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Purpose: Multiple myeloma (MM) patients with triple- and penta-refractory disease have a poor survival and limited treatment options. Selinexor, in combination with bortezomib and dexamethasone, demonstrated clinical activity in the STOMP study as well as in the BOSTON study in previously treated patients with disease refractory to a proteasome inhibitor (PI). Patients and Methods: Here, we report a real-world case series of 7 heavily pretreated MM patients who had been extensively pretreated with bortezomib and had disease refractory to PIs, including carfilzomib; who were administered a starting dose of 100 mg of selinexor, 20– 40 mg dexamethasone and 1.3 mg/m2 of bortezomib, each once weekly. The majority of these patients (6 patients, 86.0%) had penta-refractory disease, with 5 patients (71.4%) having disease refractory to bortezomib and carfilzomib, and all 7 patients having pomalidomide refractory disease. The median number of prior lines of therapy was 8 (range 4– 12). Results: The seven patients in this case series received selinexor for a median of 5 cycles (range 1– 10). Four patients (57.1%) had a dose reduction of selinexor. Five patients (71.4%) had a response, of which 2 (29.0%) had a very good partial response (VGPR) and 3 (43.0%) had a partial response (PR). One patient (14.3%) had stable disease (SD) and 1 (14.3%) had progressive disease (PD). There were no new safety signals. Conclusion: The selinexor, bortezomib, and dexamethasone triplet combination demonstrates activity in PI-resistant MM and patients with heavily pretreated MM with refractory disease and after multiple lines of therapy. [ABSTRACT FROM AUTHOR]

Summary: Multiple myeloma (MM) is a malignancy with varying survival outcomes and drivers of disease progression. Existing MM staging tools were developed using data from newly diagnosed patients. As patient characteristics and disease‐related factors change between diagnosis and the initiation of second‐line (2L) treatment, an unmet need exists for a tool that can evaluate risk of death at first relapse. We have developed a risk stratification algorithm (RSA) using data from patients with MM who were at 2L. Hazard ratios for independent predictors of overall survival (OS) were derived from a Cox models, and individual patient scores were calculated for total risk. K‐adaptive partitioning for survival was used to stratify patients into groups based on their scores. Relative risk doubled with ascending risk group; median OSs for patients in group 1 (lowest risk)–4 (highest risk) were 61·6, 29·6, 14·2 and 5·9 months, respectively. Differences in OS between risk groups were significant. Similar stratification was observed when the RSA was applied to an external validation data set. In conclusion, we have developed a validated RSA that can quantify total risk, frailty risk and disease aggressiveness risk, and stratify patients with MM at 2L into groups with profoundly different survival expectations. [ABSTRACT FROM AUTHOR]

The article presents a study on antigen excess detection by automated assays for free light chains. Topics discussed include role of free light chains (FLCs) in diagnosis, prognosis and follow-up of patients with monoclonal gammopathy; information on antigen excess detection system; and the issues relating to the multiple myeloma, a cancer that forms in a type of white blood cell.

The FIRST trial demonstrated that continuous therapy with lenalidomide and dexamethasone (Rd) prolongs overall survival (OS) and improves health-related quality of life (HRQoL) during the first 18 months of therapy in newly diagnosed multiple myeloma (NDMM) patients. However, patient-reported HRQoL data were not collected after 18 months. We therefore estimated HRQoL scores based on time-varying data collected during progression-free follow-up after 18 months. During the initial 18 months of Rd, observed changes from baseline were within the 95% confidence interval of the predictive models at 33 of 35 time points across 7 HRQoL scores. Predicted scores after 18 months of therapy showed that observed HRQoL improvements during therapy were maintained or improved. Therefore, the survival gain observed with Rd does not come at a cost of declining HRQoL during continuous therapy beyond 18 months, supporting long-term Rd as a standard of care for initial myeloma therapy. [ABSTRACT FROM AUTHOR]

To understand the long-term experience of patients receiving ide-cel chimeric antigen receptor T (CAR T) cell therapy for relapsed or refractory multiple myeloma in the pivotal phase 2 KarMMa trial. This qualitative study analyzed semi-structured patient interviews 6–24 months after ide-cel infusion. Thematic analysis with quantitative and longitudinal analyses explored patient perceptions of ide-cel treatment experience, advantages and disadvantages, and long-term health-related quality of life impact. Patient journeys were developed from narrative analysis of perceived treatment benefits with known remission length. Interviews with 45 patients 6–24 months postinfusion were analyzed; all reported ≥ 1 ide-cel treatment advantage, most often related to efficacy (n = 42/45, 93%), few or no side effects (n = 35/45, 78%), and avoidance of other treatments (n = 34/45, 76%). Patients generally reported 6-month improvements in physical health, functioning, emotional well-being, social life, and outlook on the future; these improvements mostly remained "stable" through 18 and 24 months. The most common patient journeys comprised physical, functioning, or emotional benefit with remission < 2 years. Longitudinal analysis of patient experiences showed sustained benefits and preference for ide-cel up to 24 months after treatment. Trial Registration Number and Date: NCT03361748. December 5, 2017. [Display omitted] • Patients preferred ide-cel to other treatments for efficacy and side effect profile. • Despite impactful side effects, patients still considered ide-cel advantageous. • Quality-of-life improved 6 months after treatment and stabilized through 24 months. • Patients would repeat their ide-cel treatment and recommend ide-cel to others. [ABSTRACT FROM AUTHOR]

The treatment of multiple myeloma is considered a continuously evolving paradigm as a result of the growing availability of new and highly effective drugs, including first- and second-generation proteasome inhibitors, immunomodulatory agents, and monoclonal antibodies. Clinical trials advocate long-term rather than short-term treatment schedules with combinations of these new anti–myeloma drug classes. Although the overall toxicity profile of the recommended regimens can be considered favorable, their increasing complexity and prolonged use warrant a heightened vigilance for early and late side effects, a priori because real-life patients can be more frail or present with 1 or more comorbidities. The treatment decision process, at diagnosis and at relapse, therefore requires myeloma physicians to carefully balance efficacy and toxicity profiles for each individual patient. Early and/or unnecessary tapering or treatment discontinuation for drug-related adverse events may not only reduce patients’ quality of life, but also negatively impact their outcome. Accurate knowledge in recognizing and managing the potential side effects of present-day treatment regimens is therefore a cornerstone in myeloma care. Using 5 case vignettes, we discuss how to prevent and manage the most common nonhematological adverse events of anti–myeloma treatment regimens containing proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies. [ABSTRACT FROM AUTHOR]

With increasing number of therapies available for the treatment of multiple myeloma, it is timely to examine the course of patients' journeys. We investigated patient characteristics, treatment durations and outcomes, and symptom burden across the treatment pathway in Belgium, France, Germany, Italy, Spain, Switzerland and the UK. In total, 435 physicians retrospectively reviewed 4997 patient charts. Profiles of patients diagnosed with multiple myeloma during the last 12 months were similar across countries; bone pain was the most common presentation. Median duration of first-line therapy was 6 months, followed by a median treatment-free interval of 10 months; both these decreased with increasing lines of therapy, as did time to progression. Depth of response, as assessed by the treating physician, also decreased with each additional line of therapy: 74% of patients achieved at least a very good partial response at first line, compared with only 11% at fifth line. Deeper responses were associated with longer time to progression, although these were physician-judged. Toxicities and co-morbidities increased with later treatment lines, and were more likely to have led to discontinuation of treatment. These real-world data provide an insight into patient outcomes and treatment decisions being made in clinical practice. [ABSTRACT FROM AUTHOR]

Bortezomib is a first-generation proteasome inhibitor used in the treatment of multiple myeloma (MM). A few reports have linked bortezomib exposure with the development of thrombotic microangiopathy (TMA). We describe a case of biopsy-proven renal thrombotic microangiopathy associated with the use of bortezomib in a 51-year-old man with IgG lambda MM. To our knowledge, this is the first biopsy-proven case. In addition, reexposure to bortezomib 18 months later was associated with recurrence of TMA. This supports a possible causal role of bortezomib. The exact mechanisms remain to be elucidated. [ABSTRACT FROM AUTHOR]

The article reports on lack of clinical benefit of zoledronic acid in myelofibrosis, a results of multi-center phase II trial. It states that bisphosphonates inhibitors of osteoclast mediated bone resorption and an established treatment for hypercalcemia of malignancy, osteoporosis and solid tumors. It mentions that zoledronic acid to provide benefit over treatment with the nitrogen-containing bisphosphonates (N-BPs) and has beneficial effect on blood counts became apparent after infusion.

