Kumar, Shaji

Background: Liver involvement in light chain amyloidosis (AL) is seen in up to 20% of patients and is typically encountered as part of multi-organ involvement. Liver involvement is associated with a poor prognosis. The goal of this study was to assess the prognostic impact of the hepatic response criteria, which were published in 2005 and were not broadly assessed for their prognostic value. Patients and methods: Ten centers across the USA and Europe participated in this study.AL amyloidosis patients who were diagnosed between 2010 and 2015, had liver involvement with serum alkaline phosphatase (AP) >1.5 upper reference limit (URL), and achieved hematologic response to therapy were included in this study. Hepatic response was assessed at 6, 12, and 24 months from therapy initiation and at best response. Based on a receiver operation characteristic analysis, a 50% reduction in AP was set as the optimal cut point for discrimination of 5-year overall survival (OS) in the 12-months response assessment landmark (area under the curve 0.67). Therefore, hepatic response was defined as a reduction in AP >50% from baseline value in addition to AP normalization, regardless of AP percentage reduction. Hepatic progression was defined as >50% increase in serum AP. OS was assessed from therapy initiation until death or last follow-up and was plotted using the Kaplan-Meier method. The log-rank test used to compare survival between groups. For fixed-time point survival analysis, patients who died before the landmark were excluded. Hepatic response at a fixed time points, when missing, was imputed based on available data from adjacent time points (imputation of hepatic response was performed in 15%, 23%, and 22% of evaluable patients at 6-, 12-, and 24-month landmarks, respectively). Multivariate Cox proportional models were set to determine independent prognostic factors for OS using variables with p-value <0.1 in a univariate analysis. P-values <0.05 were considered significant. Results: One hundred and sixteen patients (n=116) are included. The median age was 60 years, and the median serum AP was X2.6 URL. Concomitant kidney involvement was present in 63.8% of patients, while coexisting heart involvement was seen in 56% of patients. Hematologic VGPR or better was achieved in 69% of patients. AP decrease deepened with time, with a median reduction at 6-, 12-, 24-months and best response being 22%, 34%, 53%, and 56%, respectively. Overall, 65% of patients (n=75) achieved hepatic response, of whom 71 patients based on reduction in AP >50% and 4 patients for reaching AP within normal reference but not meeting >50% reduction in AP (40- 46% reduction in AP). The median time to hepatic response was 13.8 months, longer for patients undergoing autologous stem cell transplantation (ASCT) as their primary therapy compared to non-transplant therapies (24 vs 12.6 months, P=0.1). With a median follow-up of 105 months, 42 patients died (36.2% of the study cohort). The 2-, 5- and 10-year OS rates were 83%, 67%, and 61%, respectively. Achievement of hepatic response as early as 12 months and at best response was associated with a longer survival (Figure). Hepatic response was an independent prognostic factor in a multivariate analysis, after adjusting for other known prognostic factors (age, cardiac stage, hematologic response, and primary therapy). Predictors of hepatic response include higher baseline AP level, lower total bilirubin, hematologic ≥VGPR, and cardiac and renal responses, when applicable. Hepatic progression was borderline associated with inferior OS (5-year OS 47% vs 70% among non-progressors, P=0.08). Conclusions: Hepatic response and progression measured by the change in alkaline phosphatase are prognostic in AL amyloidosis. These criteria are independent of other prognostic markers, and thus may have clinical implications for patients' care.

