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Objectives: To describe the incorporation of monoclonal antibodies (mAb) in real-world (RW) practice for the treatment of patients with relapsed refractory multiple myeloma (RRMM) in a setting with other treatment alternatives., Methods: This was an observational, multicenter, ambispective study of RRMM treated with or without a mAb., Results: A total of 171 patients were included. For the group treated without mAb, the median (95% CI) progression-free survival (PFS) to relapse was 22.4 (17.8-27.0) months; partial response or better (≥PR) and complete response or better (≥CR) was observed in 74.1% and 24.1% of patients, respectively; and median time to first response in first relapse was 2.0 months and in second relapse was 2.5 months. For the group of patients treated with mAb in first or second relapse, the median PFS was 20.9 (95% CI, could not be evaluated) months; the ≥ PR and ≥ CR rates were 76,2% and 28.6%, respectively; and the median time to first response in first relapse was 1.2 month and in second relapse was 1.0 months. The safety profiles for the combinations were consistent with those expected., Conclusions: The incorporation of mAb in RW practice for the treatment of RRMM has shown good quality and speed of response with a similar safety profile shown in randomized clinical trials.

In this clinical trial, we demonstrate that ultrarapid fast infusion of rituximab (Truxima) in 30 min with oral premedication is feasible and secure for patients, and reduce the day-care hospital stays., Competing Interests: EPP: Presentation: Amgen, Sanofi Kern. Travel and accomodation: Abbvie, Sanofi. XGO: Advisory boards for Janssen, BMS, Sanofi, GSK, Amgen, Astrazeneca, Gilead, JazzPharma. Presentations: Janssen, BMS, Sanofi, GSK, Amgen, SOBI, Abbvie. JMGC: Presentations: Kern. Advisory board for Novartis, Pfizer, and Alexion. LCP, BBU, AUC, AVG, BBI, MCMF, ACO, BBD, JJGA, and MAAM declare not conflict of interest., (© 2023 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Background: Most patients with multiple myeloma (MM) relapse or become refractory, resulting in high health care costs. However, real-world data regarding the utilization of health care services among the relapsed/refractory MM (RRMM) population are scarce., Methods: Observational, cross-sectional, multicenter study of the utilization of health care services by RRMM patients who had relapsed within the previous 6 months in Spain in a real-world setting. Data were collected from the clinical records and during a single structured interview and included sociodemographic and clinical characteristics at last relapse, the treatment and health care services nature, and were presented using descriptive statistics., Results: The 276 patients enrolled (53.3% males), with a mean [SD] age of 67.4 [10.5] years, had experienced their most recent relapse a median (IQR) of 1.61 (0.74, 3.14) months before entering the study. Patients lived a median (IQR) of 9.0 (3.0, 30.0) km away from the hospital and visited the hospital a median (IQR) of 3.0 (2.0, 5.0) times/month to receive treatment for their most recent relapse. They spent a median (IQR) of 15.84 (5.0, 42.0) euros/month on transportation. Since their most recent relapse, most patients had been admitted to a hospital unit (n = 155, 56.2%), had required ≥1 diagnostic tests (n = 227, 82.2%), and had consulted the hematologist (n = 270, 97.8%) a mean (SD) of 5.5 (5.4) times. In half of the visits, patients were accompanied by an actively working caregiver (n = 112, 54.4%)., Conclusions: RRMM treatments are associated with a high utilization of health care services and pose a significant burden for patients and caregivers., Trial Registration Number: NCT03188536., Competing Interests: Disclosure EMO has received research support from GSK; honoraria from BMS/Celgene, Janssen, Sanofi, GSK, Oncopeptides, Amgen, MSD, and Takeda; and consultancy fees from BMS/Celgene, Janssen, GSK, Pfizer, Amgen, Sanofi, Secura-Bio, Oncopeptides, Karyopharm, and Takeda. EP-P has received fees as consultant from Celgene, Amgen, Takeda, and Janssen; and fees as speaker from Roche, Celgene, Amgen, Janssen, Abbvie, and Jazz Pharmaceutical. MS has received financial support from Celgene, Janssen, and Takeda. JMA has received consultancy fees from BMS, Amgen, Janssen, Abbvie, GSK, and Sanofi; and honoraria from Novartis, Takeda, Janssen, BMS, Roche, Sanofi, Abbvie, GSK, and Amgen. RR has received consultancy fees from Becton-Dickinson, Sanofi, and The Binding Site. LR has received honoraria from Janssen, Celgene, Amgen, and Takeda. MG, AF, and AN are employees of Takeda. CM-G, GB, SG, EG, VG-C, YG, and DM declare no conflicts of interest., (Copyright © 2023. Published by Elsevier Inc.)