To understand the experience of patients with relapsed and refractory multiple myeloma (RRMM) receiving idecabtagene vicleucel (ide-cel), a B-cell maturation antigen-directed chimeric antigen receptor T cell therapy, in the pivotal, phase 2 KarMMa trial. Optional semi-structured interviews before leukapheresis (pre-treatment) captured expectations and after ide-cel infusion (1, 2, and 3 months post-treatment), assessed treatment experience, ide-cel advantages/disadvantages, and health and well-being. In a mixed-method analysis, treatment experiences were categorized by clinical response status, health and well-being, and self-reported recovery after infusion. Pre-treatment interviews indicated unmet treatment needs. In post-treatment interviews, most patients reported the positives of ide-cel outweighed negatives (69%, n = 27/39). Most common advantages of ide-cel were efficacy (18–64%), favorable side-effect profile (46–68%), and recovery time (13–18%); most common disadvantages were related to side effects (13–20%). When analyzed by clinical response, patients most often had stringent complete or very good partial response and improved health and well-being with mild or severe recovery from the infusion (27/58, 47%). Most patients with minimal clinical response reported mild infusion recovery (5/6, 83%). Patient interviews before ide-cel treatment showed unmet needs in triple-class exposed RRMM. Post-treatment experiences generally favored ide-cel versus previously received treatments. [Display omitted] • Patient interviews before ide-cel treatment showed substantial unmet needs in RRMM. • Patients expressed prominent hopes for remission and improved health and well-being. • Patients reported positive impressions of treatment with ide-cel. • Advantages of treatment with ide-cel substantially outweighed disadvantages. • Patient journeys assessed patients' experiences in the context of several factors. [ABSTRACT FROM AUTHOR]

The author reflects on an article published in the previous issue of the periodical regarding improvement in progression-free survival, overall response rate, and overall survival with the addition of bortezomib to the lenalidomide-dexamethasone combination (VRd) compared with lenalidomide and dexamethasone for treatment of multiple myeloma. It mentions drugs and new treatment concepts are on the horizon of myeloma care such as passive immunotherapies targeting monoclonal antibodies.

Abstract: Background: Most patients with myelodysplastic syndromes (MDS) require transfusions at the risk of iron overload and associated organ damage, and death. Emerging evidence indicates that iron chelation therapy (ICT) could reduce mortality and improve survival in transfusion-dependent MDS patients, especially those classified as International Prognostic Scoring System (IPSS) Low or Intermediate-1 (Low/Int-1). Methods: Follow-up of a retrospective study. Sample included 127 Low/Int-1 MDS patients from 28 centers in Belgium. Statistical analysis stratified by duration (≥6 versus <6months) and quality of chelation (adequate versus weak). Results: Crude chelation rate was 63% but 88% among patients with serum ferritin ≥1000μg/L. Of the 80 chelated patients, 70% were chelated adequately mainly with deferasirox (26%) or deferasirox following deferoxamine (39%). Mortality was 70% among non-chelated, 40% among chelated, 32% among patients chelated ≥6m, and 30% among patients chelated adequately; with a trend toward reduced cardiac mortality in chelated patients. Overall, median overall survival (OS) was 10.2 years for chelated and 3.1 years for non-chelated patients (p <0.001). For patients chelated ≥6m or patients classified as adequately chelated, median OS was 10.5 years. Mortality increased as a function of average monthly transfusion intensity (HR=1.08, p =0.04) but was lower in patients receiving adequate chelation or chelation ≥6m (HR=0.24, p <0.001). Conclusion: Six or more months of adequate ICT is associated with markedly better overall survival. This suggests a possible survival benefit of ICT in transfusion-dependent patients with lower-risk MDS. [Copyright &y& Elsevier]

Objectives The phase 3 VISTA study ( NCT00111319) in transplant-ineligible myeloma patients demonstrated superior efficacy with bortezomib-melphalan-prednisone ( VMP; nine 6-wk cycles) vs. melphalan-prednisone ( MP) but also increased toxicity. Health-related quality of life ( HRQoL; exploratory endpoint) was evaluated using the European Organization for Research and Treatment of Cancer ( EORTC) Quality of Life Questionnaire ( QLQ-C30). The phase 3 VISTA study ( NCT00111319) in transplant-ineligible myeloma patients demonstrated superior efficacy with bortezomib-melphalan-prednisone ( VMP; nine 6-wk cycles) vs. melphalan-prednisone ( MP) but also increased toxicity. Health-related quality of life ( HRQoL; exploratory endpoint) was evaluated using the European Organization for Research and Treatment of Cancer ( EORTC) Quality of Life Questionnaire ( QLQ-C30). Methods EORTC QLQ-C30 was administered at screening, on day 1 of each cycle, at the end-of-treatment visit, and every 8 wk until progression. EORTC QLQ-C30 scores were evaluated among patients with a valid baseline and at least one post-baseline HRQoL assessment. Results At baseline, domain scores were similar between arms. By cycle 4, mean differences were clinically meaningful for most domains, indicating poorer health status with VMP. From cycle 5 onwards, improvements relative to baseline/ MP were observed for all domains with VMP. Mean scores were generally improved by the end-of-treatment assessment vs. baseline in both arms. Among responding patients, mean scores generally improved from time of response to end-of-treatment assessment, substantially driven by patients achieving complete response ( CR). Multivariate analysis showed a significant impact of duration of response/ CR on improving global health status, pain, and appetite loss scores. Analyses by bortezomib dose intensity indicated better HRQoL in patients receiving lower dose intensity. Conclusions These findings demonstrate clinically meaningful, transitory HRQoL decrements with VMP and relatively lower HRQoL vs. MP during early treatment cycles, associated with the expected additional toxicities. However, HRQoL is not compromised in the long term, recovering by the end-of-treatment visit to be comparable vs. MP. [ABSTRACT FROM AUTHOR]

Transfusion dependency and iron overload are common among patients with myelodysplastic syndromes (MDS) treated with red blood cell (RBC) transfusions. Transfusion dependency is associated with leukemic progression and shorter survival. Guidelines recommend iron chelation therapy to manage iron overload, however little is known about the chelation patterns in daily clinical practice. The objective of this multicenter, retrospective, cross-sectional, observational study was to evaluate iron status and its management in transfusion-dependent MDS patients. A total of 193 patient records from 29 centers were eligible for inclusion. Median patient age was 76, and median age at diagnosis of MDS was 74. Patients had received an average of 13.4 ± 7.6 RBC units in the past 4 months; 44% had received more than 50 units since their MDS diagnosis. Medium serum ferritin was 1,550 μg/L. Ninety patients (46.6%) received iron chelation therapy with either deferoxamine (41%), deferasirox (36%), and deferoxamine followed by deferasirox (23%). There were no statistically significant differences between chelated and nonchelated patients in terms of International Prognostic Scoring System (IPSS), French-American-British (FAB), and/or World Health Organization (WHO) status, though chelated patients had received more RBC transfusions ( p = 0.014). Iron chelation therapy may be underutilized in transfusion-dependent patients. Undertreatment can be reduced by complementing sound clinical judgment with the generally accepted guidelines of a serum ferritin level >1,000 μg/L and/or two or more RBC transfusions per month for the past year; considering patients on the basis of their IPSS, FAB, and/or WHO status; and individually tailored treatment regimens. Prospective randomized trials are necessary to establish causally the efficacy of iron chelation therapy in MDS. [ABSTRACT FROM AUTHOR]

