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Multiple myeloma (MM), the second most common hematologic malignancy, remains incurable, and its incidence is rising. Chimeric Antigen Receptor T-cell (CAR-T cell) therapy has emerged as a novel treatment, with the potential to improve the survival and quality of life of patients with relapsed/refractory multiple myeloma (rrMM). In this systematic review and meta-analysis, conducted in accordance with PRISMA guidelines, we aim to provide a concise overview of the latest developments in CAR-T therapy, assess their potential implications for clinical practice, and evaluate their efficacy and safety outcomes based on the most up-to-date evidence. A literature search conducted from 1 January 2019 to 12 July 2023 on Medline/PubMed, Scopus, and Web of Science identified 2273 articles, of which 29 fulfilled the specified criteria for inclusion. Our results offer robust evidence supporting CAR-T cell therapy's efficacy in rrMM patients, with an encouraging 83.21% overall response rate (ORR). A generally safe profile was observed, with grade ≥ 3 cytokine release syndrome (CRS) at 7.12% and grade ≥ 3 neurotoxicity at 1.37%. A subgroup analysis revealed a significantly increased ORR in patients with fewer antimyeloma regimens, while grade ≥ 3 CRS was more common in those with a higher proportion of high-risk cytogenetics and prior exposure to BCMA therapy. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is a very heterogeneous disease with multiple symptoms and clinical manifestations.MMaffects mainly elderly patients and is difficult tomanage in the presence of comorbidities, polypharmacy, frailty and adverse events of diseasetargeted drugs. The rapid changes in MM treatment resulting from constant innovations in this area, together with the introduction of numerous new drugs with distinct mechanisms of action and toxicity profiles, have led to an increased complexity in the therapeutic decision-making and patient management processes. The prolonged exposure to novel agents, sometimes in combination with conventional therapies, makes this management even more challenging. A careful balance between treatment efficacy and its tolerability should be considered for every patient. During treatment, a closemonitoring of comorbidities, disease-related manifestations and treatment side effects is recommended, as well as a proactive approach, with reinforcement of information and patient awareness for the early recognition of adverse events, allowing prompt therapeutic adjustments. In this review, we discuss various issues that must be considered in the treatment of MM patients, while giving practical guidance for monitoring, prevention and management of myeloma-related manifestations and treatment-related toxicities. [ABSTRACT FROM AUTHOR]

Patients affected by multiple myeloma (MM) have an increased risk of severe acute respiratory syndrome coronavirus type 2 (SARS‐CoV‐2) infection and subsequent coronavirus (20)19 disease (COVID‐19)‐related death. The changing epidemiological and therapeutic scenarios suggest that there has been an improvement in severity and survival of COVID‐19 during the different waves of the pandemic in the general population, but this has not been investigated yet in MM patients. Here we analyzed a large cohort of 1221 patients with MM and confirmed SARS‐CoV‐2 infection observed between February 2020, and August 2022, in the EPICOVIDEHA registry from 132 centers around the world. Median follow‐up was 52 days for the entire cohort and 83 days for survivors. Three‐hundred and three patients died (24%) and COVID‐19 was the primary reason for death of around 89% of them. Overall survival (OS) was significantly higher in vaccinated patients with both stable and active MM versus unvaccinated, while only a trend favoring vaccinated patients was observed in subjects with responsive MM. Vaccinated patients with at least 2 doses showed a better OS than those with one or no vaccine dose. Overall, according to pandemic waves, mortality rate decreased over time from 34% to 10%. In multivariable analysis, age, renal failure, active disease, hospital, and intensive care unit admission, were independently associated with a higher number of deaths, while a neutrophil count above 0.5 × 109/L was found to be protective. This data suggests that MM patients remain at risk of SARS‐CoV‐2 infection even in the vaccination era, but their clinical outcome, in terms of OS, has progressively improved throughout the different viral phases of the pandemic. [ABSTRACT FROM AUTHOR]

