Higher Mortality in Patients With Diffuse Large B-cell Lymphoma Pre-Existing Arterial Hypertension-Real World Data of the Polish Lymphoma Research Group.

BACKGROUND: Arterial hypertension is mentioned as a risk factor in Cardio-oncology. This study aimed to assess the long-term prognostic value of arterial hypertension (AH) in diffuse large B-cell lymphoma (DLBCL). METHODS: We analysed data collected by the Polish Lymphoma Research Group for the evaluation of the outcomes associated with the use of first-line rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone therapy in patients with DLBCL with coexisting AH. Patients with other cardiovascular comorbidities or premature chemotherapy discontinuation due to cardiovascular toxicity were excluded. RESULTS: Pre-existing AH was diagnosed in 65 of 232 patients with DLBCL (28%) included in the study, and was associated with significantly shorter overall survival values (p<0.00001). The rates of DLBCL recurrence, administration of second-, third-, or fourth-line chemotherapy, and lymphoma-related deaths were similar in patients with and those without AH. Cardiovascular deaths were significantly more frequently observed in patients with pre-existing AH (38.5% vs 3.6%, p<0.0001). In the univariate analysis, AH (p=0.000001), older age (p<0.000001), and diabetes (p=0.0065) were identified as significant predictors of all-cause mortality; however, cardiovascular mortality was associated with AH (p<0.000001), older age (p=0.000008), and dyslipidaemia (p=0.03). Multivariate analysis revealed AH as an age-independent significant predictor of all-cause (p=0.00045) and cardiovascular mortality (p<0.000001). CONCLUSION: In the long-term follow-up of patients with DLBCL, the role of AH, as an important age-independent predictor of premature cardiovascular mortality, was so strong that it may have value for use in close surveillance in cardio-oncology clinics.

Outcomes of Modified Mayo Stage IIIa and IIIb Cardiac Light-Chain Amyloidosis: Real-World Experience in Clinical Characteristics and Treatment-67 Patients Multicenter Analysis.

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.

Rheological properties of blood in multiple myeloma patients.

Multiple myeloma (MM) is considered to be one of the hematological malignancies formed by excessive and abnormal proliferation of plasmocytes. Among other parameters, several blood tests are used to diagnose multiple myeloma. The hemorheological profile in multiple myeloma is not widely studied. Hemorheology includes the study of measuring the deformability and aggregation of erythrocytes, blood viscosity, and sedimentation rate. The degree of deformability of blood cells is necessary to maintain proper vital functions. Proper deformability of red blood cells ensures proper blood circulation, tissue oxidation and carbon dioxide uptake. The aim of the study was to compare morphology and blood rheology parameters in patients with MM and healthy individuals. The study included 33 patients with MM, and 33 healthy subjects of the same age. The hematological blood parameters were evaluated using ABX MICROS 60 hematology analyzer. The LORCA Analyzer to study erythrocyte aggregation and deformability. Patients with MM had lower red blood cells count (RBC) (9.11%) (p < 0.001) and half time of total aggregation (T1/2) (94.29%) (p < 0.001) values and higher mean corpuscular volume (MCV) (5.50%) (p < 0.001), aggregation index (AI) (68.60%) (p < 0.001), total extent of aggregation (AMP) (87.92%) (p < 0.001) values than the healthy control group. Aggregation in patients with MM is different compared to healthy individuals. It was observed that the percentage of cell aggregation is almost 50% higher than in the control group. The study of morphology, aggregation and deformability of erythrocytes in patients with suspected MM may be helpful in making clinical decisions.

Daratumumab, Bortezomib, Lenalidomide, and Dexamethasone for Multiple Myeloma.