Bone disease is a key presenting feature of myeloma. This post hoc analysis of the phase III VISTA trial of bortezomib plus melphalan-prednisone (VMP) vs. MP in previously untreated myeloma patients assessed clinical bone disease events and changes in alkaline phosphatase (ALP), a marker for osteoblast activation, and serum Dickkopf-1 (DKK-1), an inhibitor of osteoblast differentiation, during treatment. Patients received nine 6-wk cycles of VMP (bortezomib 1.3 mg/m, days 1, 4, 8, 11, 22, 25, 29, 32, cycles 1-4, days 1, 8, 22, 29, cycles 5-9, plus melphalan 9 mg/m and prednisone 60 mg/m, days 1-4, cycles 1-9; N = 344) or MP alone ( N = 338). Rates of bisphosphonates use during treatment (73% vs. 82%), progression because of worsening bone disease (3% vs. 11%), and requirement for subsequent radiotherapy (3% vs. 8%) were lower with VMP vs. MP. Median maximum ALP increase was significantly higher with VMP vs. MP overall (49.7% vs. 30.3%, P = 0.029), and higher by response group (complete response [CR]: 68.7% vs. 43.9%; partial response [PR]: 41.5% vs. 31.2%). Greater maximum ALP increase was strongly associated with achievement of CR ( P ≤ 0.0001) and CR/PR ( P ≤ 0.01). Median DKK-1 decreased with VMP by 694.4 pg/mL and increased with MP by 1273.3 pg/mL from baseline to day 4 ( P = 0.0069). Available radiologic data revealed evidence of bone healing in 6/11 VMP-treated patients, who achieved best responses of three CR, one PR, and two stable disease. These results suggest a positive effect of bortezomib on bone metabolism and potentially bone healing in myeloma. [ABSTRACT FROM AUTHOR]

Summary: Introduction of the proteasome inhibitor bortezomib and the immunomodulatory drugs thalidomide and lenalidomide has substantially improved outcomes for patients with multiple myeloma. As a result, these drugs have become cornerstones of current antimyeloma treatment regimens. However, after several years of clinical experience it has become apparent that peripheral neuropathy is the most common and potentially disabling non-haematological side-effect associated with thalidomide and bortezomib. Maximising treatment benefit while preserving quality of life therefore requires a careful balance between achieving optimum activity and minimising toxicity, including neuropathy, to further enhance efficacy. In this review, we discuss all aspects of drug-induced peripheral neuropathy in myeloma, with a particular focus on thalidomide and bortezomib. [ABSTRACT FROM AUTHOR]

Myelodysplastic syndromes (MDS) are clonal disorders of an immature hematopoietic progenitor cell. MDS hematopoiesis is characterized by abnormal progenitor proliferation and impaired cellular differentiation and maturation. As a consequence, the majority of MDS patients have a gradual evolution towards progressive bone marrow failure and/or leukemic transformation. The efforts made by several research groups during the last few years have helped to unravel the complex underlying pathogenesis of MDS. In this review, we will focus on the principal cytogenetic and molecular abnormalities involved in MDS initiation and disease progression. Additionally, we will discuss the influence of the marrow microenvironment on survival and proliferation of hematopoietic progenitors in MDS.The Hematology Journal (2003) 4, 303-309. doi:10.1038/sj.thj.6200315 [ABSTRACT FROM AUTHOR]

Amifostine is a phosphorylated aminothiol that has besides anti-oxidative and cytoprotective properties, also survival- and growth-promoting effects on hematopoietic progenitor cells. Clinical studies have demonstrated that infusions with amifostine are able to increase erythro-, myelo-, and thrombopoiesis in some patients with myelodysplastic syndromes (MDS). Since clonal and non-clonal progenitors can coexist in early phase MDS, we have studied if amifostine exerts a selective growth-promoting effect on clonal or non-clonal cells. For this purpose, purified CD34+ marrow progenitors from nine female MDS patients were grown in short- and long-term cultures. Clonality was studied on individual colonies using polymorphisms in the human androgen receptor assay (HUMARA) locus. Three patients had growth of residual non-clonal progenitors at baseline. Continuous exposure to 100 nM amifostine exerted a growth-promoting effect on progenitors in 50% of the patients. HUMARA patterns of individual colony-forming unit granulocyte macrophage (CFU-GM; 5/9) and 5 week long-term culture-initiating cells (LTC-IC; 2/9) were compared without and with amifostine exposure. We did not observe preferential stimulation of clonal or non-clonal progenitors. Based on these results, the stimulation of committed and immature progenitor growth in MDS by amifostine, is non-selective and does not favor nor suppress the growth of residual non-clonal cells. [Copyright &y& Elsevier]

CASSIOPEIA part 1 demonstrated superior depth of response and prolonged progression-free survival with daratumumab in combination with bortezomib, thalidomide, and dexamethasone (D-VTd) versus bortezomib, thalidomide, and dexamethasone (VTd) alone as an induction and consolidation regimen in transplant-eligible patients newly diagnosed with myeloma. In CASSIOPEIA part 2, daratumumab maintenance significantly improved progression-free survival and increased minimal residual disease (MRD)-negativity rates versus observation. Here, we report long-term study outcomes of CASSIOPEIA. CASSIOPEIA was a two-part, open-label, phase 3 trial of patients done at 111 European academic and community-based centres. Eligible patients were aged 18–65 years with transplant-eligible newly diagnosed myeloma and an Eastern Cooperative Oncology Group performance status of 0–2. In part 1, patients were randomly assigned (1:1) to pre-transplant induction and post-transplant consolidation with D-VTd or VTd. Patients who completed consolidation and had a partial response or better were re-randomised (1:1) to intravenous daratumumab maintenance (16 mg/kg every 8 weeks) or observation for 2 years or less. An interactive web-based system was used for both randomisations, and randomisation was balanced using permuted blocks of four. Stratification factors for the first randomisation (induction and consolidation phase) were site affiliation, International Staging System disease stage, and cytogenetic risk status. Stratification factors for the second randomisation (maintenance phase) were induction treatment and depth of response in the induction and consolidation phase. The primary endpoint for the induction and consolidation phase was the proportion of patients who achieved a stringent complete response after consolidation; results for this endpoint remain unchanged from those reported previously. The primary endpoint for the maintenance phase was progression-free survival from second randomisation. Efficacy evaluations in the induction and consolidation phase were done on the intention-to-treat population, which included all patients who underwent first randomisation, and efficacy analyses in the maintenance phase were done in the maintenance-specific intention-to-treat population, which included all patients who were randomly assigned at the second randomisation. This analysis represents the final data cutoff at the end of the study. The trial is registered with ClinicalTrials.gov , NCT02541383. Between Sept 22, 2015 and Aug 1, 2017, 1085 patients were randomly assigned to D-VTd (n=543) or VTd (n=542); between May 30, 2016 and June 18, 2018, 886 were re-randomised to daratumumab maintenance (n=442) or observation (n=444). At the clinical cutoff date, Sept 1, 2023, median follow-up was 80·1 months (IQR 75·7–85·6) from first randomisation and 70·6 months (66·4–76·1) from second randomisation. Progression-free survival from second randomisation was significantly longer in the daratumumab maintenance group than the observation-alone group (median not reached [95% CI 79·9–not estimable (NE)] vs 45·8 months [41·8–49·6]; HR 0·49 [95% CI 0·40–0·59]; p<0·0001); benefit was observed with D-VTd with daratumumab maintenance versus D-VTd with observation (median not reached [74·6–NE] vs 72·1 months [52·8–NE]; 0·76 [0·58–1·00]; p=0·048) and VTd with daratumumab maintenance versus VTd with observation (median not reached [66·9–NE] vs 32·7 months [27·2–38·7]; 0·34 [0·26–0·44]; p<0·0001). The long-term follow-up results of CASSIOPEIA show that including daratumumab in both the induction and consolidation phase and the maintenance phase led to superior progression-free survival outcomes. Our results confirm D-VTd induction and consolidation as a standard of care, and support the option of subsequent daratumumab monotherapy maintenance, for transplant-eligible patients with newly diagnosed multiple myeloma. Intergroupe Francophone du Myélome, Dutch-Belgian Cooperative Trial Group for Hematology Oncology, and Janssen Research & Development. [ABSTRACT FROM AUTHOR]

