Search

A list of papers to be published in forthcoming issues of the periodical related to several medical diseases including multiple myeloma, chronic lymphocytic leukemia and thrombocytosis is presented.

Objective: Multiple myeloma (MM) is a bone marrow cancer that profoundly affects plasma cells involved in the immune response. Myeloma cells alter the average production of cells in the bone marrow. Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapy allows genetic modifications of an individual's T-cells to increase the expression of CARs used to identify and attach BCMA proteins to the malignant cells. Our main objective is to perform a systematic review and meta-analysis to explore the efficacy and safety of anti-BCMA CAR T-cell therapy for MM. Material and Methods: We searched five databases, PubMed, CNKI, EMBASE, Cochrane, Web of Science, and CNKI, for studies published on anti-BCMA,CAR-T-cell treatment for MM. Inclusion criteria involved prospective single-arm studies either single or multi-center, in various MM phases and studies that reported anti-BCMA,CAR-T-cell treatment for MM. We excluded non-English publications and conference papers. All statistical analyses were performed in R software and Review Manager 5.4.1. Results: Thirteen articles were included in the analysis. We found that the overall response survival complete response increase was statistically significant. Similarly, the reduction in cytokine release syndrome grades 3 and 4 and neurotoxicity after follow-up was statistically significant. However, the reduction in minimal residual disease negativity (MRDN) was not statistically significant. Conclusion: Using anti-BCMA CAR T-cell therapy in MM was highly efficacious and safe in lowering the adverse outcomes and improving the survival outcomes, complete response, and overall response. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is a disease of older people, yet factors relating to comorbidity and frailty may threaten treatment tolerability for many of this heterogenous group. There has been increasing interest in defining specific and clinically relevant frailty assessment tools within the MM population, with the goal of using these frailty scores, not just as a prognostic instrument, but also as a predictive tool to allow for a frailty‐adapted treatment approach. This paper reviews the various frailty assessment frameworks used in the evaluation of patients with MM, including the International Myeloma Working Group Frailty Index (IMWG‐FI), the Mayo Frailty Index and the simplified frailty scale. While the IMWG‐FI remains the most widely accepted tool, the simplified frailty scale is the most user‐friendly in busy day‐to‐day clinics based on its ease of use. This paper summarises the recommendations from the Myeloma Scientific Advisory Group (MSAG) of Myeloma Australia, on the use of frailty assessment tools in clinical practice and proposes a frailty‐stratified treatment algorithm to aid clinicians in tailoring therapy for this highly heterogeneous patient population. [ABSTRACT FROM AUTHOR]

Simple Summary: Currently, few papers have been published regarding the possible interactions between radiotherapy and systemic agents for the treatment of multiple myeloma. In this paper, we retrospectively analyze the data from 312 patients (577 lesions) who received radiotherapy at our institution from 2005 to 2020, with the aim of clarifying the clinical impact of radiotherapy dose and concurrent systemic treatment (CST). The safety profile of the radiotherapy was excellent; high biologically effective doses (BEDs) and CST were associated with higher toxicity rates at the end of radiotherapy, but not after one and three months. The pain control rate was 87.4% at the end of treatment and further increased at three and six months. Radiological progression was reported only for 4.4% of the lesions at six months (based on the data available for 181 lesions) and was significantly more frequent for lesions treated without CST or BED < 15 Gy. Background and purpose: Although chemotherapy, biological agents, and radiotherapy (RT) are cornerstones of the treatment of multiple myeloma (MM), the literature regarding the possible interactions of concurrent systemic treatment (CST) and RT is limited, and the optimal RT dose is still unclear. Materials and methods: We retrospectively analyzed the records of patients who underwent RT for MM at our institution from 1 January 2005 to 30 June 2020. The data of 312 patients and 577 lesions (treated in 411 accesses) were retrieved. Results: Most of the treated lesions involved the vertebrae (60%) or extremities (18.9%). Radiotherapy was completed in 96.6% of the accesses and, although biologically effective doses assuming an α/β ratio of 10 (BED 10) > 38 Gy and CST were significantly associated with higher rates of toxicity, the safety profile was excellent, with side effects grade ≥2 reported only for 4.1% of the accesses; CST and BED 10 had no impact on the toxicity at one and three months. Radiotherapy resulted in significant improvements in performance status and in a pain control rate of 87.4% at the end of treatment, which further increased to 96.9% at three months and remained at 94% at six months. The radiological response rate at six months (data available for 181 lesions) was 79%, with only 4.4% of lesions in progression. Progression was significantly more frequent in the lesions treated without CST or BED 10 < 15 Gy, while concurrent biological therapy resulted in significantly lower rates of progression. Conclusion: Radiotherapy resulted in optimal pain control rates and fair toxicity, regardless of BED 10 and CST; the treatments with higher BED 10 and CST (remarkably biological agents) improved the already excellent radiological disease control. [ABSTRACT FROM AUTHOR]

Simple Summary: It is recognized that patients with multiple myeloma (MM) experience a high burden of disease and treatment-related symptoms that impact upon their quality of life (QoL). In these patients, patient-reported outcome (PRO) measures are important in providing information on how treatment affects their QoL. In the past 10 years in the MM setting, the main focus has been to achieve the most durable remission with the best QoL as primary goals of therapy. Optimizing the QoL of patients with MM is an important treatment goal and the use of PROs in clinical trials has the potential to improve treatment outcomes. The present report, on behalf of the European Hematology Association (EHA), provides evidence-based guidelines for the use and reporting of PROs in patients with MM that have been developed according to the EHA's core Guidelines Development Methodology. Currently, there is considerable variation in the measurement of QoL in MM trials, thus underlining the importance of systematic measurements. These Guidelines will aid clinicians, regulatory agencies and the pharmaceutical industry in the measurement of QoL in patients with MM in clinical trials. In the era of personalized medicine there is an increasing need for the assessment of patient-reported outcomes (PROs) to become a standard of patient care. Patient-reported outcome measures (PROM) are important in assessing significant and meaningful changes as a result of an intervention based on a patient's own perspective. It is well established that active multiple myeloma (MM) can be characterized by a high burden of disease and treatment-related symptoms, with considerable worsening of quality of life (QoL). In general, and over the past decade, the focus has shifted to obtaining the most durable remissions with the best QoL as primary goals for MM treatment. Patients place considerable value on their QoL and communicating about QoL data prior to treatment decisions allows them to make informed treatment choices. Consequently, optimization of QoL of patients with MM is an important therapeutic goal and the incorporation of PROs into clinical trials has the potential of improving treatment outcomes. In this regard, guidance for the use and reporting of PROMs in MM in clinical trials is warranted. Under the auspices of the European Hematology Association, evidence-based guidelines for the use and reporting of PROs in patients with MM have been developed according to the EHA's core Guidelines Development Methodology. This document provides general considerations for the choice of PROMs in MM clinical trials as well as a series of recommendations covering a selection of PROMs in MM clinical trials; the mode of administration; timing of assessments; strategies to minimize missing data; sample size calculation; reporting of results; and interpretation of results. [ABSTRACT FROM AUTHOR]

Lenalidomide is an integral, yet evolving, part of current treatment pathways for both transplant-eligible and transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM). It is approved in combination with dexamethasone as first-line therapy for transplant-ineligible patients with NDMM, and as maintenance treatment following autologous stem cell transplantation (ASCT). Although strong clinical trial evidence has supported the integration of lenalidomide into current treatment paradigms for NDMM, applying those paradigms to individual patients and determining which patients are most likely to benefit from lenalidomide treatment are more complex. In this paper, we utilize the available clinical trial evidence to provide recommendations for patient selection and lenalidomide dosing in both the first-line setting in patients ineligible for ASCT and the maintenance setting in patients who have undergone ASCT. In addition, we provide guidance on management of those adverse events that are most commonly associated with lenalidomide treatment, and consider the optimal selection and sequencing of next-line agents following long-term frontline or maintenance treatment with lenalidomide. [ABSTRACT FROM AUTHOR]