Background Teclistamab, the first-in-class B-cell maturation antigen (BCMA) x CD3 bispecific therapy was recently approved by the FDA for the treatment of triple-class exposed relapsed or refractory multiple myeloma (MM) after ≥ 4 prior lines of therapy. Because of the risk of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), the step-up dosing (SUD) of teclistamab is commonly administered in an inpatient setting among early users. Mayo Clinic has a well-established hospital-based outpatient program for novel immunotherapies. Since the FDA approval, teclistamab SUD has been administered as part of this program. Each dose of the SUD is administered in an outpatient setting, and the patient is given a remote monitoring kit to regularly measure vital signs and stay connected with the command center for signs and symptoms of CRS and ICANS throughout the entire SUD period. This study aimed to evaluate early safety outcomes and healthcare resource utilization during SUD in real-world (RW) patients who initiated teclistamab under the outpatient administration model across 3 Mayo Clinic locations (Rochester, MN, Phoenix/Scottsdale, AZ, Jacksonville, FL). Methods This was a retrospective study using Mayo Clinic's electronic medical records from October 26, 2022 to June 12, 2023. Eligible patients were adults diagnosed with MM who had initiated commercial teclistamab at any of the 3 Mayo Clinic locations. Patient characteristics, rates and severity of CRS and ICANS, as well as healthcare resource utilization during SUD were described. Time between teclistamab administration and patient check-out was reported for SUD and treatment doses, respectively. Results At the time of data cutoff, 39 patients received at least 1 teclistamab dose across the 3 locations (median age 67.2 years; male: 74%; White: 87%; non-Hispanic: 92%), including 36 patients who initiated teclistamab SUD directly in an outpatient setting. A total of 8 (21%) patients had MM with high-risk cytogenetics and 14 (36%) had prior exposure to other BCMA-targeted therapies. Prevalent comorbidities prior to receiving teclistamab included anemia (77%), hypertension (56%), lytic bone lesions (51%), neutropenia (49%), and hypogammaglobulinemia (41%). Renal impairment or failure was observed in 31% of the patients (Table 1). Almost all patients received acetaminophen (95%), diphenhydramine (95%), and dexamethasone (92%) as pre-medications on the same day as teclistamab administrations during SUD. Of the teclistamab doses with clinic time data, the majority (62%) of doses during SUD required 30 minutes to 1 hour of clinic time for monitoring between administration and check-out. After SUD, the clinic time for weekly treatment doses decreased to less than 30 minutes for most (79%) doses (Figure 1). In patients who completed SUD by data cutoff (n = 37), most patients (70%) received the SUD on a 3-day dose interval (i.e., day 1, 4, 7). The mean time between the first and third doses was 6.3 days. Among the 37 patients with complete SUD, 12 (32%) developed CRS. The highest CRS grade was grade 1 for 10 patients; 1 patient had a grade 2 CRS, and 1 patient had a grade 4 CRS. The patient with grade 4 CRS concurrently decompensated during a dialysis session and all symptoms were considered for CRS grading. A total of 6 patients had recurrent CRS, including 1 patient with 3 events during SUD. All patients who developed CRS during SUD (n=12) were admitted to the hospital for treatment, with a total of 19 admissions across all patients and a median length of stay of 1.7 days per admission. Among patients who were admitted for CRS (n=12), the majority were treated with acetaminophen (92%), diphenhydramine (83%) and dexamethasone (83%); tocilizumab was given to the 2 patients with CRS grade 2 or higher. Only 1 ICANS event (grade 2) was observed in 1 patient during SUD, after dose 3, and the patient was admitted to the hospital for treatment. Conclusion This study evaluated early RW safety outcomes of teclistamab under an outpatient administration model and found the CRS rate and severity to be comparable with other RW evidence generated from various data sources. Outcomes related to teclistamab SUD from Mayo Clinic supported the safety and feasibility of outpatient administration model as a potential option to reduce healthcare resource utilization and improve treatment experiences.

