Go, Ronald S.

SummaryIbrutinib‐related data in Waldenström macroglobulinaemia (WM) remain sparse, particularly outside of trials. We report on 80 patients [previously treated, n = 67 (84%), treatment‐naïve, n = 13 (16%)] with WM, evaluated consecutively at Mayo Clinic, who received ibrutinib off‐study after its approval in 2015 for WM. Overall response rate (ORR) was 91%; major‐response rate (MRR) was 78%. The median time to first response and best response was 2·9 [95% confidence interval (CI): 2–4] and 5·7 (95% CI: 4–12) months, respectively. The median follow‐up was 19 (95% CI: 14–21) months; 18‐month progression‐free survival (PFS) was 82%. The median time on therapy was 12·5 (95% CI: 9·3–16·7) months, and the median duration‐of‐response was 32 (range: 23–32) months. Twenty‐five patients (31%) had discontinued therapy at last follow‐up (68% due to treatment‐related toxicities) and 18% of patients required dose reduction. Fatigue (12%) and atrial‐fibrillation (11%) were common non‐haematological toxicities. IgM rebound occurred in 36% of patients who abruptly discontinued ibrutinib. Following ibrutinib discontinuation, 84% of patients received subsequent treatment, achieving an ORR of 57% and MRR of 50%. The median PFS from commencement of subsequent salvage therapy was 18 months. Ibrutinib therapy, outside of clinical trials, is effective in WM, but is associated with toxicities and challenges, including IgM rebound and a high drug discontinuation rate for reasons other than disease progression.

Summary Improvement in survival in Light chain (AL) amyloidosis has been seen over recent decades, enabling more patients to achieve long‐term survival. Patients with AL amyloidosis who survived ≥10 years from time of diagnosis ( n = 186) were the subject of this study. Ten‐year survivors represented 22% of the total population. These patients were characterized by favourable patient, organ and plasma cell features. Of note, trisomies were less common among 10‐year survivors compared to those who did not survive to 10 years. All‐time best haematological response was complete response in 67%, very good partial response in 30%, partial response in 2% and no response in 1%, with 11% having received a consolidative strategy for inadequate response to first line therapy. The overall organ response rate to first‐line therapy was 76%, which increased to 86% when considering subsequent line(s) of therapy. Forty‐seven percent of the 10‐year survivors did not require a second‐line therapy. The median treatment‐free survival (TFS) among the 10‐year survivors was 10·5 years (interquartile range 7·4‐12·2). On multivariate analysis independent predictors for TFS were the achievement of complete haematological response and lack of cardiac involvement. Long‐term survivors are increasingly seen in AL amyloidosis and present distinct patient, organ and clonal disease features.

AbstractObjectivesDescribe the clinical presentation, treatment, and outcomes of postsurgical thrombotic microangiopathy (TMA).MethodsIn this retrospective study, records of individuals diagnosed with TMA developing within 30 days of a surgical procedure at Mayo Clinic from 2000 to 2016 were reviewed. Available literature regarding postsurgical TMA was comparatively reviewed.ResultsTwenty patients were diagnosed with TMA developing within 30 (median 6.5, range (1‐28)) days) following a procedure. Preceding procedures included orthopedic (n = 4), vascular (n = 4), abdominal (n = 8), thoracic (n = 2), and other (n = 2). Review of the literature identified 65 patients with postsurgical TMA and cardiovascular procedures were the most common preceding surgery. The majority of patients in the current cohort and literature were treated with therapeutic plasma exchange (TPE). Among the evaluable patients in the current cohort, 100% demonstrated response to TPE; however, 25% required the addition of other therapy including eculizumab to maintain a response 80% of patients in the literature demonstrated a response to TPE.ConclusionsAlthough rare, early recognition and treatment of postsurgical TMA can lead to good outcomes. More research is necessary to determine the underlying pathophysiology and optimal treatment for postsurgical TMA.

