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AL amyloidosis is a systemic amyloidosis and is associated with an underlying plasma cell dyscrasia. High dose intravenous melphalan and autologous stem cell transplantation was developed for the treatment of AL amyloidosis in the early 1990s and was prompted by its success in multiple myeloma. This application has evolved significantly over the past three decades. These guidelines provide a comprehensive assessment of eligibility criteria, stem cell collection and mobilisation strategies and regimens, risk-adapted melphalan dosing, role for induction and consolidation therapies, specific supportive care management, long-term outcome with respect to survival, haematologic response and relapse and organ responses following stem cell transplantation. These guidelines are developed by the experts in the field on behalf of the stem cell transplant working group of the International Society of Amyloidosis (ISA) and European Haematology Association (EHA). [ABSTRACT FROM AUTHOR]

Cure for multiple myeloma is rare; the success of treatment is measured by response, and length of remissions and survival. Initial treatment for patients young and fit enough is high-dose chemotherapy with autologous stem cell transplantation. Various chemotherapy regimens are employed as initial therapy in patients who cannot withstand the autologous stem cell transplantation regimen, and for treatment of refractory or relapsed disease. Commonly used agents either alone or in combination have included dexamethasone, vincristine, doxorubicin, melphalan, cyclophosphamide, etoposide, cisplatin and, more recently, thalidomide. Within the past few years, the first-in-class proteasome inhibitor bortezomib has been introduced for the treatment of relapsed multiple myeloma with data demonstrating efficacy and safety. Throughout Europe, a faculty of experts conducted a series of debates with over 450 clinicians to discuss the efficacy of bortezomib vis-à-vis other available therapies. Of primary concern was the place of bortezomib in maximizing efficacy throughout the course of the disease and treatment by increasing response rates and improving duration of response, while maintaining an acceptable level of toxicity. The experts concluded that bortezomib, with its unique mechanism of action and demonstrated clinical efficacy and safety, should be considered as standard, early treatment in patients with relapsed multiple myeloma, especially after first relapse. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Treatment for multiple myeloma typically is chemotherapy, high-dose therapy with stem cell transplantation or radiation. Thalidomide shows promise, but to improve knowledge and understanding of this drug, more clinical data is required. Workshops designed to propose new studies providing much needed data on the use of thalidomide as first-line therapy, as maintenance therapy and as treatment for refractory or relapsed disease are reported here. Thalidomide has been shown to be effective in previously untreated patients as monotherapy (36% remission), although greater remission is seen in combination therapy, for example, thalidomide with dexamethasone (72% remission). Thalidomide is an interesting maintenance therapy. It has the advantages of being effective in the bone marrow and having a long-lasting effect but suffers because of its significant side-effect profile; however, it is tolerated by most patients. The adverse effects are thought to be dose-limiting, and most are seen in all patients at the beginning of treatment. Further clinical evidence is needed to determine the effectiveness of thalidomide as maintenance therapy in patients with multiple myeloma, having been shown to be active against refractory multiple myeloma, even in patients who relapse after high-dose chemotherapy. The workshop acknowledged the problems associated with designing a phase III study, and it is clear that many areas need to be addressed in the use of thalidomide for the treatment of multiple myeloma. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Bortezomib is a highly selective, reversible inhibitor of the 26S proteasome that is indicated for single-agent use in the treatment of patients with multiple myeloma who have received at least 2 prior therapies and are progressing on their most recent therapy. Clinical investigations have been completed or are under way to evaluate the safety and efficacy of bortezomib alone or in combination with chemotherapy in multiple myeloma, both at relapse and presentation, as well as in other cancer types. The antiproliferative, proapoptotic, antiangiogenic, and antitumor activities of bortezomib result from proteasome inhibition and depend on the altered degradation of a host of regulatory proteins. Exposure to bortezomib has been shown to stabilize p21, p27, and p53, as well as the proapoptotic Bid and Bax proteins, caveolin-1, and inhibitor κB-α, which prevents activation of nuclear factor κB-induced cell survival pathways. Bortezomib also promoted the activation of the proapoptotic c-Jun-NH2 terminal kinase, as well as the endoplasmic reticulum stress response. The anticancer effects of bortezomib as a single agent have been demonstrated in xenograft models of multiple myeloma, adult T-cell leukemia, lung, breast, prostate, pancreatic, head and neck, and colon cancer, and in melanoma. In these preclinical in vivo studies, bortezomib treatment resulted in decreased tumor growth, angiogenesis, and metastasis, as well as increased survival and tumor apoptosis. In several in vitro and/or in vivo cancer models, bortezomib has also been shown to enhance the antitumor properties of several antineoplastic treatments. Importantly, bortezomib was generally well tolerated and did not appear to produce additive toxicities when combined with other therapies in the dosing regimens used in these preclinical in vivo investigations. These findings provide a rationale for further clinical trials using bortezomib alone or in combination regimens with chemotherapy, radiation therapy, immunotherapy, or novel agents in patients with hematologic malignancies or solid tumors. [ABSTRACT FROM AUTHOR]

Simple Summary: Choosing the optimal therapy for elderly patients with multiple myeloma (MM) poses a difficult challenge for clinicians. Older patients are an extremely heterogeneous population, they are underrepresented in clinical trials, and data on octogenarians have been mainly limited to real-life settings. Treatment options for intermediate and frail patients might include dose-adapted combinations and less toxic combinations based on novel agents. Moreover, the discriminative power of the International Myeloma Working Group (IMWG) frailty score in detecting frailty and vulnerability could be improved by combining together aging-related factors (performance status, comorbidities, functional status) with disease-related factors (International Staging System stage, cytogenetic risk). Objective parameters could improve the reproducibility of this score and limit the subjectivity determined by patient-reported questionnaires on functional evaluations. Efforts are ongoing to simplify the IMWG frailty score and expand its use in real-life clinical practice. Multiple myeloma (MM) mostly affects elderly patients, which represent a highly heterogeneous population. Indeed, comorbidities, frailty status and functional reserve may vary considerably among patients with similar chronological age. For this reason, the choice of treatment goals and intensity is particularly challenging in elderly patients, and it requires a multidimensional evaluation of the patients and the disease. In recent years, different tools to detect patient frailty have been developed, and the International Myeloma Working Group frailty score currently represents the gold standard. It identifies intermediate-fit and frail patients requiring gentler treatment approaches compared to fit patients, aiming to preserve quality of life and prevent toxicities. This subset of patients is underrepresented in clinical trials, and studies exploring frailty-adapted approaches are scarce, making the choice of therapy extremely challenging. Treatment options for intermediate-fit and frail patients might include dose-adapted combinations, doublets, and less toxic combinations based on novel agents. This review analyzes the available tools for the assessment of frailty and possible strategies to improve the discriminative power of the scores and expand their use in real-life and clinical trial settings. Moreover, it addresses the main therapeutic challenges in the management of intermediate-fit and frail MM patients at diagnosis and at relapse. [ABSTRACT FROM AUTHOR]