Predictive or prognostic analysis plays an increasingly important role in the era of personalized medicine to identify subsets of patients whom the treatment may benefit the most. Although various time-dependent covariate models are available, such models require that covariates be followed in the whole follow-up period. This article studies a new class of functional survival models where the covariates are only monitored in a time interval that is shorter than the whole follow-up period. This paper is motivated by the analysis of a longitudinal study on advanced myeloma patients who received stem cell transplants and T cell infusions after the transplants. The absolute lymphocyte cell counts were collected serially during hospitalization. Those patients are still followed up if they are alive after hospitalization, while their absolute lymphocyte cell counts cannot be measured after that. Another complication is that absolute lymphocyte cell counts are sparsely and irregularly measured. The conventional method using Cox model with time-varying covariates is not applicable because of the different lengths of observation periods. Analysis based on each single observation obviously underutilizes available information and, more seriously, may yield misleading results. This so-called partial follow-up study design represents increasingly common predictive modeling problem where we have serial multiple biomarkers up to a certain time point, which is shorter than the total length of follow-up. We therefore propose a solution to the partial follow-up design. The new method combines functional principal components analysis and survival analysis with selection of those functional covariates. It also has the advantage of handling sparse and irregularly measured longitudinal observations of covariates and measurement errors. Our analysis based on functional principal components reveals that it is the patterns of the trajectories of absolute lymphocyte cell counts, instead of the actual counts, that affect patient's disease-free survival time. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is a type of haematological bone marrow malignancy. Cancer Research UK reports that MM is the 18th most common cancer in the UK, accounting for 2% of all new cancer cases, yet, non-haematologists often lack familiarity with the pathology and initial investigations. This paper aims to demonstrate the diagnostic features, relevant investigations and basic management plan for the non-specialist. [ABSTRACT FROM AUTHOR]

The National Institute for Health and Care Excellence (NICE), as part of the institute's single technology appraisal (STA) process, invited the manufacturer of pomalidomide (POM; Imnovid®, Celgene) to submit evidence regarding the clinical and cost effectiveness of the drug in combination with dexamethasone (POM + LoDEX) for the treatment of relapsed and refractory multiple myeloma (RRMM) after at least two regimens including lenalidomide (LEN) and bortezomib (BOR). Kleijnen Systematic Reviews Ltd (KSR) and Erasmus University Rotterdam were commissioned as the Evidence Review Group (ERG) for this submission. The ERG reviewed the evidence submitted by the manufacturer, validated the manufacturer's decision analytic model, and conducted exploratory analyses in order to assess the robustness and validity of the presented clinical and cost-effectiveness results. This paper describes the company submission, the ERG assessment, and NICE's subsequent decisions. The company conducted a systematic review to identify studies comparing POM with comparators outlined in the NICE scope: panobinostat with bortezomib and dexamethasone (PANO + BOR + DEX), bendamustine with thalidomide and dexamethasone (BTD) and conventional chemotherapy (CC). The main clinical effectiveness evidence was obtained from MM-003, a randomized controlled trial (RCT) comparing POM + LoDEX with high-dose dexamethasone (HiDEX; used as a proxy for CC). Additional data from other studies were also used as nonrandomized observational data sources for the indirect treatment comparison of POM + LoDEX with BTD and PANO + BOR + DEX. Covariate or treatment switching adjustment methods were used for each comparison. The model developed in Microsoft® Excel 2010 using a semi-Markov partitioned survival structure, submitted in the original submission to NICE for TA338, was adapted for the present assessment of the cost effectiveness of POM + LoDEX. Updated evidence from the clinical-effectiveness part was used for the survival modelling of progression-free survival and overall survival. For POM + LoDEX, the patient access scheme (PAS) discount was applied to the POM price. Three separate comparisons were conducted for each comparator, each comparison using a different dataset and adjustment methods. The ERG identified and corrected some errors, and the corrected incremental cost-effectiveness ratios (ICERs) for POM + LoDEX versus each comparator were presented: approximately £45,000 per quality-adjusted life-year (QALY) gained versus BTD, savings of approximately £143,000 per QALY lost versus PANO + BOR + DEX, and approximately £49,000 per QALY gained versus CC. The ERG also conducted full incremental analyses, which revealed that CC, POM + LoDEX and PANO + BOR + DEX were on the cost-effectiveness frontier. The committee's decision on the technology under analysis deemed that POM + LoDEX should be recommended as an option for treating multiple myeloma in adults at third or subsequent relapse of treatments including both LEN and BOR, contingent on the company providing POM with the discount agreed in the PAS. [ABSTRACT FROM AUTHOR]

At the design of clinical trial operation, a question of a paramount interest is how long it takes to recruit a given number of patients. Modelling the recruitment dynamics is the necessary step to answer this question. Poisson-gamma model provides very convenient, flexible and realistic approach. This model allows predicting the trial duration using data collected at an interim time with very good accuracy. A natural question arises: how to evaluate the parameters of recruitment model before the trial begins? The question is harder to handle as there are no recruitment data available for this trial. However, if there exist similar completed trials, it is appealing to use data from these trials to investigate feasibility of the recruitment process. In this paper, the authors explore the recruitment data of two similar clinical trials (Intergroupe Francais du Myélome 2005 and 2009). It is shown that the natural idea of plugging the historical rates estimated from the completed trial in the same centres of the new trial for predicting recruitment is not a relevant strategy. In contrast, using the parameters of a gamma distribution of the rates estimated from the completed trial in the recruitment dynamic model of the new trial provides reasonable predictive properties with relevant confidence intervals. Copyright © 2017 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Patients living with multiple myeloma (MM) have a substantial disease burden and face multiple barriers to care. Building upon our previous research using mixed methods, this focus group research aimed to identify patients' priorities regarding specific social and identity-related needs, map these prioritized needs to the disease journey, and describe patient-generated ideas to improve patient support. Participants noted that patients with MM need a range of emotional, social, and financial support throughout the disease journey. They identified initial MM diagnosis and treatment adherence as two critical points in the MM journey where patients need the most support and assistance. The findings of this research suggest that overall, patients with MM need comprehensive support, ideally from a multidisciplinary team consisting of health care providers, patient advocates, social workers, and psychologists to help patients understand their disease and treatment options, make informed treatment decisions, adhere to treatment, and ultimately reduce their disease burden and improve outcomes. This research revealed that patients with MM need varying types and levels of support, with the most common needs including information on disease and treatment, connections to financial resources and support systems, assistance with navigating insurance options, and transportation and logistical support for medical appointments. [ABSTRACT FROM AUTHOR]

Copyright of Pamukkale Medical Journal is the property of Pamukkale Journal of Medicine and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Approximately 5,700 people are diagnosed with myeloma each year in the UK. The standard of care is to receive an autologous stem cell transplant after completion of induction therapy. There are no specific dietary recommendations for people with myeloma, however they are at risk of malnutrition due to symptoms and side effects of treatments. This report describes the journey of a 73-year-old male diagnosed with immunoglobulin A (IgA) lambda myeloma in April 2021. The patient lost 23% of his body weight during 6 months of systemic anti-cancer treatment (SACT), resulting in postponing his transplant twice due to reduced fitness. This report describes an effective, although late, multidisciplinary intervention which was successful for the patient who managed to reestablish a healthy weight and good quality of life. The patient received his transplant in January 2023. This case highlights two important aspects of patient care that should not be underestimated in dietetic clinical practice: early screening and multidisciplinary collaboration. Monitoring the nutritional status of patients and providing early nutrition support can prevent hospital admissions, treatment delays and reduce the associated costs. Multidisciplinary teamwork can improve patient care and clinical outcomes, and it is fundamental to strengthen communication and collaboration among clinical disciplines. [ABSTRACT FROM AUTHOR]

