropathies (15%). One‐half reported TCM use in the past year, and 28% reported high adherence to Western rheumatic medications. In multivariable analysis, high adherence was associated with TCM use (odds ratio [OR] 3.96, P< 0.001), being married (OR 3.69, P= 0.004), medication regimen complexity (OR 1.13, P= 0.004), and older age (OR 1.06, P< 0.001), and was negatively associated with anxiety (OR 0.94, P= 0.001). While adherence to Western rheumatic medications was low in this cohort, interestingly, it was higher among TCM users compared to nonusers. TCM use appears to represent a complementary rather than an alternate approach to disease management for these patients. Future studies should evaluate whether TCM use is associated with better disease outcomes.

To evaluate the longitudinal responsiveness (sensitivity to change) of the Patient‐Reported Outcomes Measurement Information System (PROMIS) Global Health Short Form (PROMIS10) in outpatients with systemic lupus erythematosus (SLE). Outpatients with SLE who were receiving care at an academic medical center completed the PROMIS10 at 2 visits that were a minimum of 1 month apart. Responsiveness of the PROMIS10 global physical and mental health domains to Patient‐Reported improvement or deterioration of health status was evaluated, as measured by standard validated instruments. Effect sizes of changes in PROMIS10 scores between visits were evaluated using Kruskal‐Wallis testing. A total of 223 SLE patients enrolled and completed baseline surveys, with 186 (83.4%) completing a second set of questionnaires. The PROMIS10 demonstrated mild‐to‐moderate responsiveness to Patient‐Reported improvement (effect size 0.29) and worsening (effect sizes –0.27 and –0.54) of health status for both global physical health and global mental health. Changes in the PROMIS10 correlated poorly with changes in physician‐reported measures of disease activity. The PROMIS10 showed responsiveness over time to Patient‐Reported changes in SLE health status, but not physician‐assessed changes. These data suggest that the PROMIS10 can be used to efficiently measure and monitor important aspects of the SLE patient experience that are not captured by standard physician‐derived metrics. Further studies are needed to evaluate the role of the PROMIS10 in optimizing longitudinal disease management in SLE and to determine its responsiveness in other chronic health conditions.

To determine whether racial disparities in total knee replacement (TKR) failure are explained by poverty. Black and white New York state residents, enrolled in a prospective single‐institution TKRregistry January 1, 2008 to February 6, 2012, who underwent primary unilateral TKR(n = 4,062) were linked to the New York Statewide Planning and Research Cooperative System database (January 1, 2008 to December 31, 2014) to capture revisions performed at outside institutions. Patients were linked by geocoded addresses to residential census tracts. Multivariable Cox regression was used to assess predictors of TKRrevision. Multivariable logistic regression was used to analyze predictors of TKRfailure, defined as TKRrevision in New York state ≤2 years after surgery, or as Hospital for Special Surgery (HSS) TKRquality of life score “not improved” or “worsened” 2 years after surgery. The mean ± SDage was 68.4 ± 10 years, 64% of patients were female, 8% lived in census tracts with >20% of the population under the poverty line, and 9% were black. Median follow‐up time was 5.3 years. A total of 3% of patients (122 of 4,062) required revision a median 454 days (interquartile range 215–829) after surgery. TKRrevision risk was higher in blacks than whites, with a hazard ratio of 1.69 (95% confidence interval 1.01–2.81), but in multivariable analysis, only younger age, male sex, and constrained prosthesis were predictors of TKRrevision. TKRfailure occurred in 200 of 2,832 cases (7%) with 2‐year surveys. Risk factors for TKRfailure were non‐osteoarthritis TKRindication, low surgeon volume, and low HSSExpectations Survey score, but not black race. Community poverty was not associated with TKRrevision or failure. There was a trend toward higher TKRrevision risk in blacks, but poverty did not modify the relationship between race and TKRrevision or failure.

Objective.Chinese Americans are a fast-growing immigrant group with more severe rheumatic disease manifestations than whites and often a strong cultural preference for traditional Chinese medicine (TCM). We aimed to examine TCM use patterns and association with patient-reported outcomes (PRO) among Chinese American rheumatology patients.Methods.Chinese Americans actively treated for systemic rheumatic diseases were recruited from urban Chinatown rheumatology clinics. Data on sociodemographics, acculturation, clinical factors, and TCM use (11 modalities) were gathered. Self-reported health status was assessed using Patient Reported Outcomes Measurement Information System (PROMIS) short forms. TCM users and nonusers were compared. Factors independently associated with TCM use were identified using multivariable logistic regression.Results.Among 230 participants, median age was 57 years (range 20–97), 65% were women, 71% had ≤ high school education, 70% were on Medicaid insurance, 47% lived in the United States for ≥ 20 years, and 22% spoke English fluently. Half used TCM in the past year; these participants had worse self-reported anxiety, depression, fatigue, and ability to participate in social roles and activities compared with nonusers. In multivariable analysis, TCM use was associated with belief in TCM, female sex, ≥ 20 years of US residency, reporting Western medicine as ineffective, and shorter rheumatic disease duration.Conclusion.Among these Chinese American rheumatology patients, TCM users had worse PRO in many physical and mental health domains. TCM use may be a proxy for unmet therapeutic needs. Asking about TCM use could help providers identify patients with suboptimal health-related quality of life who may benefit from targeted interventions.

Hemophilic arthropathy (HA) is a debilitating degenerative joint disease that is a major manifestation of the bleeding disorder hemophilia A. HA typically begins with hemophilic synovitis that resembles inflammatory arthritides, such as rheumatoid arthritis, and frequently results in bone loss in patients. A major cause of rheumatoid arthritis is inappropriate release of the proinflammatory cytokine tumor necrosis factor-α (TNF-α) by the TNF-α convertase (TACE; also referred to as ADAM17) and its regulator, iRhom2. Therefore, we hypothesized that iRhom2/ADAM17-dependent shedding of TNF-α also has a pivotal role in mediating HA. Here, we show that addition of blood or its components to macrophages activates iRhom2/ADAM17-dependent TNF-α shedding, providing the premise to study the activation of this pathway by blood in the joint in vivo. For this, we turned to hemophilic FVIII-deficient mice (F8−/− mice), which develop a hemarthrosis following needle puncture injury with synovial inflammation and significant osteopenia adjacent to the affected joint. We found that needle puncture–induced bleeding leads to increased TNF-α levels in the affected joint of F8−/− mice. Moreover, inactivation of TNF-α or iRhom2 in F8−/− mice reduced the osteopenia and synovial inflammation that develops in this mouse model for HA. Taken together, our results suggest that blood entering the joint activates the iRhom2/ADAM17/TNF-α pathway, thereby contributing to osteopenia and synovitis in mice. Therefore, this proinflammatory signaling pathway could emerge as an attractive new target to prevent osteoporosis and joint damage in HA patients.