Background: Ibrutinib demonstrated remarkable efficacy and favorable tolerability in patients with untreated or relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL), including those with high-risk genetic alterations. The IBRORS-CLL study assessed the characteristics, clinical management and outcome of CLL patients receiving ibrutinib in routine clinical practice in Spain., Patients: Observational, retrospective, multicenter study in CLL patients who started single-agent ibrutinib as first-line treatment or at first or second relapse between January 2016 and January 2019., Results: A total of 269 patients were included (median age: 70.9 years; cardiovascular comorbidity: 55.4%, including hypertension [47.6%] and atrial fibrillation [AF] [7.1%]). Overall, 96.7% and 69% of patients underwent molecular testing for del(17p)/TP53 mutation and IGHV mutation status. High-risk genetic features included unmutated IGHV (79%) and del(17p)/TP53 mutation (first-line: 66.3%; second-line: 23.1%). Overall, 84 (31.2%) patients received ibrutinib as first-line treatment, and it was used as second- and third-line therapy in 121 (45.0%) and 64 (23.8%) patients. The median progression-free survival and overall survival were not reached irrespective of del(17p)/TP53, or unmutated IGHV. Common grade ≥3 adverse events were infections (12.2%) and bleeding (3%). Grade ≥3 AF occurred in 1.5% of patients., Conclusion: This real-world study shows that single-agent ibrutinib is an effective therapy for CLL, regardless of age and high-risk molecular features, consistent with clinical trials. Additionally, single-agent ibrutinib was well tolerated, with a low rate of cardiovascular events. This study also emphasized a high molecular testing rate of del(17p)/TP53 mutation and IGHV mutation status in clinical practice according to guideline recommendations., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Chronic Lymphocytic Leukemia (CLL) is the most prevalent leukemia in Western countries and is notable for its variable clinical course. This variability is partly reflected by the mutational status of IGHV genes. Many CLL samples have been studied in recent years by next-generation sequencing. These studies have identified recurrent somatic mutations in NOTCH1, SF3B1, ATM, TP53, BIRC3 and others genes that play roles in cell cycle, DNA repair, RNA metabolism and splicing. In this study, we have taken a deep-targeted massive sequencing approach to analyze the impact of mutations in the most frequently mutated genes in patients with CLL enrolled in the REM (rituximab en mantenimiento) clinical trial. The mutational status of our patients with CLL, except for the TP53 gene, does not seem to affect the good results obtained with maintenance therapy with rituximab after front-line FCR treatment., Competing Interests: J.A. Garcia-Marco has received honoraria for advisory board and speaker’s bureau from Mundipharma, Glaxo, AbbVie, Roche, Gilead, and Janssen, and research support from Hoffman-La Roche and Janssen. Jaime Pérez de Oteyza declares a consulting and advisory role for Hoffman-La Roche. The other authors have no conflicts of interest to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Despite the significant proportion of older patients with newly diagnosed multiple myeloma (MM), most clinical trials driving therapeutic decisions in routine practice include younger and presumably healthier patients than those in the real world. Furthermore, longitudinal studies suggest that elderly, transplant-ineligible patients with MM are not benefitting enough from new anti-MM agents. We retrospectively analyzed the profile of and treatment patterns and outcomes in 675 transplant-ineligible patients with MM who started frontline therapy in routine practice. The mean (SD) age was 75.6 (6.7) years; 152 (47.4%) had Eastern Cooperative Oncology Group performance status (ECOG PS) 2-4, and 73 (25.1%) had high cytogenetic risk. The most frequent frontline therapy was non-VMP bortezomib-based regimens (n=207; 30.7%), which were more frequent among patients with ECOG PS 0/1 and higher risk (e.g., international staging system (ISS) stage III, severely impaired glomerular filtrate rate (GFR), high lactate dehydrogenase (LDH), and high-risk cytogenetics); 185 patients (27.4%) started an attenuated (lite) VMP regimen, and 159 (23.6%) a VMP (VISTA) regimen. Median progression-free survival and overall survival (OS) were 15.3 months (95%CI 14.0-16.9) and 33.5 months (95%CI 29.1-37.2), respectively; 405 patients (78.2%) achieved partial response or better. Age, ECOG PS, ISS stage, serum LDH, GFR, cytogenetic risk, and treatment regimen significantly influenced OS. In this study, a remarkable proportion of transplant-ineligible patients with MM were older, frontline regimens were highly heterogeneous, and patients at higher risk often received less efficacious combinations. These findings suggest that clinicians have limited objective criteria for therapeutic decisions for this patient group.

