Diagnosis Of Plasma Cell Disorders Research Articles

Artificial Intelligence Enabled ECG Interpretation Informs Outcomes after Autologous Transplantation for Multiple Myeloma

High dose chemotherapy followed by autologous hematopoietic cell transplantation (auto HCT) is a standard therapy for patients with plasma cell disorders (PCD). A barrier to improving candidate selection for auto HCT is appraisal of risk for transplant related complications. Electrocardiography (ECG) is a standard pre-HCT test to evaluate the potential for arrhythmia and structural heart disease. We hypothesized that an artificial intelligence (AI) based interpretation of ECG waveform data (AI-ECG) could enhance risk prediction for cardiac-specific and other outcomes following auto HCT for patients with PCD. To test this hypothesis, we used several AI-ECG tools developed using a deep-learning based approach that were trained to predict comorbidity (Attia et al, Lancet 2019 & Grogan et al, Mayo Clin Proc 2021). Model outputs include a scaled prediction value indicating increasing risk for atrial fibrillation/flutter (AF), reduced ejection fraction (EF), or cardiac amyloidosis. We evaluated this tool in 9,225 ECGs obtained from 849 patients (median 6 ECGs/patient, inter-quartile range: 3-12) who underwent first or subsequent auto HCT at Memorial Sloan Kettering Cancer Center between 2016-2022 and who had a diagnosis of multiple myeloma (N = 810), amyloidosis (N = 37), or other PCD (N = 2). The endpoints were to determine whether baseline AI-ECG prediction of AF risk correlated with peri-transplant AF events, and to explore whether model outputs correlated with survival and other cardiac clinical outcomes. The mean age of patients was 61.0 years (range 23.7 - 81.2) and median follow up was 2.7 years post auto HCT. Contributing cardiovascular risk factors included a prior history of AF (N = 101, 11.9%), coronary or cerebrovascular disease (N = 95, 11.2%), and diabetes mellitus (N = 98, 11.5%). Reduced dose melphalan (< 200 mg/m 2) was administered in 26%. The HCT-comorbidity index (HCT-CI) was high risk (≥3) in 52.7%. The one-year overall survival and progression-free survival in the whole cohort was 94% (95% confidence interval (95% CI): 92 - 95%) and 86% (84 - 89%), respectively. Among patients not in AF at pre HCT evaluation, the 90-day cumulative incidence of AF was 5.6% (4.2 - 7.3%). In univariable competing risk regression, baseline pre HCT AI-ECG appraisal of AF risk was strongly correlated with incidence AF in patients who were in sinus rhythm before HCT (hazard ratio (HR): 25.1, 95% CI: 11.7 - 53.7, p < 0.001). In a multivariable model adjusting for patient age and HCT-CI, AI-ECG AF predicted risk remained associated with incidence of post HCT AF (HR: 13.4, 95% CI: 5.9 - 30.4, p < 0.001). Considering a decision threshold identified during original model training, AI-ECG predicted AF events with an accuracy of 75% (Mcnemar's p < 2 x 10 -16). The precision, recall, and F1-score were 0.94, 0.77, and 0.85, respectively. AI-ECG predicted age correlated highly with actual patient age (Spearman rho = 0.59, p < 2 x 10 -16). Amyloid risk scores were highly correlated with a known clinical history of amyloidosis (median 0.45 versus 0.05, Wilcoxon rank-sum p < 0.001). Patients with EF < 50% had greater prediction scores for cardiomyopathy compared to patients with normal EF (median 0.23 versus 0.01, Wilcoxon rank-sum p <0.001). In univariable analysis, increasing AI-ECG predicted age (HR 1.02, CI: 1.003 - 1.04, p = 0.02) and predicted AF risk score (HR: 3.2, CI: 1.4 - 7.2, p = 0.006) were associated with risk for death, whereas predicted amyloid score and predicted low EF were not associated with decreased survival. In multivariable analysis of all patients that considered patient age, hematopoietic comorbidity index, and remission status at HCT, increasing predicted AF score trended towards association with increased risk for death (HR: 2.3, 95%CI: 1.0 - 5.5, p = 0.059). Predicted AF score correlated highly with the HCT-CI and patient age. Finally, we examined whether risk prediction for low EF correlated with peri-HCT fluid overload (FO) defined by absolute weight gain. The incidence of ≥ 10% weight gain (grade 2 FO) and ≥ 20% weight gain (grade 3 FO) at 180 days post HCT was 7.4% (95% CI: 5.8%, 9.3%) and 1.0% (95% CI: 0.5%, 1.8%), respectively. Predicted low EF was not associated with development of either grade 2 or grade 3 FO in this population. In summary, AI-ECG predicts episodes of AF in patients undergoing auto HCT for PCD and may augment transplant risk appraisal when considered in conjunction with other measures of comorbidity.