Background: In a phase 1b study, intravenous daratumumab plus pomalidomide and dexamethasone induced a very good partial response or better rate of 42% and was well tolerated in patients with heavily pretreated multiple myeloma. We aimed to evaluate whether daratumumab plus pomalidomide and dexamethasone would improve progression-free survival versus pomalidomide and dexamethasone alone in patients with previously treated multiple myeloma.Methods: In this ongoing, open-label, randomised, phase 3 trial (APOLLO) done at 48 academic centres and hospitals across 12 European countries, eligible patients were aged 18 years or older, had relapsed or refractory multiple myeloma with measurable disease, had an Eastern Cooperative Oncology Group performance status of 0-2, had at least one previous line of therapy, including lenalidomide and a proteasome inhibitor, had a partial response or better to one or more previous lines of antimyeloma therapy, and were refractory to lenalidomide if only one previous line of therapy was received. Patients were randomly assigned (1:1) by an interactive web-response system in a random block size of two or four to receive pomalidomide and dexamethasone alone or daratumumab plus pomalidomide and dexamethasone. Randomisation was stratified by number of previous lines of therapy and International Staging System disease stage. All patients received oral pomalidomide (4 mg, once daily on days 1-21) and oral dexamethasone (40 mg once daily on days 1, 8, 15, and 22; 20 mg for those aged 75 years or older) at each 28-day cycle. The daratumumab plus pomalidomide and dexamethasone group received daratumumab (1800 mg subcutaneously or 16 mg/kg intravenously) weekly during cycles 1 and 2, every 2 weeks during cycles 3-6, and every 4 weeks thereafter until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov, NCT03180736.Findings: Between June 22, 2017, and June 13, 2019, 304 patients (median age 67 years [IQR 60-72]; 161 [53%] men and 143 [47%] women) were randomly assigned to the daratumumab plus pomalidomide and dexamethasone group (n=151) or the pomalidomide and dexamethasone group (n=153). At a median follow-up of 16·9 months (IQR 14·4-20·6), the daratumumab plus pomalidomide and dexamethasone group showed improved progression-free survival compared with the pomalidomide and dexamethasone group (median 12·4 months [95% CI 8·3-19·3] vs 6·9 months [5·5-9·3]; hazard ratio 0·63 [95% CI 0·47-0·85], two-sided p=0·0018). The most common grade 3 or 4 adverse events were neutropenia (101 [68%] of 149 patients in the daratumumab plus pomalidomide and dexamethasone group vs 76 [51%] of 150 patients in the pomalidomide and dexamethasone group), anaemia (25 [17%] vs 32 [21%]), and thrombocytopenia (26 [17%] vs 27 [18%]). Serious adverse events occurred in 75 (50%) of 149 patients in the daratumumab plus pomalidomide and dexamethasone group versus 59 (39%) of 150 patients in the pomalidomide and dexamethasone group; pneumonia (23 [15%] vs 12 [8%] patients) and lower respiratory tract infection (18 [12%] vs 14 [9%]) were most common. Treatment-emergent deaths were reported in 11 (7%) patients in the daratumumab plus pomalidomide and dexamethasone group versus 11 (7%) patients in the pomalidomide and dexamethasone group.Interpretation: Among patients with relapsed or refractory multiple myeloma, daratumumab plus pomalidomide and dexamethasone reduced the risk of disease progression or death versus pomalidomide and dexamethasone alone and could be considered a new treatment option in this setting.Funding: European Myeloma Network and Janssen Research and Development. [ABSTRACT FROM AUTHOR]

Background: Treatment decision-making in patients with relapsed/refractory multiple myeloma (RRMM) is challenging for a number of reasons including, the heterogeneity of disease at relapse and the number of possible therapeutic approaches. This study broadly aims to generate new evidence-based data to facilitate clinical decision-making in RRMM patients. The primary objective is to investigate the prognostic value of patient self-reported fatigue severity for overall survival.Methods: This multicenter prospective observational study will consecutively enroll 312 patients with multiple myeloma who have received at least 1 prior line of therapy and are considered as RRMM according to the International Myeloma Working Group (IMWG) criteria. Eligible RRMM participants will be adults (≥ 18 years old) patients and will be enrolled irrespective of comorbidities and performance status. At the time of study inclusion, data to calculate the frailty score are to be available. Patients will be followed up for 30 months and patient-reported outcome (PRO) assessment is planned at baseline and thereafter at 3, 6, 12, and 24 months. The following PRO validated questionnaires will be used: the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30), the EORTC QLQ-MY20 and the EORTC QLQ-INFO25. Satisfaction with care and preference for involvement in treatment decisions will also be evaluated. Clinical, laboratory and treatment related information will be prospectively collected in conjunction with pre scheduled PRO assessments. Cox regression analyses will be used to assess the prognostic value of baseline fatigue severity (EORTC QLQ-C30) and other patient-reported health-related quality of life parameters.Discussion: Clinical decision-making in RRMM is a challenge and outcome prediction is also an important aspect to enhance personalized treatment planning. Given the paucity of PRO data in this population, this prospective observational study aims to provide novel information that may facilitate patients' management in routine practice.Trial Registration: This trial is registered as identifier NCT03190525 . [ABSTRACT FROM AUTHOR]

The authors support the use of melphalan plus thalidomide (MPT) in the care of elderly patients with multiple myeloma since adverse events linked to MPT are manageable. They refer to the article "Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06)," by T. Facon and others in this issue.

Abstract: Objectives: To assess long‐term treatment patterns and outcomes in patients with persistent or chronic immune thrombocytopenia (ITP), also considering the impact of the treatment with thrombopoietin receptor agonists (TPO‐RAs) prior to splenectomy. Methods: Medical records of all patients with persistent or chronic ITP seen at our institution between January 1985 and December 2016 were reviewed. Data on demographic and clinical characteristics were analyzed using descriptive statistics. Wilcoxon rank‐sum test was used to compare medians between groups of patients. Results: Among 80 patients with persistent or chronic ITP, 34 underwent splenectomy and 59 were treated with TPO‐RAs. Twenty patients were both splenectomized and treated with TPO‐RAs; among them, 9 received TPO‐RAs before splenectomy. Median time to splenectomy from diagnosis of ITP was 25 months in the group of patients pretreated with TPO‐RAs vs 14.5 months in the group of splenectomized patients. These differences were not statistically significant. Conclusions: Our study provides some initial data on the potential benefits of the treatment with TPO‐RAs that may allow splenectomy to be safely deferred for prolonged periods. More research is needed to evaluate the impact of the treatment with TPO‐RAs prior to splenectomy. [ABSTRACT FROM AUTHOR]