Background: Cytopenias are a common complication of and prolonged (beyond month 3 post CAR-T infusion), severe (grade 3 or higher) cytopenias can be difficult to manage. Stem cell boosts have been reported to restore hematopoiesis; however, stem cells would need to be available prior to CAR-T therapy for potential use post CAR-T. Most lymphoma patients and limited number of myeloma patients may have pre-collected stem cells in storage. Identifying patients at high risk for prolonged and severe cytopenia post CAR-T at the time of CAR-T evaluation (baseline), before leukapheresis, can help identify the patients for coordination of stem cell collection during CAR-T manufacturing and increase the likelihood that the collected stem cells would be used. In this study, we aim to identify clinical variables at the time of CAR-T evaluation, prior to leukapheresis, that are associated with severe cytopenias at month 3 post CAR-T infusion and identify patients who could be considered for pre-emptive stem cell collection prior to CAR-T therapy. Methods: We conducted a retrospective analysis of patients with multiple myeloma (MM) and non-Hodgkin lymphoma (NHL) who received CAR-T products at Mayo Clinic from 01/2016 to 06/2022. Patients with progressive disease in the first year post CAR-T were excluded from the analysis. Baseline (at CAR-T evaluation, prior to leukapheresis) variables were compared between those with and without severe cytopenia at month 3 post CAR-T. Severe cytopenias were defined as hemoglobin (Hg) < 8 g/dL, absolute neutrophil count (ANC) < 0.5 x 10 9/L, and/or platelet count (PLT) < 50 x 10 9/L. Statistically significant variables (p<0.05) by analysis were examined for statistical significance in multivariate analysis (MVA). Results: Among the 166 patients who received CAR-T (88 NHL, 78 MM) during the study period, 31 (18.67%) had a severe cytopenia at month . Twenty baseline variables were examined; HGB, PLT, ANC, and c-reactive protein (CRP) We devised a cytopenia risk score using 1 point each for Hg<10 or PLT<100k at baseline, with a range of 0 to 2. Demographics and clinical outcome by cytopenia risk score is shown in Table 1B. A higher percentage of patients with a score of 1 or 2 had a severe cytopenia at month 3 (Figure 1). In particular, there was a . In addition Conclusion: Baseline cytopenias before leukapheresis may identify patients with increased risk for severe cytopenias at month 3 post CAR-T. These patients can have continued slow hematopoietic recovery in the first year. Stem cell collection, if feasible, could be considered before CAR-T to alleviate post-CAR-T severe prolonged cytopenias.

Introduction: BCMA-directed CAR-T and Bispecific T-cell engager (BiTE) therapies have shown remarkable overall response rates in heavily pretreated patients with relapsed/refractory multiple myeloma (RRMM). This has led to the approval of idecabtagene vicleucel, ciltacabtagene autoleucel and teclistamab by the FDA, EMA and other regulatory agencies. We performed a global survey on accessibility, practice patterns, and toxicity management of commercially available CAR-T and BiTE therapies. Methods: An online survey was completed by clinicians attending the International Myeloma Society's Immune Effector Cell Therapies in Multiple Myeloma Workshop, in-person or virtually, made available for 30 days after the meeting held in March 2023, Boston, MA. Results: 87 clinicians from 16 countries completed the survey, most practicing in an academic practice (86%) and in an urban environment (89%). Sixty-four percent of the respondents practice in North America followed by Europe (25.3%) including Germany, United Kingdom, Ireland, Italy, Netherlands, Spain, France, Greece, and Cyprus, and 6.9% from Asia and 3.4% from Australia. Seventy-seven percent reported CAR-T cell therapy was approved in their country with 44.8% treating 1-5 patients and 14.9% treating >5 patients per month; 67% reported BiTE therapy was approved in their country with 