Total knee arthroplasty (TKA) outcomes are worse for patients from poor neighborhoods, but whether education mitigates the effect of poverty is not known. We assessed the interaction between education and poverty on 2‐year Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and function. Patient‐level variables from an institutional registry were linked to USCensus Bureau data (census tract [CT] level). Statistical models including patient and CT‐level variables were constructed within multilevel frameworks. Linear mixed‐effects models with separate random intercepts for each CTwere used to assess the interaction between education and poverty at the individual and community level on WOMACscores. Of 3,970 TKApatients, 2,438 (61%) had some college or more. Having no college was associated with worse pain and function at baseline and 2 years (P= 0.0001). Living in a poor neighborhood (>20% below poverty line) was associated with worse 2‐year pain (P= 0.02) and function (P= 0.006). There was a strong interaction between individual education and community poverty with WOMACscores at 2 years. Patients without college living in poor communities had pain scores that were ~10 points worse than those with some college (83.4% versus 75.7%; P< 0.0001); in wealthy communities, college was associated with a 1‐point difference in pain. Function was similar. In poor communities, those without college attain 2‐year WOMACscores that are 10 points worse than those with some college; education has no impact on TKAoutcomes in wealthy communities. How education protects those in impoverished communities warrants further study.

Objective.Rates of total knee arthroplasty (TKA) and total hip arthroplasty (THA) remain high for patients with rheumatoid arthritis (RA), who are at risk of flaring after surgery. We aimed to describe rates, characteristics, and risk factors of RA flare within 6 weeks of THA and TKA.Methods.Patients with RA were recruited prior to elective THA and TKA surgery and prospectively followed. Clinicians evaluated RA clinical characteristics 0–2 weeks before and 6 weeks after surgery. Patients answered questions regarding disease activity including self-reported joint counts and flare status weekly for 6 weeks. Per standard of care, biologics were stopped before surgery, while glucocorticoids and methotrexate (MTX) were typically continued. Multivariable logistic regression was used to identify baseline characteristics associated with postsurgical RA flares.Results.Of 120 patients, the mean age was 62 years and the median RA duration 14.8 years. Ninety-eight (82%) met 2010/1987 American College of Rheumatology/European League Against Rheumatism criteria, 53 (44%) underwent THA (and the rest TKA), and 61 (51%) were taking biologics. By 6 weeks, 75 (63%) had flared. At baseline, flarers had significantly higher disease activity (as measured by the 28-joint Disease Activity Score), erythrocyte sedimentation rate, C-reactive protein, and pain. Numerically more flarers used biologics, but stopping biologics did not predict flares, and continuing MTX was not protective. A higher baseline disease activity predicted flaring by 6 weeks (OR 2.12, p = 0.02).Conclusion.Flares are frequent in patients with RA undergoing arthroplasty. Higher baseline disease activity significantly increases the risk. Although more patients stopping biologics flared, this did not independently predict flaring. The effect of early postsurgery flares requires further study.

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Objective.To assess the feasibility, validity, and reliability of the Patient Reported Outcomes Measurement Information System Global Health Short Form (PROMIS10) in outpatients with systemic lupus erythematosus (SLE).Methods.SLE outpatients completed PROMIS10, Medical Outcomes Study Short Form-36 (SF-36), LupusQoL-US, and selected PROMIS computerized adaptive tests (CAT) at routine visits at an SLE Center of Excellence. Construct validity was evaluated by correlating PROMIS10 physical and mental health scores with PROMIS CAT, legacy instruments, and physician-derived measures of disease activity and damage. Test-retest reliability was determined among subjects reporting stable SLE activity at 2 assessments 1 week apart using intraclass correlation coefficients (ICC).Results.A diverse cohort of 204 out of 238 patients with SLE (86%) completed survey instruments. PROMIS10 physical health scores strongly correlated with physical function, pain, and social health domains in PROMIS CAT, SF-36, and LupusQoL, while mental health scores strongly correlated with PROMIS depression CAT, SF-36, and LupusQoL mental health domains (Spearman correlations ≥ 0.70). Active arthritis, comorbid fibromyalgia (FM), and anxiety were associated with worse PROMIS10 scores, but sociodemographic factors and physician-assessed flare status were not. Test-retest reliability for PROMIS10 physical and mental health scores was high (ICC ≥ 0.85). PROMIS10 required < 2 minutes to complete.Conclusion.PROMIS10 is valid and reliable, and can efficiently screen for impaired physical function, pain, and emotional distress in outpatients with SLE. With strong correlations to LupusQoL and SF-36 but significantly reduced responder burden, PROMIS10 is a promising tool for measuring patient-reported outcomes in routine SLE clinical care and value-based healthcare initiatives.

Objective.The aims of this study were to assess the construct validity and the test-retest reliability of Patient Reported Outcomes Measurement Information System (PROMIS) computerized adaptive tests (CAT) in patients with systemic lupus erythematosus (SLE).Methods.Adults with SLE completed the Medical Outcomes Study Short Form-36, LupusQoL-US version (“legacy instruments”), and 14 selected PROMIS CAT. Using Spearman correlations, PROMIS CAT were compared with similar domains measured with legacy instruments. CAT were also correlated with the Safety of Estrogens in Lupus Erythematosus National Assessment–Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) disease activity and the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) scores. Test-retest reliability was evaluated using ICC.Results.There were 204 outpatients with SLE enrolled in the study and 162 completed a retest. PROMIS CAT showed good performance characteristics and moderate to strong correlations with similar domains in the 2 legacy instruments (r = −0.49 to 0.86, p < 0.001). However, correlations between PROMIS CAT and the SELENA-SLEDAI disease activity and SDI were generally weak and statistically insignificant. PROMIS CAT test-retest ICC were good to excellent, ranging from 0.72 to 0.88.Conclusion.To our knowledge, these data are the first to show that PROMIS CAT are valid and reliable for many SLE-relevant domains. Importantly, PROMIS scores did not correlate well with physician-derived measures. This disconnect between objective signs and symptoms and the subjective patient disease experience underscores the crucial need to integrate patient-reported outcomes into clinical care to ensure optimal disease management.

Cardiac resynchronization therapy (CRT) improves mitral regurgitation (MR) in a subset of patients. We hypothesized that biomarkers (amino-terminal pro-B type natriuretic peptide, high-sensitivity troponin I, galectin-3 [gal-3], and soluble ST2) might predict MR response after CRT.

This analysis aimed to perform a head-to-head comparison of 3 of the promising biomarkers of cardiovascular (CV) outcomes in heart failure (HF)—soluble ST2 (sST2), growth differentiation factor (GDF)-15, and highly-sensitive troponin T (hsTnT)—and to evaluate the role of serial measurement of these biomarkers in patients with chronic HF.

To investigate predictors of trial start-up times, high attrition, and poor protocol adherence in amyotrophic lateral sclerosis (ALS) trials.