BackgroundThere exist insufficient data characterizing patients with multiple myeloma (MM) who experienced prolonged survival. A population‐based analysis of long‐term survivors was conducted to investigate the roles of sociodemographic factors and upfront stem cell transplantation (SCT).MethodsThe National Cancer Data Base is a US cancer database of approximately 34 million patients from >1500 cancer centers. Patients with MM were identified using the International Classification of Diseases for Oncology (ICD‐O) code 9732 from January 2004 to December 2006 and were divided into 4 groups based on overall survival (OS). Sociodemographic characteristics, treatment facility, and use of SCT were recorded. The univariate and multivariate analyses were performed using multiple logistic regression and Pearson chi‐square tests.ResultsA total of 26,986 patients with MM were identified. The median OS was 2.74 years. The majority of patients were male (54%), white (77%), insured (93%) and otherwise healthy (78%), lived in a metropolitan area (82%), were of high income (66%) and educational (58%) levels, and received treatment at nonacademic facilities (63%). Upfront SCT was used in 10% of patients. One in 6 patients (16%) were long‐term survivors (group 4). When comparing group 4 (OS of ≥8.22 years) with the other groups (OS of <8.22 years), young age, female sex, high income and educational levels, residence in a rural area, insured status, no comorbidity, receipt of upfront SCT, and treatment at high‐volume facilities were associated with long‐term survival.ConclusionsKey differences in sociodemographic characteristics, patient volume at treatment facilities, and upfront SCT were associated with long‐term survival. Improvements in health care access and health literacy, upfront SCT, and treatment at high‐volume facilities might prolong patient survival.

Abstract The high-risk abnormality del(17p) can be detected by fluorescence in situ hybridization on malignant plasma cells (PCs) and has an adverse prognostic impact in patients with multiple myeloma (MM). Patients with del(17p) have reduced overall survival (OS). Patients who acquire del(17p) later during the disease course are not well described. The disease characteristics at diagnosis predicting for acquired del(17p) and its overall impact on patient survival is not known. We compared 76 patients with MM who were negative for del(17p) at diagnosis and acquired it later with 152 control MM patients who did not acquire del(17p) at a comparable time point. Patients acquired del(17p) at a median of 35.6 months (range, 4.6-116.1 months) from diagnosis of MM after a median of 2 lines of therapy (range, 1-10 lines of therapy). When compared with controls, patients with acquired del(17p) had shorter median progression-free survival (PFS) (30.1 vs 23.0 months; P = .032) and OS (106.1 vs 68.2 months; P &lt; .001) from diagnosis. After the detection of del(17p), the median PFS was 5.4 months and the median OS was 18.1 months. High lactate dehydrogenase level (odds ratio [OR], 3.69; 95% confidence interval [CI], 1.11-12.24) and presence of t(4;14) (OR, 2.66; 95% CI, 1.09-6.48) or any high-risk translocation (OR, 2.23; 95% CI, 1.00-4.95) at diagnosis predicted acquisition of del(17p). High PC proliferative rate predicted shorter OS from detection of del(17p) (hazard ratio, 2.28; 95% CI, 1.31-3.96; P = .004). Our study shows that acquisition of del(17p) is an important molecular event associated with reduction in OS in MM. Certain baseline factors may predict acquisition of del(17p). This needs validation in prospective data sets.

