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Introduction: Therapeutic adherence (TA) is one of the most important factors influencing the effectiveness of treatment. Oral anti-cancer drugs are increasingly used to treat malignancy including multiple myeloma (MM). Our study aimed to determine TA of patients with MM treated with IMiDs, to identify TA risk factors, and to determine satisfaction with medical care during the treatment with IMiDs., Methods: A cross-sectional survey-based study involving adult patients with MM treated with IMiDs., Results: Between January 2021 and May 2021, 267 patients with MM were enrolled in the study. The dosing schedule was declared as easy by 71.8% of patients, as standard for 24.0%, and difficult for 4.2% of patients. During MM treatment, 85.0% of patients did not skip any IMiDs dose, and 87.6% did not skip the IMiDs dose in the last cycle of chemotherapy. Identified factors affecting TA included the treatment duration and education level. In addition, depending on the patient's well-being, gender, and household companionship influenced TA. Satisfaction with medical care during the treatment with IMiDs was declared by 95.5% of patients with MM. In our cohort, 95.5% of patients were satisfied with the information they received from the hematologist during treatment with IMiDs., Conclusions: Patients with MM treated with IMiDs are highly adherent to treatment. With time from the beginning of treatment, patients need more attention and motivation to adhere to the therapy rules., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Non-secretory multiple myeloma (NSMM) accounts for approx. 2-3% of multiple myeloma (MM) cases. Due to the rare occurrence and ineligibility of patients with NSMM to participate in clinical trials, we have limited data on treatment efficacy and the clinical course in these patients. Most of the literature consists of case reports and small retrospective studies., Objectives: The study aimed to analyze patient characteristics, prognostic factors and treatment outcomes in newly diagnosed (ND) NSMM., Material and Methods: This is a multicenter, retrospective analysis of 43 patients with NSMM diagnosed between June 2010 and September 2021, conducted in 8 Polish hematology centers., Results: The median overall survival (OS) was 103 months (95% confidence interval (95% CI): 20-72). The most common cause of death was MM disease progression. The overall response rate (ORR) was 84.6%; complete response (CR), very good partial response (VGPR), partial response (PR), and no response (NR) rates were 20.5%, 46.2%, 17.9%, and 15.4%, respectively. In multivariable analysis, factors contributing to worse OS included International Staging System stage 3 (ISS-3) (p = 0.0277), anemia (Hb <10 g/dL or >2 below upper limit of normal value (ULN), p = 0.0270), renal insufficiency (RI, serum creatinine >2 mg/dL, p = 0.0476), and serum albumin <5.5 mg/L (0.0408)., Conclusions: Non-secretory multiple myeloma is a rare subtype of MM. This small study demonstrates that outcomes are comparable to secretory MM. However, the inclusion of this subset of patients in clinical trials is essential to assess prognosis, treatment efficacy and clinical outcomes.

Light-chain amyloidosis (AL) is a rare multisystem disorder characterized by the deposition of misfolded amyloid fibrils derived from monoclonal immunoglobulin light chains in various organs. One of the most common organs involved in AL is the heart, with 50-70% of patients clinically symptomatic at diagnosis. We conducted a multi-center, retrospective analysis of 67 patients diagnosed between July 2012 and August 2022 with the European 2012 modification of Mayo 2004 stage III cardiac AL. The most important factors identified in the univariate Cox analysis contributing to a longer OS included Eastern Cooperative Oncology Group performance status (ECOG PS) ≤ 1, New York Heart Association functional classification (NYHA FC) ≤ 2, the use of autologous stem cell transplantation (ASCT) after induction treatment, achieving a hematological response (≥very good partial response) and cardiac (≥partial response) response after first-line treatment. The most important prognostic factors with the most significant impact on OS improvement in patients with modified Mayo stage III cardiac AL identified by multivariate Cox analysis are ECOG PS ≤ 1, NYHA FC ≤ 2, and achieving hematological response ≥ VGPR and cardiac response ≥ PR after first-line treatment.

Previous studies suggest that postautologous stem cell transplant (ASCT) recovery of polyclonal immunoglobulin from immunoparesis in patients with multiple myeloma is a positive prognostic marker. We performed a longitudinal analysis of polyclonal immunoglobulin concentrations and unique B-cell sequences in patients enrolled in the phase 3 ATLAS trial that randomized 180 subjects to either carfilzomib, lenalidomide, dexamethasone (KRd) or lenalidomide (R) maintenance. In the KRd arm, standard-risk patients with minimal residual disease negativity after six cycles de-escalated to R alone after cycle 8. One year from the initiation of maintenance at least partial recovery of polyclonal immunoglobulin was observed in more patients on the R arm (58/66, p < 0.001) and in those who de-escalated from KRd to R (27/38, p < 0.001) compared to the KRd arm (9/36). In patients who switched from KRd to R, the concentrations of uninvolved immunoglobulin and the number of B-cell unique sequences increased over time, approaching values observed in the R arm. There were no differences in progression-free survival between the patients with at least partial immunoglobulin recovery and the remaining population. Our analysis indicates that patients receiving continuous therapy after ASCT experience prolonged immunoparesis, limiting prognostic significance of polyclonal immunoglobulin recovery in this setting., (© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Background: There is an increased risk of second primary malignancies (SMPs) in patients with multiple myeloma (MM). This multinational 'real-world' retrospective study analyzed the characteristics and outcomes of MM patients that developed SPMs., Results: 165 patients were analyzed: 62.4% males; 8.5% with a prior cancer; 113 with solid SPMs, mainly ≥stage 2; and 52 with hematological SPM (hemato-SPM), mainly MDS/AML. Patients with hemato-SPM were younger ( p = 0.05) and more frequently had a prior AutoHCT ( p = 0.012). The time to SPM was shorter in the older (>65 years) and more heavily pretreated patients. One hundred patients were actively treated at the time of SPM detection. Treatment was discontinued in 52, substituted with another anti-MM therapy in 15, and continued in 33 patients. Treatment discontinuation was predominant in the patients diagnosed with hemato-SPM (76%). The median OS following SPM detection was 8.5 months, and the main cause of death was SPM. A poor ECOG status predicted a shorter OS (PS 3 vs. 0, HR = 5.74, 2.32-14.21, p < 0.001), whereas a normal hemoglobin level (HR = 0.43, 0.19-0.95, p = 0.037) predicted longer OS., Conclusions: With the continuing improvement in OS, a higher proportion of MM patients might develop SPM. The OS following SPM diagnosis is poor; hence, frequent surveillance and early detection are imperative to improve outcomes.