OBJECTIVES To describe the characteristics and outcomes after resection of incidentally discovered, nonfunctioning pancreatic endocrine tumors (PETs). DESIGN Case series. SETTING Academic hospital. PATIENTS Consecutive patients with an incidentally identified, nonfunctioning PET resected from May 1, 1977, through July 31, 2009. MAIN OUTCOME MEASURES Operative morbidity and survival after resection. RESULTS A total of 139 patients with median age of 56 years (range, 21-85 years) underwent resection; tumor size ranged from 0.4 to 17.0 cm, with median size of 3.0 cm. No perioperative deaths were reported. Sixty-one patients (43.9%) experienced a perioperative complication. Twenty-six tumors (18.7%) were classified as benign, 39 (28.1%) as malignant, and 72 (51.8%) as uncertain. We were unable to confidently classify 2 tumors due to lack of information regarding mitotic rate in the pathology report. Complete follow-up was available for 112 patients (80.6%) (median, 34.2 months). Five-year actuarial survival rates were 88.8% for patients with benign disease, 92.5% for patients with tumors of uncertain biology, and 49.8% for those with malignant tumors (P = .01). Late metastasis, tumor recurrence, or disease progression were seen in 1 patient (3.8%) with tumors initially classified as benign, 8 patients (11.1%) with uncertain tumors, and 15 patients (38.5%) with tumors classified as malignant (P &lt; .001). Of the 39 patients with tumors 2 cm or smaller, 3 (7.7%) had late metastases or recurrence. When compared with patients with symptomatic, nonfunctioning PETs, no large difference was observed in tumor size, patient age, disease, or survival. CONCLUSIONS Incidentally detected, nonfunctioning PETs can display aggressive behavior, even when small. Although patients with malignant disease had diminished survival and increased rates of recurrence, benign histologic findings did not eliminate the possibility of progression. Patients with incidentally discovered, nonfunctioning PETs should undergo tumor resection and careful postoperative surveillance, even if surgical pathologic findings suggest benign disease.Arch Surg. 2011;146(5):534-538--

The impact of cumulative dosing and premature drug discontinuation (PMDD) of bortezomib (V), thalidomide (T), and dexamethasone (D) on overall survival (OS), event-free survival (EFS), time to next therapy, and post-relapse survival in Total Therapy 3 were examined, using time-dependent methodology, relevant to induction, peritransplantation, consolidation, and maintenance phases. Univariately, OS and EFS were longer in case higher doses were used of all agents during induction, consolidation (except T), and maintenance (except V and T). The favorable OS and EFS impact of D induction dosing provided the rationale for examining the expression of glucocorticoid receptor NR3C1, top-tertile levels of which significantly prolonged OS and EFS and rendered outcomes independent of D and T dosing, whereas T and D, but not V, dosing was critical to outcome improvement in the bottom-tertile NR3C1 setting. PMDD of V was an independent highly adverse feature for OS (hazard ratio = 6.44; P < .001), whereas PMDD of both T and D independently imparted shorter time to next therapy. The absence of adverse effects on postrelapse survival of dosing of any VTD components and indeed a benefit from V supports the use up-front of all active agents in a dose-dense and dose-intense fashion, as practiced in Total Therapy 3, toward maximizing myeloma survival.

The Total Therapy 3 trial 2003-33 enrolled 303 newly diagnosed multiple myeloma patients and was noted to provide superior clinical outcomes compared with predecessor trial Total Therapy 2, especially in gene expression profiling (GEP)–defined low-risk disease. We report here on the results of successor trial 2006-66 with 177 patients, using bortezomib, lenalidomide, and dexamethasone maintenance for 3 years versus bortezomib, thalidomide, and dexamethasone in year 1 and thalidomide/dexamethasone in years 2 and 3 in the 2003-33 protocol. Overall survival (OS) and event-free survival (EFS) plots were super-imposable for the 2 trials, as were onset of complete response and complete response duration (CRD), regardless of GEP risk. GEP-defined high-risk designation, pertinent to 17% of patients, imparted inferior OS, EFS, and CRD in both protocols and, on multivariate analysis, was the sole adverse feature affecting OS, EFS, and CRD. Mathematical modeling of CRD in low-risk myeloma predicted a 55% cure fraction (P< .001). Despite more rapid onset and higher rate of CR than in other molecular subgroups, CRD was inferior in CCND1 without CD20 myeloma, resembling outcomes in MAF/MAFB and proliferation entities. The robustness of the GEP risk model should be exploited in clinical trials aimed at improving the notoriously poor outcome in high-risk disease.

Landmark analyses are used to investigate the importance for survival of achieving complete response (CR), an important initial goal of myeloma therapy. With median times to CR in Total Therapy (TT) trials of approximately 1 year, this approach excludes a sizeable fraction of patients dying before such a landmark. To permit inclusion of all trial participants, we investigated the prognostic implications of both onset and duration of CR as time-dependent variables. Superseding the adverse effects of cytogenetic abnormalities and other standard prognostic parameters, both failure to achieve CR (non-CR) and, especially, loss of CR (los-CR) were independently associated with inferior survival in TT1, TT2, and TT3 protocols. In the context of gene array–defined risk, available in TT2 and TT3 subsets, both los-CR and non-CR terms were retained in the survival model as dominant adverse variables, stressing the prognostic importance of sustaining CR status, especially in high-risk disease.

We report on prognostic implications for postrelapse survival (PRS) of a gene expression profiling (GEP)–defined risk score at relapse available in 120 myeloma patients previously enrolled in tandem transplantation trial Total Therapy 2. Among the 71 patients with additional GEP baseline information, 3-year PRS was 71% in 40 patients with low risk present both at baseline and relapse contrasting with only 17% in 28 patients with high risk at relapse, 12 of whom with baseline low-risk status fared better than the remainder (P = .08). On multivariate analysis of relapse parameters available in 104 patients, high risk conferred short PRS (hazard ratio = 4.00, P < .001, R2 = 33%), whereas relapse hyperdiploidy predicted long PRS (hazard ratio = 0.37, P = .022, cumulative R2 = 41%). In case the initial partial response lasted less than 2 years, relapse low-risk identified 26 patients with superior 3-year PRS of 61% versus 9% among 32 with relapse high-risk (P < .001). Based on its PRS predictive power, GEP analysis should be an integral part of new agent trials in search of better therapy for high-risk myeloma.

The survival of patients with Waldenstrom macroglobulinemia (WM) varies enormously. The development of prognostic models in WM has been fraught by limited follow-up in current studies. Here, we update the outcome of a prospective WM trial with a median follow-up of 10 years for live patients. Of the 59 previously untreated patients who initially were observed, only 12 patients (21%) required therapy at a median follow-up of 100 months. Multivariate analysis among the 183 patients requiring therapy reaffirmed age 70 years or greater, previous nonprotocol therapy, and β-2 microglobulin (B2M) of 3 mg/dL or greater as prognostic factors. Importantly, increased serum lactate dehydrogenase (LDH) was identified as an additional independent variable, which improved risk assessment beyond the recent WM international prognostic scoring system (ISSWM). By using age, previous therapy, B2M, and LDH, we identified 3 risk groups with 8-year survival estimates of 55%, 33%, and 5% (P < .001). These data provide novel insights into factors predicting long-term outcome in WM. This trial has been registered with www.cancer.gov under ID 4852904.