14.9% treating >5 patients per month. Of evaluable responses (n = 40), 62% administered CAR-T therapy inpatient and 15% administered CAR-T therapy outpatient ≥ 50% of the time. Length of time between decision to treat with CAR-T therapy to infusion was 6-12 weeks for 42% of responders and <6 weeks for only 20%. Most (75%) reported inpatient administration of BiTE therapy step-up dosing; 17.5% reported outpatient step-up dosing administered ≥ 50% of the time. Use of institutional or practice SOPs for CAR-T and BiTE therapy patient selection was reported by 85% and 58%, respectively, with the factors influencing SOP outlined in Table 1. Of available CAR-T therapies, 53% prefer cilta-cel and 23% reported CAR-T therapy preference depended most on patients' co-morbidities/frailty (89%), timing of next available apheresis (67%), age (56%), CNS disease (44%) and other factors. Maintenance therapy after CAR-T therapy was reportedly used by 25% and 5% of respondents in 1-10% and 11-50% of their patients, respectively, to “maintain level of response achieved” (50%) or “achieve a deeper level of response” (25%). About half (43%) of the respondents reported using an SOP or particular criteria for secondary Hemophagocytic Lympho-Histiocytosis/Macrophage Activation Syndrome/CAR-related-HLH (sHLH/MAS/CarHLH) management that varied between the use of ASTCT Working Group IEC associated HLH-like syndrome Criteria (47%) (Hines 2023), CARTOX HLH Criteria (24%) (Neelapu 2017) and HLH-2004 criteria (6%). Tocilizumab was used as cytokine release syndrome (CRS) prophylaxis only by one responder. Keppra neurologic prophylaxis was used by 47.5% and 15% of responders for CAR-T and BiTE therapy, respectively. Delayed neurotoxicity with CAR-T was reported in 1-5% of patients by 57.5% of responders and 6-10% of patients by 15% of responders; most common manifestations were other movement/neuromuscular disorder (62%), nerve palsy (55%), and Parkinsonism (45%). Infectious prophylaxis was used to protect against HSV (92.5%), PJP (90%), bacterial pathogens (55%), fungal pathogens (60%), and IVIG (77.5%). However, criteria for infectious prophylaxis use varies widely incorporating IgG levels, infectious history, CD4+ count, B-cell aplasia and cytopenias (48.1 - 88.9%). Most respondents (46.3 - 86.5%) reported completing an infectious work-up including CMV, EBV, Hep B/C, and HIV ( Table 2). Conclusions: Trends of CAR-T and BiTE therapy use and patterns of concurrent prophylactic and supportive care in MM vary widely among academic centers across the globe, demonstrating a need for further understanding of toxicity pathogenesis, toxicity management and consistent guidelines. This survey also demonstrates the great unmet need for access beyond urban centers among the international myeloma community. Prospective studies and claims data analysis should be utilized to evaluate the longitudinal cost of care, quality of life, duration of response and management of infectious disease, neurological or related complications of CAR-T and bispecific TCE therapies.

Introduction Lymphoid malignancy (LM) is a heterogenous neoplasm with respect to biology, aggressiveness, and treatment with over 100 subtypes, including Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL), and multiple myeloma (MM). Genome-wide association studies have identified common variants associated with risk of specific LM subtypes, but less is known about the contribution of rare inherited pathogenic variants (PV) in the genetic architecture of LM risk. Rare PV have been shown to contribute to the genetic architecture of solid tumor cancer risk, many of which have been found in genes that are important to the DNA-damage repair (DDR) pathway (e.g., BRCA1, BRCA1, ATM). Here, we investigated the prevalence of PV in cancer predisposition genes regularly included on multi-gene panel testing based on NCCN guidelines and correlated with risk of LM overall and by common subtypes. Methods In this association study, cases were newly