Multiple myeloma (MM) is a hematologic malignancy characterized by severely profound immune dysfunction. Therefore, the efficacy of drugs targeting the immune environments, such as immune checkpoint inhibitors (ICIs), is of high clinical importance. However, several clinical trials evaluating ICIs in MM in different therapeutic combinations revealed underwhelming results showing a lack of clinical efficacy and excessive side effects. The underlying mechanisms of resistance to ICIs observed in the majority of MM patients are still under investigation. Recently, we demonstrated that inappropriate expression of PD-1 and CTLA-4 on CD4 T cells in active MM is associated with adverse clinical outcomes and treatment status. The aim of the current study was to determine the usefulness of immune checkpoint expression assessment as a predictive biomarker of the response to therapeutic inhibitors. For this purpose, along with checkpoint expression estimated by flow cytometry, we evaluated the time to progression (TTP) of MM patients at different clinical stages (disease diagnosis and relapse) depending on the checkpoint expression level; the cut-off point (dividing patients into low and high expressors) was selected based on the median value. Herein, we confirmed the defective levels of regulatory PD-1, CTLA-4 receptors, and the CD69 marker activation in newly diagnosed (ND) patients, whereas relapsed/refractory patients (RR) exhibited their recovered values and reactivity. Additionally, substantially higher populations of senescent CD4 + CD28 - T cells were found in MM, primarily in NDMM subjects. These observations suggest the existence of two dysfunctional states in MM CD4 T cells with the predominance of immunosenescence at disease diagnosis and exhaustion at relapse, thus implying different responsiveness to the external receptor blockade depending on the disease stage. Furthermore, we found that lower CTLA-4 levels in NDMM patients or higher PD-1 expression in RRMM patients may predict early relapse. In conclusion, our study clearly showed that the checkpoint level in CD4 T cells may significantly affect the time to MM progression concerning the treatment status. Therefore, when considering novel therapies and potent combinations, it should be taken into account that blocking PD-1 rather than CTLA-4 might be a beneficial form of immunotherapy for only a proportion of RRMM patients.

Multiple myeloma (MM) and chronic lymphocytic leukemia (CLL) patients have increased morbidity and mortality rates of COVID-19 due to immunosuppression associated with the disease and ongoing therapy. The same immune impairment accompanying CLL and MM also affects suboptimal vaccine response. The study assessed the effectiveness of the humoral and T cell-mediated immunity following mRNA COVID-19 vaccination (using either BNT162b2 or mRNA-1273) in short-term (2-5 weeks after second dose) and long-term follow-up (12 weeks after vaccination). Between March and August 2021, blood samples were obtained from 62 CLL and 60 MM patients from eight different hematology departments in Poland. Total anti-RBD antibodies were detected in 37% MM patients before vaccination, increased to 91% and 94% in short- and long-term follow-up, respectively. In CLL, serological responses were detectable in 21% of patients before vaccination and increased to 45% in the short-term and 71% in long-term observation. We detected a tendency to higher frequencies of specific CD8+ T cells against SARS-CoV-2 after vaccination compared to samples before vaccination in MM patients and no changes in frequencies of specific T cells in CLL patients. Our study provides novel insights into mRNA vaccination efficacy in immunocompromised MM and CLL patients, and our findings highlight that specific CD8+ T cells against SARS-CoV-2 might be induced by vaccination but do not correlate positively with serological responses., (© 2022 UICC.)