Introduction: Treatment of relapsed/refractory multiple myeloma (RRMM) is highly challenging, especially for patients with disease refractory to initial therapy, and in particular for disease developing refractoriness to lenalidomide. Indeed, with currently approved treatments, median progression-free survival (PFS) in the lenalidomide-refractory setting is less than 10 months, reflecting the difficulty in treating this patient population. Pomalidomide is a second-generation immunomodulatory drug that has shown activity in lenalidomide-refractory disease in the setting of different combinations., Patients and Methods: A real-world study was conducted by the Spanish Myeloma group in a cohort of patients with RRMM treated with pomalidomide, cyclophosphamide, and dexamethasone (PomCiDex). One hundred patients were treated with a median of 3 prior lines of therapy., Results: Overall response rate was 39%, with a clinical benefit rate of 93%. Median PFS was 7.6 months; median overall survival (OS) was 12.6 months. Median PFS and OS survival were consistent across the different subgroups analyzed. Prolonged PFS and OS were found in patients with responsive disease., Conclusion: Our results compared favorably with those obtained with different pomalidomide-based combinations in a similar patient population. PomCiDex remains a manageable, cost-effective, and all-oral triplet combination for RRMM patients., (Copyright © 2021. Published by Elsevier Inc.)

Although case-control analyses have suggested an additive value with the association of clarithromycin to continuous lenalidomide and dexamethasone (Rd), there are not phase III trials confirming these results. In this phase III trial, 286 patients with MM ineligible for ASCT received Rd with or without clarithromycin until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). With a median follow-up of 19 months (range, 0-54), no significant differences in the median PFS were observed between the two arms (C-Rd 23 months, Rd 29 months; HR 0.783, p = 0.14), despite a higher rate of complete response (CR) or better in the C-Rd group (22.6% vs 14.4%, p = 0.048). The most common G3-4 adverse events were neutropenia [12% vs 19%] and infections [30% vs 25%], similar between the two arms; however, the percentage of toxic deaths was higher in the C-Rd group (36/50 [72%] vs 22/40 [55%], p = 0.09). The addition of clarithromycin to Rd in untreated transplant ineligible MM patients does not improve PFS despite increasing the ≥CR rate due to the higher number of toxic deaths in the C-Rd arm. Side effects related to overexposure to steroids due to its delayed clearance induced by clarithromycin in this elderly population could explain these results. The trial was registered in clinicaltrials.gov with the name GEM-CLARIDEX: Ld vs BiRd and with the following identifier NCT02575144. The full trial protocol can be accessed from ClinicalTrials.gov. This study received financial support from BMS/Celgene.