This guideline has been developed jointly by the European Society of Haematology and International Society of Amyloidosis recommending non-transplant chemotherapy treatment for patients with AL amyloidosis. A review of literature and grading of evidence as well as expert recommendations by the ESH and ISA guideline committees. The recommendations of this committee suggest that treatment follows the clinical presentation which determines treatment tolerance tempered by potential side effects to select and modify use of drugs in AL amyloidosis. All patients with AL amyloidosis should be considered for clinical trials where available. Daratumumab-VCD is recommended from most untreated patients (VCD or VMDex if daratumumab is unavailable). At relapse, the two guiding principles are the depth and duration of initial response, use of a class of agents not previously exposed as well as the limitation imposed by patients' fitness/frailty and end organ damage. Targeted agents like venetoclax need urgent prospective evaluation. Future prospective trials should include advanced stage patients to allow for evidence-based treatment decisions. Therapies targeting amyloid fibrils or those reducing the proteotoxicity of amyloidogenic light chains/oligomers are urgently needed. [ABSTRACT FROM AUTHOR]

A review of the article "A phase 2 study of modified lenalidomide bortezomib, and dexamethasone in transplant ineligible multiple myeloma" by EK O'Donnell is presented.

Background: Combined therapy with carfilzomib, bendamustine, and dexamethasone was evaluated in this multicenter phase 1/2 trial conducted within the European Myeloma Network (EMN09 trial). Methods: Sixty‐three patients with relapsed/refractory multiple myeloma who had received ≥2 lines of prior therapy were included. The phase 1 portion of the study determined the maximum tolerated dose of carfilzomib with bendamustine set at 70 mg/m2 on days 1 and 8. After 8 cycles, responding patients received maintenance therapy with carfilzomib and dexamethasone until progression. Results: On the basis of the phase 1 results, the recommended phase 2 dose for carfilzomib was 27 mg/m2 twice weekly in weeks 1, 2, and 3. Fifty‐two percent of patients achieved a partial response or better, and 32% reached a very good partial response or better. The clinical benefit rate was 93%. After a median follow‐up of 21.9 months, the median progression‐free survival was 11.6 months, and the median overall survival was 30.4 months. The reported grade ≥3 hematologic adverse events (AEs) were lymphopenia (29%), neutropenia (25%), and thrombocytopenia (22%). The main nonhematologic grade ≥3 AEs were pneumonia, thromboembolic events (10%), cardiac AEs (8%), and hypertension (2%). Conclusions: In heavily pretreated patients who have relapsed/refractory multiple myeloma, combined carfilzomib, bendamustine, and dexamethasone is an effective treatment option administered in the outpatient setting. Infection prophylaxis and attention to patients with cardiovascular predisposition are required. In patients with heavily pretreated relapsed/refractory multiple myeloma, combined carfilzomib, bendamustine, and dexamethasone is an effective, well tolerated, and affordable treatment option safely administered in the outpatient setting. However, infection prophylaxis and attention to patients with cardiovascular predisposition are required. [ABSTRACT FROM AUTHOR]

Multiple available combinations of proteasome inhibitors, immunomodulators (IMIDs), and monoclonal antibodies are shifting the relapsed/refractory multiple myeloma (RRMM) treatment landscape. Lack of head-to-head trials of triplet regimens highlights the need for real-world (RW) evidence. We conducted an RW comparative effectiveness analysis of bortezomib (V), carfilzomib (K), ixazomib (I), and daratumumab (D) combined with either lenalidomide or pomalidomide plus dexamethasone (Rd or Pd) in RRMM. A retrospective cohort of patients initiating triplet regimens in line of therapy (LOT) ≥ 2 on/after 1/1/2014 was followed between 1/2007 and 3/2018 in Optum's deidentified US electronic health records database. Time to next treatment (TTNT) was estimated using Kaplan-Meier methods; regimens were compared using covariate-adjusted Cox proportional hazard models. Seven hundred forty-one patients (820 patient LOTs) with an Rd backbone (VRd, n = 349; KRd, n = 218; DRd, n = 99; IRd, n = 154) and 348 patients (392 patient LOTs) with a Pd backbone (VPd, n = 52; KPd, n = 146; DPd, n = 149; IPd, n = 45) in LOTs ≥2 were identified. More patients ≥75 years received IRd (39.6%), IPd (37.8%), and VRd (36.7%) than other triplets. More patients receiving VRd/VPd were in LOT2 vs other triplets. Unadjusted median TTNT in LOT ≥ 2: VRd, 13.9; KRd, 8.7; IRd, 11.4; DRd, not estimable (NE); and VPd, 12.0; KPd, 6.7; IPd, 9.5 months; DPd, NE. In covariate-adjusted analysis, only KRd vs DRd was associated with a significantly higher risk of next LOT initiation/death (HR 1.72; P = 0.0142); no Pd triplet was significantly different vs DPd in LOT ≥ 2. Our data highlight important efficacy/effectiveness gaps between results observed in phase 3 clinical trials and those realized in the RW. [ABSTRACT FROM AUTHOR]

We analyzed variations in terms of chromosomal abnormalities (CA) by fluorescence in situ hybridization (FISH) analysis on purified bone marrow plasma cells throughout the progression from monoclonal gammopathy of undetermined significance/smoldering multiple myeloma (MGUS/SMM) to newly diagnosed MM/plasma cell leukemia (NDMM/PCL) at diagnosis and from diagnostic samples to progressive disease. High risk was defined by the presence of at least del(17p), t(4;14), and/or t(14;16). 1p/1q detection (in the standard FISH panel from 2012 onward) was not available for all patients. We analyzed 139 MM/PCL diagnostic samples from 144 patients, with a median follow-up of 71 months: high-risk CA at diagnosis (MGUS/SMM or NDMM) was present in 28% of samples, whereas 37–39% showed high-risk CA at relapse. In 115 patients with NDMM who evolved to relapsed/refractory MM, we identified 3 different populations: (1) 31/115 patients (27%) with gain of new CA (del13, del17p, t(4;14), t(14;16) or 1q CA when available); (2) 10/115 (9%) patients with loss of a previously identified CA; and (3) 74 patients with no changes. The CA gain group showed a median overall survival of 66 months vs. 84 months in the third group (HR 0.56, 95% CI 0.34–0.92, p = 0.023). Clonal evolution occurs as disease progresses after different chemotherapy lines. Patients who acquired high-risk CA had the poorest prognosis. Our findings highlight the importance of performing FISH analysis both at diagnosis and at relapse. [ABSTRACT FROM AUTHOR]

Immunotherapy is increasingly used in the treatment of multiple myeloma (MM). Monoclonal antibodies (mAbs) are safe and effective ways to elicit immunotherapeutic responses. In 2015, daratumumab has become the first mAb approved by the Food and Drug Administration for clinical use in MM and, in the last 5 years, a lot of clinical and preclinical research has been done to optimize the use of this drug class. Currently, mAbs have already become part of standard-of-care combinations for the treatment of relapsed/refractory MM and very soon they will also be used in the frontline setting. The success of simple mAbs ('naked mAbs') prompted the development of new types of molecules. Antibody–drug conjugates (ADCs) are tumor-targeting mAbs that release a cytotoxic payload into the tumor cells upon antigen binding in order to destroy them. Bispecific antibodies (BiAbs) are mAbs simultaneously targeting a tumor-associated antigen and an immune cell-associated antigen in order to redirect the immune cell cytotoxicity against the tumor cell. These different constructs produced solid preclinical data and promising clinical data in phase I/II trials. The aim of this review article is to summarize all the recent developments in the field, including data on naked mAbs, ADCs and BiAbs. [ABSTRACT FROM AUTHOR]

A letter to the editor in response to the report by B. Bruno and colleagues, "Allografting or Autografting for Myeloma," that was published in the March 15, 2007 issue is presented.

