A randomised controlled trial in patients undergoing arthroscopic shoulder surgery comparing interscalene block with either 10 ml or 20 ml levobupivacaine 0.25.

The interscalene brachial plexus block is recommended for analgesia after shoulder surgery but it may cause hemidiaphragmatic dysfunction. We tested whether ipsilateral hemidiaphragmatic contraction was better after a smaller dose of local anaesthetic without impairing analgesic effect. We randomly allocated 48 adults to 10 ml or 20 ml levobupivacaine 0.25% before arthroscopic shoulder surgery. The primary outcome was hemidiaphragmatic paralysis, defined as inspiratory thickness < 1.2 times expiratory thickness, measured by ultrasound 4 h after block. Hemidiaphragmatic paralysis was recorded for 6/24 vs. 23/24 supine participants after 10 ml vs. 20 ml levobupivacaine 0.25%, respectively, and for 4/24 vs. 23/24 sitting participants, respectively, p < 0.001 for both. Pain scores after 10 ml injectate were not worse than after 20 ml injectate. Median (IQR [range]) morphine doses in the first 24 postoperative hours after 10 ml and 20 ml levobupivacaine 0.25% were 2 (0-6 [0-23]) mg vs. 1 (0-2 [0-11]) mg, respectively, p = 0.12. No participant had a complication after 10 ml interscalene levobupivacaine, whereas seven had complications after 20 ml levobupivacaine, p = 0.009. Hemidiaphragmatic function was better after 10 ml vs. 20 ml interscalene levobupivacaine 0.25% without impairing analgesia for 24 postoperative hours.

Papain-treated panels are a simple method for the identification of alloantibodies in multiple myeloma patients treated with anti-CD38-based therapies.

OBJECTIVES: To report our 2 years of experience navigating the interference of anti-CD38 monoclonal antibodies (MAs) in 33 patients and describe papain-treated panels as a complementary method to dithiothreitol (DTT). BACKGROUND: Novel anti-CD38 MAs are now approved or undergoing clinical trials to evaluate their activity in patients with multiple myeloma. A concern with the use of these drugs is that they interfere with blood bank tests in a group of patients who often require blood transfusions. METHODS: Clinical data and whole blood samples were collected from patients receiving daratumumab or isatuximab. Routine blood bank serological tests were performed. RESULTS: A total of 9·1% of patients presented with alloantibodies prior to treatment. All patients exhibited nonspecific reactivity in indirect antiglobulin tests, and 26% had positive direct antiglobulin tests after beginning treatment. This interference disappeared in all patients after discontinuing treatment. Papain panels avoided this reactivity and allowed us to identify alloantibodies. Phenotyped blood units were transfused, and no patient suffered any transfusion-related complications. CONCLUSION: Anti-CD38 MAs produce nonspecific interference in blood bank tests. This interference can be overcome by various methods, including DTT or papain treatment as proposed here. These methods have limitations that can be resolved using phenotyped blood units.

Second primary malignancies in multiple myeloma: an overview and IMWG consensus.

Background: Therapeutic advancements following the introduction of autologous stem cell transplantation and 'novel' agents have significantly improved clinical outcomes for patients with multiple myeloma (MM). Increased life expectancy, however, has led to renewed concerns about the long-term risk of second primary malignancies (SPMs). This review outlines the most up-to-date knowledge of possible host-, disease-, and treatment-related risk factors for the development of SPMs in patients with MM, and provides practical recommendations to assist physicians. Design: A Panel of International Myeloma Working Group members reviewed the most relevant data published in the literature as full papers, or presented at meetings of the American Society of Clinical Oncology, American Society of Hematology, European Hematology Association, or International Myeloma Workshops, up to June 2016. Here, we present the recommendations of the Panel, based on this literature review. Results: Overall, the risk of SPMs in MM is low, multifactorial, and partially related to the length of patients' survival and MM intrinsic susceptibility. Studies suggest a significantly increased incidence of SPMs when lenalidomide is administered either following, or concurrently with, oral melphalan. Increased SPM incidence has also been reported with lenalidomide maintenance following high-dose melphalan, albeit to a lesser degree. In both cases, the risk of death from MM was significantly higher than the risk of death from SPMs, with lenalidomide possibly providing a survival benefit. No increase in SPM incidence was reported with lenalidomide plus dexamethasone (without melphalan), or with bortezomib plus oral melphalan, dexamethasone, or thalidomide. Conclusion: In general, the risk of SPMs should not alter the current therapeutic decision-making process in MM. However, regimens such as lenalidomide plus dexamethasone should be preferred to prolonged exposure to lenalidomide plus oral melphalan. SPM risk should be carefully discussed with the patient in the context of benefits and risks of different treatment options.