diagnosed lymphomas (excluding chronic lymphocytic leukemia) from Mayo Clinic who were enrolled between 2002 and 2015 in the Lymphoma SPORE Molecular Epidemiology Resource (MER) and MM from Mayo Clinic enrolled primarily between 1998 and 2022 in a clinical registry. Controls were from the Mayo Clinic Biobank who were enrolled between 2009 and 2016, from which we excluded individuals with a history of hematologic malignancy. All participants provided a blood sample for whole exome sequencing, performed by Regeneron on an Illumina NovaSeq panel (mean coverage of 48X). Variants were called using GATK v4 and variant annotation was performed using BioR. All loss-of-function variants (i.e., nonsense, frameshift, and consensus splice sites) and pathogenic missense in 19 cancer predisposition genes with a minor allele frequency < 0.5% were included in the analyses. Logistic regression was used to estimate odds ratio (OR) and 95% confidence intervals (CI) for the association between mutation status by gene (burden test) and risk of LM overall, and by subtype that had more than 5 mutation carriers. All analyses were adjusted for age (at diagnosis for cases and at enrollment for controls) and sex. Results A total of 6990 cases and 42432 controls were included. Median age was 63 years for both cases and controls (case range 18-94 years, control range 18-99 years). Males accounted for 58.5% (n=4090) of the cases and 41.7% (n=17762) of the controls. MM accounted for 31% (n=2138) of the cases, followed by diffuse large B-cell lymphoma (DLBCL, n=1146) and follicular lymphoma (FL, n=1132) each accounting for 16% of cases. CHEK2 (1.0%), ATM (0.4%), BRCA2 (0.4%), and BRCA1 (0.3%) had the most PV carriers in controls; these frequencies are in the range of published control populations. A total of 1816 (3.7%) individuals had a PV across the 19 genes, with 4.7% of cases and 3.5% of controls carrying any PV (OR=1.34, 95% CI: 1.18-1.51). ATM (OR=1.86, 95% CI: 1.36-2.49), CHEK2 (OR=1.74, 95% CI: 1.42-2.13) and TP53 (OR=9.07, 95% CI: 4.51-18.87) were all significantly associated with increased risk of LM overall (Figure 1). When investigating subtypes (Table 1), CHEK2 (OR=1.93, 95% CI: 1.23-2.89) and TP53(OR=10.97, 95% CI: 3.06-31.43) were significantly associated with DLBCL. ATM (OR=2.22, 95% CI: 1.13-3.90) was significantly associated with FL. ATM (OR=1.97, 95% CI: 1.16-3.12), CHEK2 (OR=1.75, 95% CI: 1.24-2.41) and TP53 (OR=7.67, 95% CI: 2.43-20.72) were significantly associated with MM and ATM (OR=8.62, 95% CI: 4.47-15.12), NBN (OR=6.94, 95% CI: 2.41-15.76) and TP53 (OR=38.30, 95% CI: 10.27-116.69) were significantly associated with mantle cell lymphoma (MCL). When subset to LM cases overall, there was no evidence of enrichment for young onset (age <60 years), male sex, or family history of hematologic malignancy between PV carriers and non-PV carriers. However, FL cases with an ATM PV tended to be less than 60 years (OR=3.21, P=0.09) compared to non- ATM PV carriers. Similarly, MM cases with a TP53 PV tended to be less than 60 years of age (OR=7.39, P=0.07) compared non-carriers. Discussion In this large case-control study, PV in established cancer predisposition genes were associated with increased risk of LM overall, demonstrating that rare inherited variants may play an important etiologic role. This study also suggests that PV in cancer predisposition genes may be subtype specific. These results will help inform LM risk for individuals who undergo genetic testing of cancer predisposition genes.