Background: Lenalidomide is a cornerstone of maintenance therapy in patients with newly diagnosed multiple myeloma after autologous stem-cell transplantation. We aimed to compare the efficacy and safety of maintenance therapy with carfilzomib, lenalidomide, and dexamethasone versus lenalidomide alone in this patient population., Methods: This study is an interim analysis of ATLAS, which is an investigator-initiated, multicentre, open-label, randomised, phase 3 trial in 12 academic and clinical centres in the USA and Poland. Participants were aged 18 years or older with newly diagnosed multiple myeloma, completed any type of induction and had stable disease or better, autologous stem-cell transplantation within 100 days, initiated induction 12 months before enrolment, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (1:1) using permuted blocks of sizes 4 and 6 and a web-based system to receive up to 36 cycles of carfilzomib, lenalidomide, and dexamethasone (28-day cycles of carfilzomib 20 mg/m 2 administered intravenously in cycle one on days 1 and 2 then 36 mg/m 2 on days 1, 2, 8, 9, 15, and 16 in cycles one to four and 36 mg/m 2 on days 1, 2, 15, and 16 from cycle five up to 36 [per protocol]; lenalidomide 25 mg administered orally on days 1-21; and dexamethasone 20 mg administered orally on days 1, 8, 15, and 22) or lenalidomide alone (10 mg administered orally for the first three cycles and then at the best tolerated dose [≤15 mg for 28 days in 28-day cycles]) until disease progression or unacceptable toxicity as maintenance therapy. After 36 cycles, patients in both treatment groups received lenalidomide maintenance. Randomisation was stratified by response to previous treatment, cytogenetic risk factors, and country. Investigators and patients were not masked to treatment allocation. Patients in the carfilzomib, lenalidomide, and dexamethasone group with no detectable minimal residual disease after cycle six (as per International Myeloma Working Group criteria) and standard-risk cytogenetics were switched to lenalidomide maintenance as of cycle nine. The primary endpoint was progression-free survival in the intention-to-treat population (defined as all randomly assigned patients). Safety was analysed in all randomly assigned patients who received at least one dose of study treatment. This unplanned interim analysis was triggered by the occurrence of 59 (61%) of the expected 96 events for the primary analysis and the results are considered preliminary. This trial is registered with ClinicalTrials.gov, NCT02659293 (active, not recruiting) and EudraCT, 2015-002380-42., Findings: Between June 10, 2016, and Oct 21, 2020, 180 patients were randomly assigned to receive either carfilzomib, lenalidomide, and dexamethasone (n=93) or lenalidomide alone (n=87; intention-to-treat population). The median age of patients was 59·0 years (IQR 49·0-63·0); 84 (47%) patients were female and 96 (53%) were male. With a median follow-up of 33·8 months (IQR 20·9-42·9), median progression-free survival was 59·1 months (95% CI 54·8-not estimable) in the carfilzomib, lenalidomide, and dexamethasone group versus 41·4 months (33·2-65·4) in the lenalidomide group (hazard ratio 0·51 [95% CI 0·31-0·86]; p=0·012). The most common grade 3 and 4 adverse events were neutropenia (44 [48%] in the carfilzomib, lenalidomide, and dexamethasone group vs 52 [60%] in the lenalidomide group), thrombocytopenia (12 [13%] vs six [7%]), and lower respiratory tract infections (seven [8%] vs one [1%]). Serious adverse events were reported in 28 (30%) patients in the carfilzomib, lenalidomide, and dexamethasone group and 19 (22%) in the lenalidomide group. One treatment-related adverse event led to death (respiratory failure due to severe pneumonia) in the carfilzomib, lenalidomide, and dexamethasone group., Interpretation: This interim analysis provides support for considering carfilzomib, lenalidomide, and dexamethasone therapy in patients with newly diagnosed multiple myeloma who completed any induction regimen followed by autologous stem-cell transplantation, which requires confirmation after longer follow-up of this ongoing phase 3 trial., Funding: Amgen and Celgene (Bristol Myers Squibb)., Competing Interests: Declaration of interests DD reports speaker honoraria and participation in advisory boards for Amgen and Celgene (Bristol Myers Squibb) and had conference fees paid by Amgen. TW reports honoraria from AbbVie, Amgen, BeiGene, Celgene (Bristol Myers Squibb), Gilead, GlaxoSmithKline, Janssen-Cilag, Novartis, Pfizer, Roche, and Takeda; conference fees or travel support (or both) from AbbVie, Amgen, Celgene (Bristol Myers Squibb), Gilead, GlaxoSmithKline, Janssen-Cilag, Pfizer, Roche, and Takeda; and advisory board participation for AbbVie, Amgen, BeiGene, Celgene (Bristol Myers Squibb), Gilead, GlaxoSmithKline, Janssen-Cilag, Pfizer, Roche, Novartis, and