The genomic profiling of high-risk smoldering myeloma patients treated with an intensive strategy unveils potential markers of resistance and progression.

Smoldering multiple myeloma (SMM) precedes multiple myeloma (MM). The risk of progression of SMM patients is not uniform, thus different progression-risk models have been developed, although they are mainly based on clinical parameters. Recently, genomic predictors of progression have been defined for untreated SMM. However, the usefulness of such markers in the context of clinical trials evaluating upfront treatment in high-risk SMM (HR SMM) has not been explored yet, precluding the identification of baseline genomic alterations leading to drug resistance. For this reason, we carried out next-generation sequencing and fluorescent in-situ hybridization studies on 57 HR and ultra-high risk (UHR) SMM patients treated in the phase II GEM-CESAR clinical trial (NCT02415413). DIS3, FAM46C, and FGFR3 mutations, as well as t(4;14) and 1q alterations, were enriched in HR SMM. TRAF3 mutations were specifically associated with UHR SMM but identified cases with improved outcomes. Importantly, novel potential predictors of treatment resistance were identified: NRAS mutations and the co-occurrence of t(4;14) plus FGFR3 mutations were associated with an increased risk of biological progression. In conclusion, we have carried out for the first time a molecular characterization of HR SMM patients treated with an intensive regimen, identifying genomic predictors of poor outcomes in this setting.

Quality of life and economic impact of refractory epilepsy in Spain: the ESPERA study.

INTRODUCTION: Despite use of currently available anti-epileptic drugs (AED), 30% of epilepsy patients are not seizure-free. The purpose of this study was to estimate the quality of life and economic impact in Spain of drug-resistant epilepsy (DRE), as defined by the International League Against Epilepsy (ILAE). METHODS: Observational retrospective 12-month study conducted in Spain including adults with focal epilepsy treated with at least two AEDs. Direct costs (€ 2010) were calculated based on health care resources used and their official unit costs. Costs were analysed from the perspectives of the Spanish National Health System (SNS) and society. The impact of DRE on patients' quality of life was examined using the QOLIE 31-P, EQ-5D-3L, and NDDIE questionnaires. RESULTS: We analysed 263 patients out of the 304 recruited. According to ILAE criteria, 70.0% of the patients had drug-resistant epilepsy, while 20.3% achieved seizure freedom. From the viewpoint of the SNS, annual costs for resistant and seizure-free patients were € 4964 and € 2978 respectively (P<.01). Compared to resistant patients, seizure-free patients showed better scores on QOLIE-31P (70.8 vs 56.4, P<.0001) and EQ-5D-3L (75.6 vs 64.7, P<.001). Seizure-free patients showed a lower incidence of major depression compared to resistant patients according to the NDDIE scale (23 vs 8.3%, P<.05). CONCLUSIONS: Results suggest that DRE is associated with increased use of healthcare resources and consequently with higher costs, poorer quality of life and higher incidence of major depression compared to seizure-free patients, thus representing a considerable burden to the SNS and society.

Consensus-recommended diagnostic and therapeutic guidelines for drug-resistant epilepsy in Spain (Consenso RATE-España).