Improved understanding as to the biology of multiple myeloma (MM) and the bone marrow microenvironment has led to the development of new drugs to treat MM. This explosion of new and highly effective drugs has led to dramatic advances in the management of MM and underscores the need for supportive care. Impressive and deep response rates to chemotherapy, monoclonal antibodies, and small molecule drugs provide hope of a cure or prolonged remission for the majority of individuals. For most patients, long-term, continuous therapy is often required to suppress the malignant plasma cell clone, thus requiring clinicians to become more astute in assessment, monitoring, and intervention of side effects as well as monitoring response to therapy. Appropriate diagnosis and monitoring strategies are essential to ensure that patients receive the appropriate chemotherapy and supportive therapy at relapse, and that side effects are appropriately managed to allow for continued therapy and adherence to the regimen. Multiple drugs with complex regimens are currently available with varying side effect profiles. Knowledge of the drugs used to treat MM and the common adverse events will allow for preventative strategies to mitigate adverse events and prompt intervention. The purpose of this paper is to review updates in the diagnosis and management of MM, and to provide strategies for assessment and monitoring of patients receiving chemotherapy for MM. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is more recently being recognized as a heterogeneous group of disease with variability in outcomes based on specific clinical and biologic predictors. MM patients can be broadly categorized into standard, intermediate and high risk for disease relapse, morbidity and mortality. The high-risk features include patient-specific factors such as old age, poor performance status and comorbidities; clinical features such as primary plasma cell leukemia and extramedullary disease; disease-specific biologic features such as deletion 17p, t(4;14) and high-risk gene expression profiling signatures. The current paper reviews the available data on best therapeutic approaches for high-risk MM. [ABSTRACT FROM AUTHOR]

Simple Summary: Outcomes for high-risk myeloma patients are still poor, despite many advances in treatment. In addition, scarce data exist on double maintenance in transplant-eligible high-risk newly diagnosed multiple myeloma (NDMM) patients. We present the results of a prospective study on 120 transplant-eligible NDMM patients with prolonged cytogenetic risk-based all-oral maintenance with lenalidomide + ixazomib (IR) for high-risk patients and lenalidomide (R) alone for non-high-risk patients after ixazomib–lenalidomide–dexamethasone (IRD) induction plus autologous stem cell transplantation followed by IRD consolidation. We found that high-risk cytogenetics had no impact on the proportion of patients achieving sustained undetectable minimal residual disease or on the rate of progression-free survival with IR maintenance. Our data suggest that prolonged use of all-oral double maintenance with IR with reasonable adverse effects would be a potential option for high-risk myeloma patients. Scarce data exist on double maintenance in transplant-eligible high-risk (HR) newly diagnosed multiple myeloma (NDMM) patients. This prospective phase 2 study enrolled 120 transplant-eligible NDMM patients. The treatment consisted of four cycles of ixazomib–lenalidomide–dexamethasone (IRD) induction plus autologous stem cell transplantation followed by IRD consolidation and cytogenetic risk-based maintenance therapy with lenalidomide + ixazomib (IR) for HR patients and lenalidomide (R) alone for NHR patients. The main endpoint of the study was undetectable minimal residual disease (MRD) with sensitivity of <10−5 by flow cytometry at any time, and other endpoints were progression-free survival (PFS) and overall survival (OS). We present the preplanned analysis after the last patient has been two years on maintenance. At any time during protocol treatment, 28% (34/120) had MRD < 10−5 at least once. At two years on maintenance, 66% of the patients in the HR group and 76% in the NHR group were progression-free (p = 0.395) and 36% (43/120) were CR or better, of which 42% (18/43) had undetectable flow MRD <10−5. Altogether 95% of the patients with sustained MRD <10−5, 82% of the patients who turned MRD-positive, and 61% of those with positive MRD had no disease progression at two years on maintenance (p < 0.001). To conclude, prolonged maintenance with all-oral ixazomib plus lenalidomide might improve PFS in HR patients. [ABSTRACT FROM AUTHOR]

The purpose of this study was to investigate the level of resilience in multiple myeloma patients and to identify the impact of symptom experience, cancer coping, and social support on resilience. Methods: Data were collected from January 2022 to May 2022 using self-report structured questionnaires administered to 162 outpatients who were undergoing chemotherapy or follow-up care after multiple myeloma treatment. The measured variables included symptom experience, cancer coping, social support, and resilience. The collected data were analyzed using SPSS/WIN 25 for descriptive statistics, the independent t-test, one-way analysis of variance, the Scheffeé test, Pearson correlation coefficients, and hierarchical regression analysis. Results: The mean resilience score of the participants was 66 out of 100 points. The levels of resilience were significantly higher in patients who had a job, recognized the importance of religion, and had a good economic status. Significantly higher levels of resilience were also observed in patients with lower physical performance status, fewer symptom experiences, more positive cancer coping, and higher support from healthcare staff. Conclusion: Monitoring the symptom experience and physical performance ability of patients with multiple myeloma is important for enhancing their resilience. Positive coping strategies need to be developed and additional support from nurses should be provided to strengthen the personal resilience of patients with multiple myeloma. [ABSTRACT FROM AUTHOR]

Simple Summary: In the last two decades, the use of small molecules as chemical inhibitors of different targets in signaling pathways has been of great interest for therapeutic purposes. In the case of multiple myeloma, it has not been an exception, with researchers focusing in part on the p38 pathway. However, the search continues for more specific p38 inhibitors according to differently expressed p38 isoforms. One of the latest reviews on this topic is from 10 years ago, so in this review, we highlight the research in this context from the last 10 years, showing the advances in the use of more effective inhibitors alone or in combination with other therapeutic agents. Resistance to therapy and disease progression are the main causes of mortality in most cancers. In particular, the development of resistance is an important limitation affecting the efficacy of therapeutic alternatives for cancer, including chemotherapy, radiotherapy, and immunotherapy. Signaling pathways are largely responsible for the mechanisms of resistance to cancer treatment and progression, and multiple myeloma is no exception. p38 mitogen-activated protein kinase (p38) is downstream of several signaling pathways specific to treatment resistance and progression. Therefore, in recent years, developing therapeutic alternatives directed at p38 has been of great interest, in order to reverse chemotherapy resistance and prevent progression. In this review, we discuss recent findings on the role of p38, including recent advances in our understanding of its expression and activity as well as its isoforms, and its possible clinical role based on the mechanisms of resistance and progression in multiple myeloma. [ABSTRACT FROM AUTHOR]

Multiple myeloma associated with bleeding events secondary to von Willebrand syndrome is underdiagnosed. The management of this entity is highly complex, and aims to control the hemorrhagic syndrome and reduce plasma viscosity with plasmapheresis and multiple myeloma-specific treatment. The authors report the rare case of a young patient with high-risk multiple myeloma complicated by hyperviscosity syndrome and presenting an acquired von Willebrand syndrome with hemorrhagic manifestations, requiring urgent therapeutic management to save the patient's life. [ABSTRACT FROM AUTHOR]

The article discusses research which investigated the safety of Sun Pharmaceutical Industries Ltd.'s generic doxorubicin (DXR) hydrochloride liposomal injection in comparison with the reference drug, Caelyx for the treatment of multiple myeloma. The design of the study and the eligibility and exclusion criteria are discussed. Also mentioned are the pharmacokinetic parameters and analysis of variance (ANOVA) of the study and the findings of bioequivalence between DXR and the reference drug.