BACKGROUND: Daratumumab, a monoclonal antibody targeting CD38, has been approved for use with standard myeloma regimens. An evaluation of subcutaneous daratumumab combined with bortezomib, lenalidomide, and dexamethasone (VRd) for the treatment of transplantation-eligible patients with newly diagnosed multiple myeloma is needed. METHODS: In this phase 3 trial, we randomly assigned 709 transplantation-eligible patients with newly diagnosed multiple myeloma to receive either subcutaneous daratumumab combined with VRd induction and consolidation therapy and with lenalidomide maintenance therapy (D-VRd group) or VRd induction and consolidation therapy and lenalidomide maintenance therapy alone (VRd group). The primary end point was progression-free survival. Key secondary end points were a complete response or better and minimal residual disease (MRD)-negative status. RESULTS: At a median follow-up of 47.5 months, the risk of disease progression or death in the D-VRd group was lower than the risk in the VRd group. The estimated percentage of patients with progression-free survival at 48 months was 84.3% in the D-VRd group and 67.7% in the VRd group (hazard ratio for disease progression or death, 0.42; 95% confidence interval, 0.30 to 0.59; P<0.001); the P value crossed the prespecified stopping boundary (P = 0.0126). The percentage of patients with a complete response or better was higher in the D-VRd group than in the VRd group (87.9% vs. 70.1%, P<0.001), as was the percentage of patients with MRD-negative status (75.2% vs. 47.5%, P<0.001). Death occurred in 34 patients in the D-VRd group and 44 patients in the VRd group. Grade 3 or 4 adverse events occurred in most patients in both groups; the most common were neutropenia (62.1% with D-VRd and 51.0% with VRd) and thrombocytopenia (29.1% and 17.3%, respectively). Serious adverse events occurred in 57.0% of the patients in the D-VRd group and 49.3% of those in the VRd group. CONCLUSIONS: The addition of subcutaneous daratumumab to VRd induction and consolidation therapy and to lenalidomide maintenance therapy conferred a significant benefit with respect to progression-free survival among transplantation-eligible patients with newly diagnosed multiple myeloma. (Funded by the European Myeloma Network in collaboration with Janssen Research and Development; PERSEUS ClinicalTrials.gov number, NCT03710603; EudraCT number, 2018-002992-16.).

Efficacy and safety of melflufen plus daratumumab and dexamethasone in relapsed/refractory multiple myeloma: results from the randomized, open-label, phase III LIGHTHOUSE study.

Melphalan flufenamide (melflufen), a first-in-class alkylating peptide-drug conjugate, plus dexamethasone was approved in Europe for use in patients with triple-class refractory relapsed/refractory multiple myeloma (RRMM) with ≥3 prior lines of therapy and without prior autologous stem cell transplantation (ASCT) or with a time to progression >36 months after prior ASCT. The randomized LIGHTHOUSE study (NCT04649060) assessed melflufen plus daratumumab and dexamethasone (melflufen group) versus daratumumab in patients with RRMM with disease refractory to an immunomodulatory agent and a proteasome inhibitor or who had received ≥3 prior lines of therapy including an immunomodulatory agent and a proteasome inhibitor. A partial clinical hold issued by the US Food and Drug Administration for all melflufen studies led to financial constraints and premature study closure on February 23rd 2022 (data cut-off date). In total, 54 of 240 planned patients were randomized (melflufen group, N=27; daratumumab group, N=27). Median progression-free survival (PFS) was not reached in the melflufen group versus 4.9 months in the daratumumab group (Hazard Ratio: 0.18 [95% Confidence Interval, 0.05-0.65]; P=0.0032) at a median follow-up time of 7.1 and 6.6 months, respectively. Overall response rate (ORR) was 59% in the melflufen group versus 30% in the daratumumab group (P=0.0300). The most common grade ≥3 treatment-emergent adverse events in the melflufen group versus daratumumab group were neutropenia (50% vs. 12%), thrombocytopenia (50% vs. 8%), and anemia (32% vs. 19%). Melflufen plus daratumumab and dexamethasone demonstrated superior PFS and ORR versus daratumumab in RRMM and a safety profile comparable to previously published melflufen studies.

The Effect of a Six-Week Nordic Walking Training Cycle on Oxidative Damage of Macromolecules and Iron Metabolism in Older Patients with Multiple Myeloma in Remission-Randomized Clinical Trial.