OBJECTIVE: To ascertain the opinions of an Epilepsy Expert Group and prepare a consensus document on the definition of drug-resistant epilepsy (DRE) according to the International League Against Epilepsy (ILAE) and the different healthcare levels for the patient with epilepsy in Spain. MATERIAL AND METHODS: The study was conducted using the Delphi method, by means of successive rounds of questionnaires. A scientific committee prepared a preliminary document and fourteen associated questions, which were sent by e-mail to the panel of experts. They included items related to the concept of DRE, health care levels and the route between these levels for patients with DRE. RESULTS: A total of 41 experts answered the questionnaire. They agreed regarding the necessity and applicability of the DRE definition according to the ILAE, the need for an expert panel on epilepsy, specialist epilepsy clinics, and clinical epilepsy units stratified depending on the level of activities they carried out. There was moderate consensus on the resources and activity of the clinical units of reference and there was no consensus on the referral of patients who have suffered an epileptic seizure to an epilepsy clinic. CONCLUSIONS: The expert panel agreed with the definition of DRE according to the ILAE and on referring patients with DRE for a detailed study in an epilepsy clinic or epilepsy clinical unit. They highlighted the need for video-EEG monitoring in the study of patients with DRE and the need to propose other forms of treatment in selected patients.

Ethical problems arising from the use of placebo in clinical trials with drugs for migraine. Their analysis by the moral deliberation method.

INTRODUCTION: Migraine is characterised as episodes of headache plus a variety of accompanying symptoms. Its pharmacological control remains unsatisfactory for some patients. The use of placebo in drug clinical trials on migraine commonly leads to numerous ethical uncertainties. METHODS: The purpose of this paper is to illustrate how the deliberation method helps in analysing the issues and finding solutions to selected ethical problems. Ethical decisions that try to solve conflicts arising from placebo use in clinical trials may be adopted using the moral deliberation method. Thus, the conflict is systematically assessed by identifying the following: Relevant facts; Values in conflict; Duties, or in other words, possible courses of action. Moral duty is following the optimal course of action. To identify this, it is recommended to state extreme courses of action, then intermediate courses of action, and then to proceed to the optimal course(s) of action. RESULTS AND CONCLUSIONS: In this paper, the application of this method is shown in several conflicting situations arising in two placebo-controlled clinical trials with drugs under development for the prophylaxis and acute treatment of migraine.

Diaphragmatic paralysis, respiratory function, and postoperative pain after interscalene brachial plexus block with a reduced dose of 10 ml levobupivacaine 0.25% versus a 20 ml dose in patients undergoing arthroscopic shoulder surgery: study protocol for the randomized controlled double-blind REDOLEV study.

BACKGROUND: Arthroscopic shoulder surgery causes severe postoperative pain. An interscalene brachial plexus block provides adequate analgesia, but unintended spread of the local anesthetic administered may result in a phrenic nerve block, usually associated with a nonnegligible incidence of acute hemidiaphragmatic paralysis. The main purpose of this trial will be to analyze the incidence of hemidiaphragmatic paralysis ensuing after interscalene brachial plexus block in patients undergoing arthroscopic shoulder surgery administered a standard volume (20 ml) vs. a low volume (10 ml) of levobupivacaine 0.25%. METHODS: This will be a prospective double-blind randomized controlled single-center two-arm comparative trial. Forty-eight patients will be included. The primary goal will be to ultrasonographically determine the incidence of hemidiaphragmatic paralysis by calculating the diaphragmatic thickness ratio in each group. The secondary goals will be to compare the two arms in terms of (1) decrease in forced vital capacity and (2) in forced expiratory volume at 1 s by spirometry; (3) decrease in diaphragmatic excursion by ultrasound; (4) 24-h total intravenous morphine consumption; (5) time to first opioid request of a patient-controlled analgesia pump; and (6) postoperative complications. DISCUSSION: This trial will demonstrate that a low-volume interscalene brachial plexus block decreases hemidiaphragmatic paralysis following arthroscopic shoulder surgery according to spirometry and ultrasound measurements and does not provide inferior postoperative analgesia to the standard volume, as measured by opioid requirements. TRIAL REGISTRATION: EudraCT and Spanish Trial Register (REec) registration number: 2019-003855-12 (registered on 7 January 2020). ClinicalTrials.gov identification number: NCT04385966 (retrospectively registered on 8 May 2020). Ethics Committee approval: EC19/093 (18 December 2019).