Minimal residual disease (MRD) detection represents a sensitive tool to appropriately measure the response obtained with therapies for multiple myeloma (MM). The achievement of MRD negativity has superseded the conventional complete response (CR) and has been proposed as a surrogate endpoint for progression-free survival and overall survival. Several techniques are available for the detection of MRD inside (next-generation sequencing, flow cytometry) and outside (PET/CT, magnetic resonance) the bone marrow, and their complementary use allows a precise definition of the efficacy of anti-myeloma treatments. This review summarizes MRD data and results from previous clinical trials, highlights open issues related to the role of MRD in MM and discusses how MRD could be implemented in clinical practice to inform on patient prognosis and drive therapeutic decisions. [ABSTRACT FROM AUTHOR]

Immunotherapy is the latest innovation for the treatment of multiple myeloma (MM). Monoclonal antibodies (mAbs) entered the clinical practice and are under evaluation in clinical trials. MAbs can target highly selective and specific antigens on the cell surface of MM cells causing cell death (CD38 and CS1), convey specific cytotoxic drugs (antibody-drug conjugates), remove the breaks of the immune system (programmed death 1 (PD-1) and PD-ligand 1/2 (L1/L2) axis), or boost it against myeloma cells (bi-specific mAbs and T cell engagers). Two mAbs have been approved for the treatment of MM: the anti-CD38 daratumumab for newly-diagnosed and relapsed/refractory patients and the anti-CS1 elotuzumab in the relapse setting. These compounds are under investigation in clinical trials to explore their synergy with other anti-MM regimens, both in the front-line and relapse settings. Other antibodies targeting various antigens are under evaluation. B cell maturation antigens (BCMAs), selectively expressed on plasma cells, emerged as a promising target and several compounds targeting it have been developed. Encouraging results have been reported with antibody drug conjugates (e.g., GSK2857916) and bispecific T cell engagers (BiTEs®), including AMG420, which re-directs T cell-mediated cytotoxicity against MM cells. Here, we present an overview on mAbs currently approved for the treatment of MM and promising compounds under investigation. [ABSTRACT FROM AUTHOR]

Practical, safe, and effective hemostatic approach to orthopedic surgery using Extended Half‐Life factor IX in hemophilia B. By intraindividual comparison, we found a lower FIX consumption, number of infusions, and cost compared to plasma‐derived FIX. [ABSTRACT FROM AUTHOR]

PURPOSE: Data collection in clinical trials is becoming complex, with a huge number of variables that need to be recorded, verified, and analyzed to effectively measure clinical outcomes. In this study, we used data warehouse (DW) concepts to achieve this goal. A DW was developed to accommodate data from a large clinical trial, including all the characteristics collected. We present the results related to baseline variables with the following objectives: developing a data quality (DQ) control strategy and improving outcome analysis according to the clinical trial primary end points. METHODS: Data were retrieved from the electronic case reporting forms (eCRFs) of the phase III, multicenter MCL0208 trial (ClinicalTrials.gov identifier: NCT02354313) of the Fondazione Italiana Linfomi for younger patients with untreated mantle cell lymphoma (MCL). The DW was created with a relational database management system. Recommended DQ dimensions were observed to monitor the activity of each site to handle DQ management during patient follow-up. The DQ management was applied to clinically relevant parameters that predicted progression-free survival to assess its impact. RESULTS: The DW encompassed 16 tables, which included 226 variables for 300 patients and 199,500 items of data. The tool allowed cross-comparison analysis and detected some incongruities in eCRFs, prompting queries to clinical centers. This had an impact on clinical end points, as the DQ control strategy was able to improve the prognostic stratification according to single parameters, such as tumor infiltration by flow cytometry, and even using established prognosticators, such as the MCL International Prognostic Index. CONCLUSION: The DW is a powerful tool to organize results from large phase III clinical trials and to effectively improve DQ through the application of effective engineered tools. [ABSTRACT FROM AUTHOR]

Purpose: Granulocyte colony-stimulating factors (G-CSFs) are indicated for prophylaxis or management of chemotherapy-induced neutropenia (CIN) and febrile neutropenia (FN). Guidelines recommend G-CSF 24-72 h following chemotherapy; however, some evidence suggests that G-CSF initiated < 24 h may benefit some patients.Methods: MONITOR-GCSF was a prospective, observational, multicenter, pan-European study of 1447 chemotherapy-treated patients receiving daily biosimilar (standard) filgrastim (Zarzio®/Zarxio®, filgrastim-sndz, Hexal AG, Sandoz Inc.). In this analysis, cycles were classified as same-day, per-guidelines, or late if G-CSF support was initiated < 24 h, 24-72 h, and > 72 h after chemotherapy. Outcomes included occurrence of CIN of any grade (CIN1/4), grade 3 or 4 (CIN3/4), grade 4 (CIN4), or FN: CIN/FN-related hospitalization or CIN/FN-related chemotherapy disturbance.Results: A total of 5930 chemotherapy cycles from 1423 evaluable patients from MONITOR-GCSF had data for day of G-CSF initiation: 795 cycles (13.4%) classified as same-day, 3320 (56.0%) as per-guidelines, and 1815 (30.6%) as late. Groups did not differ as to CIN1/4 and FN episodes, or CIN/FN-related hospitalizations or chemotherapy disturbances. Patients in the same-day and per-guidelines groups had statistically similar odds of not experiencing any outcomes of interest in any given cycle. Patients in the late group had worse odds of experiencing CIN1/4, CIN3/4, and CIN4 episodes in any given cycle. Proportions of patients reporting clinical events of interest were generally similar.Conclusions: This real-world evidence indicates that CIN/FN prophylaxis initiated with biosimilar filgrastim within 24-72 h post-chemotherapy is effective and safe. Filgrastim administration on the day of chemotherapy may be appropriate in some patients. [ABSTRACT FROM AUTHOR]