Clonal Bone Marrow Plasma Cells Are Common in Patients with Vexas Syndrome

Introduction Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant plasma cell disorder. Its prevalence increases with age, reaching 5.3% at 70 years and older. MGUS progression rate to multiple myeloma (MM) or lymphoplasmacytic malignancies is about 1% per year. Patients with autoimmune diseases are at increased risk for developing MGUS and MM. VEXAS ( vacuoles, E1 enzyme, X-linked, autoinflammatory and somatic syndrome), an autoinflammatory disorder caused by somatic mutations in ubiquitin-activating enzyme, UBA1 gene, has been associated with plasma cell disorders, specifically MGUS, but the rate of progression is unknown. Cyclin D1, important in cell cycle progression, is regulated by ubiquitin-proteasome mediated degradation, and deregulated cyclin D1 degradation appears to be responsible for the increased levels of cyclin D1 in several cancers. We aim to assess marrow characteristics of plasma cell disorders (MGUS and MM) in VEXAS, and the impact of a defective UBA1 gene product on protein expression of cyclin D1. Methods We assessed 28 patients with VEXAS for the presence of plasma cell disorders, and studied the clinical and laboratory characteristics of those with clonal plasma cells (PC) in the marrow. Bone marrow biopsies and aspirates were evaluated by morphology, immunohistochemistry (IHC) dual staining CD138/cyclin D1, dual staining MUM-1/CD20), in situ hybridization (Kappa and Lambda light chains) and flow cytometry (FC) using antibodies for CD45, CD19, CD20, CD38, CD138, CD56, CD27, CD81, and cytoplasmic Kappa and Lambda immunoglobulins. Serum free kappa and lambda light chains, IgG, IgM, and IgA, and level of M paraprotein by serum protein electrophoresis with immunofixation were obtained. Fluorescent in situ hybridization (FISH) analysis for MM was performed in most patients with clonal PCs. Results Patients' characteristics are shown in Table 1. Eight out of 28 (28.6%) patients with VEXAS syndrome, all males, had clonal plasma cells in their bone marrows: 3 MGUS, and 5 MM (3 smoldering, SMM; 2 active MM). Median age at diagnosis of plasma cell disorder was 69.5 years (range 60-75). All patients had pathogenic UBA1 somatic mutations (5 M41T, 1 each with M41V, M41L, and splice). Clinically, monoclonal protein size was small, with no specific selection of the type of M protein. Strikingly, most (7/8) clonal plasma cells showed cyclin D1 expression by IHC (dual immunohistochemical stain cyclinD1/CD138 shows double-positive plasma cells; figure not shown), displaying nuclear immunoreactivity in 6 cases, and cytoplasmic immunoreactivity in 1 case. FC showed positive CD20 expression of clonal plasma cells in 4 cases, dim to negative CD19 expression in 4 cases, variable CD56 (positive in 3 cases, partial positive in 1 case, negative in 2 cases), dim to negative CD27 in 3 cases, dim to negative CD81 in 3 cases. FISH for MM revealed: t(11;14) in 4 cases, gain of 11q (CCND1) in 2 cases (in one case, CCND1 gain was present in addition to t(11;14); in the second case, CCND1 gain was associated with gains of 1q and 17p(TP53). The cyclin D1-negative MM case was negative for t(11;14) but had t(4;14). All cases with t(11;14) were positive for cyclin D1 by IHC (nuclear staining). The one MM case with negative nuclear staining for cyclin D1 but positive cytoplasmic staining, was negative for t(11;14) but had gain of 11q (CCND1).One patient evolved from SMM to active MM after 4 years. No evolution to MM was seen in patients with MGUS with median follow-up of 30 months. Conclusions Patients with VEXAS have a high prevalence of clonal plasma cell disorders. Clonal plasma cells in VEXAS patients are associated with t(11;14), and with nuclear cyclin D1 expression by IHC. Cytoplasmic cyclin D1 staining in the absence or weak nuclear staining was observed with CCND1 gain and absence of t(11;14). Cytoplasmic cyclin D1 expression may be related to lack of cyclin D1 protein degradation by a defective UBA1 gene product. Our results suggest that defective UBA1 and autoinflammation pose an increased risk for developing MGUS or multiple myeloma.

Expert-Level Immunofixation Electrophoresis Image Recognition based on Explainable and Generalizable Deep Learning.

Immunofixation electrophoresis (IFE) is important for diagnosis of plasma cell disorders (PCDs). Manual analysis of IFE images is time-consuming and potentially subjective. An artificial intelligence (AI) system for automatic and accurate IFE image recognition is desirable. In total, 12 703 expert-annotated IFE images (9182 from a new IFE imaging system and 3521 from an old one) were used to develop and test an AI system that was an ensemble of 3 deep neural networks. The model takes an IFE image as input and predicts the presence of 8 basic patterns (IgA-, IgA-, IgG-, IgG-, IgM-, IgM-, light chain and ) and their combinations. Score-based class activation maps (Score-CAMs) were used for visual explanation of the models prediction. The AI model achieved an average accuracy, sensitivity, and specificity of 99.82, 93.17, and 99.93, respectively, for detection of the 8 basic patterns, which outperformed 4 junior experts with 1 years experience and was comparable to a senior expert with 5 years experience. The Score-CAMs gave a reasonable visual explanation of the prediction by highlighting the target aligned regions in the bands and indicating potentially unreliable predictions. When trained with only the new system images, the models performance was still higher than junior experts on both the new and old IFE systems, with average accuracy of 99.91 and 99.81, respectively. Our AI system achieved human-level performance in automatic recognition of IFE images, with high explainability and generalizability. It has the potential to improve the efficiency and reliability of diagnosis of PCDs.

Fatigue in Hematopoietic Cell Transplantation Survivors: Correlates, Care Team Communication, and Patient-Identified Mitigation Strategies