Smoldering multiple myeloma (SMM) is usually followed expectantly without therapy. We conducted a phase 2 trial in 76 eligible patients with SMM, combining thalidomide (THAL, 200 mg/d) with monthly pamidronate. In the first 2 years, THAL dose reduction was required in 86% and drug was discontinued in 50%. Within 4 years, 63% improved, including 25% qualifying for partial response (PR); by then, 34 patients had progressed and 17 required salvage therapy. Unexpectedly, attaining PR status was associated with a shorter time to salvage therapy for disease progression (P < .001), perhaps reflecting greater drug sensitivity of more aggressive disease. Low beta-2-microglobulin levels less than 2 mg/L were independently associated with superior overall and event-free survival. Four-year survival and event-free survival estimates of 91% and 60%, respectively, together with a median postsalvage therapy survival of more than 5 years justify the conduct of a prospective randomized clinical trial to determine the clinical value of preemptive therapy in SMM. Trial registered at http://www.clinicaltrials.gov under identifier NCT00083382.

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Introduction:Spatial risk factors are increasingly recognized to predict cardiovascular events independently of traditional risk factors. However, these spatial risk factors have been studied only individually and primarily in high-income countries.Hypothesis:We hypothesize that spatial risk factors independently predict all-cause and cardiovascular mortality.Methods:We developed exposure models for the following spatial risk factors in Golestan Provence, Iran: outdoor air pollution, proximity to traffic, proximity to health facilities, population density, land cover, socioeconomic environment, and light-at-night. Spatial exposures were assigned to 50,045 individuals in the Golestan Cohort Study, who have been followed-up for up to 12 years. Using a multivariable Cox proportional hazards spatial frailty model, we determined the impact of these exposures, as well as household fuel use and traditional risk factors, on cardiovascular mortality.Results:Spatial surfaces demonstrated spatial variability of the spatial risk factors (Figure), and outdoor air pollution also displayed temporal variability. Exposure to outdoor air pollution 5 years prior to enrollment, household kerosene and biomass fuel use, and proximity to advanced health facilities independently increased total and cardiovascular mortality (Table).Conclusions:Both outdoor air pollution and household fuel use independently predicted cardiovascular mortality in a middle-income country. Following this approach, future studies can better estimate the total impact of the environment on cardiovascular events.

Recent developments in computed tomography (CT) technology have fulfilled the prerequisites for the clinical application of myocardial CT perfusion (CTP) imaging. The evaluation of myocardial perfusion by CT can be achieved by static or dynamic scan acquisitions. Although both approaches have proved clinically feasible, substantial barriers need to be overcome before its routine clinical application. The current review provides an outline of the current status of CTP imaging and also focuses on disparities between static and dynamic CTPs for the evaluation of myocardial blood flow.

Genetic heterogeneity is a well-known characteristic of MM. Two broad subtypes, Hyperdiploid MM (>46) and Non Hyperdiploid MM (≤46), are defined by chromosome number and are each associated with a distinct prognosis. However, karyotype in MM is informative in no more than one-third of newly diagnosed cases. DNA flow cytometry has given excellent results in the quantification of the cell DNA content. Furthermore, the combined DNA and cytoplasmic Immunoglobulin (DNA/cIg) flow cytometric analysis offers a number of distinct advantages in the study of MM compared to other assays. The relative quantification of cIg is feasible even for cases of non-secreting MM, the characterization of the ploidy of that clone, or even the identification of more than one abnormal clone in the same monoclonal population based on differential DNA content.480 patients that met the criteria for symptomatic or progressive MM were enrolled to the Total Therapy (TT) 3A & B protocols as previously published. The number of distinct DNA ploidy clones (NC) found on DNA/cIg analysis, their percentages and their respective DNA Index (DI) and cIg Index (cIgI), and percentage of cells in S phase, were evaluated alone and in relevance with known powerful prognostic parameters as previously published (Table 1). A DI between 0.99 and 1.01 referred to diploidy, lesser than 0.99 to hypodiploidy and more than 1.01 to hyperdiploidy. Cox proportional hazards regression was used to perform univariate and multivariate analysis of the various prognostic factors for overall survival (OS) and progression-free survival (PFS).Of the total cohort of TT3 patients, 98% had DNA/cIg flow cytometry done on initial diagnosis. In 28%, no clone was identified; in 22% one clone, in 37% two clones, in 13% three clones and in 0.5% four clones were identified. Of 342 patients with at least one cell clone, hyperdiploidy was the feature of the dominant clone in 49% (169/342), diploidy in 42% (147/342) and hypodiploidy in 8% (26/342). The median values for DI and cIgI were 1.01 (0.72–2.02) and 3.4 (1.0–22), respectively. In the univariate analysis for OS, NC was highly significant (p<0.001, HR=1.32). The characterization of the ploidy of the dominant clone by DNA/cIg did not achieve statistical significance (p=0.172, HR=1.29). Nevertheless, when the DI of this clone was evaluated as a continuous numerical variable, DI>1 was statistically significant (p=0.021, HR=0.65). The same was also true for the cIgI of the dominant clone (p=0.019, HR=0.74). Regarding PFS, NC (p=0.005, HR=1.23), diploidy of the dominant clone (p=0.042, HR=1.40), the DI>1 of the dominant (p=0.006, HR=0.63) and the secondary (p=0.031, HR=1.58) clone as well as the cIgI of the dominant clone (p=0.037, HR=0.81) were statistically significant. In the multivariate analysis regarding OS, the NC was able to enter both models with and without GEP (p=0.007, HR=1.26 and p=0.002, HR=1.29 respectively). Regarding PFS, NC yielded similar results (p=0.054, HR=1.15 and p=0.013, HR=1.19 for the GEP including and non-including model respectively). Implementation of GEP and DNA/cIg was able to identify 3 distinct prognostic groups in hyperdiploidy both for OS and PFS (Figure 1).Hyperdiploidy is the most common ploidy status in MM. The level of cIg production has a prognostic impact in MM. Clonal heterogeneity as portrayed by the NC in DNA/cIg is a major prognostic factor in MM. When DNA/cIg is combined with GEP in hyperdiploid cases, it is able to stratify them into three distinct prognostic groups.No relevant conflicts of interest to declare.