Background: Minimal residual disease (MRD) is one of the most relevant prognostic factors in patients with multiple myeloma (MM); however, the impact of maintenance therapy on MRD levels remains unclear. Among patients with newly diagnosed MM (NDMM) who received lenalidomide maintenance until they developed disease progression, the role of MRD status as a predictor of progression-free survival (PFS) was evaluated by multiparameter flow cytometry (MFC) and allelic-specific oligonucleotide real-time quantitative polymerase chain reaction (ASO-RQ-PCR) analysis.Methods: Seventy-three patients with NDMM enrolled in the RV-MM-EMN-441 (clinical trials.gov identifier, NCT01091831) and RV-MM-COOP-0556 (clinicaltrials.gov identifier, NCT01208766; European Myeloma Network EMN02/HO95 MM Trial) phase 3 trials who achieved at least a very good partial response after intensification/consolidation were included. The median patient age was 57 years (interquartile range, 53-61 years), and all patients received lenalidomide maintenance until they developed progression. MRD was evaluated on bone marrow after intensification/consolidation, after 6 courses of maintenance, and every 6 months thereafter until clinical relapse using both ASO-RQ-PCR (sensitivity, 10-5 ) and MFC (sensitivity, from 10-4 to 10-5 ).Results: After intensification/consolidation, 33 of 72 patients (46%) achieved a molecular complete response (m-CR), and 44 of 70 (63%) achieved a flow complete response (flow-CR). Almost 27% of patients who were MRD-positive after consolidation became MRD-negative during maintenance. After a median follow-up of 38 months, PFS was prolonged in patients who achieved negative MRD status during maintenance according to results from both ASO-RQ-PCR analysis (hazard ratio, 0.29; 95% confidence interval, 0.14-0.62; P = .0013) and MFC (hazard ratio, 0.19; 95% confidence interval, 0.09-0.41; P < .001). The impact of negative MRD status on PFS was similar in all subgroups (ASCT and no-ASCT; International Staging System stages I, II, and III; high-risk and standard-risk cytogenetics), and the two techniques were highly correlated.Conclusions: MRD status is a stronger predictor of PFS than standard risk factors, and lenalidomide maintenance further increases the rate of negative MRD results. [ABSTRACT FROM AUTHOR]

The article presents a retrospective study which examined the effectiveness of rituximab, dexamethasone, cytarabine, cisplatin/oxaliplatin (R-DHAP/Ox) as treatment for early progressing follicular lymphoma. Also cited are the effectiveness of R-DHAP/Ox against diffuse large B cell lymphoma (DLCBL) with germinal centre subtype, and the use of the Kaplan-Meier method in estimating the subjects' survival probability.

Summary: Erythropoiesis‐stimulating agents (ESAs) were combined with ruxolitinib in 59 anaemic myelofibrosis patients (93% with Dynamic International Prognostic Scoring System [DIPSS] intermediate‐2/high risk; 52·5% transfusion‐dependent). Anaemia response (AR) rate was 54% and 76% of patients responded at 5 years. A further 15% displayed minor improvement in anaemia and 78% of patients reduced spleen size. Endogenous erythropoietin levels <125 u/l correlated with a higher AR rate (63% vs. 20%, P = 0·008). No thrombotic events or other toxicities occurred. Overall survival was 62% at 4 years, influenced by DIPSS and transfusion dependency. ESAs seem effective in improving anaemia in ruxruxolitinib‐treated myelofibrosis patients. [ABSTRACT FROM AUTHOR]

Before the introduction of “new drugs,” we designed a trial in which 162 newly diagnosed myeloma patients were biologically randomized to receive either an autologous stem cell transplant (auto-SCT) followed by a nonmyeloablative allogeneic stem cell transplant (allo-SCT) or a double auto-SCT. Fifty-eight patients in the allo-SCT arm and 46 in the double auto-SCT arm completed the assigned treatment. At a median follow-up of 12.3 years from allo-SCT and 12.1 years from second auto-SCT, median overall survival (OS) was 11.4 in the allo-SCT arm and 3.9 years in the auto-SCT -arm ( P  = .007), whereas event-free survival was 3.6 and 1.5 years ( P  < .001), respectively. A subset of allo-SCT patients showed persistent molecular remission. Two-year cumulative incidence of chronic graft-versus-host disease was 67.2%. At 5 years, 39% of these patients were alive, disease-free, and off immunosuppression; 36.6% had relapsed and 12.2% were still on immunosuppression. Thirty-three of 58 patients (allo-SCT arm) and 39 of 46 (auto-SCT arm) relapsed at least once and were rescued with new drugs. In the allo-SCT arm, 2 patients in biochemical relapse did not reach clinical criteria for treatment. Overall 28 (90%) were treated with new drugs and 14 (45%) received donor lymphocyte infusions (DLIs). In 28 of 31 patients (90%) DLIs were given with new drugs. Median OS from first relapse was 7.5 years in the allo-SCT arm and 2 years in the auto-SCT arm ( P  = .01). Patients who received DLI showed significantly longer OS (hazard ratio, .38; P  = .042) as compared with auto-SCT patients. This difference was slightly lower when only allo-SCT patients who did not receive DLIs were considered (hazard ratio, .56; P  = .154). In summary, long-term disease-free survival and survival outcomes after treating relapse with new drugs with or without DLIs were better in allo-SCT patients. [ABSTRACT FROM AUTHOR]

Background: Mantle Cell Lymphoma (MCL) is a B cell aggressive neoplasia accounting for about the 6% of all lymphomas. The most common molecular marker of clonality in MCL, as in other B lymphoproliferative disorders, is the ImmunoGlobulin Heavy chain (IGH) rearrangement, occurring in B-lymphocytes. The patient-specific IGH rearrangement is extensively used to monitor the Minimal Residual Disease (MRD) after treatment through the standardized Allele-Specific Oligonucleotides Quantitative Polymerase Chain Reaction based technique. Recently, several studies have suggested that the IGH monitoring through deep sequencing techniques can produce not only comparable results to Polymerase Chain Reaction-based methods, but also might overcome the classical technique in terms of feasibility and sensitivity. However, no standard bioinformatics tool is available at the moment for data analysis in this context. Results: In this paper we present HashClone, an easy-to-use and reliable bioinformatics tool that provides B-cells clonality assessment and MRD monitoring over time analyzing data from Next-Generation Sequencing (NGS) technique. The HashClone strategy-based is composed of three steps: the first and second steps implement an alignment-free prediction method that identifies a set of putative clones belonging to the repertoire of the patient under study. In the third step the IGH variable region, diversity region, and joining region identification is obtained by the alignment of rearrangements with respect to the international ImMunoGenetics information system database. Moreover, a provided graphical user interface for HashClone execution and clonality visualization over time facilitate the tool use and the results interpretation. The HashClone performance was tested on the NGS data derived from MCL patients to assess the major B-cell clone in the diagnostic samples and to monitor the MRD in the real and artificial follow up samples. Conclusions: Our experiments show that in all the experimental settings, HashClone was able to correctly detect the major B-cell clones and to precisely follow them in several samples showing better accuracy than the state-of-art tool. [ABSTRACT FROM AUTHOR]