Background:Venetoclax is a B cell lymphoma 2 (BCL‐2) inhibitor that has shown activity as a single agent and in combination with other therapies in patients with multiple myeloma, particularly those harboring t(11;14) associated with high BCL‐2 expression. Although early clinical trial data is encouraging (monotherapy response rate of 21% and 40% amongst t(11;14) and a response rate of 97% when used in combination with bortezomib and dexamethasone), data on outcomes in patients treated outside of clinical trial setting are sparse.Aims:We aimed to identify the efficacy of venetoclax in patients with multiple myeloma treated outside clinical trial.Methods:We conducted a retrospective review of all patients with multiple myeloma treated with venetoclax between December 2016 and February of 2019 at the Mayo Clinic outside of a clinical trial setting.Results:A total of 29 patients that were treated with venetoclax for relapsed or refractory multiple myeloma were identified. Characteristics of the cohort are reported in Table 1. Two thirds of the cohort had t(11;14) detected on cytogenetic studies and 48% (n = 14) had presence of high risk abnormalities. Median number of prior therapies was 6 (range 1–15) and 21% (n = 6) of patients had received ≥10 prior lines of therapy. Eighty three percent (n = 24) of patients had received prior autologous transplant and 76% (n = 22) were penta refractory or exposed. Median time from diagnosis of myeloma to initiation of venetoclax therapy was 5.3 years (range 0.8–23.6 years).Venetoclax used as monotherapy or a doublet in combination with dexamethasone in 59% (n = 17) of patients and a triplet or quadruplet in 41% (n = 12) given at 800 mg (55%) or 400 mg (35%) daily. Triplet and quadruplet regimens combined venetoclax with a variety of proteasome inhibitors or daratumumab. One patient had a quadruplet of venetoclax, carfilzomib, pomalidomide and dexamethasone. 93% (n = 27) patients were refractory to at least on proteasome inhibitor and immunomodulatory drug. Dose titration and escalation was used in 31% (n = 9) of patients. None of the patients experienced tumor lysis syndrome. At last follow‐up 55% (n = 16) of patients remain on venetoclax therapy. Overall response rate in the 24 patients evaluable for response was 46% (21% CR, 8% VGPR, 17% PR). Patients with t(11;14) had a numerically higher response rate than those without (50% vs 33%, p = 0.64). Patients with high risk cytogenetic abnormalities were less likely to respond (ORR 69% for standard risk vs 18% for high risk, p = 0.019). Median time to response was 2.6 months (range 1.1–6.9 months). Median duration of response was 5.2 months (range 2.2–12.9 months). After a median follow‐up time of 7.2 months for the cohort, the median PFS and OS are 5.8 and 14.6 months, respectively, Figure 1A/B. High risk cytogenetic abnormalities were associated with a shorter PFS (median PFS 3 months vs 14 months for standard risk, p = 0.002). The outcomes with venetoclax monotherapy and combination therapies are reported separately in the Table.Summary/Conclusion:Venetoclax is an effective oral agent in relapsed and/or refractory myeloma and can produce deep and durable responses in heavily pretreated patients. Further studies are needed to elucidate its role earlier in the disease and its effectiveness in combination with other anti‐myeloma therapies.image

Background:Previous literature has established “long‐term survivors” as patients who survive greater than 10 years from diagnosis of active multiple myeloma (MM). With the rapid discovery and evolving use of novel therapeutic agents, a greater proportion of patients are reaching this milestone. Although these patients share in their extended survival, they also constitute a heterogeneous group in terms of treatments and outcomes.Aims:The aim of this study is to examine a large cohort of long‐term survivors with protracted follow‐up as an attempt to identify a subset of patients within ten‐year survivors who have longstanding disease remission, and examine the predictors of their especially exceptional prognosis.Methods:All patients with active MM evaluated at Mayo Clinic, Rochester between January 1, 1999 and July 1, 2008 were included in the study. Patients with MGUS, smoldering MM, and solitary plasmacytoma were excluded. The overall survival (OS) was calculated from time of symptomatic disease requiring treatment. Patients with greater than 10 year survival from diagnosis were then divided into three cohorts based upon treatment and remission status: Cohort 1 included patients off therapy ≥ 5 years and in sustained remission, Cohort 2 included patients on maintenance therapy ≥ 5 years and in sustained remission, and Cohort 3 included patients who had relapsed within the past 5 years. Differences between the groups were compared using Wilcoxon, Chi‐square, and Fisher's exact test as applicable. “Early” stem cell transplant was defined as patients who received a stem cell transplant within one year of diagnosis.Results:During the time frame of the study, 2,125 patients were identified who fulfilled the diagnostic criteria for active MM. Three‐hundred ninety nine (19%) had survived at least 10 years from diagnosis. Among these patients, based on the available data regarding remission and ongoing treatment status, 332 patients were categorized into three cohorts, seen in Table 1. Sixty patients (18% of long‐term survivors) comprised Cohort 1, 48 patients (14% of long‐term survivors) comprised Cohort 2, and 224 patients (68% of long‐term survivors) comprised Cohort 3. Sex difference was statistically significant between the groups, with more females constituting Cohorts 1 and 2 (p = 0.03). Within Cohort 1, 77% of patients underwent an autologous stem cell transplant (ASCT). The median progression free survival following ASCT in this cohort was not reached (95% CI 15–NR, p < 0.001). In addition, patients in Cohort 1 and Cohort 2 were more likely to undergo an early ASCT as compared to patients in Cohort 3 (p = 0.002). There were no significant differences in high or intermediate risk FISH/cytogenetics at diagnosis, ISS at diagnosis, or induction therapies used at diagnosis among the three groups.Summary/Conclusion:Our study identified a small subset (3% of all patients diagnosed with active MM) of long‐term survivors who are off of therapy and remain in sustained longstanding remission. Female sex, progression free survival following ASCT, and receiving an early ASCT were factors that portended a positive prognosis amongst long term survivors.image