Dexamethasone remains a key component of myeloma therapy. We previously showed that expression levels of the nuclear glucocorticoid receptor NR3C1 were associated with OS and PFS in patients treated on Total Therapy 3 (TT3). Post relapse survival (PRS) is an important component of OS following initial PFS. In this study we investigate the effect of NR3C1 expression levels at baseline (BL) and at relapse (RL) on OS, PFS and PRS for patients treated on Total Therapy 2 (TT2).TT2 was a randomized phase-III trial evaluating the impact of the up-front addition of thalidomide (T) to a multi-agent chemotherapy and high-dose melphalan program supported by tandem autotransplants. Between October 1998 and February 2004, 668 patients with newly diagnosed progressive or symptomatic multiple myeloma up to age 75 were enrolled. 351 patients had gene expression profiling (GEP) obtained at BL and 121 had GEP data obtained at RL. There was no significant difference in OS, PFS or PRS between patients with or without GEP data at BL or at RL. This analysis is based on the cohort of patients with GEP data with a cut-off date of April 22, 2011. OS and PFS were measured from the time of initiation of protocol-based therapy while PRS was measured from the initiation of salvage therapy.Among patients randomized to the control arm (-T), OS improved progressively with the transition from lower to middle to upper NR3C1 tertiles. No such difference was noted in the experimental group with T (+T). Examining treatment arms within NR3C1 expression tertiles showed significant benefit from T in both OS and PFS among patients presenting with lower tertile expression; in the mid tertile, this effect was limited to PFS while such benefit was absent in the top-tertile subgroup. Multivariate analysis accounting for the interaction between NR3C1 expression and T showed that randomization to T and lower tertile NR3C1 expression reduced the hazard of death, while high risk designation by GEP, elevated B2M, elevated LDH, cytogenetic abnormalities and MS subgroup designation all conveyed a higher HR for death. With an overall median PRS of 3.0 years, there was no difference related to the initial treatment randomization or between baseline NR3C1 expression levels. In the context of treatment arms in patients randomized to -T, high- and mid-tertile NR3C1 levels at baseline dramatically improved PRS; such an effect was not observed in +T. We next investigated the implications of NR3C1 levels at relapse on PRS, revealing a significant shortening of PRS with transition from top- to mid- to low-tertile expression. Patients maintaining low NR3C1 levels also at relapse had the shortest PRS, followed by those who lost mid to high expression levels of NR3C1 at relapse, while those with higher than low-tertile levels at relapse enjoyed the longest PRS regardless of NR3C1 expression levels at baseline. Multivariate analysis including data from baseline and relapse as well as accounting for interaction between NR3C1 and T identified GEP high risk status at relapse as the only feature linked to inferior PRS whereas upper tertile expression of NR3C1 conveyed improved PRS.Low expression of NR3C1 at baseline is associated with poor PFS and OS in patients treated on the control arm of TT2. This confirms our previously reported findings in TT3. Addition of T overcomes the poor OS in patients with low NR3C1 expression. Low expression of NR3C1 at relapse correlated with poor PRS. This study indicates that patients with low NR3C1 expression levels at baseline benefit from the addition of T and offers a scientific rationale for NR3C1 gene expression level testing. Future trials, that include thalidomide or lenalidomide in their treatment regimen, will have to take NR3C1 expression levels into account.Shaughnessy: Myeloma Health, Celgene, Genzyme, Novartis: Consultancy, Employment, Equity Ownership, Honoraria, Patents & Royalties. Barlogie:Celgene: Consultancy, Honoraria, Research Funding; IMF: Consultancy, Honoraria; MMRF: Consultancy; Millennium: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy; Novartis: Research Funding; NCI: Research Funding; Johnson & Johnson: Research Funding; Centocor: Research Funding; Onyx: Research Funding; Icon: Research Funding.

Pom is a third generation immunomodulatory drug (IMiD) which has demonstrated safety and efficacy in RRMM with prior exposure/resistant to other IMiDs and bortezomib. This is the first report on the UARK Pom compassionate use experience in RRMM. Methods: First cycle Pom was given at 4mg orally Days 1–21 every 28 days; dexamethasone (DEX) was given to 9/23 patients at doses varying from 12 to 40 mg on schedules ranging from Days 1–4, weekly, twice a week, or three times a week. In the absence of at least PR, Pom dose was escalated to 5mg. 1patient also received bortezomib and 1 patient received bortezomib and cytoxan. Cox regression modeling was employed for univariate and multivariate analyses, whereas Kaplan-Meier curves were used for overall survival (OS) and progression free survival (PFS). Results: 23 patients with RRMM were enrolled. Baseline characteristics included age >=65yr in 43%, ISS stage >=II was seen in 78% of patients, cytogenetic abnormalities (CA) within 6 months in 80%, and GEP-defined high risk in 41% of patients. 22/23 patients (96%) had prior autologous stem cell transplant. 19/23 patients (83%) had at least 2 transplants. All 23 patients had disease progression after having received regimens containing bortezomib, thalidomide, lenalidomide, melphalan and steroids. At least 1 cycle of treatment was administered to all 23 patients enrolled, 52% of patients received >1 cycle of treatment and only 13% received =>5 cycles. 10 patients (43%) discontinued therapy primarily due to progression or death. 5/23 (22%) patients achieved PR, 57% had stable disease. A trend towards PFS benefit was observed in patients receiving cycle 2 (HR=0.30, p=0.215) on univariate analysis and multivariate analysis (HR=0.40, p=0.48) after adjusting for GEP-defined risk status (HR=2.69, p=0.16). Most common toxicities, counting all toxicities (>=grade 3) were: thrombocytopenia (70%), leukopenia (61%), anemia (43%), hypophosphatemia (35%) and hypokalemia (26%). Overall and progression- free survival at 12 months were 52% and 30%, respectively. Conclusions: Pom demonstrates anti-myeloma activity in this advanced RRM population, especially in a sub-population with GEP-defined low-risk disease.Barlogie: Celgene: Consultancy, Honoraria, Research Funding; IMF: Consultancy, Honoraria; MMRF: Consultancy; Millennium: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy; Novartis: Research Funding; NCI: Research Funding; Johnson & Johnson: Research Funding; Centocor: Research Funding; Onyx: Research Funding; Icon: Research Funding.

CFZ is an epoxomicin derivative with ability to irreversibly inhibit proteosomes. It has been shown in preclinical and early clinical studies to have activity in newly diagnosed as well as RRMM. We have previously reported on the UARK compassionate use phase II study of CFZ which allowed for the addition of other anti-MM drugs in RRMM. We are now presenting data with 7 additional patients and longer follow-up, with data cut-off on August 9 2011. Methods: All patients with relapsed or resistant refractory multiple myeloma were eligible for the trial. First cycle CFZ was given at 20mg/m2 IV day 1, 2, then 27mg/m2 IV days 8, 9, 15, 16 every 28 days; 4mg of dexamethasone (DEX) was given with each CFZ dose. In the absence of at least PR, CFZ dose was escalated to 36 mg/m2 IV and DEX increased to 20mg. Additional anti-myeloma drugs were added Cycle 2 onwards in absence of PR. 16-day continuous infusion cisplatin (3–5 mg/m2/d) and doxorubicin (1.5–3 mg/m2/d) were commonly added from Cycle 2 onwards, along with other novel agents. Cox regression modeling was employed for overall survival (OS) and progression free survival (PFS). Results: 81 patients with RRMM were enrolled. Baseline characteristics included age >=65yr in 32%, ISS stage >=II was seen in 72% of patients, cytogenetic abnormalities (CA) in 68%, and GEP-defined high risk in 53% of patients. 77 patients had prior autologous stem cell transplant. 63 patients (78%) had at least 2 transplants. All 81 patients had received regimens containing bortezomib, thalidomide, lenalidomide, melphalan or steroids. At least 1 cycle of treatment was administered to all 81 patients enrolled, 69% of patients received >1 cycle of treatment and only 19% received >5 cycles. 71 patients (88%) discontinued therapy primarily due to progression, death or toxicity. 5% patients achieved nCR/CR/sCR, additional 19% patients had stable disease. OS benefit was observed in patients receiving >= cycle 3 (HR= 0.40, p=0.006) on univariate analysis and multivariate analysis (HR=0.09, p<0.001) with adjustment for GEP-defined risk status. Most common toxicities, counting all toxicities (>=grade 3) were thrombocytopenia (84%), anemia (77%), leukopenia (73%), hypophosphatemia (58%), hypokalemia (27%) and fatigue (25%). Grade 1–2 peripheral neuropathy (PN) was present at baseline in 53%, >grade 3 PN was observed in 7% (6/81) after cycle 1, whereas >grade 3 PN was observed in 8% (1/12) >5 cycles.OS and PFS at 12 months were 41% and 5%, respectively (Figure 1). Conclusions: The data presented herein, confirm and extend the previously reported results on CFZ demonstrating anti-myeloma activity and clinical benefit, alone and in combination with other agents, in our heavily pre-treated RRMM population. Surprisingly, worsening or new PN was not observed in majority of patients. Utilizing the novel proteasome inhibitor CFZ in combination with other anti-MM agents on a compassionate basis afforded us the opportunity to make observations regarding potential clinical synergy of particular combinations. In particular, combination of CFZ-DEX with lenalidomide and vorinostat has shown promise in a subset of RRMM patients.Barlogie: Celgene: Consultancy, Honoraria, Research Funding; IMF: Consultancy, Honoraria; MMRF: Consultancy; Millennium: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy; Novartis: Research Funding; NCI: Research Funding; Johnson & Johnson: Research Funding; Centocor: Research Funding; Onyx: Research Funding; Icon: Research Funding.