Purpose: In the MONITOR-GCSF study of chemotherapy-induced (febrile) neutropenia with biosimilar filgrastim, 56.6% of patients were prophylacted according to amended EORTC guidelines, but 17.4% were prophylacted below and 26.0% above guideline recommendations.Methods: MONITOR-GCSF is a prospective, observational study of 1447 evaluable patients from 140 cancers centers in 12 European countries treated with myelosuppressive chemotherapy for up to 6 cycles receiving biosimilar GCSF prophylaxis. Patients were classified as under-, correctly-, or over-prophylacted with GCSF relative to guideline recommendations based on their chemotherapy risk, individual risk factors, and type of GCSF prophylaxis (primary versus secondary).Results: Differences between under- (17.4%), correctly- (56.6%), or over-prophylacted (26.0%) groups were found in terms of patient risk factors (age, performance status, history of FN, comorbid conditions) as well as prophylaxis patterns (type of prophylaxis, day of GCSF initiation, and GCSF duration). Rates of chemotherapy-induced neutropenia (CIN) (all grades), FN, and CIN-related hospitalizations were consistently lower in over-prophylacted patients relative to under- and correctly-prophylacted patients. No differences were observed between under- and correctly-prophylacted patients except for CIN/FN-related chemotherapy disturbances. No GCSF safety differences were found between groups (except for headaches).Conclusions: The real-world evidence provided by the MONITOR-GCSF study indicates that providing GCSF support may yield better CIN, FN, and CIN/FN-related hospitalization outcomes if patients are prophylacted at levels above guideline recommendations. Patients who are under-prophylacted are at higher risk for disturbances to their chemotherapy regimens. Our findings support the guideline recommendation that CIN/FN risk be assessed at the beginning of each chemotherapy cycle. [ABSTRACT FROM AUTHOR]

Neurologic complications after hematopoietic stem cell transplantation are frequently life-threatening, and their clinical management can be highly challenging. A wide spectrum of causative factors—including drug-related toxicities; infections sustained by virus, bacteria, or invasive molds; metabolic encephalopathy; cerebrovascular disorders; immune-mediated disorders; and disease recurrence—may lead to potentially lethal complications. Moreover, given that some neurologic complications are not uncommonly diagnosed post mortem, their overall incidence is likely to be underestimated. Their prompt recognition and timely treatment are of paramount importance to reduce the risk for transplantation-related death. [ABSTRACT FROM AUTHOR]

Objective There is no strong evidence to guide therapeutic approach to multiple myeloma ( MM) patients who experience first relapse. The treatment choice can be difficult since currently all patients are exposed to novel agents as thalidomide, bortezomib and lenalidomide. Methods In this retrospective analysis, we evaluated the best therapeutic sequence, the role of retreatment, and the most beneficial cutoff of first remission in order to choose retreatment, analyzing 476 patients relapsed after first-line therapy. Results Bortezomib-based regimens upfront followed by lenalidomide-based regimens at first relapse resulted in significantly better second progression-free survival (2nd PFS), PFS2, and overall survival ( OS) compared to the opposite sequence. Changing therapy resulted in significantly better 2nd PFS in the whole population, whereas PFS2 was significantly longer only in patients who underwent maintenance therapy. Moreover, until PFS1 was shorter than 27 months, changing therapy at first relapse significantly extended 2nd PFS and PFS2 compared to retreatment, whereas similar outcomes were observed between the two strategies, when PFS1 was longer than 27 months. Conclusion Lacking randomized trials, our study could help to choose the most appropriate therapy algorithm in patients with MM. [ABSTRACT FROM AUTHOR]

Pegylated interferon (peg-IFN) was proven by phase II trials to be effective in polycythemia vera (PV); however, it is not clear whether it could improve patient outcome compared to hydroxyurea (HU). Here, we present an observational study on 65 PV patients aged 65 years or younger, who received either peg-IFN (30) or HU (35) according to the physician choice. Median follow-up was 75 months. The two cohorts were comparable for patient and disease characteristics. Eighty-seven percent of the patients treated with peg-INF responded, with a CR rate of 70% as compared to 100 and 49% with HU, respectively. Discontinuation rate was similar in the two groups (20% in peg-IFN vs 17% in HU). JAK2 allele burden was monitored in peg-INF arm only, and a reduction was observed in 88% of the patients. No thrombotic events were observed during peg-IFN treatment compared to three on HU. Disease progression to myelofibrosis or acute myeloid leukemia occurred to a patient only in peg-INF, compared to three in HU. Overall, three second malignancies were observed during the study, two in patients who received HU only, and one in a patient largely treated HU who received also peg-IFN for 3 months. Overall survival was significantly better for peg-IFN patients compared to HU, p = 0.027. Our study, albeit limited by small patient and event number and lack of randomization, confirms the efficacy of peg-INF in PV and shows a significant survival advantage for peg-INF-treated patients. Waiting for confirming data from the ongoing phase III trials, our study can support peg-INF as a first-line treatment option for PV, at least for younger patients. [ABSTRACT FROM AUTHOR]

Background: Allogeneic hematopoietic stem cell transplantation (HSCT) is potentially curative in a variety of hematological malignancies. Graft-vs.-host disease (GvHD) remains a life-threatening complication. Standard treatment is high-dose (HD) corticosteroids. Steroid-refractory (SR) GvHD is associated with poor prognosis. At present, second-line treatment is ill-defined and includes a number of agents. Novel insights into the pathophysiology of acute GvHD (aGvHD) highlight the relevant role of the host inflammatory response governed by several kinase families, including Janus kinases (JAK) 1/2. Ruxolitinib, a JAK1/2 inhibitor approved for intermediate-2/high-risk myelofibrosis, was recently employed in SR-GvHD with encouraging overall response rates. Clinical experience however remains limited. Case presentation: A 51-year-old male with refractory anemia with excess blast type-2 underwent a myeloablative allogeneic HSCT from a 9/10 HLA-matched unrelated donor after conditioning with busulfan and cyclophosphamide. GvHD prophylaxis consisted of cyclosporine, methotrexate, and thymoglobulin. CD34+ cells/kg infused were 8.69 × 106 kg. On day 29, the patient developed overall grade IV aGvHD with biopsy proven stage IV gastrointestinal (GI) GvHD refractory to HD corticosteroids. Patient conditions rapidly deteriorated and became critical despite the addition of mycophenolate mofetil and budesonide. On day 33, Ruxolitinib was started, and on day 39 the patient clinical conditions gradually improved. Complete resolution of aGvHD was also confirmed by histology on day 54. Conclusions: At 5 months from HSCT, the patient is well and in continuous hematological complete remission without flare of GvHD. Ruxolitinib was discontinued on day 156. Ruxolitinib is feasible and effective in SR-aGvHD though large prospective clinical trials are warranted. [ABSTRACT FROM AUTHOR]