Takeda. KJ reports grants paid to his institution and payment for expert testimony from Janssen; honoraria from Amgen, Celgene (Bristol Myers Squibb), GlaxoSmithKline, Janssen, Sandoz, and Takeda; financial support for attending meetings or travel support (or both) from Amgen, Celgene, and Janssen; and consulting and advisory board participation for Amgen, Celgene (Bristol Myers Squibb), Janssen, Sandoz, and Takeda. TK reports honoraria from AbbVie and Celgene (Bristol Myers Squibb) and financial support for attending meetings or travel support (or both) from Sanofi. AD-S reports honoraria for presentations and lectures from Amgen and Celgene (Bristol Myers Squibb); and financial support for attending meetings or travel support (or both) and advisory board participation from Celgene (Bristol Myers Squibb). KrG reports honoraria from Amgen and Celgene (Bristol Myers Squibb). AN reports fees for lectures and presentations from Amgen, Celgene (Bristol Myers Squibb), and Janssen; and financial support for attending meetings or travel support (or both) from Amgen, Celgene (Bristol Myers Squibb), Janssen, and Teva. BP reports grants or contracts from AbbVie, Amgen, Celgene (Bristol Myers Squibb), and Janssen; consultation fees from AbbVie, Roche, and Sandoz; honoraria for lectures and presentations from AbbVie, Amgen, Celgene (Bristol Myers Squibb), and Janssen; and financial support for attending meetings or travel support (or both) from AbbVie and Celgene (Bristol Myers Squibb). JR reports speaker honoraria and advisory board participation from Amgen, Celgene (Bristol Myers Squibb), and Janssen. LU-Z reports financial support for attending meetings or travel support (or both) from Janssen. AK reports payment for clinical trial participation from Janssen. JMZ reports grants from Celgene (Bristol Myers Squibb); financial support for attending meetings or travel support (or both) from AbbVie and Takeda; and participation on a data safety monitoring board or advisory board for Amgen, Celgene (Bristol Myers Squibb), Roche, and Takeda. JW reports personal and institutional grants from GlaxoSmithKline, Novartis, and Roche; and personal consulting, lecture and presentation fees, speaker bureaus, and educational events fees from AbbVie, Gilead, Novartis, Roche, and Takeda. DM reports lecture and presentation fees from Amgen and Janssen. TR reports research grants from Amgen and Celgene (Bristol Myers Squibb). OBL reports participation on an advisory board for MorphoSys. JAZ reports an institutional grant from Celgene (Bristol Myers Squibb); personal consulting fees from Alnylam, Celgene (Bristol Myers Squibb), Janssen, Prothena, and Regeneron; and participation on an advisory board for Takeda. KeG reports personal payment for the statistical design of this study and consulting fees related to other studies from the University of Chicago. BAD reports consulting fees from COTA Healthcare, Janssen, and Sanofi; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing or educational events from MJH Life Sciences and Plexus Communications. AJJ reports consulting fees and honoraria for lectures and presentations from AbbVie, Amgen, Celgene (Bristol Myers Squibb), Gracell, GlaxoSmithKline, Janssen, and Sanofi-Aventis. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Monoclonal gammopathy of renal significance (MGRS) is a recognized clinical entity. Literature regarding treatment and its outcomes in MGRS is sparse due to the rarity and misdiagnosis of MGRS. We retrospectively analyzed 280 adults with an MGRS diagnosis from 2003 to 2020 across 19 clinical centers from 12 countries. All cases required renal biopsy for the pathological diagnosis of MGRS. Amyloidosis-related to MGRS (MGRS-A) was present in 180 patients; nonamyloidosis MGRS (MGRS-NA), including a broad spectrum of renal pathologies, was diagnosed in 100 patients. The median overall survival in the studied cohort was 121.0 months (95% CI: 105.0-121.0). Patients with MGRS-A had a shorter overall survival than patients with MGRS-NA (HR = 0.41, 95%CI: 0.25-0.69; p = 0.0007). Both hematologic and renal responses were associated with longer survival. Achievement of ≥VGPR was generally predictive of a renal response (OR = 8.03 95%CI: 4.04-115.96; p < 0.0001), one-fourth of patients with ≥VGPR were renal nonresponders. In MGRS-A, factors associated with poor prognosis included elevated levels of creatinine, beta-2-microglobulin, and hemodialysis at diagnosis. In MGRS-NA, only age >65 years was associated with increased risk of death. Treatments provided similar hematologic response rates in both types of MGRS. Autologous stem cell transplantation led to better response than other treatments. This multicenter and international effort is currently the largest report on MGRS., (© 2022 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