The clonality of mature peripheral blood-derived myeloid and lymphoid cells and bone marrow haemopoietic progenitors from 18 females with myelodysplasia (MDS) (five refractory anaemia, RA; one RA with ringed sideroblasts, RARS; three chronic myelomonocytic leukaemia, CMML; four RA with excess of blasts, RAEB; five RAEB in transformation, RAEB-t) was studied by X-chromosome inactivation analysis. Using the human androgen-receptor (HUMARA) assay, we analysed the clonal patterns of highly purified immature CD34+38- and committed CD34+38+ marrow-derived progenitors, and CD16+14- granulocytes, CD14+ monocytes, CD3+ T and CD19+ B lymphocytes from peripheral blood. In high-risk patients (RAEB, RAEB-t), clonality analysis was performed before and after intensive remission-induction treatment. All patients, except one with RA, had predominance of a single clone in their granulocytes and monocytes. The same clonal pattern was found in CD34+ progenitor cells. In contrast, CD3+ T lymphocytes were polyclonal or oligoclonal in 14/18 patients. X-chromosome inactivation patterns of CD19+ B cells were highly concordant with CD3+ T cells except for two patients (one RA, one CMML) with monoclonal B and polyclonal T lymphocytes, therefore suggesting a clonal mutation in a progenitor common to the myeloid and B-lymphoid lineages or the coexistence of MDS and a B-cell disorder in these particular patients. After high-dose non-myeloablative chemotherapy, polyclonal haemopoiesis was reinstalled in the mature myeloid cells and immature and committed marrow progenitors in three of four patients achieving complete haematological remission. Therefore we conclude that most haematological remissions in MDS are associated with restoration of polyclonal haemopoiesis. [ABSTRACT FROM AUTHOR]

This document provides a summary of a study on proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID), a kidney disease characterized by the presence of a monoclonal immunoglobulin. The study analyzed 15 patients with PGNMID in Belgium and The Netherlands and provided detailed information on patient demographics, kidney function, biopsy findings, and treatment regimens. The study found that patients who received clone-directed therapy had a better renal response compared to those who did not. Recurrence of PGNMID after kidney transplantation was common, and the study calls for further research to improve diagnostic and therapeutic strategies for this disease. [Extracted from the article]

This document presents the findings of a study comparing two treatments for patients with relapsed/refractory multiple myeloma (RRMM) who have been exposed to multiple classes of drugs. The study analyzed data from the KarMMa trial and the DREAMM-2 trial to compare the efficacy and health-related quality of life (HRQoL) outcomes of idecabtagene vicleucel (ide-cel) and belantamab mafodotin (bela-maf). The analysis showed that ide-cel had better overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and HRQoL outcomes compared to bela-maf in patients with RRMM. The results were consistent across different populations and sensitivity analyses. The study suggests that ide-cel may provide clinically relevant improvements in both clinical efficacy and HRQoL outcomes for patients with RRMM. [Extracted from the article]

Simple Summary: The emergence of new therapeutic agents for multiple myeloma (MM) over the last 2 decades has resulted in a significant improvement in overall survival (OS). However, this improvement might be associated with the increased incidence of second primary malignancies (SPMs). Most studies in the field reviewed patients that participated in phase 2–3 clinical studies, focusing on the incidence of SPMs. The current study evaluated the characteristics, management, and outcomes of MM patients diagnosed with SPMs outside clinical studies. In our study, we present real-world data of 165 MM patients that were diagnosed with SPM during the course of their disease; we offer detailed data on SPM characteristics and management, as well as valuable insights into the management of MM post-SPM detection and the actual prognosis of MM patients following SPM diagnosis. Background: There is an increased risk of second primary malignancies (SMPs) in patients with multiple myeloma (MM). This multinational 'real-world' retrospective study analyzed the characteristics and outcomes of MM patients that developed SPMs. Results: 165 patients were analyzed: 62.4% males; 8.5% with a prior cancer; 113 with solid SPMs, mainly ≥stage 2; and 52 with hematological SPM (hemato-SPM), mainly MDS/AML. Patients with hemato-SPM were younger (p = 0.05) and more frequently had a prior AutoHCT (p = 0.012). The time to SPM was shorter in the older (>65 years) and more heavily pretreated patients. One hundred patients were actively treated at the time of SPM detection. Treatment was discontinued in 52, substituted with another anti-MM therapy in 15, and continued in 33 patients. Treatment discontinuation was predominant in the patients diagnosed with hemato-SPM (76%). The median OS following SPM detection was 8.5 months, and the main cause of death was SPM. A poor ECOG status predicted a shorter OS (PS 3 vs. 0, HR = 5.74, 2.32–14.21, p < 0.001), whereas a normal hemoglobin level (HR = 0.43, 0.19–0.95, p = 0.037) predicted longer OS. Conclusions: With the continuing improvement in OS, a higher proportion of MM patients might develop SPM. The OS following SPM diagnosis is poor; hence, frequent surveillance and early detection are imperative to improve outcomes. [ABSTRACT FROM AUTHOR]

Background: No adequate data exist on the impact of multiple myeloma (MM) with extramedullary disease (EMD) after autograft and maintenance therapy. Methods: We identified 808 patients with newly diagnosed MM who received first autograft, of whom 107 had EMD (83 paraskeletal and 24 organ involvement), and who had been reported to the EBMT registry December 2018. Distribution according to type of involvement was similar between the treatment groups (p =.69). For EMD, 46 (40%) received thalidomide, 59 (51%) lenalidomide, and 11 (10%) bortezomib. Results: The median follow‐up from maintenance start was 44 months. Three‐year progression‐free survival (PFS) was 52% (48%–57%) for no EMD, 56% (44%–69%) for paraskeletal involvement, and 45% (22%–68%) for organ involvement (p =.146). Early PFS (within first year) appeared to be significantly worse for organ involvement (hazard ratio, 3.40), while no significant influence was found after first year from maintenance start. Three‐year overall survival (OS) was 81% (77%–84%), 88% (80%–96%), and 68% (47%–89%; p =.064), respectively. With thalidomide as reference, lenalidomide was significantly associated with better PFS and OS, whereas bortezomib appeared to improve outcome specifically in EMD. Conclusion: Lenalidomide maintenance is standard of care for MM without EMD, whereas extramedullary organ involvement remains a significant risk factor for worse outcome, especially for early events after maintenance start. [ABSTRACT FROM AUTHOR]