6596 Background: Several previous systematic reviews and meta-analyses have attempted to summarize toxicity of Immune checkpoint inhibitors (ICIs). However, very soon after each one of these reviews has been published, it became outdated. ICIs are currently used in 14 different cancers and data is rapidly evolving from new clinical trials. A living Systematic review, which is defined as a systematic review that is continually updated to incorporate relevant new evidence as it becomes available, is necessary in this situations. Therefore, we performed an updated systematic review and a meta-analysis which will serve as a foundation of a living Systematic review. Methods: MEDLINE, EMBASE and Cochrane were searched to identify phase 2 and 3 RCTs of PD-1/PD-L1 ICIs. Included studies compared either immunotherapy alone or combination with existing standard of care treatment and reported data for AE’s of interest. DerSimonian-Laird random effects Meta-Analysis was performed to derive pooled odds Ratio (OR) estimates for AE’s of interest. An infrastructure of a living systematic review is being developed and it includes monthly literature searches, cumulative meta-analysis and an online reporting platform. Results: We screened 6746 studies and 31 phase 3 and 2 phase 2 RCTs (n = 21,421) were included in the analysis. 22 RCTs used PD-1/PD-L1 ICIs as a single agent and 11 as a combination therapy. Selected toxicity estimates are summarized in a table. Conclusions: The meta-analysis updates previously published toxicity estimates and provides additional information about the risk of toxicities in single versus combination regimens. We have initiated the first living systematic review in oncology that will be continuously updated, incorporating relevant new evidence as it becomes available, and will provide accurate and up to date toxicity estimates to support clinical decision making. [Table: see text]

6581 Background: While AC is recommended for all patients with stage IIA, IIB, and IIIA NSCLC, its use and benefit among the elderly population is unclear. Methods: We identified patients with stage IIA, IIB, or IIIA NSCLC using the National Cancer Database from 2006-2014. Patients were divided into age groups ≤65, 66-70, 71-75, 76-80, > 80 years. Trends in AC use, factors influencing AC administration, and outcomes associated with AC were studied. Results: Out of 27368 patients, 13464 received AC and 13904 did not. 11% had stage IIA disease, 50% had stage IIB disease and 39% had stage IIIA disease. AC use was lower with increasing age (49% age ≤65 vs. 3% age > 80 (P < 0.0001)). Temporal use of chemotherapy for each age group was unchanged from 2006-2014. In multivariate logistic regression analysis, factors predictive of lower AC use were older age, Medicare or Medicaid insurance, academic center, and higher Charlson Comorbidity Index (CCI). Stage IIIA (OR 1.4, 95% CI 1.3-1.6) and Stage IIB (OR 1.3, 95% CI 1.2-1.4) had a higher chance of receiving AC than stage IIA. In a Cox proportional hazard model, younger age, female sex, academic center, private insurance, higher income, lower CCI, West coast center and AC were associated with better outcomes. When stratified by age and stage, AC was still associated with better survival (Table). Conclusions: AC utilization in stages IIA, IIB and IIIA NSCLC remains low, despite its association with improved survival in the elderly. Future clinical trials may be needed focused on elderly patients to establish the best regimen to optimize outcomes. [Table: see text]