Simple Summary: Available data on anti-BCMA CART-cell therapy has demonstrated efficacy and manageable toxicity in heavily pretreated R/R MM patients. Despite this, the main issues remain to be addressed. First of all, a significant proportion of patients eventually relapse. The potential strategy to prevent relapse includes sequential or combined infusion with CAR T-cells against targets other than BCMA, CAR T-cells with novel dual-targeting vector design, and BCMA expression upregulation. Another dark side of CAR T therapy is safety. Cytokine release syndrome (CRS) and neurologic toxicity are well-described adverse effects. In MM trials, most CRS events tended to be grade 1 or 2. Another critical point is the extended timeline of the manufacturing process and that only a few academic centers can perform these procedures. Recognizing these issues, the excellent response with BCMA-targeted CAR T-cell therapy makes it a treatment strategy of great promise. Despite the improvement in survival outcomes, multiple myeloma (MM) remains an incurable disease. Chimeric antigen receptor (CAR) T-cell therapy targeting B-cell maturation antigen (BCMA) represents a new strategy for the treatment of relapsed/refractory MM (R/R). In this paper, we describe several recent advances in the field of anti-BCMA CAR T-cell therapy and MM. Currently, available data on anti-BCMA CART-cell therapy has demonstrated efficacy and manageable toxicity in heavily pretreated R/R MM patients. Despite this, the main issues remain to be addressed. First of all, a significant proportion of patients eventually relapse. The potential strategy to prevent relapse includes sequential or combined infusion with CAR T-cells against targets other than BCMA, CAR T-cells with novel dual-targeting vector design, and BCMA expression upregulation. Another dark side of CART therapy is safety. Cytokine release syndrome (CRS) andneurologic toxicity are well-described adverse effects. In the MM trials, most CRS events tended to be grade 1 or 2, with fewer patients experiencing grade 3 or higher. Another critical point is the extended timeline of the manufacturing process. Allo-CARs offers the potential for scalable manufacturing for on-demand treatment with shorter waiting days. Another issue is undoubtedly going to be access to this therapy. Currently, only a few academic centers can perform these procedures. Recognizing these issues, the excellent response with BCMA-targeted CAR T-cell therapy makes it a treatment strategy of great promise. [ABSTRACT FROM AUTHOR]

Copyright of Practical Pharmacy & Clinical Remedies is the property of Editorial Department of Practical Pharmacy & Clinical Remedies and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Daratumumab (DARA) is a medication that in 2016 proved its efficacy and safety in the treatment of multiple myeloma. This product, based on a monoclonal antibody, technically generates an interference in most blood compatibility tests, artificially producing high blood pan-reactivity and incompatibility. The difficulty in finding blood compatible with the patient's serum can also mask the presence of other clinically significant alloantibodies and, above all, delays the timely delivery of erythrocyte concentrate, which, obviously, endangers the patient's life. In transfusion medicine, very different strategies have recently been described for the resolution of this technical interference. We adopted the use of dithiothreitol (or DTT) to treat the red blood cells of the possible blood donors for the patient, thus achieving the elimination of this technical discrepancy and the adequate, safe and timely selection of this blood component. In the present paper, we describe the first case of a patient with a diagnosis of multiple myeloma treated with DARA, in which the interference caused by this drug in pretransfusion tests was successfully resolved. Communication is a key element in the management of these patients. The doctor should inform the patient and the blood bank about the risk of presenting incompatible cross-tests when they are being treated with this medication. It is additionally recommended that all patients with multiple myeloma should undergo an erythrocyte phenotyping before receiving their treatment with DARA, and carry a card indicating that they are receiving this medication. Fortunately, hemolytic transfusion reactions have not yet been reported in these types of patients at the time of this publication. For the staff at blood banks, it is evident that an additional operating procedure must be in place to describe the technical and administrative operation that must be followed from the admission of these patients to the hospital. Technically speaking, we recommend, based on our experience reported in this case, the use of the DTT technique to resolve this discrepancy and technical difficulty in pretransfusion testing in patients treated with DARA. [ABSTRACT FROM AUTHOR]

Background: The analysis of time-to-event data can be complicated by competing risks, which are events that alter the probability of, or completely preclude the occurrence of an event of interest. This is distinct from censoring, which merely prevents us from observing the time at which the event of interest occurs. However, the censoring distribution plays a vital role in the proportional subdistribution hazards model, a commonly used method for regression analysis of time-to-event data in the presence of competing risks.Methods: We present the equations that underlie the proportional subdistribution hazards model to highlight the way in which the censoring distribution is included in its estimation via risk set weights. By simulating competing risk data under a proportional subdistribution hazards model with different patterns of censoring, we examine the properties of the estimates from such a model when the censoring distribution is misspecified. We use an example from stem cell transplantation in multiple myeloma to illustrate the issue in real data.Results: Models that correctly specified the censoring distribution performed better than those that did not, giving lower bias and variance in the estimate of the subdistribution hazard ratio. In particular, when the covariate of interest does not affect the censoring distribution but is used in calculating risk set weights, estimates from the model based on these weights may not reflect the correct likelihood structure and therefore may have suboptimal performance.Conclusions: The estimation of the censoring distribution can affect the accuracy and conclusions of a competing risks analysis, so it is important that this issue is considered carefully when analysing time-to-event data in the presence of competing risks. [ABSTRACT FROM AUTHOR]

Immunotherapy has recently emerged as a promising treatment for multiple myeloma (MM). There are now several monoclonal antibodies that target specific surface antigens on myeloma cells or the checkpoints of immune and myeloma cells. Elotuzumab (targeting SLAMF7), daratumumab (targeting CD38), and pembrolizumab (targeting PD-1) have shown clinical activity in clinical studies with relapsed/refractory MM. Dendritic cell vaccination is a safe strategy that has shown some efficacy in a subset of myeloma patients and may become a crucial part of MM treatment when combined with immunomodulatory drugs or immune check-point blockade. Genetically engineered T cells, such as chimeric antigen receptor T cells or T cell receptor-engineered T cells, have also shown encouraging results in recent clinical studies of patients with MM. In this paper, we discuss recent progress in immunotherapy for the treatment of MM. [ABSTRACT FROM AUTHOR]

Simple Summary: The assessment of responses is critical in patients diagnosed with multiple myeloma. Nowadays, one of the most informative parameters to discriminate responses to treatment and prognosis is minimal residual disease (MRD). Several strategies may be used to detect and quantify MRD; some of them have been widely used and standardized, but we can find additional strategies lacking such an extensive validation process. Here, we present a summary of the current state of the art of MRD detection in multiple myeloma and future directions in the field. Responses to treatment have improved over the last decades for patients with multiple myeloma. This is a consequence of the introduction of new drugs that have been successfully combined in different clinical contexts: newly diagnosed, transplant-eligible or ineligible patients, as well as in the relapsed/refractory setting. However, a great proportion of patients continue to relapse, even those achieving complete response, which underlines the need for updated response criteria. In 2014, the international myeloma working group established new levels of response, prompting the evaluation of minimal residual disease (MRD) for those patients already in complete or stringent complete response as defined by conventional serological assessments: the absence of tumor plasma cells in 100,000 total cells or more define molecular and immunophenotypic responses by next-generation sequencing and flow cytometry, respectively. In this review, we describe all the potential methods that may be used for MRD detection based on the evidence found in the literature, paying special attention to their advantages and pitfalls from a critical perspective. [ABSTRACT FROM AUTHOR]