T-cell redirecting bispecific antibodies (BsAbs) and chimeric antigen receptor T cells (CAR T cells) have revolutionised multiple myeloma therapy, but adverse events such as cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome (ICANS), cytopenias, hypogammaglobulinaemia, and infections are common. This Policy Review presents a consensus from the European Myeloma Network on the prevention and management of these adverse events. Recommended measures include premedication, frequent assessing for symptoms and severity of cytokine release syndrome, step-up dosing for several BsAbs and some CAR T-cell therapies; corticosteroids; and tocilizumab in the case of cytokine release syndrome. Other anti-IL-6 drugs, high-dose corticosteroids, and anakinra might be considered in refractory cases. ICANS often arises concomitantly with cytokine release syndrome. Glucocorticosteroids in increasing doses are recommended if needed, as well as anakinra if the response is inadequate, and anticonvulsants if convulsions occur. Preventive measures against infections include antiviral and antibacterial drugs and administration of immunoglobulins. Treatment of infections and other complications is also addressed. [ABSTRACT FROM AUTHOR]

Background aims. Myelodysplastic syndromes (MDS) are a group of clonal stem cell disorders affecting the normal hematopoietic differentiation process and leading to abnormal maturation and differentiation of all blood cell lineages. Treatment options are limited, and there is an unmet medical need for effective therapies for patients with severe cytopenias. Methods. We demonstrate that multipotent adult progenitor cells (MAPC) improve the function of hematopoietic progenitors derived from human MDS bone marrow (BM) by significantly increasing the frequency of primitive progenitors as well as the number of myeloid colonies. Results. This effect was more pronounced in a non-contact culture, indicating the importance of soluble factors produced by the MAPC cells. Moreover, the cells did not stimulate the growth of the abnormal MDS clone, as shown by fluorescent in situ hybridization analysis on BM cells from patients with a known genetic abnormality. We also demonstrate that MAPC cells can provide stromal support for patient-derived hematopoietic cells. When MAPC cells were intravenously injected into a mouse model of MDS, they migrated to the site of injury and increased the hematopoietic function in diseased mice. Discussion. The preclinical studies undertaken here indicate an initial proof of concept for the use of MAPC cell therapy in patients with MDS-related severe and symptomatic cytopenias and should pave the way for further investigation in clinical trials. [ABSTRACT FROM AUTHOR]

Real-world data describing management of patients with multiple myeloma are limited. A European (Belgium, France, Germany, Italy, Spain, Switzerland, UK) observational chart review was conducted to address this. Physicians completed questionnaires for every patient seen during a 2-4-week observation period, regardless of treatment status. A total of 435 physicians completed 7635 cross-sectional chart reviews. Overall, 47% of patients were undergoing anti-tumour drug treatment, 42% had previously received ≥1 line of treatment and 12% had never received anti-tumour drug treatment. Of the patients treated by oncologists, onco-haematologists or internists, 95% received, or were expected to receive, at least one line of anti-tumour drug treatment, 61% received ≥2 lines of therapy and 38% received ≥3 lines. Except in the UK, the most commonly used induction therapies contained bortezomib (48%); lenalidomide was the most commonly used first-line maintenance therapy (45%) and second- and third-line agent overall (60% and 52% of patients at those lines, respectively). Bortezomib retreatment was used in 47% of patients who received it first line. Treatment patterns became more diverse with subsequent treatment lines. This study provides insight into real-world treatment patterns in Europe. While treatment practices are broadly similar across countries, some notable differences in the agents used exist. [ABSTRACT FROM AUTHOR]

Heavy chain diseases are rare variants of B-cell lymphomas that produce one of three classes of immunoglobulin heavy chains, without corresponding light chains. We describe two patients with asymptomatic heavy chain monoclonal gammopathy. The first patient is a 51-year-old woman with alpha paraprotein on serum immunofixation. The second case is a 46-year-old woman with gamma paraprotein on urine immunofixation. Neither patient had corresponding monoclonal light chains. Workup for multiple myeloma and lymphoma was negative in both patients. These two cases illustrate that heavy chain monoclonal gammopathy can exist in the absence of clinically apparent malignancy. Only a few reports of “heavy chain MGUS” have been described before. In the absence of specialized guidelines, we suggest a similar follow-up as for MGUS, while taking into account the higher probability of progression to lymphoma than to myeloma. [ABSTRACT FROM AUTHOR]

We provide updated guidance and standards for the indication, acquisition, and interpretation of [18F]FDG PET/CT for plasma cell disorders. Procedures and characteristics are reported and different scenarios for the clinical use of [18F]FDG PET/CT are discussed. This document provides clinicians and technicians with the best available evidence to support the implementation of [18F]FDG PET/CT imaging in routine practice and future research. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented which is concerned with patients with myelodysplastic syndrome and two clones with different interstitial deletions of the long arm of chromosome 5.

Background: Lenalidomide has tumoricidal and immunomodulatory activity against multiple myeloma. This double-blind, multicenter, randomized study compared melphalan–prednisone–lenalidomide induction followed by lenalidomide maintenance (MPR-R) with melphalan–prednisone–lenalidomide (MPR) or melphalan–prednisone (MP) followed by placebo in patients 65 years of age or older with newly diagnosed multiple myeloma. Methods: We randomly assigned patients who were ineligible for transplantation to receive MPR-R (nine 4-week cycles of MPR followed by lenalidomide maintenance therapy until a relapse or disease progression occurred [152 patients]) or to receive MPR (153 patients) or MP (154 patients) without maintenance therapy. The primary end point was progression-free survival. Results: The median follow-up period was 30 months. The median progression-free survival was significantly longer with MPR-R (31 months) than with MPR (14 months; hazard ratio, 0.49; P<0.001) or MP (13 months; hazard ratio, 0.40; P<0.001). Response rates were superior with MPR-R and MPR (77% and 68%, respectively, vs. 50% with MP; P<0.001 and P=0.002, respectively, for the comparison with MP). The progression-free survival benefit associated with MPR-R was noted in patients 65 to 75 years of age but not in those older than 75 years of age (P=0.001 for treatment-by-age interaction). After induction therapy, a landmark analysis showed a 66% reduction in the rate of progression with MPR-R (hazard ratio for the comparison with MPR, 0.34; P<0.001) that was age-independent. During induction therapy, the most frequent adverse events were hematologic; grade 4 neutropenia was reported in 35%, 32%, and 8% of the patients in the MPR-R, MPR, and MP groups, respectively. The 3-year rate of second primary tumors was 7% with MPR-R, 7% with MPR, and 3% with MP. Conclusions: MPR-R significantly prolonged progression-free survival in patients with newly diagnosed multiple myeloma who were ineligible for transplantation, with the greatest benefit observed in patients 65 to 75 years of age. (Funded by Celgene; MM-015 ClinicalTrials.gov number, NCT00405756.) [ABSTRACT FROM PUBLISHER]

A letter to the editor is presented regarding the cytogenetic status in multiple myeloma (MM).