With improved survival after hematopoietic cell transplantation (HCT), the number of individuals at risk for persistent or late effects is increasing. The importance of optimizing HCT survivor health and well-being is mounting. Fatigue is a common post-transplantation symptom that impairs quality of life, yet it remains poorly understood and inadequately addressed. Multiple challenges to addressing fatigue exist, including its multidimensional presentation, multiple (often concomitant) causes, patient-clinician communication barriers, and few highly effective, evidence-based interventions that can be readily implemented. To address these challenges, we sought to better describe the impact and potential causes of fatigue in the post-transplantation setting, fatigue-related communication with clinicians, and the most effective patient-identified mitigation strategies (PIMS) for fatigue. A total of 1703 adult HCT recipients from a single center completed a survey including the Medical Outcomes Survey Short Form-36 (SF-36), PROMIS Fatigue, and other fatigue-related items between July 2017-June 2018. The survey was offered to recipients at their post-transplantation anniversary occurring during this interval. Two independent raters categorized free-text responses about fatigue PIMS. PROMIS Fatigue scores were dichotomized into low (≤55) or high (>55). Associations between high fatigue and participant characteristics and health outcomes were evaluated using the Fisher exact test for categorical variables and the Student 2-sample t test for continuous variables. Among the 1660 respondents with evaluable fatigue scores, 67% underwent allogeneic HCT. The majority of these (n=1588; 96%) had a malignancy, with hematologic malignancy the most common diagnostic category (n=1555; 94%). The median time post-transplantation was 11 years (interquartile range, 4 to 20 years). PROMIS item responses indicate that 44% of patients were at least somewhat fatigued and 37% were at least somewhat bothered by it. The mean fatigue score was 50.2 ± 11; 591 patients (36%) had high fatigue, which was associated with worse SF-36 scores across all domains (General Health, Physical Functioning, Emotional Well-being/Mental Health, Social Functioning, Role Limitation due to Physical Health, Role Limitation due to Emotional Health, Vitality [eg, energy], and Bodily Pain). High fatigue also was associated with self-reported chronic graft-versus-host disease, anxiety, depression and sleep problems. Diagnosis of plasma cell disorder and receipt of an autologous transplant were associated with high fatigue (P=.001). Among the 553 individuals who received an autologous transplant, 226 (41%) had multiple myeloma. Compared with the autologous transplant recipients without myeloma group, those with multiple myeloma were significantly more likely to have high fatigue (109 of 226 [48%] versus 118 of 325 [36%]; P < .01). Twenty percent of the patients with high fatigue did not discuss it with their care team. Among the 89 different reasons provided for not discussing it, the most common was "thought they already knew the answer" (n=21). The 370 survivors with high fatigue who identified at least 1 most effective PIMS generated a total of 639 PIMS. Although the PIMS for fatigue spanned a wide array of strategies, most PIMS were related to sleep/rest (n=192; 30%) or exercise (n=139; 22%). Although fatigue is associated with worse HCT survivor-reported outcomes, it is only sometimes discussed with care teams. Survivors identify specific strategies that are most effective. Given its prevalence and impact, clinicians should promote communication about fatigue, treat underlying causes, and recommend sleep/rest and exercise, recognizing that individualized approaches also may be beneficial.

Serum Free Light-Chain Ratio at Diagnosis Is Associated with Early Renal Damage in Multiple Myeloma: A Case Series Real-World Study.

The serum free light-chain (FLC) ratio is a sensitive tool for the differential diagnosis of plasma cell disorders and is biomarker of multiple myeloma (MM) progression from premalignant conditions. Here, we investigate the potential role of FLC ratio at diagnosis in identifying early renal damage in MM patients and other correlations with clinical, laboratory, and molecular findings. A total of 34 MM patients who had undergone autologous stem cell transplantation were included in this retrospective case series study, and FLC quantification was performed with nephelometric assays. In our study, sFLC ratio was significantly associated with light-chain MM and β-2 microglobulin levels, likely indicating a high disease burden at diagnosis, especially in patients without heavy chain M-protein at serum electrophoresis. Moreover, the sFLC ratio was inversely correlated with glomerular filtration rate, possibly identifying early renal damage in MM patients. Our preliminary results confirm the importance of early sFLC evaluation, especially in patients with the light-chain MM type and low disease burden, to minimize the risk of late renal failure.

Quantitative Cross-Sectional Analyses of Quality-of-Life Outcomes Related to Race, Sex, Age, and Clinical Stage Among Multiple Myeloma Patients at an Urban Center

Introduction. Multiple myeloma (MM) patients suffer from disease symptoms and impact on quality of life (QoL) - a patient's sense of enjoyment, well-being, and ability to carry out activities of daily living. Reports on QoL in MM have focused on clinical trials that usually involve younger patients with adequate performance status (PS), mostly Caucasians. The median age of MM onset is 69 years; advanced age is associated with multiple comorbidities and deteriorating PS. Blacks have twice the incidence of MM compared to Caucasians; they also have a higher risk of dying due to poor healthcare utilization. Here, we explored the multifactorial nature of race, sex, age, and clinical stage in patient reported QoL outcomes using quantitative cross-sectional analyses from a single center in urban setting.Methods. Participants with a diagnosis of plasma cell disorders at various stages: MGUS, smoldering myeloma (SMM), or MM (newly diagnosed, maintenance, relapsed/refractory) were sequentially enrolled for a one-time measurement of QOL outcomes. Consent and study questionnaire were conducted verbally. Participants simply responded ‘yes’ or ‘no’ to nine question prompts outlined in Table 1, followed by verbal reasoning which was transcribed by the interviewer. The questionnaire included three main domains of QoL assessment based on existing literature review and feedback with our patient population. The first is physical symptoms and function (disease-related symptoms, treatment-related adverse events, sexual health and satisfaction with care), the second is mental health (depression, spirituality), and the third is social impact (financial burden, family support). Data were analyzed using chi-square test of independence. Participants will be re-approached for a second interview to determine changes to impact across the same QoL variables over time. The questionnaires validated within the current study will be used for a longitudinal cohort study to investigate whether a greater degradation is observed in one or more QoL domains during a specific time-point of MM disease course.Results. A total of 100 patients (males n=52) were enrolled. Median age was 64 years (IQR 55 - 68); 59 were Caucasian, 34 were Black, and 7 from other racial groups. At the time of interview: 7 were newly diagnosed or receiving induction therapy, 25 were undergoing stem cell transplant (SCT), 22 were on maintenance therapy, 33 were relapsed on salvage therapy, and 13 on no therapy (MGUS/SMM). Regardless of race, age, or sex, patients on therapy felt their QOL was impacted by fatigue (67%), and myeloma symptoms (65%). Black participants reported more fatigue as an impact on their QoL compared to other racial groups, p = .009. Women reported more impact from MM on sexual intimacy, p = .04, and impact from financial burden than male participants, p = .03. Younger patients <60 years old (n=38) reported more impact from treatment-related adverse events, p = .004, disease-related symptoms, p = .02, and dissatisfaction with information received about their disease and/or treatment, p = .004, compared to patients aged >60 years. Not surprisingly, patients with active MM (n=87); newly diagnosed on therapy, those undergoing SCT, or on maintenance, and relapsed disease) reported more MM symptoms p = <.001, and suffered from more fatigue, p = <.02, with higher impact on QoL compared to those with early-stage plasma cell disorders (MGUS, SMM). However, early-stage patients felt more dissatisfaction with information received and uncertainty about what to expect, p = <.001, compared to MM patients receiving therapy. Interestingly, there were no age, sex, race, or clinical stage dependent effects observed from SCT experience, spirituality or religion, and dissatisfaction with cancer care.Conclusions. Patients <60 years were impacted more by disease-related symptoms, treatment-related adverse events, in comparison to patients >60 years. Women felt their QoL was impacted by MM's affect on sexual intimacy and resulting financial burden in comparison to men. Black participants felt greater impact from fatigue in comparison to Caucasian and other races. Active MM patients on treatment were more impacted by disease-related symptoms and fatigue compared to early-stage patients. MGUS/SMM patients not on therapy were more impacted by dissatisfaction of information received compared to patients receiving treatment at time of data collection. [Display omitted] DisclosuresBadros: Janssen: Research Funding; J&J: Research Funding; BMS: Research Funding; GlaxoSmithKline: Research Funding.