Introduction: Improvements in outcomes of patients with multiple myeloma (MM) depend on the use of regimens approved based on results from large phase III randomized controlled trials (RCTs) demonstrating their efficacy. However, many real-world (RW) patients would not have met the stringent RCTs inclusion criteria. Therefore, the effectiveness of these drugs in the RW setting is unknown. Understanding this efficacy-effectiveness gap is important to contextualize the expected outcomes in the current RW setting. Therefore, we conducted a retrospective population-based study to compare the efficacy versus effectiveness of registration RCTs with RW patients using standard of care (SoC) MM regimens for the primary outcomes of 1) progression free survival [PFS]; 2) overall survival [OS] and 3) serious adverse events (AEs). Methods: RW data was obtained from the Institute for Clinical Evaluative Sciences, an administrative database capturing all health records in the publicly funded health care system in Ontario, Canada. Adult patients treated between Jan 2007 to Dec 2020 with SoC regimens were included. Only regimens with corresponding registrational phase III RCTs which led to the public reimbursement in Ontario were included (lenalidomide/dex [Rd] and bortezomib/Rd [VRd] for newly diagnosed transplant ineligible patients, and relapsed MM (RRMM) regimens included carfilzomib/Rd [KRd], carfilzomib/dex [Kd], daratumumab/Rd [DRd], daratumumab/bortezomib/dex [DVd], pomalidomide/dex [Pd]). In the RW cohort, PFS was defined as the time from initiation of index regimen to death, initiation of subsequent MM treatment, or last follow-up, and patients remaining on the index regimen as last follow up were censored. Kaplan-Meier curves from pivotal phase 3 RCTs were manually digitized to provide individual patient-level estimates of PFS and OS. Meta-analyses were performed to compare the gap of PFS and OS outcomes of RW versus RCT patients, and effect estimates were summarized using hazard ratios (HR). The frequency of serious AE data was abstracted from published RCTs. Given that serious AEs in RCTs would have resulted in hospitalization, hospital admission during treatment with the index regimen was used as a surrogate for serious AEs in the RW cohort. Differences in RW and RCT safety outcomes were reported descriptively. Results & Discussion: A total of 3951 RW MM patients, treated with 7 standard of care MM regimens, were included. Baseline characteristics of patients in the RW and RCT cohorts are shown in table 1. Overall, patients in the RW cohort were older than in the RCTs. For relapsed regimens, there was a longer time between MM diagnosis and start of the regimen in the real-world versus RCT. With regards to the efficacy-effectiveness gap, MM patients treated in routine practise in the RW had a worse PFS despite overestimated of RW PFS compared to highly selected RCT patients for 6 of the 7 MM regimens evaluated, with a pooled HR of 1.44 (95% CI 1.34-1.54) in the meta-analysis (Figure 1A). Similarly, RW patients had a worse OS compared to RCT patients treated with 6 of the 7 regimens, with a pooled HR of 1.75 (95% ci 1.63-1.88) in the meta-analysis (Figure 1B). RRMM patients in the RW had higher rates of prior lenalidomide exposure compared to RCT patients. The only regimen which showed a trend towards performing better in the RW as compared to RCTs was Pd. The reason for this is likely multifactorial but perhaps patients included in the MM-003 RCT may have had more refractory MM (given the higher prior immunomodulatory drug exposure and longer time from diagnosis to treatment among Pd RCT patient) compared to RW patients in this study. With regards to safety, the percentage of patients with inpatient hospitalization during treatment in the real-world cohort and reported serious AEs in RCT were comparable (VRD 57% vs not reported [NR]; Rd 64% vs NR; Kd 57% vs 59%; KRd 53% vs 60%; DVd 36% vs NR; DRd 46% vs 49%; Pd 59% vs 61%). Conclusion: This is one the largest population-level studies highlighting the significant efficacy-effectiveness gap between registrational RCTs and RW usage of these regimens, with RW patients experiencing 44% worse PFS and 75% worse OS compared to RCT patients. Our data emphasize the importance of ongoing evaluation of RW data to contextualize effectiveness and toxicity of selected regimens in the clinic, and better inform both clinicians and patients for shared treatment decision making.