Simple Summary: About 35% of patients with multiple myeloma are ≥75 years old at diagnosis, and their treatment should be individualized according to their fragility score. Fragility assessment scales include the International Myeloma Working Group Palumbo Fragility Scale, the Revised Initial Myeloma Comorbidity Index, and the Mayo score. However, they are time-consuming, but more importantly, there are no convincing data from a real world experience supporting their usefulness in everyday clinical practice. Patients with multiple myeloma over 75 years of age are instantly classified as intermediate fit or frail. These patients should be offered non-intensive treatment in reduced doses or palliative care. In the prospective observational, multicenter study, we showed that most patients over 75 years of age qualified for treatment are safely treated with three-drug regimens regardless of their fragility categorization. Current fragility scores for patients with MM over 75 years old have limited value in daily practice. Fragility scales are intended to help in therapeutic decisions. Here, we asked if the fragility assessment in MM patients ≥ 75 years old qualified for treatment by the local physician correlates with the choice of treatment: a two- or three-drug regimens. Between 7/2018 and 12/2019, we prospectively enrolled 197 MM patients at the start of treatment from the 13 Polish Myeloma Group centers. The data to assess fragility were prospectively collected, but centrally assessed fragility was not disclosed to the local center. The activity of daily living (ADL) could be assessed in 192 (97.5%) and was independent in 158 (80.2%), moderately impaired in 23 (11.7%), and 11 (5.6%) in completely dependent. Patients with more than three comorbidities made up 26.9% (53 patients). Thus, according to the Palumbo calculator, 43 patients were in the intermediate fitness group (21.8%), and the rest belonged to the frailty group (153, 77.7%). Overall, 79.7% of patients (157) received three-drug regimens and 20.3% (40) received two-drug regimens. In each ECOG group, more than three out of four patients received three-drug regimens. According to the ADL scale, 82.3% of the independent 65.2% of moderately impaired, and 81.8% of the dependent received three-drug regimens. Out of 53 patients with at least four comorbidities, 71.7% received three-drug regimens, and the rest received two-drug regimens. Thirty-four patients from the intermediate fit group (79.0%), and 123 (79.9%) from the frail group received three-drug regimens. Early mortality occurred in 25 patients (12.7%). No one discontinued treatment due to toxicity. To conclude, MM patients over 75 are mainly treated with triple-drug regimens, not only in reduced doses, regardless of their frailty scores. However, the absence of prospective fragility assessment did not negatively affect early mortality and the number of treatment discontinuations, which brings into question the clinical utility of current fragility scales in everyday practice. [ABSTRACT FROM AUTHOR]

Simple Summary: Multiple myeloma has remained largely incurable despite improvements in patient outcomes in the era of targeted anti-myeloma agents. Targeted therapies used in oncology in recent years have significantly changed the way myeloma is treated and thus improved the prognosis for patients. We sought to identify new biomarkers for patient stratification and the prediction of treatment outcomes by applying targeted capture hybridization DNA sequencing (tchDNA-Seq) technology. We have evaluated plasma and bone marrow samples from a homogenous population of 23 patients, which IG rearrangements have the potential to provide important diagnostic, prognostic, and predictive information. We will likely be able to offer a more targeted and risk-adapted therapeutic approach to MM patients at different stages of their disease guided by these potential biomarkers. Multiple myeloma (MM) is a hematological malignancy characterized by the clonal proliferation of pathogenic CD138+ plasma cells (PPCs) in bone marrow (BM). Recent years have seen a significant increase in the treatment options for MM; however, most patients who achieve complete the response ultimately relapse. The earlier detection of tumor-related clonal DNA would thus be very beneficial for patients with MM and would enable timely therapeutic interventions to improve outcomes. Liquid biopsy of "cell-free DNA" (cfDNA) as a minimally invasive approach might be more effective than BM aspiration not only for the diagnosis but also for the detection of early recurrence. Most studies thus far have addressed the comparative quantification of patient-specific biomarkers in cfDNA with PPCs and BM samples, which have shown good correlations. However, there are limitations to this approach, such as the difficulty in obtaining enough circulating free tumor DNA to achieve sufficient sensitivity for the assessment of minimal residual disease. Herein, we summarize current data on methodologies to characterize MM, and we present evidence that targeted capture hybridization DNA sequencing (tchDNA-Seq) can provide robust biomarkers in cfDNA, including immunoglobulin (IG) rearrangements. We also show that detection can be improved by prior purification of the cfDNA. Overall, liquid biopsies of cfDNA to monitor IG rearrangements have the potential to provide important diagnostic, prognostic, and predictive information in patients with MM. [ABSTRACT FROM AUTHOR]

Simple Summary: Multiple myeloma (MM), a plasma cell neoplasm, is an incurable hematological malignancy. Gain/amplification of chromosome arm 1q21 (1q21+) is the most common adverse genomic abnormality associated with disease progression and drug resistance. While possible mechanisms of 1q21+ occurrence and candidate genes in the 1q21 amplicon have been suggested, the precise pathogenesis of MM with 1q21+ is unknown. Herein, we review the current knowledge about the clinicopathological features of 1q21+ MM, which can assist in effective therapeutic approaches for MM patients with 1q21+. Multiple myeloma (MM), a plasma cell neoplasm, is an incurable hematological malignancy characterized by complex genetic and prognostic heterogeneity. Gain or amplification of chromosome arm 1q21 (1q21+) is the most frequent adverse chromosomal aberration in MM, occurring in 40% of patients at diagnosis. It occurs in a subclone of the tumor as a secondary genomic event and is more amplified as the tumor progresses and a risk factor for the progression from smoldering multiple myeloma to MM. It can be divided into either 1q21 gain (3 copies) or 1q21 amplification (≥4 copies), and it has been suggested that the prognosis is worse in cases of amplification than gain. Trisomy of chromosome 1, jumping whole-arm translocations of chromosome1q, and tandem duplications lead to 1q21+ suggesting that its occurrence is not consistent at the genomic level. Many studies have reported that genes associated with the malignant phenotype of MM are situated on the 1q21 amplicon, including CKS1B, PSMD4, MCL1, ANP32E, and others. In this paper, we review the current knowledge regarding the clinical features, prognostic implications, and the speculated pathology of 1q21+ in MM, which can provide clues for an effective treatment approach to MM patients with 1q21+. [ABSTRACT FROM AUTHOR]

Simple Summary: While novel therapies have improved outcomes in multiple myeloma (MM), physicians are calling for greater caution when managing this hematologic malignancy in older patients due to their fragility, which increases their vulnerability to toxic events. Additionally, this patient population may be excluded from clinical trials due to comorbidities, whereby available data are not always applicable in real-word clinical practice. This review delves into available frailty assessment tools that can be used to identify patients who are unfit or frail and tailor therapy to achieve better outcomes while minimizing toxicity. Current therapeutic strategies for managing transplant-ineligible patients with newly diagnosed MM and relapsed or refractory MM are also described, with the aim of guiding physicians when selecting treatment options. Multiple myeloma (MM) mostly affects older patients, who represent a highly heterogeneous population. In the last few years, the introduction of novel agents led to a significant improvement in the outcome of MM patients. Nonetheless, this positive trend is less likely to occur in all older patients due to comorbidities/disabilities and major susceptibility to toxic events. Furthermore, older patients with major comorbidities are usually excluded or underrepresented in most registrational clinical trials. In this context, physicians have called for greater caution in the management of the disease. Several scores allow for the identification of frail and unfit patients and establish the possibility of tailoring therapy, reducing toxicity. This review explores the available tools for the assessment of frailty and what has been done to improve the discriminative power of the available scores. Thereafter, it describes the main therapeutic strategies for the management of transplant-ineligible (NTE) newly diagnosed (ND) MM patients and relapsed/refractory (RR) MM patients, in order to better guide physicians in choosing treatment options and to suggest possible strategies for more frail patients. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

In 2015, as part of the Reproducibility Project: Cancer Biology, we published a Registered Report (Kandela et al., 2015) that described how we intended to replicate selected experiments from the paper "BET bromodomain inhibition as a therapeutic strategy to target c-Myc" (Delmore et al., 2011). Here we report the results of those experiments. We found that treatment of human multiple myeloma (MM) cells with the small-molecular inhibitor of BET bromodomains, (+)-JQ1, selectively downregulated MYC transcription, which is similar to what was reported in the original study (Figure 3B; Delmore et al., 2011). Efficacy of (+)-JQ1 was evaluated in an orthotopically xenografted model of MM. Overall survival was increased in (+)-JQ1 treated mice compared to vehicle control, similar to the original study (Figure 7E; Delmore et al., 2011). Tumor burden, as determined by bioluminescence, was decreased in (+)-JQ1 treated mice compared to vehicle control; however, while the effect was in the same direction as the original study (Figure 7CD; Delmore et al., 2011), it was not statistically significant. The opportunity to detect a statistically significant difference was limited though, due to the higher rate of early death in the control group, and increased overall survival in (+)-JQ1 treated mice before the pre-specified tumor burden analysis endpoint. Additionally, we evaluated the (-)-JQ1 enantiomer that is structurally incapable of inhibiting BET bromodomains, which resulted in a minimal impact on MYC transcription, but did not result in a statistically significant difference in tumor burden or survival distributions compared to treatment with (+)-JQ1. Finally, we report meta-analyses for each result. [ABSTRACT FROM AUTHOR]