Drug development: assessment of pharmacogenetic studies by Spanish research ethics committees.

The decision taken by research ethics committees (RECs) while assessing pharmacogenetic (PGx) substudies as part of international clinical trials is almost unknown. A total of 255 applications of 36 PGx substudies embedded in clinical trials (12 phase 2, 24 phase 3) were submitted to 72 RECs in 2006-2007 by GlaxoSmithKline in Spain. These were trials of 17 different compounds, aimed to be conducted in the five continents. Of the 255 applications, 226 (89%) were directly approved by RECs without raising any queries to the sponsor; 1% (3/255) were plainly rejected by two RECs. The rest (10%) were followed by 64 queries asked by 16 RECs on 25 PGx substudies. Following responses from the sponsor, all but two applications were approved. Thus, the RECs involved finally approved 98% (250/255) of the submitted applications. The requirements specifically raised by two RECs (PGx samples to be transferred to a public biobank or alternatively destroyed immediately, or storage permitted only 5 years after the trial is concluded) could not be met by the sponsor. It can be inferred from the results obtained that ethical and scientific standards implemented by the sponsor in the design, conduct and sample management of PGx substudies satisfied the vast majority (70/72; 97%) of RECs involved in this study.

Subsyndromal depressive symptoms in patients with bipolar and unipolar disorder during clinical remission.

BACKGROUND: Subsyndromal depressive symptoms seem to be quite prevalent in mood disorders although very few studies have assessed them in patients considered to be in remission by clinical and psychometric criteria. This study sought to evaluate the presence of subsyndromal depressive symptoms in bipolar and unipolar patients in clinical remission. METHODS: One-hundred seventy-six patients with DSM-IV bipolar (62 bipolar I, 58 bipolar II) or unipolar mayor depression (n=58) in clinical remission and 60 healthy subjects were assessed using several psychometric instruments including the 17 items Hamilton Depression Rating Scale (HDRS). To be considered in clinical remission patients assessed with the Clinical Impression for Bipolar Disorder-Modified (CGI-BP-M) had to be stable for 6 months and scoring 6 or less in the Young Mania Rating Scale (YMRS) and 8 or less in the HDRS. RESULTS: Both Unipolar Disorder (UD) and Bipolar Disorder (BD) patients in clinical remission presented statistically significant higher HRSD scores, than healthy subjects. The HRSD scores were statistically higher in UD patients under remission than in BD patients. The subsyndromal symptoms more strongly associated with a clinical diagnosis of either UD or BD were Depressed Mood, Somatic Anxiety, Impact on Work and Activities, Psychic Anxiety, Gastrointestinal and Somatic Symptoms, Retardation during the Interview and Genital Symptoms. CONCLUSION: Subsyndromal depressive symptoms are present in affective disorder patients, both UD and BD, who apparently are in clinical remission. Remitted unipolar patients may have more residual symptoms than bipolar patients, particularly in items related to anxiety and somatic complaints.

Prognostic and biological implications of genetic abnormalities in multiple myeloma undergoing autologous stem cell transplantation: t(4;14) is the most relevant adverse prognostic factor, whereas RB deletion as a unique abnormality is not associated with adverse prognosis.

Fluorescence in situ hybridization (FISH) has become a powerful technique for prognostic assessment in multiple myeloma (MM). However, the existence of associations between cytogenetic abnormalities compels us to re-assess the value of each abnormality. A total of 260 patients with MM at the time of diagnosis, enrolled in the GEM-2000 Spanish transplant protocol, have been analyzed by FISH in order to ascertain the independent influence on myeloma prognosis of IGH translocations, as well as RB and P53 deletions. Survival analyses showed that patients with t(4;14), RB or P53 deletions had a significantly shorter survival than patients without these abnormalities. However, patients with RB deletions without other abnormalities in FISH analysis, displayed a similar outcome to those patients without genetic changes by FISH (46 vs 54 months, P=0.3). In the multivariate analysis the presence of t(4;14), RB deletion associated with other abnormalities, age >60 years, high proportion of S-phase cells and advanced stage of the disease according to the International Staging System retained their independent prognostic influence. In summary, RB deletion as a sole abnormality does not lead to a shortening in the survival of MM patients, whereas t(4;14) confers the worst prognosis in MM patients treated with high-dose chemotherapy.

