Kumar, Shaji K

SummaryWe sought to dissect the tumour microenvironment in a small cohort (N = 10) of patients with POEMS at diagnosis and after therapy using mass cytometry. We included 10 MGUS patients as controls. We identified 29 immune cell subsets in the CD45+ and CD3+ compartments. Double positive T cells and PD‐1 positive CD4 T cells were expanded and naïve CD4 T cells were decreased in the bone marrow of patients with newly diagnosed/progressing POEMS. These findings provide evidence for possible antigenic‐driven selection as a driver of disease pathogenesis in POEMS.

Background Thromboprophylaxis is routinely used with lenalidomide‐based regimens in multiple myeloma because of a substantial risk of venous thromboembolism (VTE). However, little is known about the incidence of VTE with contemporary lenalidomide‐based regimens. The objective of the current study was to estimate the incidence of VTE despite thromboprophylaxis with currently used lenalidomide‐based regimens in patients with myeloma. Methods The Ovid MEDLINE, Embase, and Cochrane databases were queried from study inception to January 2019 for keywords to cover the following concepts: “lenalidomide,” “venous thromboembolism,” and “multiple myeloma.” Phase 1, 2, and 3 clinical trials evaluating lenalidomide‐based regimens with thromboprophylaxis were included. The pooled incidence rate of VTE was estimated using a random‐effects model. Results The search generated 1372 citations, with 51 clinical trials and 9069 patients included for analysis. The most common thromboprophylaxis agents were aspirin, low‐molecular‐weight heparin or warfarin, administered either per risk‐stratification or at investigators' discretion. The pooled incidence of VTE in trials of patients who had newly diagnosed and relapsed/refractory myeloma was 6.2% (95% CI, 5.4%‐7.1%) over median treatment durations ranging from 2 to 34 cycles, which translated into 1.2 VTE events per 100 patient‐cycles (95% CI, 0.9‐1.7 VTE events per 100 patient‐cycles). Among contemporary regimens, the risk of VTE was low with combined lenalidomide and low‐dose dexamethasone (0.2 [95% CI, 0.1‐0.6] events/100 patient‐cycles) and lenalidomide maintenance (0.0 [95% CI, 0.0‐0.7] events per 100 patient‐cycles). VTE risk was higher with combined lenalidomide and low‐dose dexamethasone plus proteasome inhibitors (1.3 [95% CI, 0.7‐2.3] events per 100 patient‐cycles). Conclusions Despite adequate thromboprophylaxis, lenalidomide‐based regimens have a substantial risk of VTE in controlled clinical trial settings. Further studies are needed on new thromboprophylaxis strategies with regimens that have a high VTE risk.

The treatment of multiple myeloma has evolved markedly in the last decade, but mortality remains high, emphasizing the need for more effective therapies. Daratumumab, a fully human monoclonal antibody targeting CD38, has shown clinical efficacy in relapsed/refractory multiple myeloma both as monotherapy and in combination with other drugs, including novel agents. More recently, promising results have been reported in patients with untreated newly diagnosed multiple myeloma (NDMM). Clinical trials thus far have shown enhanced efficacy and tolerability of several daratumumab-based combinations in both transplant ineligible and eligible patients, without compromising transplant ability. However, benefit in high-risk subpopulations is still unclear. A subcutaneous formulation of daratumumab has been introduced to decrease the risk of infusion reactions, with preliminary results showing non-inferior efficacy. The antimyeloma activity of daratumumab is achieved through multiple mechanisms including direct, Fc-dependent, and immunomodulatory mechanisms. Enhanced efficacy of daratumumab in combination with immunomodulatory drugs and proteasome inhibitors is supported by preclinical data showing synergism. This review will focus on the role of daratumumab in untreated NDMM patients, highlighting the results of major clinical trials, and listing ongoing trials that are evaluating various daratumumab-based combinations in this setting.

High-dose therapy (HDT) and autologous stem-cell transplantation (ASCT) has historically been an essential part of multiple myeloma (MM) management since early studies demonstrated its efficacy in relapsed disease, and subsequent phase III trials demonstrated better responses and improved survival with this modality compared with standard chemotherapy. With further advances in the MM treatment landscape, including the development of potent novel agents, there has been an increasing debate around various aspects of ASCT, including the optimal timing, role of single versus tandem ASCT, and the practice of consolidation and maintenance therapy post-ASCT. Routine incorporation of the novel agents at each of the treatment phases, induction, consolidation when used, and maintenance has led to better responses as reflected by increasing rates of minimal residual disease (MRD) negativity, longer progression-free survival (PFS) with improvement in overall survival (OS) and in some of the trials. The phase III trials over the last decade have provided significant clarity on the current approach, and have raised important questions regarding the applicability of this modality in all patients. This review aims to summarize the latest literature in the field and discusses how these findings impact the practice of ASCT today.

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.

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.