Multiple myeloma (MM) is an incurable disease and patients become refractory to the treatment in the course of the disease. Bendamustine-based regimens containing steroids and other agents are among the therapeutic options offered to MM patients. Here, we investigated the safety and the efficacy of bendamustine used in patients with refractory/relapsed MM (RRMM). The patients were treated with bendamustine and steroids ( n = 52) or bendamustine, steroids and immunomodulatory agents or proteasome inhibitors ( n = 53). Response rates, progression-free survival (PFS), overall survival (OS) and frequency of adverse events were compared between both study groups. Most efficacy measurements were better in patients treated with three-drug regimens: overall response rate (55% versus 37%, p = 0.062), median PFS (9 months versus 4 months, p < 0.001), median OS survival (18 months versus 12 months, p = 0.679). The benefit from combining bendamustine and steroids with an additional agent was found in subgroups previously treated with both lenalidmide and bortezomib, with stem cell transplant and with more than two previous therapy lines. Toxicity was similar in both study groups and bendamustine-based therapies were generally well-tolerated. Our study suggests that bendamustine may be an effective treatment for patients with RRMM. Three-drug regimens containing bendamustine, steroids and novel agents produced better outcomes and had acceptable toxicity. The efficacy of bendamustine combined with steroids was limited.

Unlike solid-tumor patients, a disappointingly small subset of multiple myeloma (MM) patients treated with checkpoint inhibitors derive clinical benefits, suggesting differential participation of inhibitory receptors involved in the development of T-cell-mediated immunosuppression. In fact, T cells in MM patients have recently been shown to display features of immunosenescence and exhaustion involved in immune response inhibition. Therefore, we aimed to identify the dominant inhibitory pathway in MM patients to achieve its effective control by therapeutic interventions. By flow cytometry, we examined peripheral blood (PB) CD4 T cell characteristics assigned to senescence or exhaustion, considering PD-1, CTLA-4, and BTLA checkpoint expression, as well as secretory effector function, i.e., capacity for IFN-γ and IL-17 secretion. Analyses were performed in a total of 40 active myeloma patients (newly diagnosed and treated) and 20 healthy controls. At the single-cell level, we found a loss of studied checkpoints' expression on MM CD4 T cells (both effector (Teff) and regulatory (Treg) cells) primarily at diagnosis; the checkpoint deficit in MM relapse was not significant. Nonetheless, PD-1 was the only checkpoint distributed on an increased proportion of T cells in all MM patients irrespective of disease phase, and its expression on CD4 Teff cells correlated with adverse clinical courses. Among patients, the relative defect in secretory effector function of CD4 T cells was more pronounced at myeloma relapse (as seen in declined Th1/Treg and Th17/Treg cell rates). Although the contribution of PD-1 to MM clinical outcomes is suggestive, our study clearly indicated that the inappropriate expression of immune checkpoints (associated with dysfunctionality of CD4 T cells and disease clinical phase) might be responsible for the sub-optimal clinical response to therapeutic checkpoint inhibitors in MM.

INTRODUCTION Despite the progress made in the treatment of multiple myeloma (MM), approximately 10% to 15% of patients die within the first year of diagnosis. OBJECTIVES The aim of the study was to determine risk factors of early mortality in patients with newly diagnosed MM treated with new drugs in clinical practice. PATIENTS AND METHODS This multicenter analysis included 197 patients with symptomatic MM, diagnosed between October 2006 and November 2019, with a survival of less than 12 months. RESULTS The median overall survival was 2.5 months. The most common causes of early mortality were infections (35%), MM progression (23.8%), and cardiovascular disease (14.2%). In a multivariable analysis, the Zubrod performance score (P = 0.02), history of cardiovascular disease (P = 0.04), dependence on renal dialysis (P = 0.03), and MM response (P <0.001) were associated with early mortality. CONCLUSIONS Early mortality in MM patients requires further studies. When qualifying patients with newly diagnosed MM for chemotherapy, it is necessary to consider performance status and the history of comorbidities, including cardiovascular diseases.

Background: Platelet reactivity and response to antiplatelet drugs, acetylsalicylic acid (ASA) and clopidogrel, in patients with thrombocytopenia and thrombocythemia can have a potentially important effect on the outcome. The effectiveness and safety of antiplatelet drugs in such patients has not been well examined. Measuring the effect of ASA and clopidogrel on platelets could help guide the therapy. Nevertheless, platelet response to antiplatelet drugs is not routinely measured in platelet count disorders and relevant evidence is scarce., Aims: The study aimed to measure platelet reactivity and response to ASA and clopidogrel in patients with platelet count disorders., Materials and Methods: This was a cross-sectional study of consecutive patients hospitalized in cardiology and hematology departments in the years 2018-2019. The study included patients with thrombocytopenia (PLT < 150 G/L) and thrombocythemia (PLT > 450 G/L) on ASA or dual antiplatelet therapy (DAPT; ASA plus clopidogrel). Controls included patients on antiplatelet drugs with normal platelet count. Platelet reactivity was measured in whole blood (Multiplate aggregometer, Roche, Switzerland) using arachidonic acid (AA), adenosine-5'-diphosphate (ADP), and thrombin receptor agonist peptide-6 (TRAP) as agonists. Platelet aggregation was expressed in arbitrary units (AU). AA-induced aggregation was used as a measure of response to ASA with a cut-off above 30 AU showing high on-treatment platelet reactivity to ASA (HTPR-A). ADP-induced aggregation measured response to clopidogrel with a cut-off above 48 AU for high on-treatment platelet reactivity to clopidogrel (HTPR-C). TRAP-induced aggregation measured baseline platelet reactivity not affected by oral antiplatelet drugs., Results: The study included 174 patients. There were 64 patients with thrombocytopenia, 30 patients with chronic thrombocythemia, and 80 controls. All patients were on 75 mg of ASA and 32% of them additionally on 75 mg of clopidogrel due to a history of recent coronary artery angioplasty. AA- and ADP-induced aggregation was comparable between thrombocytopenic patients and controls (median (IQR) 19 (7-28) vs. 23 (15-38) for AA AU and 32 (16-44) vs. 50 (32-71) for ADP AU, respectively), while it was significantly higher in thrombocythemic patients (median (IQR) 80 (79-118) for AA AU and 124 (89-139) for ADP AU). TRAP-induced aggregation showed significantly lowest aggregation in thrombocytopenic (median (IQR) 41 (34-60) for TRAP AU) and highest in thrombocythemic patients (median (IQR) 137 (120-180) for TRAP AU). HTPR-A was frequent in thrombocythemic patients in comparison with thrombocytopenic patients and controls (60% vs. 4% vs. 15%, respectively; p < 0.0002). HTPR-C was highly common in thrombocythemic patients and least common in thrombocytopenic ones in comparison with controls (80% vs. 8% vs. 40%, respectively; p < 0.001)., Conclusion: Chronic thrombocytopenia does not significantly affect platelet reactivity and response to ASA and clopidogrel in comparison with controls. Thrombocytosis significantly increases platelet reactivity and attenuates response to both ASA and clopidogrel., Competing Interests: The authors declare that they have no conflicts of interest regarding the publication of this paper., (Copyright © 2021 Wiktor Kuliczkowski et al.)