Prognostic value of antigen expression in multiple myeloma: a PETHEMA/GEM study on 1265 patients enrolled in four consecutive clinical trials.

Persistence of minimal residual disease (MRD) after treatment for myeloma predicts inferior outcomes, but within MRD-positive patients there is great heterogeneity with both early and very late relapses. Among different MRD techniques, flow cytometry provides additional information about antigen expression on tumor cells, which could potentially contribute to stratify MRD-positive patients. We investigated the prognostic value of those antigens required to monitor MRD in 1265 newly diagnosed patients enrolled in the GEM2000, GEM2005MENOS65, GEM2005MAS65 and GEM2010MAS65 protocols. Overall, CD19pos, CD27neg, CD38lo, CD45pos, CD81pos, CD117neg and CD138lo expression predicted inferior outcomes. Through principal component analysis, we found that simultaneous CD38lowCD81posCD117neg expression emerged as the most powerful combination with independent prognostic value for progression-free survival (HR:1.69; P=0.002). This unique phenotypic profile retained prognostic value among MRD-positive patients. We then used next-generation flow to determine antigen stability throughout the course of the disease, and found that the expression of antigens required to monitor MRD is mostly stable from diagnosis to MRD stages, except for CD81 whose expression progressively increased from baseline to chemoresistant tumor cells (14 vs 28%). Altogether, we showed that the phenotypic profile of tumor cells provides additional prognostic information, and could be used to further predict risk of relapse among MRD-positive patients.

Cross validation with the mood disorder questionnaire (MDQ) of an instrument for the detection of hypomania in Spanish: the 32 item hypomania symptom check list (HCL-32).

BACKGROUND: The detection and diagnosis of present or past hypomanic episodes is of key importance for the differential diagnosis between depressive disorders and type II bipolar disorder. However, there are few instruments available to satisfactorily screen for the latter condition. The Hypomania Symptom Checklist-32 (HCL-32) is a self-applied questionnaire with 32 hypomania items and 8 severity and functional impact items which is being developed in several European countries for this purpose. Our aim was to develop and validate the psychometric properties of the HCL-32 scale in Spain in patients with bipolar disorder and to compare its properties with other instruments available for the detection of bipolar II disorder. METHODS: Patients were selected from 15 psychiatric outpatient departments, diagnosed with type I or type II bipolar disorder (BDI and BDII) and unipolar major depression (MD) according to DSM-IV-TR criteria. A control group of healthy subjects (HS) was likewise assessed. The patient selection criteria included a well-established diagnosis and a stable disorder and pharmacological treatment. The HCL-32 was administered to 237 subjects distributed among the above groups, on two occasions four weeks apart. We analysed the internal consistency, test-retest reliability and discriminative capacity of the HCL-32. RESULTS: The internal consistency of the Spanish version of the HCL-32, evaluated by Cronbach's alpha, was 0.94. Mean of affirmative questions by group were 21.2 (SD 5.8) for BDI, 19.3 (SD 6.2) for BDII, 8.6 (SD 6.6) for MD and 6.6 (SD 6.1) for HS, with statistically significant differences between them (Kruskal-Wallis test, p<0.001). Concurrent validity using the diagnosis variable was 0.72. Test-retest reliability was 0.90. We analysed the best cut-off point by means of a ROC curve analysis; for 14 affirmative responses, a sensitivity of 0.85 95%CI (0.78, 0.91) and specificity of 0.79, 95%CI (0.72, 0.87) were obtained. The positive and negative probability ratios were 4.1 and 5.3 (1/0.19 respectively). HCL-32 shows a dual factor structure of items, one as an energy-activity factor and another one as a factor involving items related to disinhibition and problems with self-control and attention. LIMITATIONS: The sample size of bipolar patients (particularly type BDII) should be increased in further studies. CONCLUSIONS: The Spanish version of the HCL-32 has good psychometric properties and sufficient sensitivity and specificity, detecting 8 out of every 10 patients with BD. The HCL-32 is a useful screening tool of patients with bipolar disorder in clinical settings. In its present form it adequately discriminates between bipolar and unipolar or healthy subjects, but not between BD I and BII.