Despite availability of novel agents, many MM patients still relapse and require salvage interventions. In the Arkansas program, we have attempted to procure initially sufficient hematopoietic precursor cells, for use in high-dose therapy salvage regimens once phase I-II trials have been exhausted. We are reporting on the efficacy in terms of response rate, EFS and OS of ARMM patients receiving S-BEAM.S-BEAM comprised standard BEAM (carmustine 300 mg/m2 on day 1, etoposide 200 mg/m2 days 1–4, cytarabine 400 mg/m2 days 1–4, melphalan 140 mg/m2 on day 5) with the addition of cisplatin (10-12.5mg/m2/d CI × 5d), bortezomib (1.3-1.5mg/m2 on days 1 + 4), thalidomide (100-200mg/d for 5 days) or lenalidomide (25-100mg/d for 5 days), DEX (40-100mg/d for 5 days) plus rapamycin (3mg d1, 1mg d2-5). Statistical methods included Cox regression modeling using significance level 0.05 and Kaplan-Meier methodology for all figures. Comparisons within figures were made using the log-rank test.The characteristics of 147 patients treated included prior transplant (Tx) in 67% (2Tx, 29%; =>3Tx, 11%), and prior exposure and resistance in virtually all patients (92%) to bortezomib, thalidomide, lenalidomide applied in VTD, VRD or with chemotherapy VTD-PACE. Pre-S-BEAM high-risk features included low albumin (<3.5g/dL; 66%) high B2M (>=3.5mg/L; 32%), high LDH (>=ULN; 44%), and presence of cytogenetic abnormalities (CA) in 70%. Clinical outcomes included at least PR in 62% including 48% with n-CR and 29% with CR. Two-year estimates of EFS and OS were 29% and 33%; TRM within 60 days was 3%. At 4 years, 23% remain alive and 15% event-free. Independently significant variables affecting both OS and EFS adversely included, in a model without GEP, high B2M (>5.5mg/L), high LDH (>=ULN), low hemoglobin (<10g/dL) and CA, whereas achieving PR improved survival. Based on R2-driven independent adverse variables, B2M, LDH and CA were linked to poor outcomes, with 1-year estimates of OS/EFS of 83%/69% with 0, 63%/52% with 1, 25%/9% with 2, and 13%/0% with more than 2 high-risk parameters. Gene expression profiling (GEP)-defined high-risk was present in 55% (70 genes, R70) and in 47% (80 genes, R80); delTP53 was noted in 21% and Proliferation Index (PI) score >=10 in 42%. When GEP data were included in a subset of 103 patients, high-risk designation, high LDH and age >=65 were identified on the basis of highest R2 values (49% for OS, 41% for EFS). Among 28 patients lacking any of these 3 features, 1-year OS/EFS was 83%/67%, with 1 variable (n=36) 53%/38%, with 2 (n=31) 22%/6% and with 3 (n=8) 0%/0% (both P<0.001). Applying a cut-off of 2 adverse variables, the 60 patients with 2 or fewer enjoyed 2-year OS of 49% and EFS of 48%, as opposed to 7% and 4%, respectively, among the remaining 36 patients with more than 2 risk features.S-BEAM provides effective salvage therapy in ARMM with 60-day TRM of 3% and prognostic factor-dependent survival expectation. We are currently evaluating S-BEAM earlier in the disease course, with PAC-MED as induction prior to and as consolidation after S-BEAM in high-risk myeloma. Overall survival by number of non-GEP risk factors (B2M, LDH, CA), selected based on maximum R2 value (38% for OS, 33% for EFS) Overall survival by number of risk factors (age, LDH, GEP high-risk), selected based on maximum R2 values (49% for OS, 41% for EFS) No relevant conflicts of interest to declare.

We have previously reported on the roles of VTD (bortezomib, thalidomide, dexamethasone) maintenance components in Total Therapy 3 (TT3), noting the important contributions of cumulative dosing of VTD components for overall survival (OS) and, especially, a detrimental effect of pre-mature drug discontinuation (PMDD) in the case of V (van Rhee et al: Blood 2010). Here we examine in a similar fashion the roles of T, D and I in TT2 toward OS.TT2 accrued a total of 668 patients, of whom 323 were randomized to the T arm and the remainder to the control arm. The cumulative dosing effects of T and D during induction, transplantation, consolidation and maintenance phases were evaluated while, in the case of I, its contribution in the maintenance phase only was examined. We also examined outcomes according to the number of induction and consolidation cycles applied prior to and after transplantation and according to the number and timeliness of administering both transplant interventions. In order to utilize the entire patient population, post-baseline treatment interventions and responses were treated as time-dependent variables. Multivariate analyses were performed to examine the collective impact on OS and EFS of baseline characteristics, treatment compliance and type of and time to salvage therapy.Randomization to T prolonged both OS and EFS, as did timely completion of second transplant and first cycle of consolidation chemotherapy. During most protocol steps, cumulative dosing of both D and T benefited OS or EFS while pre-mature discontinuation of D shortened both OS and EFS; this was upheld in multivariate analyses, whether or not GEP data were included and also when time to salvage therapy was considered. D dosing prior to relapse was an independently favorable variable for post-relapse survival, which also was longer when disease progression did not occur within 2 years. D's dosing role was apparent only in the subset of patients presenting with lowest tertile gene expression levels of the glucocorticoid receptor gene, NR3C1.In addition to confirming well-established variables (beta-2-microgobulin, lactate dehydrogenase, cytogenetic abnormalities, gene expression profiling [GEP]-derived risk and molecular subgroups), randomization to T and timely applications of second transplantation consolidation and maintenance phases favorably affected outcomes. We conclude that D dosing, especially in low NR3C1-level myeloma, is an important treatment component that favorably affects global survival.No relevant conflicts of interest to declare.

