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This study aims to develop and validate a simple score to estimate survival in the older population suffering from malignant hemopathies. We prospectively recruited 285 patients, aged ≥65 years, admitted to receive chemotherapy. At inclusion, a geriatric assessment was performed. Cox proportional hazards models were performed to assess correlations between vulnerabilities and one-year survival. We developed a frailty score, HEMA-4, based on the most powerful prognostic factors. It was externally confirmed with an independent cohort. In the development cohort, 206 patients were evaluable. Mean age was 76 years (range 65–90). The HEMA-4 score was created based on four independent predictive factors for survival: cognitive impairment (MMSE<27), comorbidities (≥2 on Charlson comorbidity index), CRP (≥10 mg/L) and low albumin level (<35 g/L). The population was stratified into three groups: good prognosis (score = 0–1, n = 141), intermediate prognosis (score = 2, n = 37) and poor prognosis (score = 3–4, n = 28). Their respective one-year survival was 74%, 51% (HR = 2.30; 95% CI =1.31–4.05; p < 0.01) and 36% (HR = 3.95; 95% CI =2.23–6.98; p < 0.01). In the validation cohort (n = 25), the one-year survival was 78% in the good prognosis group (n = 9) and 50% in the intermediate prognosis group (n = 6). The poor prognosis group had a median survival of four months in the development cohort and six months in the validation cohort (n = 10). The HEMA-4 score is a simple score that combines cognitive impairment, comorbidities, inflammation and low albumin level. Our data suggest that it predicts survival among older patients suffering from malignant hemopathies referred to receive chemotherapy regardless of their chronological age. [ABSTRACT FROM AUTHOR]

This study sought to evaluate whether velocity of naturally occurring myocardial shear waves (SW) could relate to myocardial stiffness (MS) in vivo. Cardiac SW imaging has been proposed as a noninvasive tool to assess MS. SWs occur after mechanical excitation of the myocardium (e.g., mitral valve closure [MVC] and aortic valve closure [AVC]), and their propagation velocity is theoretically related to MS, thus providing an opportunity to assess stiffness at end-diastole (ED) and end-systole. However, given that SW propagation in vivo is complex, it remains unclear whether natural SW velocity effectively relates to MS. This study prospectively enrolled 50 healthy volunteers (HV) (43.7 ± 17.1 years of age) and 18 patients with cardiac amyloidosis (CA) (68.0 ± 9.8 years of age). HV were divided into 3 age groups: group I, 20 to 39 years of age (n = 24); group II, 40 to 59 years of age (n = 11); and group III, 60 to 80 years of age (n = 15). Parasternal long-axis views were acquired using an experimental scanner. Tissue (Doppler) acceleration maps were extracted from an anatomical M-mode along the midline of the left ventricular septum. SW propagation velocity was significantly higher in CA patients than in HV after both MVC (3.54 ± 0.93 m/s vs. 6.33 ± 1.63 m/s, respectively; p < 0.001) and AVC (3.75 ± 0.76 m/s vs. 5.63 ± 1.13 m/s, respectively; p < 0.001). Similarly, SW propagation velocity differed significantly among age groups in HV, with a significantly higher value for group III than for group I, both occurring after MVC (p < 0.001) and AVC (p < 0.01). Moreover, SW propagation velocity after MVC was found to be significantly higher in patients with an increasing grade of diastolic dysfunction (p < 0.001). Finally, positive correlation was found between SW velocities after MVC and mitral inflow-to-mitral relaxation velocity ratio (E/E′) (r = 0.74; p = 0.002). End-diastole SW velocities were significantly higher in patients with CA, patients with a higher grade of diastolic dysfunction, and elderly volunteers. These findings thus suggest that the speed of naturally induced SWs may be related to MS. [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]

In the last decades, treatment of multiple myeloma (MM) has greatly improved due to the introduction of novel agents, including proteasome inhibitors (PI) and immunomodulatory agents (IMiDs). Given their generalized use at diagnosis and at relapse and their proven benefit for the large cohort of MM patients, it is of pivotal importance to also critically evaluate any benefit of these agents in very elderly (> 75 years) and frail patients. This review gives an overview of the benefits and toxicities of the currently available treatments in very elderly MM patients with a focus on first-line treatment. In addition we discuss the role of geriatric assessment to optimize treatment efficacy in the more vulnerable cohort. [ABSTRACT FROM AUTHOR]

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]

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]

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]

Objectives: In addition to blood-sparing effects, aprotinin may have cardioprotective and anti-inflammatory effects during cardiopulmonary bypass–assisted cardiac surgery. In this study, the authors examined whether aprotinin had cardioprotective and/or anti-inflammatory effects in patients undergoing off-pump coronary artery bypass grafting. Design: A prospective randomized clinical trial. Setting: University hospital. Participants: Fifty patients were randomized to control (n = 25) or aprotinin treatment (n = 25) groups. Interventions: Aprotinin was given as a loading dose (2 × 106 KIU) followed by a continuous infusion at 5 × 105 KIU/h until skin closure. Measurements and Main Results: Blood samples for cardiac troponin I; interleukin-6, interleukin-8, and interleukin-10; tumor necrosis factor α; and elastase were taken after anesthesia induction, completion of revascularization, and 6 hours, 12 hours, and 24 hours after revascularization. Blood samples were taken to assess for apoptosis in polymorphonuclear cells. Baseline plasma levels for cardiac troponin I did not differ between groups but were significantly lower in aprotinin-treated patients at the time of revascularization (p = 0.03) and 6 hours (p = 0.004) and 24 hours (p = 0.03) later. Aprotinin significantly reduced apoptosis in polymorphonuclear cells compared with control-treated patients (p = 0.04). There were no differences in plasma cytokine or elastase levels between groups. Conclusions: The authors conclude that aprotinin reduces perioperative cardiac troponin I release and attenuates apoptosis in polymorphonuclear cells but has no significant effects on plasma cytokine levels in patients undergoing off-pump coronary artery bypass graft surgery. [Copyright &y& Elsevier]