The present study aimed to determine the diagnostic performance of different testing strategies to diagnose malignant B-cell disorder or monoclonal gammopathy of unknown significance (MGUS). Sensitivity and specificity were determined in 833 consecutive patients investigated for a monoclonal gammopathy. Serum protein electrophoresis (PE), serum κ/ λ free light chain (FLC) ratio, and serum and urine immunofixation electrophoresis (IFE) were performed in all patients. Twenty-eight patients were diagnosed with a malignant plasma cell disorder, 25 with B-cell non-Hodgkin lymphoma and 156 with MGUS. Serum PE (with follow-up IFE) plus FLC had a sensitivity of 82·3% and a specificity of 96·8% and missed one plasmacytoma and 23 patients with MGUS. Serum IFE plus urine IFE had a sensitivity of 92·3% and a specificity of 100% and missed two MGUS patients. Serum IFE plus FLC had a sensitivity of 93·8% and a specificity of 96·8% and missed one MGUS patient. Serum PE plus FLC had a significantly lower sensitivity than serum IFE plus FLC or serum IFE plus urine IFE for the diagnosis of MGUS. The sensitivity of serum IFE plus FLC was comparable to the sensitivity of serum IFE plus urine IFE. The specificity of serum IFE plus FLC, however, was lower than the specificity of serum IFE plus urine IFE. [ABSTRACT FROM AUTHOR]

The prevalence, intensity, determinants and prevention of pain during bone marrow aspiration (BMA) in adults are not well defined. In the first part of this prospective study (observational phase), 132 adult hematological patients undergoing BMA after local anesthesia scored the procedural pain by means of a visual analogue scale (VAS). Moderate to severe pain was defined as a VAS score exceeding 30 mm. Eighty-six percent reported procedural pain. The VAS score (mean±SEM) was 27.2±2.1 mm. Thirty-six percent of patients graded the pain as moderate to severe. In a linear regression analysis, VAS score correlated positively with the duration of the procedure (P = 0.029) and negatively with the age of the patient (P = 0.006). In the second part of the study (interventional phase), 100 patients were randomized to 50 mg tramadol or placebo, given orally at least one hour before BMA. VAS scores during aspiration were significantly lower in tramadol recipients versus placebo recipients (16.5±3.0 mm and 28.8±3.4 mm, respectively, P = 0.003). Pretreatment with tramadol reduced the percentage of patients with at least moderate pain from 40% to 20% (P = 0.029). Four tramadol and 3 placebo recipients reported side effects (dizziness or sedation). In conclusion, notwithstanding local anesthesia, the great majority of adult hematological patients experience transient pain during BMA that is of at least moderate intensity in over a third. Pretreatment with tramadol lowers pain intensity significantly and is well tolerated. [Copyright &y& Elsevier]

Idecabtagene vicleucel (ide-cel, bb2121), a chimeric antigen receptor (CAR) T cell therapy, has been investigated in patients with relapsed and refractory multiple myeloma (RRMM) who have received an immunomodulatory drug, proteasome inhibitor, and anti-CD38 antibody in the single-arm phase 2 KarMMa clinical trial. Two therapies with distinct mechanisms of action – selinexor plus dexamethasone (Sd) and belantamab mafodotin (BM) – are currently approved in the United States for heavily pretreated patients, including those who are triple-class refractory. To compare ide-cel versus Sd and ide-cel versus BM, matching-adjusted indirect comparisons were performed. Ide-cel extended progression-free survival (PFS) and overall survival (OS) versus both Sd and BM (hazard ratio (HR); 95% confidence interval (CI)). PFS: ide-cel versus Sd, 0.46; 0.28–0.75; ide-cel versus BM, 0.45; 0.27–0.77. OS: ide-cel versus Sd, 0.23; 0.13–0.42; ide-cel versus BM, 0.35; 0.14–0.87. These results suggest ide-cel offers clinically meaningful improvements over currently approved regimens for patients with heavily pretreated RRMM. [ABSTRACT FROM AUTHOR]

Background: CASSIOPEIA part 1 showed superior depth of response and significantly improved progression-free survival with daratumumab, bortezomib, thalidomide, and dexamethasone (D-VTd) versus bortezomib, thalidomide, and dexamethasone (VTd) as induction and consolidation in patients with autologous stem-cell transplant (ASCT)-eligible newly diagnosed multiple myeloma. In part 2, we compared daratumumab maintenance versus observation only.Methods: CASSIOPEIA is a two-part, open-label, randomised, phase 3 trial of patients aged 18-65 years with newly diagnosed multiple myeloma and Eastern Cooperative Oncology Group performance status 0-2, done in 111 European academic and community practice centres. In part 1, patients were randomly assigned (1:1) to induction and consolidation with D-VTd or VTd. Patients still on study who had a partial response or better were randomly assigned (1:1) by an interactive web-response system to daratumumab 16 mg/kg intravenously every 8 weeks (a reduced frequency compared with standard daratumumab long-term dosing) or observation only for up to 2 years. Stratification factors were induction treatment and depth of response in part 1. The part 2 primary endpoint was progression-free survival from second randomisation. This preplanned interim analysis of progression-free survival was done after 281 events and shall be considered the primary analysis of progression-free survival. Sponsor personnel and designees who were involved in the analysis were masked to treatment group until the independent data monitoring committee recommended that the preplanned interim analysis be considered the main analysis of progression-free survival in part 2. Otherwise, treatment assignments were unmasked. The interaction between induction and consolidation and maintenance was tested at a two-sided significance level of 0·05 by a stratified Cox regression model that included the interaction term between maintenance treatment and induction and consolidation treatment. Efficacy analyses were done in the maintenance-specific intention-to-treat population, which comprised all patients who underwent second randomisation. Safety was analysed in all patients in the daratumumab group who received at least one dose and all patients randomly assigned to observation only. This trial is registered with ClinicalTrials.gov, NCT02541383. Long-term follow-up is ongoing and the trial is closed to new participants.Findings: Between May 30, 2016, and June 18, 2018, 886 patients (458 [84%] of 543 in the D-VTd group and 428 [79%] of 542 in the VTd group) were randomly assigned to daratumumab maintenance (n=442) or observation only (n=444). At a median follow-up of 35·4 months (IQR 30·2-39·9) from second randomisation, median progression-free survival was not reached (95% CI not evaluable [NE]-NE) with daratumumab versus 46·7 months (40·0-NE) with observation only (hazard ratio 0·53, 95% CI 0·42-0·68, p<0·0001). A prespecified analysis of progression-free survival results showed a significant interaction between maintenance and induction and consolidation therapy (p<0·0001). The most common grade 3 or 4 adverse events were lymphopenia (16 [4%] of 440 patients in the daratumumab group vs eight [2%] of 444 patients in the observation-only group), hypertension (13 [3%] vs seven [2%]), and neutropenia (nine [2%] vs ten [2%]). Serious adverse events occurred in 100 (23%) patients in the daratumumab group and 84 (19%) patients in the observation-only group. In the daratumumab group, two adverse events led to death (septic shock and natural killer-cell lymphoblastic lymphoma); both were related to treatment.Interpretation: Daratumumab maintenance every 8 weeks for 2 years significantly reduced the risk of disease progression or death compared with observation only. Longer follow-up and other ongoing studies will shed further light on the optimal daratumumab-containing post-ASCT maintenance treatment strategy.Funding: Janssen Research & Development, the Intergroupe Francophone du Myélome, and the Dutch-Belgian Cooperative Trial Group for Hematology Oncology. [ABSTRACT FROM AUTHOR]