The European Society for Blood and Marrow Transplantation Chronic Malignancies Working Party held a preceptorship meeting in Turin, Italy on 25–26 September 2014, to discuss the role of stem cell transplantation (SCT) in the treatment of multiple myeloma and other plasma cell disorders. Scientists and clinicians working in the field gathered to discuss a variety of topics including the results of recent clinical trials, basic research, the concept of minimal residual disease, and immune modulation. As individual presentations revealed, important advances have occurred in our understanding of the pathophysiology of myeloma and the role that SCT, along with other forms of immunotherapy, plays in treating it. Each presentation stimulated discussion and exchange of ideas among the attendants. We decided to summarize and, importantly, to update the meeting proceedings in this review to share stimulating discussions and ideas on potentially novel treatment strategies among clinicians. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study is to examine the real-world treatment patterns and outcomes of chemotherapy-induced (febrile) neutropenia (chemotherapy-induced (CIN)/febrile neutropenia (FN)) prophylaxis with biosimilar filgrastim (Zarzio®).Methods: MONITOR-GCSF is an international (12 countries), multi-center (140), prospective (max. six cycles), observational, open-label, pharmaco-epidemiologic study of cancer patients (n = 1447) treated with myelosuppressive chemotherapy across a total of 6,213 cycles and receiving prophylaxis with Zarzio®. Data were analyzed using both the patient and cycle as unit of analysis.Results: Most (72.3 %) received primary prophylaxis; dosed mainly (53.2 %) at 30 MIU but differentiated by weight, chemotoxicity, and tumor type; and mainly (53.2 %) initiated in the 24-72h post-chemotherapy window but differentiated by prophylaxis type, tumor type, and chemotoxicity and for modal/median duration of 5 days. Relative to European Organisation for Research and Treatment of Cancer (EORTC) guidelines, 56.6 % were correctly prophylacted, 17.4 % under-prophylacted, and 26.0 % over-prophylacted. The following incidence rates were recorded: CIN grade 4 13.2 % of patients and 3.9 % of cycles, FN 5.9 % of patients and 1.4 % of cycles, CIN/FN-related hospitalizations 6.1 % of patients and 1.5 % of cycles, CIN/FN-related chemotherapy disturbances 9.5 % of patients and 2.8 % of cycles, and composite outcomes index 22.3 % of patients and 6.7 % of cycles. Rates varied by type of prophylaxis and tumor, chemotoxicity, initiation day, and prophylaxis duration. There were 1834 musculoskeletal events with 24.7 % of patients reporting bone pain of any grade (mostly mild to moderate), and 148 adverse drug reactions, including 4 serious, were recorded in 76 patients.Conclusions: The clinical and safety outcomes are well within the range of historically reported data for originator filgrastim underscoring the clinical effectiveness and safety of biosimilar filgrastim in daily clinical practice. [ABSTRACT FROM AUTHOR]

Anemia in the elderly is a common but challenging clinical scenario. Here we describe the case of an older woman who presented with anemia and elevated inflammation markers. After a complete diagnostic work-up, a definite etiology of the anemia could not be found so eventually a bone marrow biopsy was performed and she was diagnosed with myelodysplastic syndrome. She responded well to erythropoietin treatment but her inflammation markers remained elevated thus a positron emission tomography was performed. It turned out that the patient suffered from giant cell artheritis and her anemia completely resolved after steroid treatment. Our case outlines that it is necessary to pay particular attention to anemia of inflammation, which could be due to several and often masked conditions. Myelodysplatic syndromes should be considered when other causes have been ruled out, but their diagnosis can be difficult and requires expertise in the field. [ABSTRACT FROM AUTHOR]

Vγ9Vδ2 T cells have a natural inclination to recognize malignant B cells in vitro via receptors for stress-induced selfligands and TCR-dependent recognition of phosphoantigens (pAgs) generated in the mevalonate (Mev) pathway. This inclination is continuously challenged in vivo by the immune suppression operated by tumor cells. Multiple myeloma (MM) is a prototypic B-cell malignancy in which myeloma cells subvert the local microenvironment to reshape antitumor immune responses. In this study, we have investigated the immune competence of bone marrow (BM) Vγ9Vδ2 T cells in a large series of MM patients. We have found that the BM microenvironment significantly hampers the pAg-reactivity of BM Vγ9Vδ2 T cells, which become largely PD-1+ and are surrounded by PD-L1+ myeloma cells and increased numbers of PD-L1+ myeloid-derived suppressor cells (MDSC). Vγ9Vδ2 T-cell dysfunction is an early event that can be already detected in individuals with monoclonal gammopathy of undetermined significance (MGUS) and not fully reverted even when MM patients achieve clinical remission. Anti-PD-1 treatment increases the cytotoxic potential of Vγ9Vδ2 T cells by almost 5-fold after pAg stimulation, and appears to be a promising strategy for effective immune interventions in MM. [ABSTRACT FROM AUTHOR]

The article reports telomere length (TL) dynamics over time and its predictive value in 90 chronic lymphocytic leukaemia (CLL) patients with a longer follow-up. The two time-points under which TL was assessed include telomere loss over time which was calculated in terms of absolute loss and another that was performed on peripheral blood mononuclear cells. It was discovered that progressive telomere erosion occurs during the natural history of CLL.

The article presents a study which aims at assessing safety and efficacy of the Bortezomib, melphalan, and prednisone (VMP) regimen as salvage treatment for elderly relapsed/refractory multiple myeloma (RRMM) patients. Topics discussed include determination of VMP as standards of care for patients with multiple myeloma (MM) not eligible for transplantation; effectiveness of carfilzomib in reducing neurotoxicity; and information on monoclonal antibodies like daratumumab and elotuzumab.

We evaluated a maintenance, post-remission treatment with low-dose chemotherapy plus differentiating agents on poor-prognosis acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) patients ineligible to allografting. Patients had either age over 60 and/or secondary AML, therapy-related AML, previous relapse, high-risk MDS. Forty-five patients received the maintenance therapy based on two alternated schedules: (a) 6-thioguanine + 13-cis retinoic acid + dihydroxylated vitamin D3 and (b) low-dose cytarabine + 6-mercaptopurine + all-trans retinoic acid + dihydroxylated vitamin D3. We compared their outcome, at a median follow-up of 52 months, to that of a matched population of 49 patients who stopped treatments after consolidation. Maintenance group had a lower relapse incidence (70.3 vs. 86.4 % at 5 years p = 0.007) and a longer disease-free survival (median 21.2 vs. 8.7 months, p = 0.017). The relapse reduction improved overall survival: median 40.4 months (35.9 % at 5 years) for maintenance group vs. 15.8 (14.2 % at 5 years) for controls ( p = 0.005). At multivariate Cox analysis, both cytogenetic and maintenance therapies resulted independent outcome predictors for overall survival. Maintenance treatment also reduced minimal residual disease (detected by WT1 and CBFβ-MYH11) in five of eight evaluable patients. The present results suggest that our strategy of maintenance therapy might improve the outcome of poor-risk AML/MDS patients. [ABSTRACT FROM AUTHOR]

The article discusses a study which assessed the proportion of chronic myeloid leukemia patients treated front line with imatinib outside clinical trials who could achieve a durable molecular response (MR) and maintain after treatment discontinuation. Topics covered include the reason for therapy restart, characteristics of patients who discontinued imatinib, and comparison of dasatinib and nilotinib with imatinib.