Psoriasis (Ps), an autoimmune disease, and multiple myeloma (MM), a blood neoplasm, are characterized by immune dysregulation resulting from the imbalance between the effector and regulatory cells, including B regulatory (Breg) lymphocytes. Peripheral blood samples from 80 Ps patients, 17 relapsed/refractory MM patients before and after daratumumab (anti-CD38 monoclonal antibody) treatment, 23 healthy volunteers (HVs), and bone marrow samples from 59 MM patients were used in the study. Bregs were determined by flow cytometry using CD19, CD24, and CD38. Intracellular production of interleukin-10 (IL-10) was assessed by flow cytometry after CD40L, LPS, and CpG stimulation. IL-10 serum or plasma concentrations were tested using ELISA method. The percentage of CD19+CD24hiCD38hi Bregs was not different whereas the production of IL-10 in Bregs was significantly higher in Ps patients in comparison with HVs. The percentage of CD19+CD24hiCD38hi Bregs in MM patients was significantly higher than in HVs ( p < 0.0001). The percentage of CD19+CD24hiCD38hi Bregs was significantly higher in MM patients with the ISS stage I ( p = 0.0233) while IL-10 production in Bregs was significantly higher in ISS stage III (p = 0.0165). IL-10 serum or plasma concentration was significantly higher in Ps and MM patients when compared to HVs ( p < 0.0001). Following the treatment with daratumumab the percentages of CD19+CD24hiCD38hi Bregs significantly decreased ( p < 0.0003). Here, in the two opposite immune conditions, despite the differences in percentages of Bregs in Ps and MM we have identified some similarities in the IL-10 producing Bregs. Effective treatment of daratumumab besides the anti-myeloma effect was accompanied by the eradication of Bregs.

This study determined whether 85 patients with multiple myeloma (MM) double-refractory to primary induction therapy with triplet regimens had a homogenous prognosis. The overall response rate (ORR) after the second-line therapy was 51%. Patients who proceeded to immediate autologous stem cell transplantation (ASCT) had better ORR than those who received conventional therapies (62% vs. 31%). The ORR for patients who had ASCT directly after the frontline therapy was higher than for those treated with other regimens as the second line therapy (91% vs. 45%) and offered ASCT as the third-line therapy (91% vs. 55%). The median progression-free survival (PFS) after the second-line therapy and median overall survival were 21.6 months and 35.6 months, respectively. ASCT after the second line treatment (HR = 0.24) was an independent predictor of PFS. Eligible patients with primary refractory MM achieve the most benefit from ASCT, also performed immediately after first line induction therapy.

Background: Platelets are key players in hemostasis. These blood cells contain different types of granules. Recently, there has been a growing interest in the role of inorganic polyphosphate (polyP) structures stored in dense granules of platelets and secreted during platelet activation., Objectives: To measure platelet polyP levels in patients with thrombocytopenia and thrombocythemia, and to examine the relationship of this indicator with platelet aggregation., Material and Methods: The study included 36 patients with hematological disorders (26 with primary chronic thrombocytopenia and 10 with essential thrombocythemia (ET)) and 40 healthy subjects. Platelet reactivity was measured using whole blood impedance aggregometry. The polyP levels were isolated from lysed platelets, which were obtained from citrated platelet-rich plasma. The procedure included inactivating endogenous phosphatases, removing phosphate units derived from DNA and proteins, and finally hydrolyzing them into monophosphate units. A colorimetric assay using malachite green and ammonium molybdate was performed in order to quantify polyP levels., Results: The polyP concentrations were significantly higher in the patients with thrombocytopenia than in the patients with thrombocythemia or the controls. The polyP level was not correlated with the level of aggregation., Conclusions: The higher polyP levels observed in the patients with low platelet counts may indicate the existence of a compensatory mechanism that prevents excessive bleeding in such patients. Our study provides evidence of an essential role of polyP in platelet function and the coagulation process.

The MAF translocations, t(14;16) and t(14;20), are considered as adverse prognostic factors based on few studies with small sample sizes. We report on their prognostic impact in a large group of 254 patients - 223 (87.8%) with t(14;16) and 31 (12.2%) with t(14;20). There were no intergroup differences in survival estimates. Median progression-free survival was 16.6 months for t(14;16) and 24.9 months for t(14;20) ( p  = 0.28). Median overall survival (OS) was 54.0 months and 49.0 months, respectively ( p  = 0.62). Median OS in patients who underwent double autologous stem cell transplantation (ASCT) was 107.0 months versus 60.0 months in patients who received single ASCT ( p  < 0.001). ISS 3 was associated with shorter OS (HR = 1.89; 95% CI 1.24-3.19; p  = 0.005) in Cox analysis. Our study suggests that t(14;20) should be considered as an adverse factor of equal prognostic implication to t(14;16).