Bortezomib and thalidomide maintenance after stem cell transplantation for multiple myeloma: a PETHEMA/GEM trial.

The phase III trial GEM05MENOS65 randomized 390 patients 65 years old or younger with newly diagnosed symptomatic multiple myeloma (MM) to receive induction with thalidomide/dexamethasone, bortezomib/thalidomide/dexamethasone and Vincristine, BCNU, melphalan, cyclophosphamide, prednisone/vincristine, BCNU, doxorubicin, dexamethasone bortezomib (VBMCP/VBAD/B) followed by autologous stem cell transplantation (ASCT) with MEL-200. After ASCT, a second randomization was performed to compare thalidomide/bortezomib (TV), thalidomide (T) and alfa-2b interferon (alfa2-IFN). Maintenance treatment consisted of TV (thalidomide 100 mg daily plus one cycle of intravenous bortezomib at 1.3 mg/m2 on days 1, 4, 8 and 11 every 3 months) versus T (100 mg daily) versus alfa2-IFN (3 MU three times per week) for up to 3 years. A total of 271 patients were randomized (TV: 91; T: 88; alfa2-IFN: 92). The complete response (CR) rate with maintenance was improved by 21% with TV, 11% with T and 17% with alfa2-IFN (P, not significant). After a median follow-up of 58.6 months, the progression-free survival (PFS) was significantly longer with TV compared with T and alfa2-IFN (50.6 vs 40.3 vs 32.5 months, P=0.03). Overall survival was not significantly different among the three arms. Grade 2-3 peripheral neuropathy was observed in 48.8%, 34.4% and 1% of patients treated with TV, T and alfa2-IFN, respectively. In conclusion, bortezomib and thalidomide maintenance resulted in a significantly longer PFS when compared with thalidomide or alfa2-IFN. (no. EUDRA 2005-001110-41).

Differentiation stage of myeloma plasma cells: biological and clinical significance.

The notion that plasma cells (PCs) are terminally differentiated has prevented intensive research in multiple myeloma (MM) about their phenotypic plasticity and differentiation. Here, we demonstrated in healthy individuals (n=20) that the CD19-CD81 expression axis identifies three bone marrow (BM)PC subsets with distinct age-prevalence, proliferation, replication-history, immunoglobulin-production, and phenotype, consistent with progressively increased differentiation from CD19+CD81+ into CD19-CD81+ and CD19-CD81- BMPCs. Afterwards, we demonstrated in 225 newly diagnosed MM patients that, comparing to normal BMPC counterparts, 59% had fully differentiated (CD19-CD81-) clones, 38% intermediate-differentiated (CD19-CD81+) and 3% less-differentiated (CD19+CD81+) clones. The latter patients had dismal outcome, and PC differentiation emerged as an independent prognostic marker for progression-free (HR: 1.7; P=0.005) and overall survival (HR: 2.1; P=0.006). Longitudinal comparison of diagnostic vs minimal-residual-disease samples (n=40) unraveled that in 20% of patients, less-differentiated PCs subclones become enriched after therapy-induced pressure. We also revealed that CD81 expression is epigenetically regulated, that less-differentiated clonal PCs retain high expression of genes related to preceding B-cell stages (for example: PAX5), and show distinct mutation profile vs fully differentiated PC clones within individual patients. Together, we shed new light into PC plasticity and demonstrated that MM patients harbouring less-differentiated PCs have dismal survival, which might be related to higher chemoresistant potential plus different molecular and genomic profiles.