Diagnosing and Managing Plasma Cell Disorders: Education Gaps in Primary Care Providers and Hematologist/Oncologists

Background: Diagnosis of plasma cell disorders (PCD) may be delayed due to generalized symptoms in patients. In fact, a recent analysis demonstrated that 2 years prior to diagnosis, 58% of patients with multiple myeloma (MM) indicated they had back pain and 34% had fatigue or weight loss [Goldschmidt N et al, JABFM 2016]. Furthermore, diagnostic criteria, staging, monitoring and management of PCD has vastly changed over the past decade allowing better methods for assessment and treatment options for patients with these disorders [Rajkumar SV et al, Lancet 2014, Palumbo A et al, JCO 2015]. To elucidate the clinical practice gaps in PCD, a study was undertaken to assess the ability of primary care providers (PCPs) and hematologists/oncologists (hem/onc) to appropriately diagnose, monitor, refer, stage and manage patients with PCD.Methods: A continuing medical education-accredited clinical practice assessment survey was developed utilizing current evidence-based consensus guidelines and best practices in plasma cell disorders (http://www.medscape.org/viewarticle/866138 ). The assessment consisted of 20 multiple-choice, knowledge- and case -based questions that clinicians completed confidentially on-line starting on August 18, 2016. The questions assessed: diagnosis, risk stratification, and criteria to initiate therapy, monitoring, and management of patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), and MM. Responses from physicians were de-identified and aggregated prior to analysis.Results: As of July 11, 2017, 161 PCP and 281 hem/oncs participated in the assessment. Of the PCPs and hem/onc respondents, 45% and 38%, respectively, saw 1 to 5 patients with PCD per month. PCPs indicated that knowledge of appropriate tests was the biggest barrier in accurately diagnosing PCD (50%); whereas, hem/oncs indicated accessibility to tests was the biggest barrier (33%). Key findings included the following:Diagnosis of PCDMost clinicians were able to identify serum protein electrophoresis (SPEP) and immunofixation as necessary tests to order for diagnosing MGUS in a patient with elevated protein and mild anemia (79% PCPs and 94% hem/oncs). However, when presented with the outcome of laboratory tests, only 45% of PCPs were able to recognize that a patient may have a PCD and should be referred to a hem/onc. Based on the results of laboratory tests, less than half (42%) of PCPs were able to recognize that the patient had SMM or symptomatic myeloma and required referral. Only 24% of PCPs indicated that bone morrow examination, serum free light chain (sFLC), and testing for Bence Jones protein in urine were necessary to diagnose MM in a patient. Only 23% of PCPs and 50% of hem/oncs were aware of the new diagnostic criteria for myeloma that included sFLCs of involved/uninvolved ratio > 100.Monitoring and StagingBoth PCP and hem/oncs struggled with the frequency of assessing a patient with MGUS for progression to SMM (32% and 30% of PCPs and hem/oncs, respectively, answering the patient should be seen at 6 months). 51% of PCPs and 74% of hem/oncs were able to identify the parameters of a patient with low-risk MGUS. Based on the results of test parameters only 29% of hem/oncs were able to identify the patient had revised ISS stage III SMM, and only 40% were able to assess that the patient had high risk SMM according to the Mayo criteria.Conclusions: This educational research yielded important insights into clinical knowledge gaps for both the PCP and hem/onc. Both groups demonstrated education gaps in the areas of ordering and interpretation of tests, monitoring requirements, timing of referral, staging/risk assessment. Given the critical role that PCPs and hem/oncs play in the management of PCD, increased clinician awareness of gaps and tailored education is warranted in order to improve outcomes in patients with PCD. DisclosuresOrlowski:BioTheryX: Consultancy, Membership on an entity's Board of Directors or advisory committees. Mikhael:Celgene Corp: Research Funding; sanofi-aventis: Research Funding; Abbvie: Research Funding.