Monitoring measurable residual disease (MRD) is crucial to assess treatment response in Multiple Myeloma (MM). Detection of MRD in peripheral blood (PB) by exploring Extracellular Vesicles (EVs), and their cargo, would allow frequent and minimally invasive monitoring of MM. This work aims to detect biomarkers of MRD in EVs isolated from MM patient samples at diagnosis and remission and compare the MRD-associated content between BM and PB EVs. EVs were isolated by size-exclusion chromatography, concentrated by ultrafiltration, and characterized according to their size and concentration, morphology, protein concentration, and the presence of EV-associated protein markers. EVs from healthy blood donors were used as controls. It was possible to isolate EVs from PB and BM carrying MM markers. Diagnostic samples had different levels of MM markers between PB and BM paired samples, but no differences between PB and BM were found at remission. EVs concentration was lower in the PB of healthy controls than of patients, and MM markers were mostly not detected in EVs from controls. This study pinpoints the potential of PB EVs from MM remission patients as a source of MM biomarkers and as a non-invasive approach for monitoring MRD. [ABSTRACT FROM AUTHOR]

Monoclonal gammopathy of undetermined significance (MGUS) may be associated with pathologies with severe neuromuscular manifestations such as sporadic late‐onset nemaline myopathy (SLONM). We describe a difficult to diagnose case of SLNOM with marked clinical improvement after achieving gammopathy complete hematologic response. [ABSTRACT FROM AUTHOR]

Abstract Background Multiple Myeloma (MM) is the commonest indication for autologous stem cell transplantation (ASCT). Methods We retrospectively analysed data from 85 patients with MM submitted to ASCT in our centre from 2000 to 2010: 132 ASCT were realized, 80 of them as tandem. Results After induction, 17.6% were in complete remission (CR), 41.2% in very good partial remission (VGPR) and 41.2% in partial remission (PR). After transplant 44.7% were in CR, 15.3% in VGPR and 40% in PR. With 22 months (range – 3 to 117 months) of median follow-up, median overall survival (OS) was 43 months and progression-free survival (PFS) 22 months. At 5 years, OS was 45.3% (36.7-53.9%, 95%) and PFS 24.5% (18-31%, 95%). Patients with CR after ASCT had significantly longer PFS as compared to patients with PR (27 vs 7 months; p = 0.034) but not when compared to patients with VGPR (27 vs 19 months, p = 0.485). The tandem approach represented an advantage in OS and PFS when compared to only one ASCT (31 vs 19 months - p = 0.018, and 40 vs 31 - p = 0.04, respectively). Conclusions Our results highlight the impact of response to transplant in patients PFS and tandem modality showed to carry better PFS and OS then the single transplant.

Abstract Autologous stem cell transplantation (ASCT) is the gold standard therapy for suitable multiple myeloma (MM) patients after induction with high dose therapy. To date, the evidence of a reliable marker of prognosis in these cases remains scarce. Our aim was to evaluate appearance of unrelated atypical serum immunofixation patterns (ASIPs) as a marker of prognosis in MM patients submitted to ASCT. We retrospectively analysed data from 65 patients. Interestingly, we observed that presence of ASIPs was associated with longer progression-free survival and longer overall survival. Our results suggested that presence of ASIPs could be a novel marker of good prognosis in MM patients submitted to ASCT.