BACKGROUND Idecabtagene vicleucel (ide-cel, also called bb2121), a B-cell maturation antigen directed chimeric antigen receptor (CAR) T-cell therapy, has shown clinical activity with expected CAR T-cell toxic effects in patients with relapsed and refractory multiple myeloma. METHODS In this phase 2 study, we sought to confirm the efficacy and safety of ide-cel in patients with relapsed and refractory myeloma. Patients with disease after at least three previous regimens including a proteasome inhibitor, an immunomodulating agent, and an anti-CD38 antibody were enrolled. Patients received ide-cel target doses of 150 x 106 to 450 x 106 CAR-positive (CAR+) T cells. The primary end point was an overall response (partial response or better); a key secondary end point was a complete response or better (comprising complete and stringent complete responses). RESULTS Of 140 patients enrolled, 128 received ide-cel. At a median follow-up of 13.3 months, 94 of 128 patients (7396) had a response, and 42 of 128 (33%) had a complete response or better. Minimal residual disease (MRD)-negative status (<10-5 nucleated cells) was confirmed in 33 patients, representing 26% of all 128 patients who were treated and 79% of the 42 patients who had a complete response or better. The median progression-free survival was 8.8 months (95% confidence interval, 5.6 to 11.6). Common toxic effects among the 128 treated patients included neutropenia in 117 patients (91%), anemia in 89 (70%), and thrombocytopenia in 81 (63%). Cytokine release syndrome was reported in 107 patients (84%), including 7 (5%) who had events of grade 3 or higher. Neurotoxic effects developed in 23 patients (18%) and were of grade 3 in 4 patients (3%); no neurotoxic effects higher than grade 3 occurred. Cellular kinetic analysis confirmed CAR+ T cells in 29 of49 patients (59%) at 6 months and 4 of 11 patients (36%) at 12 months after infusion. CONCLUSIONS Ide-cel induced responses in a majority of heavily pretreated patients with refractory and relapsed myeloma; MRD-negative status was achieved in 26% of treated patients. Almost all patients had grade 3 or 4 toxic effects, most commonly hematologic toxic effects and cytokine release syndrome. (Funded by bluebird bio and Celgene, a Bristol-Myers Squibb company; KarMMa ClinicalTrials.gov number, NCT03361748.) [ABSTRACT FROM AUTHOR]

Background: Bortezomib, thalidomide, and dexamethasone (VTd) plus autologous stem-cell transplantation is standard treatment in Europe for transplant-eligible patients with newly diagnosed multiple myeloma. We evaluated whether the addition of daratumumab to VTd before and after autologous stem-cell transplantation would improve stringent complete response rate in patients with newly diagnosed multiple myeloma.Methods: In this two-part, randomised, open-label, phase 3 CASSIOPEIA trial, we recruited transplant-eligible patients with newly diagnosed multiple myeloma at 111 European sites. Patients were randomly assigned (1:1) to receive four pre-transplant induction and two post-transplant consolidation cycles of VTd alone (VTd group) or in combination with daratumumab (D-VTd group). The primary endpoint of part 1 was stringent complete response assessed 100 days after transplantation. Part 2 (maintenance) is ongoing. The trial is registered with ClinicalTrials.gov, number NCT02541383.Findings: Between Sept 22, 2015, and Aug 1, 2017, 1085 patients were enrolled at 111 European sites and were randomly assigned to the D-VTd group (n=543) or the VTd group (n=542). At day 100 after transplantation, 157 (29%) of 543 patients in the D-VTd group and 110 (20%) of 542 patients in the VTd group in the intention-to-treat population had achieved a stringent complete response (odds ratio 1·60, 95% CI 1·21-2·12, p=0·0010). 211 (39%) patients in the D-VTd group versus 141 (26%) in the VTd group achieved a complete response or better, and 346 (64%) of 543 versus 236 (44%) of 542 achieved minimal residual disease-negativity (10-5 sensitivity threshold, assessed by multiparametric flow cytometry; both p<0·0001). Median progression-free survival from first randomisation was not reached in either group (hazard ratio 0·47, 95% CI 0·33-0·67, p<0·0001). 46 deaths on study were observed (14 vs 32, 0·43, 95% CI 0·23-0·80). The most common grade 3 or 4 adverse events were neutropenia (28% vs 15%), lymphopenia (17% vs 10%), and stomatitis (13% vs 16%).Interpretation: D-VTd before and after autologous stem-cell transplantation improved depth of response and progression-free survival with acceptable safety. CASSIOPEIA is the first study showing the clinical benefit of daratumumab plus standard of care in transplant-eligible patients with newly diagnosed multiple myeloma.Funding: The Intergroupe Francophone du Myélome and Dutch-Belgian Cooperative Trial Group for Hematology Oncology. [ABSTRACT FROM AUTHOR]

To the Editor, Free light chains (FLCs) are valuable laboratory markers to support the diagnosis, prognosis and follow-up of patients with monoclonal gammopathies. / ratio by N-Latex and Freelite in MGUS and MM: The / ratio was determined in 525 samples from 255 MGUS patients (described in [[8]]) and the results were classified as normal or abnormal. When the minimum and maximum / ratio determined in the 282 controls in this study was used, then 39.4% of the samples from MGUS patients in this study had an abnormal / ratio with both assays, 9% with only Freelite, and 7.6% with only N-Latex. [Extracted from the article]

To the Editor: The worldwide COVID-19 pandemic is expected to be a devastating infection in patients with chronic hematological disorders. So far, no data have been reported in multiple myeloma (MM), a disease characterized by a severe humoral and cellular immune deficiency that exposes patients to infectious complications. In order to assess the impact of COVID-19 in the Belgian MM community, we collected data on the disease by sending questionnaires to 30 different cancer centers. [Extracted from the article]

Abstract: Objective: The efficacy and safety of bortezomib‐based therapy for relapsed/refractory multiple myeloma (RRMM) in clinical trials may differ from the oncology practice experience. The electronic VELCADE® OBservational Study was designed to prospectively evaluate bortezomib for multiple myeloma (MM) in real‐world medical practice. Method: Patients scheduled to receive intravenous bortezomib for MM were eligible. The primary objective was to evaluate clinical outcomes, including response, time to response, time to next therapy, treatment‐free interval, progression‐free survival (PFS), and overall survival (OS). Secondary objectives included safety and healthcare resource utilization. Results: In total, 873 patients with a median of two therapy lines prior to initiating bortezomib were included. The overall response rate (≥partial response) was 69%, including 37% complete response/near‐complete response. Median time to response was 1.8 months, median time to next therapy was 9.7 months, and median treatment‐free interval was 7.9 months. After 22.6 months’ median follow‐up, median PFS was 12.0 months and median OS was 36.1 months. The most common adverse events (AEs) were neuropathy not otherwise specified (19%), diarrhea NOS, and thrombocytopenia (each 17%); 230 (26%) patients discontinued bortezomib due to AEs. Of 689 (79%) patients without baseline peripheral neuropathy (PN), the rate of new‐onset any‐grade PN increased to 51% (12% grade 3/4) by cycle 8. Overall, 244 (28%) patients were hospitalized, 372 (43%) attended an outpatient visit, and 341 (39%) underwent a diagnostic/therapeutic procedure during bortezomib treatment. Conclusion: These prospective real‐world data demonstrate the effectiveness and safety of bortezomib‐based therapy for RRMM and confirm high response rates and long OS for this population. [ABSTRACT FROM AUTHOR]

We report a multicentre retrospective study that analysed clinical characteristics and outcomes in 117 patients with primary plasma cell leukaemia (pPCL) treated at the participating institutions between January 2006 and December 2016. The median age at the time of pPCL diagnosis was 61 years. Ninety-eight patients were treated with novel agents, with an overall response rate of 78%. Fifty-five patients (64%) patients underwent upfront autologous stem cell transplantation (ASCT). The median followup time was 50 months (95% confidence interval [CI] 33; 76), with a median overall survival (OS) for the entire group of 23 months (95% CI 15; 34). The median OS time in patients who underwent upfront ASCT was 35 months (95% CI 24·3; 46) as compared to 13 months (95% CI 6&3183;3; 35·8) in patients who did not receive ASCT (P = 0&3183;001). Multivariate analyses identified age ≥60 years, platelet count ≤100 9 109/l and peripheral blood plasma cell count ≥20 9 109/l as independent predictors of worse survival. The median OS in patients with 0, 1 or 2–3 of these risk factors was 46, 27 and 12 months, respectively (P < 0·001). Our findings support the use of novel agents and ASCT as frontline treatment in patients with pPCL. The constructed prognostic score should be independently validated. [ABSTRACT FROM AUTHOR]