Proteomic Profiling Reveals Targetable Pathways in MGUS (SLAMF6, TNFRSF8, TIMP1, TRL2) That May Contribute to Disease Progression

Introduction: Monoclonal gammopathy of undetermined significance (MGUS), is a pre-malignant plasma cell disorder that affects roughly 4% of the population older than 55 and is associated with a 1% per year risk of progression to multiple myeloma (MM). Successfully intercepting disease progression from MGUS to MM requires a deeper understanding of MGUS biology, identification of prognostic biomarkers and potential targets for interception. With these aims, a cohort of samples were profiled from the Olmstead County Study, which followed >20,000 subjects for over 20 years as they aged and developed a variety of diseases, including MGUS and MM (Kyle, et al. Oncology 2011). Samples were utilized from 2 cohorts: 1) healthy normal individuals with no subsequent diagnosis of plasma cell disorder, and 2) healthy normal individuals who go on to develop MGUS, with a second sample at the time of MGUS diagnosis. Broad proteomic profiling was performed on these samples, to identify pathways involved in the early stages of MGUS disease biology.Methods: Proteomic profiling was performed on 727 serum samples using the SOMAscan Assay 1.3k (SomaLogic, Inc., Boulder, CO): 267 from normals who remained without evidence of MGUS, 235 from normals who later progressed to MGUS, and 225 from these MGUS patients from the time of progression. Various univariate, multivariate, and co-expression statistical testing methods were applied on age matched sample sets for data exploration and for potential predictive marker/signature identification.Results: A set of serum markers were identified that were differential between age-matched normal and MGUS patients, including albumin, PDGFB, AKT2, SLAMF6, TRL2, and Cathepsin A. Subtle differences in protein levels were observed in serum of normal individuals who remained plasma cell disorder free versus those who later progressed to MGUS including SCARF1, TIMP1, TNFRSF8, H2AFZ, renin, IL34, ADSL, SLAMF6 (Figure), which may help develop a potential serum diagnostic for assessing risk of MGUS.Conclusions: Proteomic profiling allowed detection of markers that are potentially indicative of early event pathogenesis and disease progression in MGUS patient serum samples. These findings may contribute to biological understanding of pre-malignant disease. Interestingly, some of the proteins identified, such as SLAMF6, are currently being evaluated as therapeutic targets in MM, adding validity that these pathways are early contributors to disease progression and may be important for interception and prevention. [Display omitted] DisclosuresCasneuf:Janssen: Employment. Tryputsen:Janssen: Employment. Adams:Janssen: Employment. Lysaght:Janssen: Research Funding. Sasser:Janssen: Employment. Kumar:Skyline: Honoraria; Celgene, Millennium/Takeda, Onyx, AbbVie, Janssen, Sanofi, Novartis, Amgen, Genentech, Merck, Oncopeptides, Roche, Skyline Diagnostics: Research Funding; Celgene, Millennium, BMS, Onyx, Janssen, Noxxon, AbbVie, Amgen, Merck, Oncopeptides, Skyline Diagnostics, Takeda: Consultancy.

The influence of clinical stage, race, and gender on factors which impact quality of life in multiple myeloma.

e24126 Background: Multiple myeloma (MM) is unique among hematologic malignancies as an incurable disease. Patients are affected long-term by the disease symptoms as well as psychological, financial burden, and social impact, which may affect overall quality of life (QOL). The current literature related to QOL in MM is largely limited to a single clinical stage, impact concurrent with a specific treatment regimen, or focused on a single QOL factor. Changes in impact on QOL based on longitudinal follow up during the disease course have not been readily assessed. Here, we evaluated patient-reported QOL measures utilized by one time validated questionnaires. Methods: The study enrolled 100 participants in a sequential manner from the Myeloma Clinic at UMGCC with a diagnosis of plasma cell disorders at various stages: MGUS, smoldering myeloma, or multiple myeloma: newly diagnosed, maintenance, relapsed. Participants provided verbal responses to a series of questions listed in Table. Questions aligned with three main domains: physical symptoms and function, mental health, and social systems. The following is an interim analysis of the first 50 patients. Results: This sample of myeloma patients (N=50; males n=26), felt their QOL was impacted by myeloma symptoms (70%). More African American participants reported impact from financial burden (6, 50%) in comparison to Caucasian and other races (10, 26%). Interestingly, males reported less impact on sexual intimacy (3, 15%) than females (6, 43%). Females also reported more impact from financial burden (10, 42%) compared to males (6, 23%). Conclusions: Changes to impact on QOL as a function of clinical MM stage, race, and/or gender will be fully evaluated. Planned analyses include correlation statistics by age and social demographics to determine patterns in patient-reported outcomes. Finally, second interviews with current participants will be conducted to determine changes to impact across the same QOL variables over time.[Table: see text]

Diagnostic performance of computed tomography and diffusion-weighted imaging as first-line imaging modality according to the International Myeloma Working Group (IMWG) imaging algorithm for monoclonal plasma cell disorders.