Introduction: Multiple myeloma may cause a large range of problems, which are considered to be complications of this pathology.(1) Plasma cells proliferation interferes with normal production of blood cells leading to leukopenia, anemia and thrombocytopenia. Aim: This paper aim is to assess complications in multiple myeloma patients, as well as to establish a correlation with the treatment type they underwent. Methodology: The study was performed on a group of 77 patients diagnosed with multiple myeloma between January 1st 2011 and December 31st 2015 in the Hematology Department of the City Clinical Emergency Hospital Timisoara. Results: The group was studied in terms of anthropometric data, as well as of hematological, biochemical and immunological parameters. Complications present both at the time of diagnosis and after the start of polychemotherapy were shown, with statistically significant correlations being established between complications and type of treatment, as well as with the response to treatment. Conclusions: This study shows that regardless of the type of treatment delivered, complications arise from the treatment itself. The most common complications of patients diagnosed with MM are bone pain, followed by anemia, CKD and hypercalcemia. Despite the complications that may occur after polychemotherapy with Velcade and Dexamethasone, this therapy significantly improves both survival and quality of life of patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Reports of attrition rates in the treatment of multiple myeloma vary widely, indicating that despite all innovations in multiple myeloma treatment, many patients do not reach their full treatment potential. In this retrospective study, the attrition rate in the Austrian Myeloma Registry (AMR) was analysed. A total of 571 patients diagnosed between January 2009 and August 2021 were included. The result of attrition in the AMR is very encouraging compared to previous data, with 22% +/− 5% per line of treatment (LoT). Attrition is higher in the elderly and lower in patients with optimal frontline treatment, including stem cell transplantation and maintenance. The importance of achieving an optimal response is highlighted, not only in terms of attrition, but also in terms of the achievable treatment-free intervals. These promising results support the putative key role of liberal universal drug access and reimbursement. Multiple myeloma (MM) is characterized by serial relapses, necessitating the application of sequential lines of therapy (LoT). Reports on attrition rates (ARs) vary widely. The present study analysed ARs from the Austrian Myeloma Registry. Attrition was defined as being either deceased, progressive without having received another LoT, or lack of follow-up for ≥5 years. A total of 571 patients diagnosed between January 2009 and August 2021 were included (median age: 72 years; median follow-up: 50.8 months). Some 507 patients received at least one LoT. Of the total, 43.6% underwent autologous stem cell transplantation (SCT, transplant eligible = TE)) with primarily VRd (Bortezomib/Lenalidomide/Dexamethasone) given as induction (26.5%), followed by lenalidomide maintenance in 55.7% of cases. Transplant-ineligible (NTE) patients were predominantly treated with Vd (Bortezomib/Dexamethasone, 21.6%), receiving maintenance in 27.1%. A total of 37.5% received a second LoT. ARs across one to five LoTs were 16.7–27%. Frontline induction/ SCT followed by maintenance reduced ARs associated with age and achievement of deep remission in the frontline. Deep remission prolongs follow-up and time-to-next-treatment (TTNT), while high-risk-cyctogenetics negatively affected these outcomes. Our results demonstrate considerably lower ARs for MM patients within the AMR data versus other healthcare systems. Young age and the achievement of significant remissions after optimal frontline therapy resulted in particularly low ARs. These promising results support a key role for the ease of drug access and reimbursement policies in governing long-term MM patient outcomes. [ABSTRACT FROM AUTHOR]

Our main objective was to identify abundantly expressed tyrosine kinases in multiple myeloma (MM) as potential therapeutic targets. We first compared the transcriptomes of malignant plasma cells from newly diagnosed MM patients who were risk-categorized based on the patientspecific EMC-92/SKY-92 gene expression signature values vs. normal plasma cells from healthy volunteers using archived datasets from the HOVON65/GMMG-HD4 randomized Phase 3 study evaluating the clinical efficacy of bortezomib induction/maintenance versus classic cytotoxic drugs and thalidomide maintenance. In particular, ERBB1/EGFR was significantly overexpressed in MM cells in comparison to normal control plasma cells, and it was differentially overexpressed in MM cells from high-risk patients. Amplified expression of EGFR/ERBB1 mRNA in MM cells was positively correlated with increased expression levels of mRNAs for several DNA binding proteins and transcription factors with known upregulating activity on EGFR/ERBB1 gene expression. MM patients with the highest ERBB1/EGFR expression level had significantly shorter PFS and OS times than patients with the lowest ERBB1/EGFR expression level. High expression levels of EGFR/ERBB1 were associated with significantly increased hazard ratios for unfavorable PFS and OS outcomes in both univariate and multivariate Cox proportional hazards models. The impact of high EGFR/ERBB1 expression on the PFS and OS outcomes remained significant even after accounting for the prognostic effects of other covariates. These results regarding the prognostic effect of EGFR/ERBB1 expression were validated using the MMRF-CoMMpass RNAseq dataset generated in patients treated with more recently applied drug combinations included in contemporary induction regimens. Our findings provide new insights regarding the molecular mechanism and potential clinical significance of upregulated EGFR/ERBB1 expression in MM. [ABSTRACT FROM AUTHOR]

Background: Multiple myeloma (MM) is a clonal proliferation of malignant plasma cells that results in the production of a monoclonal paraprotein with a light or heavy chain that is seen in the urine and/or serum. The ultimate goal of the MM therapy is the achievement of complete response (CR). The aim of this study is to evaluate the efficacy of the commonly used therapeutic protocols of MM utilized at the National Center of Hematology in Baghdad, Iraq. Materials and Methods: Fifty-two patients with MM were enrolled consecutively for a cross-sectional study between July 2015 and May 2022 at one of Iraq's major hematology institutions, the National Center of Hematology, Mustansiriyah University. The enrolled patients were evaluated for the overall response rate (ORR), which constitutes CR, very good partial response, and partial response, in comparison to non-response (NR), which constitutes stable disease and progressive disease. Responses to the main MM triple therapeutic regimens used in Iraq, VCD, VRD, and VTD, were evaluated. These regimens are composed of cyclophosphamide (C), bortezomib (V), thalidomide (T), lenalidomide (R), and dexamethasone (D). According to its availability, subsequent autologous stem cell transplantation (ASCT) was performed for some patients. Results: Of the 52 enrolled patients, 50 (96.2%) were assessed at a median follow-up time of 60.5 months. The mean ± SD age of the enrolled patients was 61.5 ± 11.0 years, and the male-to-female ratio was 3:2. However, two patients (3.8%) died before the end of the follow-up. The most common features the patients presented with were bone pain and/or backache in 67.3% of the patients, followed by lower limb weakness and mass (1.9% each). The radiological changes include osteolytic lesions in 34.6% and vertebral wedging in 15.4% of the patients. The most frequent laboratory findings were anemia (69.2%), with hemoglobin levels of 10.0 ± 1.5g/dL, detection of IgG-kappa paraprotein (51.9%), and high levels of serum calcium in 23.1% (11.7 ± 1.1mg/dL) and serum creatinine in 21.2% (3.3 ± 1.5mg/dL) of the patients. ORR was 88.5%, while NR was reported in 11.5% of the patients. The outcomes were stratified according to the treatment used. It was found that ORR showed statistically significant differences and the VRD group demonstrated the best (P < 000.1). Twenty-one (40.4%) patients underwent subsequent ASCT, and the ORR showed non-significant differences compared to that when patients did not undergo transplantation (P > 0.05). Conclusions: In this study, VRD was the most effective protocol with a better ORR. In addition, the age of the patients presenting with MM in Iraq was less than in western countries. Also, most of the patients were presented with bone lesions, and IgG was the predominant type of myeloma paraproteins. [ABSTRACT FROM AUTHOR]