Rituximab is a standard treatment for non-Hodgkin diffuse large B-cell (DLBCL) and follicular (FL) lymphomas. A subcutaneous formulation was developed to improve the resource use of intravenous rituximab, with comparable efficacy and safety profiles except for increased administration-related reactions (ARRs). MabRella was a phase IIIb trial to assess the safety of switching from intravenous to subcutaneous administration of rituximab during first-line induction/maintenance for DLBCL or FL, focusing on ARRs. Efficacy, satisfaction and quality of life were also assessed. Patients received subcutaneous rituximab plus standard induction chemotherapy for DLBCL or FL for 4-7 cycles, and/or every 2 months maintenance monotherapy for FL for 6-12 cycles. The study included 140 patients: DLBCL, n = 29; FL, n = 111. Ninety-five percent of patients experienced adverse events, reaching grade ≥3 in 38·6% and were serious in 30·0%. AARs occurred in 48·6%, mostly (84·9%) at the injection site, with only 2·1% of patients reaching grade 3. The end-of-induction complete/unconfirmed complete response rate was 69·6%. After a median follow-up of 33·5 months, median disease-/event-/progression-free and overall survivals were not attained. The Rituximab Administration Satisfaction Questionnaire showed improvements in overall satisfaction and the EuroQoL-5D a good quality-of-life perception at induction/maintenance end. Therefore, switching to subcutaneous rituximab showed no new safety issues and maintained efficacy with improved satisfaction and quality of life., (© 2019 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Objectives: The purpose of this study was to assess the responsiveness of the newly developed Geriatric Assessment in Hematology (GAH) scale to clinical change in older patients diagnosed with hematologic malignancies., Methods: A prospective observational study conducted in 164 patients aged ≥65years and diagnosed with myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML), multiple myeloma (MM), or chronic lymphocytic leukemia (CLL). Responsiveness of the GAH scales was studied by means of the Eastern Cooperative Oncology Group (ECOG) score, the Karnofsky performance status (KPS) score, the visual analog scale (VAS), and the physician's subjective assessment, used as clinical anchors to identify whether patients had changed clinically (either improved or worsened) or not since the baseline visit. Responsiveness was evaluated on the basis of effect size (ES)., Results: 164 patients (men, 63.7%; median age, 77.0 (72.8-81.4) participated. Statistically significant correlations were obtained between the investigator's qualitative assessment and changes in ECOG, KPS, and VAS scores. Likewise, a statistically significant correlation was obtained between the investigator's qualitative assessment and changes in the GAH scale score. Responsiveness of the GAH scale to detect clinical change was satisfactory (ES 0.34)., Conclusion: Findings confirm that the GAH scale is responsive to clinical changes in patients' health status. Additionally, the GAH scale is a promising tool to improve clinical decision-making in older patients with hematological malignancies., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Objectives: The purpose of this study was to develop a new brief, comprehensive geriatric assessment scale for older patients diagnosed with different hematological malignancies, the Geriatric Assessment in Hematology (GAH scale), and to determine its psychometric properties., Materials and Methods: The 30-item GAH scale was designed through a multi-step process to cover 8 relevant dimensions. This is an observational study conducted in 363 patients aged≥65years, newly diagnosed with different hematological malignancies (myelodysplasic syndrome/acute myeloblastic leukemia, multiple myeloma, or chronic lymphocytic leukemia), and treatment-naïve. The scale psychometric validation process included the analyses of feasibility, floor and ceiling effect, validity and reliability criteria., Results: Mean time taken to complete the GAH scale was 11.9±4.7min that improved through a learning-curve effect. Almost 90% of patients completed all items, and no floor or ceiling effects were identified. Criterion validity was supported by reasonable correlations between the GAH scale dimensions and three contrast variables (global health visual analogue scale, ECOG and Karnofsky), except for comorbidities. Factor analysis (supported by the scree plot) revealed nine factors that explained almost 60% of the total variance. Moderate internal consistency reliability was found (Cronbach's α: 0.610), and test-retest was excellent (ICC coefficients, 0.695-0.928)., Conclusion: Our study suggests that the GAH scale is a valid, internally reliable and a consistent tool to assess health status in older patients with different hematological malignancies. Future large studies should confirm whether the GAH scale may be a tool to improve clinical decision-making in older patients with hematological malignancies., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The introduction of novel antimyeloma therapies, including thalidomide, lenalidomide, and bortezomib, has expanded treatment options for patients with this disease. These compounds have altered the natural history of multiple myeloma, resulting in substantial improvements in patient outcomes. However, like with any other drug, their use is associated with a specific toxicity profile. The major adverse events (AEs) associated with lenalidomide include: hematological toxicities (myelosuppression), mainly neutropenia, venous thromboembolism, gastrointestinal disturbance, skin toxicity, atrial fibrillation, asthenia, and decreased peripheral blood stem cell yield during stem cell collection when lenalidomide is used after a long period of time. These AEs are predictable, consistent, and manageable with patient monitoring, supportive care, and dose adjustment. In this article, using three clinical cases as examples, we discuss the diagnoses and management of the most frequent AEs associated with lenalidomide treatment in patients with multiple myeloma.