High-risk MM remains a very difficult clinical challenge despite advances in therapy for the majority of patients who have benefited from the use of high-dose therapies and novel agents. Recognizing that MM from the outset represents a genomically highly complex malignancy with even further accelerated acquisition of mutations with every further relapse, we have tried to develop multi-agent combinations employing drugs with efficacy in other high-grade tumors such as large cell lymphomas and incorporated novel agents as well. Eighty-four patients with AHRMM were given PACMED comprising cisplatin (15-25mg/m2 CI × 3d), cytarabine (1.0-1.5g/m2/d × 3), cyclophosphamide (1.0-1.5g/m2/d CI × 3), mesna (1.0-1.5g/m2/d CI × 3), etoposide (0.3-0.5g/m2/d × 3) and DEX (40-100mg/d × 3); additional agents included bortezomib (1.0-1.6mg/m2 on days 1 + 4), thalidomide (100-200mg/d × 4d) or lenalidomide (25-100mg/d × 4) and rapamycin (3mg d 1, 1mg d 2–4) with or without HPC boost. Statistical methods included Cox regression modeling for OS and EFS, along with Kaplan-Meier methodology for survival and cumulative incidence plots. Survival comparisons were made using the logrank test.Baseline characteristics included age >=65 in 18%, B2M >=3.5mg/L in 68% and >5.5mg/L in 38%, CRP >=8mg/L in 60%, LDH >=ULN in 57%, and cytogenetic abnormalities (CA) in 62%. Gene expression profiling (GEP)-defined high-risk (70 genes, R70; 80 genes, R80) was present in 80% and 71%; PR (Proliferation), MF and MS subtypes were present in 44%, 27% and 14%. Prior transplants (Tx) had been given to 96%, including 40% who received 2Tx, 25% with 3Tx and 14% with >3Tx. PR was achieved by 29%, including 14% n-CR and 8% CR. 1-year estimates of OS and EFS were low at 13% and 8%, and median durations were 5 and 3 months. Increased age and high LDH were the only baseline characteristics adversely affecting both OS and EFS. The 29 patients with neither of these risk factors experienced 1-yr OS/EFS rates of 31%/17%; the corresponding values with 1 risk factor (n=47) were 5%/4% and with both risk factors (n=8) 0%/0%. Single cycle PACMED provides only transient tumor control in this heavily pretreated population with 80% displaying GEP-defined high-risk and 62% CA, as a manifestation of end-stage MM. We are currently evaluating repeated cycles of PACMED earlier in the disease course in high-risk MM, in the context of a Super-BEAM transplant regimen.No relevant conflicts of interest to declare.

While the prognosis of patients with MM has been drastically improved with the introduction of novel agents into the treatment armamentarium, relapse management remains a difficult task, especially in the post-transplant and high-risk MM setting, as defined by the presence of cytogenetic abnormalities (CA) and gene expression profiling (GEP).We have explored the efficacy and safety of SB in 95 patients with MM. The regimen comprised BCNU at 300mg/m2 on day 1, etoposide 200mg/m2 on days 1-4; cytarabine 400mg/m2 on days 1-5; melphalan 140mg/m2 on day 5 plus: bortezomib 1.0-1.3mg/m2 on days 1+4, thalidomide 100-200mg on days 1-5, dexamethasone 20-40mg days 1-5, cisplatin 10-12.5mg/m2/d by continuous infusion on days 1-5, rapamycin 3mg on day 1 and 1mg on days 2-5; followed by autotransplant (AT) on day 6.Patient characteristics included age >=65, 19%; LDH>ULN, 43%; CA, 67%; GEP high-risk, 44%; GEP MF, 15%; GEP delTP53, 22%; prior AT, 75% including 46% with 2AT and 12% with 3 AT. CR and near-CR status was documented in 50%; TRM occurred within 100 days in 6%. Three-year estimates of overall survival (OS) and event-free survival (EFS) were 34% and 18%; OS/EFS were superior: (a) without CA – 60%/50% versus 15%/5% with CA (p=0.003/0.0005); (b) with GEP low-risk – 55%/20% versus 10%/15% with high-risk MM (p=0.009/0.01); (c) with GEP Hyperdiploidy and Low Bone disease molecular subgroups – 70%/35% versus 20%/10% in the remainder (p=0,001/0.002); and (d) absence of progression prior to SB – 52%/35% versus 16%/5% for the remainder (p=0.002/0.0006). Univariately significant adverse variables for OS and EFS included low albumin, B2M>=3.5mg/L, CA, GEP high-risk and relapse just prior to SB, of which B2M, CA and pre-SB survived on multivariate analysis for the 78 patients with all variables; among the 57 with GEP data, OS was inferior with GEP high-risk MM (HR=3.55, p=0.007) whereas EFS was inferior with high LDH (HR=3.44, p=0.004), CA (HR=2.79, p=0.02) and pre-SB relapse (HR=2.94, p=0.035).We conclude that SB is a safe salvage regimen that was well-tolerated for the majority in the outpatient setting. Although beneficial to patients lacking CA and GEP high-risk status, the poor outcome also with SB in the presence of these adverse features emphasize the urgent need to discover agents/strategies effective in this setting.van Rhee: Genzyme Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Significant advances have been made in the treatment of myeloma with the introduction of thalidomide, its analogue, lenalidomide, and the proteasome inhibitor bortezomib. While these new drugs have improved the outcome of patients with myeloma, the disease still remains incurable. Effectiveness of upcoming new therapies will need to be assessed in the context of anticipated outcome with the currently available therapies. However, given the rapid pace of development over the past decade, outcome of patients who have relapsed on the new therapies remain unclear.In order to further study this group of patients, we undertook a study of patients who have relapsed on or are refractory to one of the IMiDs (thalidomide or lenalidomide) as well as bortezomib. A total of 300 cases from 8 sites in the US, 5 sites in Europe and one site in Asia were identified for this study. Enrolled patients had relapsed and refractory multiple myeloma, per the EBMT or IMWG response criteria, after at least 2 prior treatments. Patients were refractory to bortezomib, defined as having no response on a prior bortezomib-containing regimen or experiencing disease progression within 60 days of a bortezomib-containing regimen. Patients also should have relapsed, refractory, intolerant, and/or ineligible in the opinion of the investigator, to other therapies, including an IMiD (thalidomide or lenalidomide). Clinical and laboratory data pertaining to the time of diagnosis and from the time of individual relapses were obtained from the clinical records. The date patients satisfied the above entry criteria was defined as time zero.The current analysis includes the first 119 patients with complete data available. The median age at initial diagnosis was 59 years (range, 31-86 yr); 71% were males. The ISS stage distribution at diagnosis was 33%, 39% and 28% for stages 1, 2, and 3 respectively. 19 patients (37%) had high risk disease by FISH [t(4;14), t(14;16), del17p] or by cytogenetics [del 13, hypodiploidy]. The median time from diagnosis to time zero was 3.8 yrs (range 0.2-18.7 yr) and the median reported lines of therapy before time zero was 2. 74% patients had at least 1 autologous stem cell transplant prior to becoming eligible for the study. Following time zero, 77 (65%) pts had a treatment recorded, including an autologous SCT in 21 (18%), with the treatment regimen starting at a median of 1 month after time zero. A variety of treatment regimens were utilized beyond time zero (median=1; range 0-7). Thirty-two (27%) patients had a response any time following time zero, and only 8 had a subsequent response. Response to the first treatment, or supportive care for patients not treated, recorded following time zero included minor response or stable disease (n=14; 12%), PR (n=17, 14%), and VGPR or better (n=6, 5%). Patients treated with SCT had a higher rate of PR or better compared to patients receiving other treatments (85%; 17/20 vs. 26%; 15/57). In a multivariate analysis, the only significant predictor of a PR or better after time zero was younger age (<60 yrs). The median overall survival (OS) and event free survival (EFS) were 6 mos (95% CI, 4-7 mos) and 1 month (95% CI,1-2 mos) respectively. In a multivariate analysis normal creatinine predicted for a better overall survival and having an IgG M protein type predicted for better EFS. A complete analysis from all 300 patients will be presented at the meeting.This study confirms the poor outcome of patients once they become relapsed and refractory to agents that have become the mainstay of myeloma therapy. The findings highlight the incurable nature of the disease and urgent need to develop newer effective therapeutic agents for this group of patients, who currently do not have effective treatment options.Kumar: CELGENE: Research Funding; MILLENNIUM: Research Funding; BAYER: Research Funding; GENZYME: Research Funding; NOVARTIS: Research Funding. Jagannath:Merck: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees. Laubach:Novartis: . Palumbo:Ortho Biotech, Janssen-Cilag: Honoraria; Celgene: Honoraria, Speakers Bureau. Richardson:Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Johnson and Johnson: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Keryx: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. San Miguel:Millennium: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Siegel:Celgene: Speakers Bureau; Millennium: Speakers Bureau. Sonneveld:Janssen-Cilag: Honoraria. Durie:Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees.