Next Generation Flow for highly sensitive and standardized detection of minimal residual disease in multiple myeloma.

Flow cytometry has become a highly valuable method to monitor minimal residual disease (MRD) and evaluate the depth of complete response (CR) in bone marrow (BM) of multiple myeloma (MM) after therapy. However, current flow-MRD has lower sensitivity than molecular methods and lacks standardization. Here we report on a novel next generation flow (NGF) approach for highly sensitive and standardized MRD detection in MM. An optimized 2-tube 8-color antibody panel was constructed in five cycles of design-evaluation-redesign. In addition, a bulk-lysis procedure was established for acquisition of ⩾107 cells/sample, and novel software tools were constructed for automatic plasma cell gating. Multicenter evaluation of 110 follow-up BM from MM patients in very good partial response (VGPR) or CR showed a higher sensitivity for NGF-MRD vs conventional 8-color flow-MRD -MRD-positive rate of 47 vs 34% (P=0.003)-. Thus, 25% of patients classified as MRD-negative by conventional 8-color flow were MRD-positive by NGF, translating into a significantly longer progression-free survival for MRD-negative vs MRD-positive CR patients by NGF (75% progression-free survival not reached vs 7 months; P=0.02). This study establishes EuroFlow-based NGF as a highly sensitive, fully standardized approach for MRD detection in MM which overcomes the major limitations of conventional flow-MRD methods and is ready for implementation in routine diagnostics.

Natural history of relapsed myeloma, refractory to immunomodulatory drugs and proteasome inhibitors: a multicenter IMWG study.

Introduction of new myeloma therapies offers new options for patients refractory to immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs). In this multicenter study, patients with relapsed multiple myeloma, who have received at least three prior lines of therapy, are refractory to both an IMiD (lenalidomide or pomalidomide) and a PI (bortezomib or carfilzomib), and have been exposed to an alkylating agent were identified. The time patients met the above criteria was defined as time zero (T0). Five hundred and forty-three patients diagnosed between 2006 and 2014 were enrolled in this study. Median age at T0 was 62 years (range 31-87); 61% were males. The median duration between diagnosis and T0 was 3.1 years. The median number of lines of therapy before T0 was 4 (range 3-13). The median overall survival (OS) from T0 for the entire cohort was 13 (95% confidence interval (CI) 11, 15) months. At least one regimen recorded after T0 in 462 (85%) patients, with a median (95% CI) progression-free survival and OS from T0 of 5 (4, 6), and 15.2 (13, 17) months, respectively. The study provides the expected outcome of relapsed multiple myeloma that is refractory to a PI and an IMiD, a benchmark for comparison of new therapies being evaluated.

Toxicity and efficacy of busulfan and fludarabine myeloablative conditioning for HLA-identical sibling allogeneic hematopoietic cell transplantation in AML and MDS.

The safety and efficacy of a 4-day myeloablative conditioning (MAC) regimen consisting of Bu 3.2 mg/kg and fludarabine 40 mg/m(2)/day for HLA-identical sibling allogeneic hematopoietic cell transplantation (HCT) in myeloid malignancies was investigated in 133 patients (median age, 47 years; range 19-74 years) with de novo AML (60%), secondary AML (20%) or myelodysplastic syndrome (20%). All patients engrafted. Hepatic veno-occlusive disease occurred in five patients (4%), and severe toxicities, mostly mucositis, occurred in twenty-three (17%) patients. The non-relapse mortality (NRM) at 100 days was 1.5%. The incidences of acute GVHD grade 2-4 and grade 3-4 were 32 and 13%, respectively. At a median follow-up of 38 months, the cumulative incidence of chronic GVHD was 67%. The relapse incidence was 30% (27 and 31%, respectively, in patients with early- and late-stage disease), and the overall NRM was 15%. The actuarial 4-year disease-free survival (DFS) and overall survival (OS) were 54 and 62%, respectively. Patients aged <50 years had better outcomes compared with older patients (DFS 64 vs 42%, P=0.006; OS 73 vs 47%, P<0.001, respectively).