The present study explored the impact of two novel criteria; having >95% abnormal plasma cells by flow cytometry at diagnosis and the evolving subtype of the disease, as predictors of progression in 61 smouldering multiple myeloma (SMM) and 311 monoclonal gammopathy of unknown significance (MGUS) patients. Although both criteria were of prognostic value, the risk of progression was better identified by immunophenotyping [Hazard Ratio (HR) 6.2 and 17.2 for SMM and MGUS, respectively] than evolving subtype, which had independent prognostic value only in MGUS (HR 3.6). Immunophenotyping discriminated the different risk of progression within the evolving and non-evolving subgroups of SMM (P = 0.01) and MGUS (P < 0.001).

The human leukocyte antigen (HLA) system could play an essential role in multiple myeloma (MM) disease control. This report describes the results comparing HLA-DRB1 phenotypic frequencies in 181 MM patients (53 smoldering/indolent MM and 128 symptomatic MM patients) and healthy individuals. Higher DRB1*01 phenotypic frequencies were found in the smoldering patients compared with symptomatic MM patients (38% vs 14%, P = 0.001) and with the healthy individuals (38% vs 22%, P = 0.01). Additionally, higher DRB1*07 phenotypic frequencies were found in symptomatic MM compared with control population (38% vs 28%, P = 0.01). The present data suggest that HLA-DRB1*01 individuals may have a better ability to efficiently present myeloma-related antigens to immunocompetent cells, which could favor a better immune response against the tumor. This would translate into a more appropriate disease control associated with more indolent disease and prolonged survival.

Monoclonal gammopathy of uncertain significance (MGUS) and smoldering multiple myeloma (SMM) are plasma cell disorders with a risk of progression of approximately 1% and 10% per year, respectively. We have previously shown that the proportion of bone marrow (BM) aberrant plasma cells (aPCs) within the BMPC compartment (aPC/BMPC) as assessed by flow cytometry (FC) contributes to differential diagnosis between MGUS and multiple myloma (MM). The goal of the present study was to investigate this parameter as a marker for risk of progression in MGUS (n = 407) and SMM (n = 93). Patients with a marked predominance of aPCs/BMPC (> or = 95%) at diagnosis displayed a significantly higher risk of progression both in MGUS and SMM (P< .001). Multivariate analysis for progression-free survival (PFS) selected the percentage aPC/BMPC (> or = 95%) as the most important independent variable, together with DNA aneuploidy and immunoparesis, for MGUS and SMM, respectively. Using these independent variables, we have identified 3 risk categories in MGUS (PFS at 5 years of 2%, 10%, and 46%, respectively; P< .001) and SMM patients (PFS at 5 years of 4%, 46%, and 72%, respectively; P < .001). Our results show that multiparameter FC evaluation of BMPC at diagnosis is a valuable tool that could help to individualize the follow-up strategy for MGUS and SMM patients.

Acute graft-versus-host disease (aGVHD) remains one of the most severe complications after allogeneic transplantation; in particular, the presence of gut involvement has been related to increased mortality and poorer response. The use of systemic steroids remains the standard for first-line treatment despite its severe secondary effects. Beclomethasone dipropionate (BDP) is a topically active corticosteroid with low absorption, thereby avoiding many of the deleterious side effects associated with systemic steroids. In the present study we analyzed the efficacy of BDP in a series of 26 patients who were diagnosed with grade 1 and 2 gastrointestinal aGVHD. Twenty patients (77%) responded to BDP treatment, 17 (65.5%) reached complete remission (CR), and 3 (11.5%) showed partial response. Among those patients who reached CR, 5 relapsed, although 1 of them reached second CR after a second course of BDP; therefore, 13 (50%) of the 26 patients did not require systemic steroids to treat gastrointestinal aGVHD. CR rates in those showing gastrointestinal symptoms were 68% for patients with persistent nausea, 50% for those with vomiting, and 54% for those with diarrhea (P=.2). No patient included in the study developed any symptom related to adrenal axis suppression. Thirteen patients (50%) developed >or=1 infectious episode during the first 100 days after transplantation. Transplant-related mortality was 0% at 100 days, and overall transplant-related mortality was 30%, with only 2 patients dying due to infectious complications. Therefore, our study shows that monotherapy with oral BDP is an effective initial therapeutic approach for mild to moderate intestinal GVHD, which avoids complications related to systemic steroids.