CONCLUSION The most widely used multiple myeloma (MM) staging system, the Revised International Staging System (R-ISS), is based on lactate dehydrogenase (LDH), albumin, high-risk genetic markers by FISH, and beta-2 microglobulin (B2M). However, it does not account for additional risk impacted by multiple genetic abnormalities, or the risk imparted by presence of gain of chromosome 1q, and most patients are staged as R-ISS Stage 2. Two new staging systems, the Mayo Additive Staging System (MASS), and the Second Revision of the International Staging System (R2-ISS) have been recently proposed. A comparison of the performance of these two systems has not previously been done. We aimed to externally demonstrate the application of these staging systems and compare their performances in a large, contemporary cohort of patients in the United States. We conducted a retrospective cohort study using the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database, comprising de-identified patient-level structured and unstructured data, curated via technology-enabled abstraction and originating from approximately 280 US cancer clinics (~800 sites of care). The study included newly diagnosed MM patients initiating treatment between January 1, 2016 and October 1, 2022. We used the Kaplan-Meier method to evaluate real-world overall survival (rwOS) and patients were followed from first-line treatment initiation (index date) until the first of death, end of the study period or last recorded activity. The log-rank test to compare survival curves across derived stages. Multivariable analysis was conducted using stratified Cox models to account for non-proportional hazards by age with covariate adjustment for race/ethnicity, sex, practice type (academic or community) and diagnosis year (2016-2019 vs 2020-2022). Discrimination and calibration were evaluated in crude models using Harrell's c-index and the Hosmer-Lemeshow goodness-of-fit test, respectively. There were 497 patients with MM included. Patient characteristics are listed in Panel A. The distribution of patients across R-ISS stages were as follows, 24%, 63% and 13% for Stage 1, 2 and 3 respectively. rwOS differed across R-ISS stage (log-rank p = 0.0006) and the median OS (OS) was not reached (NR), 63, and 37 months for R-ISS stage 1, 2, and 3, respectively. 34%, 35% and 31% for MASS 1, 2, and 3, respectively. The corresponding survival curves were significantly different (p < 0.0001), with associated mOS of 77, 61 and 45 months for MASS stages 1, 2, and 3, respectively. R2-ISS includes four risk categories (stages I-IV) and in our cohort, 20% (n = 100) were stage I (low), 126 (25%) were stage II (low-intermediate), 229 (46%) were stage III (intermediate), and 42 (9%) were stage IV (high). Survival across stages were significantly different (p<0.0001), though the survival curves for low and low-intermediate, and intermediate-high and high, were clustered, suggesting comparable outcomes in stages I-II and stages III-IV. mOS for R2-ISS stages I, II, III, and IV was NR, 69, 50 and 51 months respectively (Panel B). In fully adjusted analyses, as compared to MASS I, the hazards of death were 2.0 (95% CI 1.3-3.2) for MASS II and 2.7 (1.7-4.2) for MASS III. The hazards of death were similar for R2-ISS low and low-int (HR for low-int vs low: 1.2 [0.7, 2.3]). As compared to R2-ISS low, the hazards of death were similarly higher for int-high and high (HRs: 2.4 [1.4, 4.1] and 2.6 [1.3, 5.2], respectively). Discrimination and calibration were similar across all staging systems (c = 0.6, and Hosmer-Lemeshow p>0.05 for all three staging systems). Application of contemporary MM staging systems in a large cohort of US patients shows that they are prognostic for OS in MM. MASS demonstrated a greater separation for OS across stages, whereas R2-ISS intermediate-high and high were largely overlapping. Although our results demonstrate similar accuracy and reliability of MASS and R2-ISS, the discrimination of patients across different stages seen with the newer staging systems, as opposed to R-ISS, calls for greater use of these newer staging systems in routine clinical practice.

Background: Frailty is a state of decreased reserve affecting multiple organ systems, thereby increasing vulnerability to stressors. Several tools have been proposed to measure frailty in multiple myeloma (MM), such as the IMWG frailty index, and the Revised Myeloma Comorbidity Index. However, these are based on clinical trial datasets, and include chronological age as one of the indicators of frailty. A frailty index based on the principle of accumulation of health deficits (Rockwood doi:10.1093/gerona/62.7.738), provides a measure of physiologic age. This index can be readily calculated using various combinations of health deficits and has been shown to predict outcomes in several populations. Social support has been associated with improved outcomes in various populations, however its impact on survival in patients with MM has not been well studied. The objective of this study was to assess the impact