Context: Nowadays, radionuclides with high β- particle energies such as (166)Ho are recommended for bone marrow ablation in patients with multiple myeloma. The addition of skeletal targeted radiotherapy to the patients can improve the response rate in phase I and II trials, with promising long-term survival data.Aims: In this work, the absorbed dose to each organ of human for (166)Ho-propylene di-amino tetra methy1enephosphonicacid (PDTMP) was evaluated based on biodistribution studies in rats and was compared with (166)Ho-tetraazacyclododecane tetramethylene-phosphonate (DOTMP) as the only clinically used Ho-166 bone marrow ablative agent.Settings and Design: In this work, the accumulated activity in animals was extrapolated to the accumulated activity in humans by mass extrapolation method. The absorbed dose to each organ of human for (166)Ho-PDTMP was evaluated by medical internal radiation dose method.Materials and Methods: In this study, 166 Ho-PDTMP complex was prepared successfully using an in-house synthesized PDTMP ligand and (166)HoCl 3. Radiochemical purity of (166)Ho-PDTMP was checked by instant thin layer chromatography (>99%). The biodistribution of (166)Ho-PDTMP in wild-type rats was checked in animal tissues up to 48 h.Statistical Analysis Used: All values were expressed as mean ± standard deviation, and the data were compared using Student's t-test. Statistical significance was defined as P < 0.05.Results: The highest absorbed dose for this complex is observed in red marrow with 0.691 mSv/MBq. (166)Ho-PDTMP demonstrated a higher red marrow: Non target organ uptake ratio compared to (166)Ho-DOTMP.Conclusions: The results showed that 166 Ho-PDTMP has considerable characteristics compared to (166)Ho-DOTMP and therefore can be a good candidate for bone marrow ablation. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to reach a consensus on a set of proposals to optimise the disease management of Multiple myeloma (MM) within the Spanish National Health System (SNHS) and to apply the Social Return on Investment (SROI) method to estimate their social impact. Methods: A Multidisciplinary Working Team (MWT) including MM main stakeholders was organised. A survey was administered to gather information from patients regarding the impact of MM on different life domains. A forecast‐type SROI analysis, with a 1‐year timeframe, was applied. Results: Fifteen proposals were selected, to optimise MM management, including actions for early diagnosis, psychological support, improvement of information for patients and quick access to palliative care, among others. The implementation of these proposals would benefit patients, their informal caregivers and the SNHS. The investment required would amount to 10.32 million euros with a social return of 43.31 million euros: 4.2 euros for each euro invested. According to the sensitivity analysis, this ratio could range from 3.38 to 5.20 euros from the worst to the best‐case scenario. Conclusions: The current management of MM could be optimised by implementing a set of proposals that would most likely result in an overall positive social return. [ABSTRACT FROM AUTHOR]

Background: Multiple myeloma (MM) is the third most common hematologic malignancy with increasing importance due to improving treatment strategies and long-term outcomes in an aging population. This study aims to analyse influencing factors on health-related quality of life (HRQoL), such as treatment strategies, participation in a clinical trial and patient characteristics like anxiety, depression, gender, and age. A better understanding of the individual factors in context with HRQoL could provide a helpful instrument for clinical decisions.Methods: In this prospective observational study, the HRQoL of MM patients with different therapies (first-line and relapse) was quantified by standardized questionnaires (EORTC QLQ-C30 and -MY20) in the context of sociodemographic data, individual anxiety and depressiveness (PHQ-4), and a selected number of clinical parameters and symptoms at defined time-points before, during, and after therapy.Results: In total, 70 patients were included in the study. The median age of the study cohort was 62 years. 44% were female and 56% were male patients. More than half of the patients were fully active with an ECOG 0. Global health status was significantly higher in patients with first-line treatment and even increased after start of therapy, while the pain level decreased. In contrast, patients with relapsed MM reported a decreasing global health status and increasing pain. Additionally, there was a higher global health status in less anxious/depressive patients. HRQoL decreased significantly after start of chemotherapy in the parameters body image, side effects of treatment, and cognitive functioning. Tandem stem-cell transplantation was not found to be a risk factor for higher impairment of HRQoL. Participation in a clinical study led to an improvement of most aspects of HRQoL. Among others, increased anxiety and depression, female gender, older age, impaired performance status, and recurrent disease can be early indicators for a reduced HRQoL.Conclusion: This study showed the importance of regular longitudinal assessments of patient reported outcomes (PROs) in routine clinical care. For the first time, to our knowledge, we were able to demonstrate a potential impact between participation in clinical trials and HRQoL. However, due to frequently restrictive inclusion criteria for clinical trials, these MM patients might not be directly comparable with patients treated within standard therapy concepts. Further studies are needed to clarify the relevance of this preliminary data in order to develop an individualized, patient-centred, therapy concept. [ABSTRACT FROM AUTHOR]

Simple Summary: The study of malignant plasma cell DNA genomics in multiple myeloma is a hot topic, which is mainly based on one-site bone marrow aspirates. In this study, we showed that circulating tumor DNA targeted next-generation sequencing analysis revealed a more comprehensive genomic architecture than bone marrow aspirates in newly diagnosed multiple myeloma. Circulating tumor DNA mutation in the transcriptional regulation pathway and DNA repair pathway were independent predictors of progression-free survival. ctDNA alterations correlated with prognosis and therapy response in newly diagnosed multiple myeloma. Multiple myeloma (MM) is highly heterogenous and dynamic in its genomic abnormalities. Capturing a representative image of these alterations is essential in understanding the molecular pathogenesis and progression of the disease but was limited by single-site invasive bone marrow (BM) biopsy-based genomics studies. We compared the mutational landscapes of circulating tumor DNA (ctDNA) and BM in 82 patients with newly diagnosed MM. A 413-gene panel was used in the sequencing. Our results showed that more than 70% of MM patients showed one or more genes with somatic mutations and at least half of the mutated genes were shared between ctDNA and BM samples. Compared to the BM samples, ctDNA exhibited more types of driver mutations in the shared driver genes, higher numbers of uniquely mutated genes and subclonal clusters, more translocation-associated mutations, and higher frequencies of mutated genes enriched in the transcriptional regulation pathway. Multivariate Cox analysis showed that age, ctDNA mutations in the transcriptional regulation pathway and DNA repair pathway were independent predictors of progression-free survival (PFS). Our results demonstrated sequencing of ctDNA provides more thorough information on the genomic instability and is a potential representative biomarker for risk stratification and in newly diagnosed MM than bone marrow. [ABSTRACT FROM AUTHOR]

Background: Chimeric antigen receptor T-cell (CAR-T) therapy represents a new frontier in multiple myeloma. It is important to understand critical success factors (CSFs) that may optimize its use in this therapeutic area. Methods: We estimated the CAR-T process using time-driven activity-based costing. Information was obtained through interviews at four US oncology centers and with payer representatives, and through publicly available data. Results: The CAR-T process comprises 13 steps which take 177 days; it was estimated to include 46 professionals and ten care settings. CSFs included proactive collaboration, streamlined reimbursement and CAR-T administration in alternative settings when possible. Implementing CSFs may reduce episode time and costs by 14.4 and 13.2%, respectively. Conclusion: Our research provides a blueprint for improving efficiencies in CAR-T therapy, thereby increasing its sustainability for multiple myeloma. [ABSTRACT FROM AUTHOR]