Although immunomodulatory drugs, alkylating agents, corticosteroids, protease inhibitors, and therapeutic monoclonal antibodies improve multiple myeloma outcomes, treatment burden is still an issue. Neutropenia is a known complication of cytotoxic cancer therapy and is often associated with infections; it is an important consideration in myeloma given the fact that patients often have a weakened immune system. The risk of febrile neutropenia increases with severe and persisting neutropenia. Recombinant granulocyte colony-stimulating factors (G-CSFs) are commonly used to reduce the incidence, duration, and severity of febrile neutropenia. Here, we review the risk and management of neutropenia associated with new and commonly used anti-myeloma agents. Few papers report the use of G-CSF in patients with multiple myeloma receiving anti-cancer treatments, and fewer describe whether G-CSF was beneficial. None of the identified studies reported G-CSF primary prophylaxis. Further studies are warranted to evaluate the need for G-CSF prophylaxis in multiple myeloma. Prophylaxis may be particularly useful in patients at high risk of prolonged severe neutropenia. [ABSTRACT FROM AUTHOR]

This FIRST trial final analysis examined survival outcomes in patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM) treated with lenalidomide and low-dose dexamethasone until disease progression (Rd continuous), Rd for 72 weeks (18 cycles; Rd18), or melphalan, prednisone, and thalidomide (MPT; 72 weeks). The primary endpoint was progression-free survival (PFS; primary comparison: Rd continuous vs MPT). Overall survival (OS) was a key secondary endpoint (final analysis prespecified ≥60 months' follow-up). Patients were randomized to Rd continuous (n = 535), Rd18 (n = 541), or MPT (n = 547). At a median follow-up of 67 months, PFS was significantly longer with Rd continuous vs MPT (hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.59-0.79; P < .00001) and was similarly extended vs Rd18. Median OS was 10 months longer with Rd continuous vs MPT (59.1 vs 49.1 months; HR, 0.78; 95% CI, 0.67-0.92; P = .0023), and similar with Rd18 (62.3 months). In patients achieving complete or very good partial responses, Rd continuous had an ≈30-month longer median time to next treatment vs Rd18 (69.5 vs 39.9 months). Over half of all patients who received second-line treatment were given a bortezomib-based therapy. Second-line outcomes were improved in patients receiving bortezomib after Rd continuous and Rd18 vs after MPT. No new safety concerns, including risk for secondary malignancies, were observed. Treatment with Rd continuous significantly improved survival outcomes vs MPT, supporting Rd continuous as a standard of care for patients with transplant-ineligible NDMM. [ABSTRACT FROM AUTHOR]

Objectives Heavily pretreated patients with relapsed and refractory multiple myeloma are susceptible to treatment-related adverse events (AEs). Managing AEs are important to ensure patients continue therapy long enough to receive the best clinical benefit. Data from the MM-002, MM-003, and MM-010 trials were pooled to further characterize the safety profile of pomalidomide plus low-dose dexamethasone and AE management. Methods This analysis included 1088 patients who received ≥ 2 prior therapies, including lenalidomide and bortezomib, and progressed ≤ 60 days of last therapy. Patients received 28-day cycles of pomalidomide 4 mg/day on days 1-21 and low-dose dexamethasone 40 mg (20 mg if aged > 75 years) weekly until disease progression or unacceptable toxicity. Thromboprophylaxis was required. Results The most common grade 3/4 AEs were neutropenia (56.2%), anemia (32.3%), and thrombocytopenia (25.8%), which occurred within the first few cycles of treatment. Grade 3/4 infections occurred in 33.7% patients, of whom 13.9% had pneumonia, and 40.3% had neutropenia. Pomalidomide dose reductions or interruptions were reported in 24.2% and 66.0% of patients, respectively. AEs were managed by dose modifications and/or supportive care. Conclusions Pomalidomide plus low-dose dexamethasone showed an acceptable safety profile, and AEs were well managed according to study protocols and established guidelines. [ABSTRACT FROM AUTHOR]

Delanzomib (CEP-18770), a reversible P2 threonine boronic acid proteasome (β5/β1 subunits) inhibitor that showed promising anti-myeloma effects in preclinical studies, was investigated in a single-agent multicenter phase I/II study in patients with relapsed/refractory myeloma. Sixty-one patients (17 during dose escalation; 44 in the expansion cohort) received delanzomib on days 1, 8, and 15 in 28-d cycles; 47 received the maximum tolerated dose (MTD), 2.1 mg/m2. Dose-limiting toxicities (DLTs) at 2.4 mg/m2 were rash and thrombocytopenia. At the MTD, the most prominent adverse events were nausea, vomiting, anorexia, fatigue, and pyrexia; grade 3/4 thrombocytopenia and neutropenia occurred in 53 and 23% of patients, respectively. Peripheral neuropathy (21%) was limited to grades 1/2. At the MTD, 26 patients (55%) had stable disease and four (9%) had a partial response (PR). Median time to progression (TTP) was 2.5 months across the cohort. Based upon the efficacy results, development of delanzomib for myeloma was discontinued. [ABSTRACT FROM AUTHOR]

Renal impairment (RI) is a major comorbidity in patients with multiple myeloma (MM). Here we present the pooled safety and efficacy analysis of three clinical trials (MM-002, MM-003, and MM-010) of pomalidomide + low-dose dexamethasone (POM + LoDEX) in patients with moderate RI (creatinine clearance [CrCl] ≥ 30 to <60 mL/min) and without RI (≥ 60 mL/min). Trial protocols were approved by the institutional review board of each site involved. Patients with RI were older than patients without RI, although other baseline characteristics were similar. The dosing and safety profile of POM + LoDEX was similar across RI subgroups. Median overall response rate, progression-free survival, time to progression, and duration of response were not significantly different between RI subgroups. However, patients with vs. without RI had significantly shorter median overall survival (10.5 vs. 14.0 months, respectively;p = .004). This analysis demonstrates that POM + LoDEX is a safe and effective treatment for patients with moderate RI. The trials were registered at ClinicalTrials.gov as NCT00833833 (MM-002), NCT01311687 (MM-003), and NCT01712789 (MM-010) and at EudraCT as 2010-019820-30 (MM-003) and 2012-001888-78 (MM-010). [ABSTRACT FROM AUTHOR]

Skin infiltration in multiple myeloma (skin MM) is a rare clinical problem. Only a few cases of skin involvement have been reported, primarily in single case reports. We analyzed and present the clinical outcomes, immunohistochemistry and cytogenetic features, and relevant laboratory data on 53 biopsy-proven skin MM cases. The median time from MM diagnosis to skin involvement was 2 years. There appears to be an overrepresentation of immunoglobulin class A (IgA) and light chain disease in skin MM. We found no correlation between CD56 negative MM and skin infiltration. We found that skin MM patients presented in all MM stages (i.e. ISS stages I to III), and there was no preferential cytogenetic abnormality. Patients with skin MM carry a very poor prognosis with a median overall survival (OS) of 8.5 months as time from skin involvement. Moreover, patients with IgA disease and plasmablastic morphology appear to have a worse OS. [ABSTRACT FROM AUTHOR]