The latest International Myeloma Working Group (IMWG) guideline recommends low-dose whole-body (WB) computed tomography (CT) as the first-line imaging technique for the initial diagnosis of plasma cell disorders. To evaluate diagnostic performances of CT and diffusion-weighted imaging (DWI) as the first-line imaging modalities and assess misclassification rates obtained following the guideline. Two independent radiologists analyzed CT (acquired as PET/CT) and DWI (3-T; b-values = 50 and 900 s/mm2) of patients newly diagnosed with plasma cell disorder, categorizing the number of bone lesions. Diagnostic performance of CT and DWI was compared using the McNemar test, and misclassification rates were calculated with a consensus WB-MRI reading as the reference standard. Differences in lesion number categories were assessed using marginal homogeneity and kappa statistics. Of 56 patients (36 men; mean age = 63.5 years), 39 had myeloma lesions. DWI showed slightly higher sensitivity for detecting myeloma lesions (97.4%) than CT (84.6%-92.3%; P > 0.05). CT showed significantly higher specificity (88.2%) than DWI (52.9%-58.8%; P<0.05). CT had a higher additional study requirement rate than DWI (7.7%-15.4% vs. 2.6%), but a lower unnecessary treatment rate (11.8% vs. 41.2%-47.1%). Both readers showed significant differences in categorization of the number of lesions on CT compared with the reference standard (P < 0.001), and one reader showed a significant difference on DWI (P = 0.006 and 0.098). CT interpreted according to the IMWG guideline is a diagnostically effective first-line modality with relatively high sensitivity and specificity. DWI alone may not be an acceptable first-line imaging modality because of low specificity.

Defining Quality Though a Collaborative Process for Multiple Myeloma Care

Background: With the increase in life expectancy, prevalence, early diagnosis of plasma cell disorders, advances in effective therapies and improved overall survival (OS) in multiple (MM); improvements in the quality standards and delivery of quality of care remain a challenge. Currently there are no standardized quality metrics and many studies have highlighted the disparities in treatment and supportive care in MM. We propose a quality model based on Donabedian's triadof structure, process and outcomes to further improve outcomes in MM. We aim to share a team process at Cleveland Clinic for defining components of quality measure for MM treatment. Structure: Multidisciplinary clinics (MDCs) have become popular over the recent years and have proven to improve patient outcomes for many malignancies. Our MDC has healthcare team composed of MM physicians, palliative care physicians, nurse coordinators, clinical pharmacists, pathologists, clinical research team, basic science laboratory collaboration, and psycho-social workers. To improve efficiency, team focus is on prompt diagnosis, easy accessibility, tissue banking, efficient EMR, access to transplant /cellular therapy /immunotherapy and efficient infusion suites with focus to reduce time to treatment in the same building. Process: With the rapid advancements in the treatment of MM, our process is focused on the comprehensive diagnosis based on tissue analysis, comprehensive staging, risk defining genetic factor testing, and evidence based treatment selection for MM based on literature, clinical practice guidelines (CPGs) like specialty society guidelines Recent studies have suggested that delays in treatment from diagnosis can result in negative patient outcomes, similarly studies have suggested that patients with MM can experience significant treatment delays. We focus on reduced time to treatment; recommend patients should undergo treatment within ten days of diagnosis. Patients should undergo evaluation for toxicity management, undergo supportive treatment based on CPGs. These should include: Risk estimation for DVT and score driven prophylaxis, bone modulation therapy, infection prophylaxis, management of anemia, frailty assessment and front line transplant eligibility assessment. Outcomes: Clinical and patient reported outcomes should be recorded, analyzed and reported. A dedicated quality improvement process should streamline data collection and select quality improvement QI projects with the aim to improve recurring issues. Figure Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.

MASS-FIX for the Diagnosis of Plasma Cell Disorders: A Single Institution Experience of 4118 Patients

MASS-FIX for the Diagnosis of Plasma Cell Disorders: A Single Institution Experience of 4118 Patients

Verification of Newly FDA-Approved Kappa and Lambda Free Light Chain Assays on a Previously Untested Platform.

κ and λ free light chains (FLCs) are monitored to aid in the diagnosis of plasma cell disorders. Our goal was to validate the Diazyme Human κ and λ assays on Beckman Coulter UniCel DxC 800 Synchron and compare to Freelite κ and λ assays on Roche Cobas Integra. Linearity verification, within- and between-run precision, method comparison, and reference range (RR) verification were conducted using CLSI guidelines. Statistical analysis was performed using EP Evaluator®. Mean, SD, CV, and bias were determined. Diazyme κ FLC assay was linear within 0.00-191.00 mg/L. Diazyme λ FLC assay was linear within 0.00-205.30 mg/L. Diazyme κ FLC QC1 had a mean of 16.70 mg/L, CV of 7.0%. QC2 had a mean of 33.37 mg/L, CV of 2.6%. Diazyme λ FLC QC1 had a mean of 21.73 mg/L, CV of 2.3%. QC2 had a mean of 42.05 mg/L, CV of 1.5%. Bias of DxC-Diazyme FLCs compared to Integra-Freelite FLCs was -2.55 mg/L (κ FLC), and 4.54 mg/L (λ FLC). Qualitative comparison of κ FLC assays indicated 100% agreement for both normal and abnormal values. For λ FLC assay, agreement was 95% for normal values and 75% for abnormal values. For κ/λ ratio there was 50% agreement for normal values, and 100% for abnormal values. For RR verification, 1 sample was outside the Diazyme κ RR. For λ, all samples were within the manufacturer's RR. Diazyme assays for FLCs have excellent precision and accuracy and are comparable to Freelite assays.