of frailty measured by a deficit accumulation frailty index and the impact of relationship status on outcomes in patients with newly diagnosed MM. Methods: This is a retrospective study including patients diagnosed with MM between January 6 th, 2005, and September 19 th, 2018. We calculated a deficit accumulation frailty index using previously published methods (McNallan et. al doi.org/10.1016/j.ahj.2013.07.008, Searle et al. doi.org/10.1186/1471-2318-8-24). We used the electronic medical record system at Mayo Clinic in Rochester, MN, to extract data on activities of daily living (14 items) provided by patient-completed questionnaires, and data on comorbidities as recorded by treating providers (16 items), within 6 months prior to diagnosis. Each item was scored as 0, 0.5, or 1, with 1 indicating the presence of deficit (Table 1). The frailty index was defined as the sum of individual scores divided that by the total number of non-missing items. Patients who had N >2 missing items were excluded. Patients with a frailty index ≥0.15 were considered frail. We also extracted data on self-reported relationship status within 6 months prior to diagnosis. Variables were compared between groups using Fisher's exact test and Wilcoxon signed-rank test for categorical and continuous variables, respectively. Univariate and multivariate analysis were performed using Cox proportional hazard models. Overall survival (OS) was estimated using the Kaplan-Meier method and compared between groups using the Log-rank test. P values <0.05 were considered statistically significant. Results: We included 578 patients. Median age was 67 (interquartile range: 59-74) years, and 40% were female. Among all patients, 226 (39%) were frail. Compared to fit patients, patients who were frail were older (median age: 70 vs. 65 years, P<0.001) and more likely to have International Staging System (ISS) III (vs. I/II) disease (47% vs. 27%, P<0.001) and ECOG performance status ≥2 (vs. 0 or 1) (45% vs. 17%, P<0.001). There was no difference in R-ISS III disease or presence of high-risk cytogenetic abnormalities between fit and frail patients. Median OS was 7.6 and 4.1 years in fit and frail patient, respectively (P<0.001). Physician assessed ECOG performance status was available for 268 patients. Among patients with ECOG performance status 0 or 1 (193 patients), 136 (70%) were fit, and 57 (30%) were frail. The OS was 8.3 and 4.6 years in the 2 groups, respectively (P=0.006) (table 2). On multivariate analysis including age, frailty status, and R-ISS stage (III vs. I/II), all were associated with OS with frailty's hazard ratio (HR): 1.4 (95%CI [1.1-1.8]), P=0.004; the HR was 1.4 (95%CI [1.1-1.9]), P=0.02, when analysis was restricted to patients ≥60 years. Among all patients, those who were married or in a committed relationship (474 patients) had improved survival (median OS: 7.0 vs. 3.7 years, respectively, P<0.001) compared to patients who were divorced/separated, widowed, or single (96 patients). On multivariate analysis, which included age, R-ISS III, frailty status, and relationship status, all were associated with OS. The HR for relationship status was 1.4 (95%CI [1.0-1.8]), P=0.0465. Conclusion: Frailty, defined by the deficit accumulation frailty index, is independently associated with decreased survival in patients with newly diagnosed MM. Being married or in a committed relationship is associated with improved survival independent of age, disease stage, and frailty.

Abstract Background: Precursor plasma cell disorders such as monoclonal gammopathy of undetermined significance (MGUS) always precede the development of active malignancies such as multiple myeloma (MM). There is a need for novel biomarkers to identify those patients with such precursor plasma cell disorders who rapidly progress to MM. Plasma-derived extracellular vesicles (EVs) may serve as a reservoir of potential biomarkers that can shed light on the pathogenesis and disease biology in MM. Methods: This study isolated small EVs (SEVs) and large EVs (LEVs) from the platelet-poor peripheral blood plasma of MGUS (n=9) and MM (n=12) patients using the size exclusion chromatography (SEC)-based method and evaluated their proteome using a label-free proteomics workflow. Results: In total, 2,055 proteins were identified in SEVs, while 2,794 proteins were identified in LEVs. The transferrin receptor (TFRC or CD71) protein was upregulated in both populations of EVs derived from MM patients compared to MGUS patients and was of prognostic significance. Similarly, three isoforms of serum amyloid A (SAA) protein, SAA1, SAA2, and SAA4, were also highly upregulated in SEVs within MM patients relative to MGUS patients. Finally, CD40 expression was also higher within the LEVs derived from MM patients than MGUS patients. Conclusions: This study demonstrates the feasibility of successfully isolating both SEVs and LEVs from the peripheral blood of patients with plasma cell disorders and quantifying protein biomarkers within these EVs that could be of prognostic and diagnostic interest.