Objective: Patients hospitalized with multiple myeloma (MM) are particularly vulnerable to depression. The present study aims to determine the frequency of depression among MM hospitalized patients, in order to assess the possible differences between those with and without depression in relation to sociodemographic and clinical variables and to measure the impact of depression on hospitalization outcomes. Methods: An observational retrospective study was performed using an administrative data set of all hospitalizations with a primary diagnosis of MM between 2000 and 2015 in Portuguese mainland public hospitals. Codes related to depressive disorders were grouped to generate the dichotomous variable of depression (yes/no). A multivariate analysis was conducted and adjusted odd ratios (aOR) calculated between different variables and depression. Results: Of a total of 14.575 MM hospitalizations studied, a concurrent code of depression was registered in 666 patients (4.6%). A greater odds of depression was observed in female patients (aOR = 2.26; 95%CI = 1.91‐2.66), transplanted patients (aOR = 1.78; 95%CI = 1.44‐2.20), patients with plasma cell leukemia (aOR = 1.79; 95%CI = 1.22‐2.64) and patients with a higher Charlson Comorbidity Index (CCI) (aOR = 1.10; 95%CI = 1.05‐1.15). Length of stay was longer in patients with a registered diagnosis of depression (aOR = 1.01; 95%CI = 1.01‐1.02) while the odds of in‐hospital mortality were lower in these patients (aOR = 0.53; 95%CI = 0.41‐0.68). Conclusions: These results may help identify MM inpatients at higher risk of presenting depression (female gender, younger age, high CCI, plasma cell leukemia, transplant procedure). This will enable timely psychological assessment and treatment to prevent worse outcomes and higher healthcare costs associated with depression. [ABSTRACT FROM AUTHOR]

Extramedullary disease is an aggressive presentation at diagnosis and relapse for multiple myeloma (MM) patients. Central nervous system (CNS) is a very rare manifestation of the extramedullary disease, accounting for less than 1% of MM on diagnosis and relapse. Neurological symptoms are unspecific and usually attributed to other causes. We present two patients with CNS-MM at relapse after autologous stem cell transplant highlighting the importance of clinical suspicion and interdisciplinarity at diagnostic workup as well as the need for intensive therapeutic options on such rare and aggressive cases. The presence of neurological abnormalities in anamnesis and physical examination on a patient with MM should always prompt to suspect of a CNS involvement, and active investigation must be undertaken. MRI is the standard radiological method to detect CNS-MM, with histopathological corroboration by stereotactic biopsy and CSF evaluation alongside. Treatment of CNS-MM should include two essential approaches—be able to cross the BBB and treat the systemic disease. There is no standard therapy for this extramedullary relapse, and a tailored and multiple therapy should be promptly started—intrathecal therapy, radiotherapy, and systemic therapy, including an immunomodulator. [ABSTRACT FROM AUTHOR]

We present the case of a 20-year-old male hospitalized with severe neutropenia and thrombocytopenia. After exclusion of other etiologies, it was concluded to be of autoimmune etiology. The prompt and sustained response of both cell lines to corticosteroids, reinforced this diagnosis. This case illustrates a very rare association of severe primary neutropenia and thrombocytopenia. The lack of serological marker makes this diagnosis delayed and resource-consuming. [ABSTRACT FROM AUTHOR]

Despite improvements in the therapeutic approaches for hematological malignancies in the last decades, refractory disease still occurs, and cancer drug resistance still remains a major hurdle in the clinical management of these cancer patients. The investigation of this problem has been extensive and different mechanism and molecules have been associated with drug resistance. MicroRNAs (miRNAs) have been described as having an important action in the emergence of cancer, including hematological tumors, and as being major players in their progression, aggressiveness and response to treatments. Moreover, miRNAs have been strongly associated with cancer drug resistance and with the modulation of the sensitivity of cancer cells to a wide array of anticancer drugs. Furthermore, this role has also been reported for miRNAs packaged into extracellular vesicles (EVs-miRNAs), which in turn have been described as essential for the horizontal transfer of drug resistance to sensitive cells. Several studies have been suggesting the use of miRNAs as biomarkers for drug response and clinical outcome prediction, as well as promising therapeutic tools in hematological diseases. Indeed, the combination of miRNA-based therapeutic tools with conventional drugs contributes to overcome drug resistance. This review addresses the role of miRNAs in the pathogenesis of hematological malignances, namely multiple myeloma, leukemias and lymphomas, highlighting their important action (either in their cell-free circulating form or within circulating EVs) in drug resistance and their potential clinical applications. [ABSTRACT FROM AUTHOR]