Simple Summary: Multiple myeloma (MM) is a complex white blood cell (plasma cell, PC) cancer. The aetiology of MM is still unknown, and it is still an incurable disease despite efforts by the scientific community. The high level of PC genetic heterogeneity renders MM a complex puzzle to be solved. Combinations of drugs are generally used to treat MM patients, with a general increase in overall survival. Relapsed and refractory MM patients are the generation of patients who resist or do not respond to first-line therapy and need additional treatments. Exploring new sources, such as marine organisms, for drug discovery is fundamental to fighting MM. Various studies have shown that marine natural products (MNPs) might have antiproliferative and cancer-specific cytotoxic properties, giving MNPs a pivotal role in anticancer drug discovery. This review recaps updated frontline treatment options, including new ones developed from MNP research. Multiple myeloma (MM) is a blood cancer that occurs in the plasma cells (PCs), a type of white blood cell. Despite the progress of several current treatments that prolong the overall patient's survival, most MM cases are incurable. For this reason, many efforts have been undertaken by the scientific community in the search for new treatments. BLENREPTM and Aplidin® are two marine-derived drugs currently in use for MM. In addition, other natural products have been identified from marine organisms, tested for their possible anticancer properties, and are in preclinical or clinical trials for MM, including cytarabine, a compound in use for leukaemia treatment. Between the most successful marine compounds in fighting MM, there are molecules with specific targets, such as the elongation factor 1-alpha 2 and proteasome inhibitors, and compounds conjugated with antibodies that recognise specific cell types and direct the drug to the correct cell target. Active compounds belong to different chemical classes, from cyclic peptides to alkaloids, highlighting the importance of screening the plethora of compounds produced by marine organisms. In this review, we summarise the current state of art of MM therapies focusing on the marine natural product emerging roles. [ABSTRACT FROM AUTHOR]

Background: For patients with multiple myeloma receiving high-dose chemotherapy followed by autologous stem cell transplantation (SCT), acute life disruptions and symptom burden may lead to worsened quality of life (QOL) and increased emotional distress. Digital life coaching (DLC), whereby trained coaches deliver personalized well-being-related support via phone calls and SMS text messaging, has been shown to improve QOL among SCT survivors. However, DLC has not been investigated during the acute peri-SCT period, which is generally characterized by symptomatic exacerbations and 2-week hospitalizations. Objective: We launched a single-arm pilot study to investigate the feasibility of patient engagement with DLC during this intensive period. Methods: We approached English-speaking adult patients with multiple myeloma undergoing autologous SCT at our center. Enrolled patients received 16 weeks of virtual access to a life coach beginning on day -5 before SCT. Coaches used structured frameworks to help patients identify and overcome personal barriers to well-being. Patients chose the coaching topics and preferred communication styles. Our primary endpoint was ongoing DLC engagement, defined as bidirectional conversations occurring at least once every 4 weeks during the study period. Secondary endpoints were electronic patient-reported outcome assessments of QOL, distress, and sleep disturbances. Results: Of the 20 patients who were screened, 17 (85%) chose to enroll and 15 (75%) underwent SCT as planned. Of these 15 patients (median age 65 years, range 50-81 years), 11 (73%) demonstrated ongoing DLC engagement. The median frequency of bidirectional conversations during the 3-month study period was once every 6.2 days (range 3.9-28 days). During index hospitalizations with median lengths of stay of 16 days (range 14-31 days), the median frequency of conversations was once every 5.3 days (range 2.7-15 days). Electronic patient-reported outcome assessments (94% adherence) demonstrated an expected QOL nadir during the second week after SCT. The prevalence of elevated distress was highest immediately before and after SCT, with 69% of patients exhibiting elevated distress on day -5 and on day +2. Conclusions: DLC may be feasible for older patients during intensive hospital-based cancer treatments such as autologous SCT for multiple myeloma. The limitations of our study include small sample size, selection bias among enrolled patients, and heterogeneity in DLC use. Based on the positive results of this pilot study, a larger phase 2 randomized study of DLC during SCT is underway to investigate the efficacy of DLC with regard to patient well-being. [ABSTRACT FROM AUTHOR]

People with multiple myeloma (MM) are second only to people with lung cancer for the poorest reported health-related quality of life (HRQoL) of all cancer types. Whether exercise can improve HRQoL in MM, where bone pain and lesions are common, requires investigation. This trial aims to evaluate the efficacy of an exercise intervention compared with control on HRQoL in people with MM. Following baseline testing, people with MM (n = 60) will be randomized to an exercise (EX) or waitlist control (WT) group. EX will complete 12-weeks of supervised (24 sessions) and unsupervised (12 sessions) individualized, modular multimodal exercise training. From weeks 12–52, EX continue unsupervised training thrice weekly, with one optional supervised group-based session weekly from weeks 12–24. The WT will be asked to maintain their current activity levels for the first 12-weeks, before completing the same protocol as EX for the following 52 weeks. Primary (patient-reported HRQoL) and secondary (bone health and pain, fatigue, cardiorespiratory fitness, muscle strength, body composition, disease response, and blood biomarkers) outcomes will be assessed at baseline, 12-, 24- and 52-weeks. Adverse events, attendance, and adherence will be recorded and cost-effectiveness analysis performed. The findings will inform whether exercise should be included as part of standard myeloma care to improve the health of this unique population. [ABSTRACT FROM AUTHOR]

Presentation of multiple myeloma with bone lesions is common. It is vital that differentiation between nonsecretory multiple myeloma and plasmocytoma be done and that each disorder be treated accordingly. In this paper, we present a patient with nonsecretory multiple myeloma, who suffered from distal humerus fracture with severe bone destruction, renal failure, hypercalcemia and anemia. [ABSTRACT FROM AUTHOR]

Aims: To assess the real-world healthcare resource utilization (HRU) and costs associated with different proteasome inhibitors (PIs) for the treatment of patients with relapsed and/or refractory multiple myeloma (RRMM) in Germany. Methods: We conducted a retrospective medical chart review of treatment patterns, outcomes, and HRU for patients with RRMM treated with bortezomib, carfilzomib, or ixazomib in second- or third-line (2L or 3L) therapy in Germany. Data were collected between 1 January 2017 and 30 June 2017. Costs were calculated based on drug prices and unit costs in Germany. Limitations: Patients with missing or incomplete follow-up data were included in the study and were accounted for using monthly cost estimates. Conclusions: Anti-myeloma drugs were the main contributor to total HRU costs associated with RRMM in Germany. Improved treatment response was associated with lower costs and reduced hospitalizations. [ABSTRACT FROM AUTHOR]

Aberrant expression of lymphoid enhancer-binding factor-1 (LEF1) has been identified in various hematological malignancies including multiple myeloma (MM). However, the exact role of LEF1 in MM remains largely unknown. Here, we showed that knockdown of LEF1 could apparently impair the proliferation, induce apoptosis and promote the ROS production in MM cell lines, suggesting that LEF1 might be involved in maintaining MM cell growth and survival. Moreover, we observed that the mRNA level of the deubiquitinase cylindromatosis (CYLD), a well-recognized tumor suppressor in MM, was significantly increased following LEF1 depletion in myeloma cells. Further study showed that LEF1 could directly associate with the promoter of CYLD gene and thus repress its transcription in MM cells. Intriguingly, LEF1 depletion-mediated CYLD upregulation was sufficient to negatively modulate NF-κB signaling pathway in MM cells. Moreover, the decrease in NF-κB activity following LEF1 knockdown could be largely rescued when CYLD was silenced in MM cells. Taken together, our study provided the compelling evidence to show that LEF1 may augment the proliferation and survival of MM cells through direct repression of CYLD transcription and subsequent activation of NF-κB signaling pathway, corroborating that LEF1 may become a potential therapeutic target against MM. [ABSTRACT FROM AUTHOR]