The t(14;16) translocation, found in 3%-5% of newly diagnosed (ND) multiple myeloma (MM), has been associated with adverse outcomes. However, the studies establishing the characteristics of t(14;16) included solely small cohorts. The goal of the current international, multicenter (n = 25 centers), retrospective study was to describe the characteristics and outcomes of t(14;16) patients in a large, real-world cohort (n = 223). A substantial fraction of patients had renal impairment (24%) and hemoglobin <10 g/dL (56%) on initial presentation. Combined therapy of both immunomodulatory drug and proteasome inhibitor (PI) in the first line was used in 35% of patients. Autologous stem cell transplantation was performed in 42% of patients. With a median follow up of 4.1 years (95% CI 3.7-18.7), the median progression-free survival (PFS) and overall survival (OS) from first line therapy were 2.1 years (95% CI 1.5-2.4) and 4.1 years (95% CI 3.3-5.5), respectively. Worse OS was predicted by age > 60 years (HR = 1.65, 95% CI [1.05-2.58]), as well as revised International Scoring System (R-ISS) 3 (vs R-ISS 2; HR = 2.59, 95% CI [1.59-4.24]). In conclusion, based on the largest reported cohort of t(14;16) patients, quarter of this subset of MM patients initially presents with renal failure, while older age and the R-ISS 3 predict poor survival., (© 2020 Wiley Periodicals, Inc.)

Introduction: Deletion of chromosome 17p [del(17p)] in patients with multiple myeloma is associated with a poor prognosis. High‑dose chemotherapy followed by autologous stem cell transplantation (ASCT) remains the standard of treatment in this population., Objectives: The aim of the study was to compare the treatment outcomes with high‑dose chemotherapy and ASCT with standard treatment in patients with del(17p)., Patients and Methods: We collected data from 12 Polish centers between 2011 and 2017. The records of 97 patients with p53 deletion were assessed, including 29 individuals treated with ACST and 68 receiving standard treatment alone., Results: During the follow‑up, 45 patients died and the overall survival (OS) for the whole group was 33 months (range, 1-66 months), with a median progression‑free survival (PFS) of 13 months (range, 1-46 months). The prognostic factors of OS in a multivariable analysis were calcium levels at diagnosis within the reference range (hazard ratio [HR], 0.24; 95% CI, 0.12-0.48) and at least partial remission achieved after the first‑line treatment (HR, 0.25; 95% CI, 0.12-0.51). Treatment with ASCT was an important factor in improving survival (HR, 3.23; 95% CI, 1.52-6.84). Abnormal kidney function at the time of diagnosis reduced the PFS (HR, 0.46; 95% CI, 0.22-0.94). When the analysis was limited only to patients who could be candidates for ASCT, the survival benefit of the procedure was lost (P = 0.21)., Conclusions: Patients with multiple myeloma with del(17p) do not benefit from high‑dose chemotherapy followed by ACST.

The present retrospective analysis evaluated the efficacy and safety of the VTD (bortezomib, thalidomide, dexamethasone) regimen in 205 newly-diagnosed patients with multiple myeloma (MM) eligible for high dose therapy and autologous stem cell transplantation (HDT/ASCT) in routine clinical practice. With a median of 6 cycles (range, 1-8), at least partial response was achieved in 94.6% and at least very good partial response (VGPR) was achieved in 67.8% of patients. Peripheral neuropathy (PN) grade 2-4 was observed in 28.7% of patients. In 72% of patients undergoing stem cell mobilization one apheresis allowed the number of stem cells sufficient for transplantation to be obtained. Following HDT/ASCT the sCR rate increased from 4.9 to 14.4% and CR from 27.8 to 35.6%. The results demonstrated that VTD as an induction regimen was highly efficient in transplant eligible patients with MM with increased at least VGPR rate following prolonged treatment (≥6 cycles). Therapy exhibited no negative impact on stem cell collection, neutrophils and platelets engraftment following ASCT. Therapy was generally well tolerated and PN was the most common reason of dose reduction or treatment discontinuation., (Copyright: © Hus et al.)

The current study assesses the characteristics and outcomes of multiple myeloma (MM) patients, treated with novel agents for hematogenous extramedullary (HEMM) relapse. Consecutive patients diagnosed with HEMM between 2010-2018 were included. Patients' characteristics at diagnosis and at HEMM presentation, response to treatment, survival and factors predicting survival were recorded and analyzed. A group of 127 patients, all diagnosed with HEMM by imaging (87.3%) and/or biopsy (79%), were included. Of those, 44% were initially diagnosed with ISS3, 57% presented with plasmacytomas, and 30% had high-risk cytogenetics. Median time to HEMM was 32 months. In multivariate analysis, ISS3 and bone plasmacytoma predicted shorter time to HEMM (P = .005 and P = .008, respectively). Upfront autograft was associated with longer time to HEMM (P = .002). At HEMM, 32% of patients had no BM plasmacytosis, 20% had non-secretory disease and 43% had light-chain disease. Multiple HEMM sites were reported in 52% of patients, mostly involving soft tissue, skin (29%), and pleura/lung (25%). First treatment for HEMM included proteasome inhibitors (50%), immunomodulatory drugs (IMiDs) (39%), monoclonal antibodies (10%), and chemotherapy (53%). Overall response rate (ORR) was 57%. IMiDs were associated with higher ORR (HR 2.2, 95% CI 1.02-4.7, P = .04). Median survival from HEMM was 6 months (CI 95% 4.8-7.2). Failure to achieve ≥VGPR was the only significant factor for worse OS in multivariate analyses (HR = 9.87, CI 95% 2.35 - 39, P = .001). In conclusion, HEMM occurs within 3 years of initial myeloma diagnosis and is associated with dismal outcome. The IMiDs might provide a higher response rate, and achievement of ≥VGPR predicts longer survival., (© 2019 Wiley Periodicals, Inc.)