Abstract: Autologous stem cell transplantation (ASCT) is the gold standard therapy for suitable multiple myeloma (MM) patients after induction with high dose therapy. To date, the evidence of a reliable marker of prognosis in these cases remains scarce. Our aim was to evaluate appearance of unrelated atypical serum immunofixation patterns (ASIPs) as a marker of prognosis in MM patients submitted to ASCT. We retrospectively analysed data from 65 patients. Interestingly, we observed that presence of ASIPs was associated with longer progression-free survival and longer overall survival. Our results suggested that presence of ASIPs could be a novel marker of good prognosis in MM patients submitted to ASCT. [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs) mediate intercellular signaling and communication, allowing the intercellular exchange of proteins, lipids, and genetic material. Their recognized role in the maintenance of the physiological balance and homeostasis seems to be severely disturbed throughout the carcinogenesis process. Indeed, the modus operandi of cancer implies the highjack of the EV signaling network to support tumor progression in many (if not all) human tumor malignancies. We have reviewed the current evidence for the role of EVs in affecting cancer hallmark traits by: (i) promoting cell proliferation and escape from apoptosis, (ii) sustaining angiogenesis, (iii) contributing to cancer cell invasion and metastasis, (iv) reprogramming energy metabolism, (v) transferring mutations, and (vi) modulating the tumor microenvironment (TME) by evading immune response and promoting inflammation. Special emphasis was given to the role of EVs in the transfer of drug resistant traits and to the EV cargo responsible for this transfer, both between cancer cells or between the microenvironment and tumor cells. Finally, we reviewed evidence for the increased release of EVs by drug resistant cells. A timely and comprehensive understanding of how tumor EVs facilitate tumor initiation, progression, metastasis and drug resistance is instrumental for the development of innovative EV-based therapeutic approaches for cancer. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is the second most common blood cancer. Treatments for MM include corticosteroids, alkylating agents, anthracyclines, proteasome inhibitors, immunomodulatory drugs, histone deacetylase inhibitors and monoclonal antibodies. Survival outcomes have improved substantially due to the introduction of many of these drugs allied with their rational use. Nonetheless, MM patients successively relapse after one or more treatment regimens or become refractory, mostly due to drug resistance. This review focuses on the main drugs used in MM treatment and on causes of drug resistance, including cytogenetic, genetic and epigenetic alterations, abnormal drug transport and metabolism, dysregulation of apoptosis, autophagy activation and other intracellular signaling pathways, the presence of cancer stem cells, and the tumor microenvironment. Furthermore, we highlight the areas that need to be further clarified in an attempt to identify novel therapeutic targets to counteract drug resistance in MM patients. [ABSTRACT FROM AUTHOR]

• Autologous haematopoietic stem cell transplantation (AHSCT) is a treatment option for refractory CIDP. • AHSCT offers long-term remission with an overall acceptable risk profile. • Severe disability caused by CIDP can be ameliorated with AHSCT. Autologous haematopoietic stem cell transplantation is an emerging treatment option in refractory chronic inflammatory demyelinating polyradiculoneuropathy. We describe a case of a 46-year-old male, with history of IgG/lambda monoclonal gammopathy, who was diagnosed with chronic inflammatory demyelinating polyradiculoneuropathy at 27 years of age. After an initial 10-year period of corticotherapy response, the patient experienced severe relapses and disease progression, evolving to a refractory state. First-line and escalating treatment could not achieve clinical stabilization, leading to severe disability. Pre-treatment with ibrutinib was initiated and autologous haematopoietic stem cell transplantation was performed without significant complications. Marked clinical improvement was observed in the following months, both subjective and objective. A significant proportion of the patients who respond to the first-line immunosuppressive therapy eventually become treatment-refractory. Autologous haematopoietic stem cell transplantation may be a treatment option, offering long-term remission with an overall acceptable side effect and risk profile. [ABSTRACT FROM AUTHOR]