This multicenter, open-label phase 2 trial determined the safety and efficacy of carfilzomib, a novel and irreversible proteasome inhibitor, in combination with cyclophosphamide and dexamethasone (CCyd) in patients with newly diagnosed multiple myeloma (NDMM) ⩾65 years of age or who were ineligible for autologous stem cell transplantation. Patients (N = 58) received CCyd for up to 9 28-day cycles followed by maintenance with carfilzomib until progression or intolerance After a median of 9 CCyd induction cycles (range 1-9), 95% of patients achieved at least a partial response, 71% achieved at least a very good partial response, 49% achieved at least a near complete response, and 20% achieved stringent complete response After a median follow-up of 18 months, the 2-year progression-free survival and overall survival rates were 76% and 87%, respectively. The most frequent grade 3 to 5 toxicities were neutropenia (20%), anemia (11%), and cardiopulmonary adverse events (7%). Peripheral neuropathy was limited to grades 1 and 2 (9%). Fourteen percent of patients discontinued treatment because of adverse events, and 21% of patients required carfilzomib dose reductions. In summary, results showed high complete response rates and a good safety profile. This trial was registered at clinicaltrials.gov as #NCT01346787. [ABSTRACT FROM AUTHOR]

Pre-emptive rituximab (pRTX) might represent an effective approach for patients with follicular (FL) and mantle cell lymphoma (MCL) experiencing molecular relapse (M-rel). However, available experience is still limited. We retrospectively collected FL and MCL cases that underwent pRTX with four weekly rituximab infusions (375 mg/m) due to molecular persistence or M-rel. M-rel was assessed using nested polymerase chain reaction (PCR) and real-time quantitative PCR using the Bcl-1/IGH, Bcl-2/IGH or the immunoglobulin heavy chain rearrangement. Twenty-three occurrences of M-rel or persistence were treated in 18 patients (nine MCL and nine FL). The pRTX reinduced molecular remission (MR) in 17/23 cases (7/9 FL and 10/14 MCL). The median time to MR reinduction was 4.5 months (range 3-12), and the median duration of the first MR reinduction was 34 months (range 12-72). In five MCL cases, pRTX was used to treat subsequent M-rels, with success in four cases. No clinical relapses were seen within 2 years of successful reinduction of MR. Progression-free survival after pRTX was 64 % at a median follow-up of 6 years. pRTX was feasible and safe and effectively reinduced MR in FL and MCL patients (74 %). Prospective trials are needed to verify the clinical benefit of similar approaches. [ABSTRACT FROM AUTHOR]

Significant benefits for zoledronic acid (ZOL) over clodronate acid (CLO) were seen in the Medical Research Council Myeloma IX randomized trial. ZOL significantly reduced skeletal-related events (SREs), and improved progression-free survival and overall survival (OS), making it the bisphosphonate of choice for newly diagnosed myeloma patients. In this analysis of Myeloma IX data, we have investigated the impact of response on bone disease in 1111 transplant-eligible patients. At posttransplant day 100, complete response (CR) was seen in 48% of patients, very good partial response (VGPR) in 20%, and partial response (PR) in 23%. For patients in VGPR or less, ZOL was superior to CLO in reducing SREs (P = .048), whereas for patients in CR, both agents were equivalent (P - .83). For OS, ZOL was associated with a significant benefit in patients in PR (P = .0091). No difference in OS was seen with patients in CR (P = .91) or VGPR (P = .74). These findings indicate that response category posttransplant may influence the impact of bisphosphonate therapy. [ABSTRACT FROM AUTHOR]

We performed a phase 1/2 trial to determine the maximum tolerated dose (MTD) of pomalidomide and to explore its efficacy when combined with cyclophosphamide-prednisone in relapsed/refractory myeloma patients. Pomalidomide was given at 1 to 2.5 mg/d, cyclophosphamide at 50 mg every other day, prednisone at 50 mg every other day, for 6 28-day cycles, followed by pomalidomide-prednisone maintenance therapy. Thromboprophylaxis was recommended. Sixty-nine patients were enrolled, 55 received the MTD (2.5 mg/d) and were evaluated. Best responses included complete response in 3 patients (5%), very good partial response in 10 (18%), partial response in 15 (27%), minimal response in 11 (20%), stable disease in 15 (27%), and progressive disease in 1 (3%), for an overall response rate of 51%. The median time-to-response was 1.83 months. After a median follow-up of 14.8 months, median progression-free survival was 10.4 months and 1-year overall survival was 69%. At the MTD, grade 3 to 4 toxicities included anemia (9%), thrombocytopenia (11%), neutropenia (42%), neurologic events (7%), dermatologic events (7%), and thromboembolism (2%). Grade 3 to 5 infections occurred in 5 patients (9%). Five patients (9%) discontinued treatment for toxicity. New grade 3 to 4 adverse events were low during maintenance. Pomalidomide-cyclophosphamide-prednisone is safe and effective in relapsed/ refractory myeloma patients. [ABSTRACT FROM AUTHOR]

A sequential approach including bortezomib induction, intermediate-dose melphalan, and autologous stem cell transplantation (ASCT), followed by lenalidomide consolidation-maintenance, has been evaluated. Efficacy and safety data have been analyzed on intention-to-treat and results updated. Newly diagnosed myeloma patients 65 to 75 years of age (n = 102) received 4 cycles of bortezomib-pegylated liposomal doxorubicin-dexamethasone, tandem melphalan (100 mg/m2) followed by ASCT (MEL100-ASCT), 4 cycles of lenalidomide-prednisone consolidation (LP), and lenalidomide maintenance (L) until disease progression. The complete response (CR) rate was 33% after MEL100-ASCT, 48% after LP and 53% after L maintenance. After a median follow-up of 66 months, median time-to-progression (TTP) was 55 months and median progression-free survival 48 months. Median overall survival (OS) was not reached, 5-year OS was 63%. In CR patients, median TTP was 70 months and 5-year OS was 83%. Median survival from relapse was 28 months. Death related to adverse events (AEs) occurred in 8/102 patients during induction or transplantation. Rate of death related to AEs was higher in patients ⩾70 years compared with younger (5/26 vs 3/76, P = .024). Bortezomib-induction followed by ASCT and lenalidomide consolidation-maintenance is a valuable option for elderly myeloma patients, with the greatest benefit in those younger than 70 years of age. [ABSTRACT FROM AUTHOR]