Evaluation of Serum Free Light Chain in Diagnosis and Monitoring of Plasma Cell Disorders

To determine diagnostic accuracy of serum free light chain assay compared to serum and urine protein electrophoresis in plasma cell disorders. Descriptive cross-sectional study. This study was conducted in the Immunology Department, Armed Forces institute of Pathology (AFIP), Rawalpindi, from May 2017 to May 2018. Patients referred to AFIP for diagnosis of plasma cell disorders or for monitoring while receiving treatment were included in study. They were tested for serum protein electrophoresis (SPE), urine protein electrophoresis (UPE), immunofixation (IF), and serum free light chain assay (sFLC). IF was used as the reference standard. Test results were compared in terms of sensitivity, specificity, positive or negative predictive value, and accuracy index. During the study period 220 patients were tested for plasma cell disorders. One hundred and sixty-seven patients tested positive. One hundred twenty-nine patients had multiple myeloma, 13 plasmacytoma, 11 monoclonal gammopathy of undetermined significance, 6 amyloidosis, 6 POEMS, and 2 Waldenstrom macroglobulinemia. SPE had a sensitivity of 70.5%, specificity of 100%; sFLC had a sensitivity of 87%, specificity of 81%; and UPE had a sensitivity of 23.5%, specificity of 97%. Accuracy index was 80.5% for SPE, 85% for sFLC, and 54% for UPE. When taken together, SPE and UPE had a combined sensitivity of 72%, specificity 97%, and accuracy index 80.5%. SPE and sFLC had combined sensitivity of 98.6%, specificity 84.3%, and accuracy index 94%. Combination of SPE and sFLC had the highest sensitivity and accuracy index for diagnosis and monitoring of plasma cell disorders compared with conventional tests.

Plasma Cell Dyscrasias in HIV, Epidemiology, Presentation and Treatment Characteristics and Its Strong Association with Hepatitis C- Report Form a Large HIV Cohort

Introduction: As people with HIV live longer, the epidemiology of plasma cell disorders (PCD) including MGUS, smoldering myeloma and Multiple myeloma (MM) becomes relevant and remains unknown. Moreover, patients with HIV have a higher incidence of monoclonal proteins which may not be related to an underlying lymphoproliferative disorder[1, 2] . There are mostly anecdotal reports and very few studies in HIV myeloma[3]. A retrospective study of 10 patients with HIV+ve symptomatic MM reported possible therapeutic benefit of ART and reported better overall survival of HIV+ve MM on ART as compared to HIV -ve MM. There is a paucity of data in PCD in this population whose incidence can be expected to increase globally. We conducted a single-institution retrospective study to look at the incidence of PCD.Methodology:We reviewed an electronic database of patients with HIV related PCD treated at Montefiore Medical Center between 2001 and 2018. All patients with a new diagnosis of PCD between January 1 2001 to July 15 2018 were identified. Data on patient demographics, HIV status, clinical outcomes (including mortality) and therapy was collected.Results: Between 2001 and 2018, 14438 patients were identified with HIV and 1986 patients had a monoclonal band in SPEP (13.8%). Based on our previous study, patients who had a definitive monoclonal band or suspected MM underwent a BM biopsy. 34 patients were diagnosed with PCD –MGUS 16 (47.05%), Smoldering MM 1 (2.94%), MM 16 (47.05%) and Primary plasma cell leukemia (PCL) 1 (2.94%).The majority of the patients were AA consistent with demographics of the Bronx. Interestingly HCV co-infection was identified in 50% (n=17) of patients and HBV co-infection was present in 15% (n=5) patients. The median CD4 count was 381 (12-1080), median viral load 237 (0-501534) and 53% patients were on ART at the time of diagnosis. The median time from HIV diagnosis was 13.9 (-2.8 to 29) years.In patients with MGUS the predominant heavy chain involvement was IgG, the median protein on SPEP was 1.1 g (0.7-1.9 g) and percentage of BM involvement was 5% (2-10%). In patients with MM IgG was the predominant heavy chain involved. On presentation, ISS Stage was Stage I in 2 patients (15.4%), 4 (30.7%) had at least Stage 2, 7 patients (53.9%) had stage 3. On presentation, 10 (58.8%) patients presented with anemia, 10 (58.8%) presented with renal impairment (Cr>=1.3), 16 (94.1%) presented with bone lesions, 6 (37.5%) presented with hypercalcemia. 5 patients (34.6%) had extramedullary presentation including 1 patient (2.9%) with PCL, 2 (5.8%) with anaplastic plasmacytoma. All patients were treated with an imid or bortezomib based regimen and there were no unusual side effects in these patients. 5 patients (29.4%) underwent autologous stem cell transplant with successful outcomes.Discussion:The prevalence of a positive SPEP is 13.8% in patients with HIV and the prevalence of plasma cell dyscrasias (PCD) in our population is 0.02%. A previous study from this cohort[2] showed that approximately 6.4% of patients with a positive SPEP developed hematological malignancy and all patients with a faint monoclonal band had lymphoma (70.5%) and those with a definite monoclonal band had myeloma (29.5%). Even though prevalence is less than the general population rate of 3%, as patients with HIV live longer this number may increase. In our study there was a high rate of co-infection with HCV in patients who had a PCD and this needs further investigation to determine causality. PCD developed at a median of 13.9 years after HIV diagnosis. The ISS staging distribution in patients presenting with myeloma is consistent with non HIV myeloma. People with HIV tolerate standard imid or proteasome inhibitor based triple drug therapy and have successful outcomes with autologous transplantation. This is the largest cohort and report describing PCD in HIV population.