Purpose: Daratumumab is a promising new agent for relapsed/refractory multiple myeloma (RRMM). However, there are limited data on its clinical activity and tolerability in the real-world patients. The purpose of this study is to determine the efficacy and toxicity profile of daratumumab monotherapy in the real-life setting., Patients and Methods: Thirty RRMM patients treated with daratumumab who had previously received at least three treatment lines including a proteasome inhibitor and an immunomodulatory drug or had been double refractory (DRMM) were included to the Polish Myeloma Group observational study., Results: The objective response rate to daratumumab was 42.8%. Median progression-free survival (PFS) and overall survival reached 9.5 and 13.8 months, respectively. Importantly, patients with DR-MM had a significantly shorter PFS than other patients (median PFS of 4.1 vs. 12.1 months). Daratumumab was generally well tolerated, however two patients had their therapy interrupted due to adverse events., Conclusion: Daratumumab monotherapy has significant activity and good tolerance in heavily pretreated RRMM patients., (Copyright © 2019 Medical University of Bialystok. Published by Elsevier B.V. All rights reserved.)

This multicenter retrospective study included 101 patients (median age 62 years) with secondary plasma cell leukemia (sPCL). The median time from initial multiple myeloma diagnosis to sPCL was 31 months. Fifty-five out of 72 patients (75%) who received any therapy were treated with immunomodulators (IMiDs) and/or proteasome inhibitors (PIs), and 14/72 (19%) underwent salvage autologous stem cell transplantation (ASCT). The overall response rate in patients who received ASCT or PI (either alone or in combination) was higher than in those who did not (93% vs. 36% and 60% vs. 30%, respectively). The median overall survival (OS) in patients who received therapy was 4.2 months (95% CI: 1.3; 8.0) with a 1-year OS of 19%. Platelet count ≤100 × 10 9 /L at sPCL diagnosis was the only independent predictor of a poorer OS in treated patients (HR = 3.98, p = .0001). These findings suggest that patients with sPCL may benefit from salvage ASCT- and PI-based regimens.

High-dose chemotherapy (HDC) followed by stem cell transplantation (HSCT) is a well-established method in patients with hematological malignancies, and for last few years, many efforts have been made to estimate short- and long-term efficacy of this method, as well as early and late complications. The present study concentrates on cardiotoxic effects, mainly early changes using biochemical markers such as N-terminal natriuretic peptide type B (NT-proBNP) and cardiac troponins (cTn). Simultaneously, the analysis of 12-lead ECG was done before and after the procedure in which the novel repolarization markers: T p-e and T p-e /QT ratio were measured, together with standard markers: QT, QTc. It was found that NT-pro BNP was significantly increased after HSCT in comparison to results before it, and no significant changes were present in Troponin levels. Simultaneously, T p-e interval and T p-e /QT ratio were significantly higher after HSCT. The use of cyclophosphamide, advanced age, and higher level of blood cholesterol concentration were risk factors for the increase in NT-proBNP and treatment with cyclophosphamide as well as fludarabine and higher creatinine levels were risk factors for the increase in T p-e /QT ratio. In conclusion, in the early term evaluation after HSCT in patients with no previously diagnosed heart disease, the mild changes in markers of heart overload and repolarization were noted. The observations suggest that in all patients undergoing HSCT, even the ones without pre-existing cardiovascular disease, the evaluation, and monitoring of heart function should be considered.

Background: Hematopoietic stem cell transplantation (HSCT) is a widely used procedure in the treatment of malignant diseases, including blood neoplasms and has increased survival in hematological diseases. The aim of the study was to analyze parameters of 24-hr ECG monitoring in patients with selected blood neoplasms in whom the procedure of hematopoietic stem cell transplantation was performed., Methods: The study group consisted of 64 adults diagnosed with hematologic cancer qualified for HSCT with the previous high dose chemotherapy (HDC). In all patients 24-hr Holter monitoring was carried out twice. First examination took place prior to the HSCT procedure, and the second after finishing the procedure of HSCT., Results: The minimal and mean heart rate (HR min and HR max) from 24-hr ECG recording was statistically significantly higher after the transplantation in comparison with the first test. The number of premature ventricular complexes (PVCs) was higher in the test after HSCT. In the second examination there was significantly higher percentage of premature ventricular complexes, incidents of tachycardia, and Mobitz type 1 second degree atrioventricular block. In regression analysis, in a group of patients with blood neoplasms after HSCT and HDC, administration of cyclophosphamide, fludarabine and total body irradiation were independent risk factors for electrocardiographic abnormalities in 24-hr Holter monitoring, that is, the increase in HR min, HR mean and PVCs., Conclusion: In patients with blood neoplasms undergoing HSCT more electrocardiographic abnormalities may be found after this procedure in comparison with the 24-hr Holter monitoring before transplantation., (© 2018 Wiley Periodicals, Inc.)