TT3-I imparted high CR rates and superior overall survival (OS) and event-free survival (EFS). Bortezomib pharmaco-genomic studies, performed concurrently, revealed that gene expression profiling (GEP) changes 48hr after a bortezomib test-dose had major prognostic significance, which we wished to validate in TT3-S. The purpose of this work is to compare clinical outcomes among the 303 TT3-I and 177 TT3-S patients.Our MM data base was scrutinized for patient characteristics and outcomes of the 2 cohorts in terms of CR rates and duration, as well as OS and EFS, in the context of major prognostic variables (cytogenetic abnormalities (CA), B2M, LDH, GEP risk).Patients in the 2 studies were comparable except for a higher incidence of several adverse features in TT3-S: albumin <3.5g/dL in 45% v 25% (p<0.001), B2M >=3.5mg/L in 57% v 45% (p=0.012) and GEP-defined high-risk in 22% v 15% (p=0.035). Outcome comparisons for TT3-S v TT3-I were almost identical: 3-year estimates of OS 80% v 82%, EFS 81% v 77%, sustained CR 61% v 62%; in GEP low-risk/no CA subgroup: OS 94% v 91%, EFS 90% v 87%, sustained CR 98% v 94% (Figure 1a); GEP low-risk/CA subgroup: OS 81% v 79%, EFS 81% v 74%, sustained CR 86% v 90%; GEP high-risk/no CA subgroup: OS 70% v 82%, EFS 75% v 46%, sustained CR 75% v 30%; GEP high-risk/CA subgroup: OS 48% v 41%, EFS 52% v 38%, sustained CR 60% v 55% (Figure 1b). None of the Kaplan-Meier plots for these GEP-risk/CA constellations were different between TT3-S and TT3-I.We have validated the remarkable success of the TT3 principle in low-risk MM, whereas high-risk disease deserves novel strategies as being pursued in TT5 with dose-dense and less dose-intense therapies.van Rhee: Genzyme Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Cytogenetic abnormalities (CA) can be detected in one-third of newly diagnosed patients with multiple myeloma (MM), reaching virtually universal presence at the terminal disease stage. According to both histopathological and radiological findings, bone marrow growth patterns are either diffusely infiltrative or characterized by focal lesion (FL) growth, around which typically osteolytic bone destruction develops. The detection of CA at diagnosis confers a poor prognosis, and the sustained suppression of CA is critical for long-term survival. Applying MRI examinations in virtually all newly diagnosed patients prior to protocol-based therapy, FL have been detected in ~80% of patients and impart, along with the detection of CA on random bone marrow examination from the posterior iliac crest, shorter event-free and overall survival. Such MRI-FL harbor viable MM cells often with CA, persist in clinical CR for a median of 1–2 years, eventually resolve in 60% and constitute sites of relapse often without M-protein secretion, collectively suggesting an important role of FL in both disease manifestation and progression. We reviewed our data base of 1202 patients enrolled in Total Therapy (TT) protocols for entries of CT-guided fine needle aspirations (FNA) from MRI-defined FL submitted to cytogenetic analysis at baseline and on any occasion prior to first transplant. We identified 320 patients with cytogenetic information on both randomly sampled (RS) and FNA from FL. Congruency between FL and RS examinations was documented in 71% including 53% without detectable CA and 18% with CA in both sites; 14% had RS-CA without FL-CA and 16% had FL-CA without RS-CA. The overall RS-based CA frequency of 31% was identical to the 31% when all 1202 RS prior to transplant were considered. The relative distribution of standard prognostic factors was similar among the 4 RS-FL constellations in terms of B2M (>5.5mg/L), albumin (<3.5g/dL) and creatinine (>=2mg/dL) levels. The frequency of gene expression profiling (GEP)-defined risk (determined on RS) was 15% among196 patients with concurrent RS and FL sampling and thus virtually identical to the 14% incidence among all 620 subjects with RS information only. However, 53% of the subgroup exhibiting both RS-CA and FL-CA had high-risk disease compared to only 6% in the remainder (p < 0.001). Analysis of overall survival according to the 4 RS-FL CA constellations revealed an adverse impact only of the concomitant presence of RS-CA and FL-CA (Figure), whereas the presence of either RS-CA or FL-CA individually was prognosis-neutral, an observation confirmed by multivariate analysis (HR of 3.27, p<0.001). The much higher frequency of GEP-defined high-risk in patients with concomitant RS-CA and FL-CA requires further study, including the examination by GEP of MM-cells procured from both RS and FL. Figure: Survival outcomes of all patients enrolled in combined Total Therapy protocols according to the presence of cytogenetic abnormalities (CA) in paired random (RS) or focal lesion (FL) sites. Comparisons a v d, p<0.0001; b v d, p<0.0001;c v d, p=0.0063 Figure:. Survival outcomes of all patients enrolled in combined Total Therapy protocols according to the presence of cytogenetic abnormalities (CA) in paired random (RS) or focal lesion (FL) sites. . / Comparisons a v d, p<0.0001; b v d, p<0.0001;c v d, p=0.0063