Natural History of Amyloidosis Isolated to Fat and Bone Marrow Aspirate

▪Background: Light chain Amyloidosis (AL) is characterized by deposition of light chain derived amyloid fibrils in major organs and/or soft tissue. An observational study on natural history and outcome of localized immunoglobulin light-chain amyloidosis without vital organ (liver, heart, kidney, peripheral and autonomic nervous system) involvement has shown extremely low rate of progression (1%) to systemic amyloidosis at a median follow-up of 74.4 months (Mahmood S et al. The Lancet Haematology; 2015; 6:e241-e250). There is, however, limited evidence in published literature on natural history of AL amyloidosis confined to fat and/or bone marrow biopsy, without involvement of vital organs or other soft tissues.Methods: We retrospectively identified patients with AL amyloidosis limited to fat and/or bone marrow aspirate in a single-institution database. Patients were evaluated for progression to systemic amyloidosis. Statistical analysis was done using JMP 10.0.0 (SAS Institute Inc.).Results: We identified 117 patients, with a median age of 70 years, who had light chain amyloidosis detected in abdominal fat aspirate and/or bone marrow biopsy, without systemic involvement. Amyloid was seen in fat only in 39%, marrow only in 54% and in both sites in 7%. The median follow up was 45.6 months (95% CI-38.1-57.7) from detection of amyloid. Of these, 64% were alive at the time of analysis. Among 117 patients, 65 were treated for a diagnosis of another plasma cell disorder made prior to or concurrent with detection of amyloid. The remaining 52 patients only had isolated fat or marrow amyloid. Among 65 patients with another diagnosis of plasma cell disorder requiring treatment, 3 progressed to systemic amyloidosis, one each with cardiac, renal and lymph node (LN) involvement detected at 32, 42 and 65 months respectively from the detection of amyloid. The first 2 patients had underlying multiple myeloma, and the third patient with LN involvement had underlying Waldenström macroglobulinemia. Among 52 patients without another diagnosis of a plasma cell disorder requiring treatment, at a median follow up of 32 months, no progression to systemic amyloidosis was observed. Median overall survival (OS) in 117 patients from detection of amyloid, using Kaplan-Meier survival estimates, was 60.2 months (95% CI-48.9-146.1).Conclusion: Our study highlights the fact that isolated amyloidosis detected in fat and/or bone marrow aspirate, in the absence of another plasma cell dyscrasias that require therapy, is unlikely to progress to systemic amyloidosis. Watchful waiting might be considered in such patients after a thorough evaluation to rule out systemic involvement. DisclosuresGertz:Smith Kline: Honoraria; Novartis: Honoraria; Onyx: Honoraria; millenium: Consultancy, Honoraria; Celgene: Honoraria. Kumar:Celgene: Consultancy, Research Funding; Abbvie: Research Funding; Millenium: Consultancy, Research Funding; Novartis: Research Funding; Onyx: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; BMS: Consultancy, Research Funding.

International Myeloma Working Group guidelines for serum-free light chain analysis in multiple myeloma and related disorders

The serum immunoglobulin-free light chain (FLC) assay measures levels of free kappa and lambda immunoglobulin light chains. There are three major indications for the FLC assay in the evaluation and management of multiple myeloma and related plasma cell disorders (PCD). In the context of screening, the serum FLC assay in combination with serum protein electrophoresis (PEL) and immunofixation yields high sensitivity, and negates the need for 24-h urine studies for diagnoses other than light chain amyloidosis (AL). Second, the baseline FLC measurement is of major prognostic value in virtually every PCD. Third, the FLC assay allows for quantitative monitoring of patients with oligosecretory PCD, including AL, oligosecretory myeloma and nearly two-thirds of patients who had previously been deemed to have non-secretory myeloma. In AL patients, serial FLC measurements outperform PEL and immunofixation. In oligosecretory myeloma patients, although not formally validated, serial FLC measurements reduce the need for frequent bone marrow biopsies. In contrast, there are no data to support using FLC assay in place of 24-h urine PEL for monitoring or for serial measurements in PCD with measurable disease by serum or urine PEL. This paper provides consensus guidelines for the use of this important assay, in the diagnosis and management of clonal PCD.

Concomitant Myelofibrosis and Plasma Cell Disorders: The Mayo Clinic Experience.

BACKGROUND: Bone marrow fibrosis might represent either a primary myeloid malignancy such as myelofibrosis with myeloid metaplasia (MMM) or a reactive phenomenon associated with other malignancies or inflammatory/infectious processes. The development of myelofibrosis in the context of a plasma cell dyscrasia is uncommon and incompletely understood from the standpoint of both pathogenesis and clinical implications. We sought to determine the origin and clinical ramifications of this phenomenon based on a consecutive series of patients with plasma cell disorders (PCD).METHODS: A retrospective search of institutional databases was performed for clinical cases of PCD with the concomitant observation of myelofibrosis. Bone marrow aspirates and trephines from the time of diagnosis of both PCD and myelofibrosis were reviewed. Clinical history was abstracted for clinical manifestations as well as disease course. DNA from archived cytogenetic pellets, when available, from the time of diagnosis, was screened for the presence of JAK2V617F.RESULTS: Among 7587 patients with a PCD seen over the last 30 years at our institution, 29 (0.3%) displayed concomitant myelofibrosis (median age 59 years, range 27–77; 52% males). The specific PCD was multiple myeloma in 25 patients, smoldering myeloma in 2, plasmacytoma in 1, and heavy chain disease in 1. Four patients (14%) had organomegaly and bone marrow histological features most consistent with MMM. Otherwise, myeloproliferative disorder (MPD)-characteristic features were infrequent and included leukocytosis and/or thrombocytosis in only 2 patients. None of the patients displayed thrombohemorrhagic complications. Archived DNA was available in 7 cases without either clinical or bone marrow histological evidence of a MPD and yet revealed the presence of JAK2V617F in 6 of the 7 cases (86%). In addition, one other patient without MPD phenotype displayed a monosomy 5 abnormality. To date, 2 patients, one with and one without a MPD phenotype underwent leukemic transformation. All other causes of death were related to PCD-associated complications. Median survival (Kaplan-Meier) for the patients with multiple myeloma was 50 months. Survival stratified by the myeloma international staging system (ISS) was similar or better than expected (published controls of 62, 44, and 29 months): median survivals for this series of 73, 51 and 37 months for stage I, II, and III disease, respectively.CONCLUSIONS: Myelofibrosis that accompanies a PCD often represents an underlying MPD and does not negatively impact the natural history of the associated PCD.