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]

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]

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]

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]

Summary: Background: Few effective treatments exist for patients with refractory or relapsed and refractory multiple myeloma not responding to treatment with bortezomib and lenalidomide. Pomalidomide alone has shown limited efficacy in patients with relapsed multiple myeloma, but synergistic effects have been noted when combined with dexamethasone. We compared the efficacy and safety of pomalidomide plus low-dose dexamethasone with high-dose dexamethasone alone in these patients. Methods: This multicentre, open-label, randomised phase 3 trial was undertaken in Australia, Canada, Europe, Russia, and the USA. Patients were eligible if they had been diagnosed with refractory or relapsed and refractory multiple myeloma, and had failed at least two previous treatments of bortezomib and lenalidomide. They were assigned in a 2:1 ratio with a validated interactive voice and internet response system to either 28 day cycles of pomalidomide (4 mg/day on days 1–21, orally) plus low-dose dexamethasone (40 mg/day on days 1, 8, 15, and 22, orally) or high-dose dexamethasone (40 mg/day on days 1–4, 9–12, and 17–20, orally) until disease progression or unacceptable toxicity. Stratification factors were age (≤75 years vs >75 years), disease population (refractory vs relapsed and refractory vs bortezomib intolerant), and number of previous treatments (two vs more than two). The primary endpoint was progression-free survival (PFS). Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01311687, and with EudraCT, number 2010-019820-30. Findings: The accrual for the study has been completed and the analyses are presented. 302 patients were randomly assigned to receive pomalidomide plus low-dose dexamethasone and 153 high-dose dexamethasone. After a median follow-up of 10·0 months (IQR 7·2–13·2), median PFS with pomalidomide plus low-dose dexamethasone was 4·0 months (95% CI 3·6–4·7) versus 1·9 months (1·9–2·2) with high-dose dexamethasone (hazard ratio 0·48 [95% CI 0·39–0·60]; p<0·0001). The most common grade 3–4 haematological adverse events in the pomalidomide plus low-dose dexamethasone and high-dose dexamethasone groups were neutropenia (143 [48%] of 300 vs 24 [16%] of 150, respectively), anaemia (99 [33%] vs 55 [37%], respectively), and thrombocytopenia (67 [22%] vs 39 [26%], respectively). Grade 3–4 non-haematological adverse events in the pomalidomide plus low-dose dexamethasone and high-dose dexamethasone groups included pneumonia (38 [13%] vs 12 [8%], respectively), bone pain (21 [7%] vs seven [5%], respectively), and fatigue (16 [5%] vs nine [6%], respectively). There were 11 (4%) treatment-related adverse events leading to death in the pomalidomide plus low-dose dexamethasone group and seven (5%) in the high-dose dexamethasone group. Interpretation: Pomalidomide plus low-dose dexamethasone, an oral regimen, could be considered a new treatment option in patients with refractory or relapsed and refractory multiple myeloma. Funding: Celgene Corporation. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented entitled "Monoclonal Gammopathy of Undetermined Significance: Significant Beyond Hematology," by Steven Vanderschueren, Marieke Mylle, Daan Dierickx, and Michel Delforge.

Abstract: We studied the immune compartment in patients with myelodysplastic syndromes. We show increased surface expression of activation markers (HLA-DR+, CD57+, CD28−, CD62L−) on T lymphocytes in blood and bone marrow (n =131). T cell activation was not restricted to any relevant clinical subgroup (FAB, IPSS, cytogenetics) and did not correlate with blood counts or need for treatment. In vitro clonogenic growth of marrow mononuclear cells (n =18) was not influenced by T cells expressing these markers. In addition, using X-chromosome inactivation analysis (n =12) we demonstrate clonal involvement of NK and B cells in half of these patients. We conclude that although activated T lymphocytes can be found in MDS, their role in disease pathogenesis remains unclear in the majority of patients. [Copyright &y& Elsevier]

Abstract: Dendritic cells (DC) are pivotal for T cell-mediated immunity. We investigated the early and terminal maturation of monocyte-derived DC (MoDC) in myelodysplastic syndromes (FAB subtypes refractory anemia (MDS-RA) or refractory anemia with ringed sideroblasts (MDS-RARS)). Immature MoDC were obtained by culture of monocytes with GM-CSF and IL-4 for 8 days. To obtain mature MoDC, TNF-α was added during the final three culture days. T cell proliferation and T cell cytokine secretion in mixed lymphocyte reactions (MLR) unveiled a strong reduction of allostimulatory capacity of mature but also of immature MoDC from MDS patients. Immature MoDC from MDS patients exhibited an almost normal immunophenotype, but secreted substantially less IL-12 and more IL-10 in response to LPS/IFN-γ than normal controls. Terminal addition of TNF-α to GM-CSF/IL-4 treated monocytes failed to extinguish cytokine production by MDS MoDC and failed to induce the expected membrane upregulation of costimulatory and other ligands as in normal controls. While our data provide further support for previous studies that have indicated an impaired differentiation of immature towards mature MoDC, they also clearly demonstrate a qualitatively and quantitatively altered cytokine secretion at the level of immature MoDC, which may in part explain the reduced allostimulatory capacity of these cells. These alterations may contribute to immune modulation of the clinical phenotype of marrow failure in MDS, and may have to be considered when designing DC-based immunotherapeutic strategies for MDS. [Copyright &y& Elsevier]