Multiple myeloma (MM) is an incurable hematologic malignancy originating from clonal plasma cell proliferation within the bone marrow, predominantly affecting older individuals. While anemia serves as a diagnostic criterion for MM, it often ameliorates upon achieving disease remission. Iron metabolism parameters have emerged as potential prognostic indicators in MM. Notably, physical exercise has been established to influence iron metabolism. This study aimed to assess alterations in serum iron, ferritin, and transferrin concentrations, as well as leukocyte gene expression, in MM patients undergoing a six-week cycle of Nordic walking training. Thirty patients divided into an exercise group (NW, n = 15, mean age 63.1 ± 8.4 years) and a control group (CG, n = 15, mean age: 63.5 ± 3.6 years) completed the study protocol. Blood samples were collected at baseline, after three and six weeks of training, and after nine weeks. Serum ferritin, transferrin, and iron concentrations were measured, along with the leukocyte expression of genes. Additionally, serum oxidative damage marker levels were determined. Following the Nordic walking training cycle, a declining trend in serum ferritin concentrations was observed. Intracellular mRNA levels of genes associated with iron metabolism were positively influenced by the training regimen, indicating the potential impact of this physical activity on gene expression and ferritin concentrations. Although positive trends were noted, extended training periods might be requisite for significant changes. To conclude, moderate-intensity exercise induces favorable shifts in the analyzed parameters among MM patients, potentially influencing disease progression. Consequently, Nordic walking training is a safe recommendation for MM patients, though sustained training beyond six weeks could be necessary for notable effects on iron metabolism factors.

Outcome of Second Primary Malignancies Developing in Multiple Myeloma Patients.

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.

The Influence of Religiosity and Spirituality on the Quality of Life of Patients With Multiple Myeloma.

INTRODUCTION: The majority of patients with advanced neoplasms have religious/spiritual needs, and for most of them religion and/or spirituality is important. The psychology of religion and spirituality is one the forms of support offered to patients with advanced cancer. R/S are factors which impact health-related quality of life (HRQoL). The aim of this paper was to assess the influence of R/S on the HRQoL of patients diagnosed with MM. MATERIALS AND METHODS: The patients filled out anonymous questionnaires about R/S and the HRQoL scale. The clinical data were collected from medical records. RESULTS: The study sample consisted of 83 patients with MM (51.8% women), with a mean age of 64.9 years. The leading denomination among the respondents was Catholic (N = 83, 100%): 36% described themselves as deep believers (N = 30), 53% as believers (N = 44), and 11% as nonpracticing believers (N = 9). Most patients were receiving ongoing treatment (59.8%), while 40.2% were in remission from the disease. Patients in remission declared a significantly higher interest in R/S issues than patients in active treatment and had a higher rate of intrapsychic R/S struggles dominated by anxiety and guilt. A moderate negative correlation between interest in R/S issues and unfavorable assessment of physical functioning and role functioning was observed. Anger towards God positively correlated with a negative assessment of emotional functioning. CONCLUSIONS: The findings highlight the importance of R/S for the HRQoL of MM patients and show that their QoL depends on the types of R/S coping used.

Therapeutic adherence and assessment of satisfaction patients with multiple myeloma treated with immunomodulatory drugs in a "real-world" study: Experiences of the Polish Myeloma Group.

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.

The Real-World Evidence on the Fragility and Its Impact on the Choice of Treatment Regimen in Newly Diagnosed Patients with Multiple Myeloma over 75 Years of Age.

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.

Increased oxidative stress response in circulating blood of systemic sclerosis patients - relation to disease characteristics and inflammatory blood biomarkers.

BACKGROUND: Systemic sclerosis (SSc) is a rare connective tissue disorder of unknown etiology characterized by organ fibrosis and microcirculation dysfunction. Emerging evidence suggests that SSc is related to increased oxidative stress, which contributes to further tissue and vascular damage. METHODS: Oxidative stress response in the peripheral blood was assessed in patients with SSc (n = 55) and well-matched controls (n = 44) using real-time monitoring of protein hydroperoxide (HP) formation by the coumarin boronic acid (CBA) assay. We also analyzed the relationship between HP generation and SSc clinics, systemic inflammation, and cellular fibronectin, an emerging biomarker of endothelial damage. RESULTS: SSc was characterized by a significantly faster (2-fold) fluorescent product generation in the CBA assay and higher cumulative HP formation (3-fold) compared to controls (p<0.001, both). The dynamics of HP generation were not associated with the form of the disease (diffuse vs. limited SSc), current immunosuppressive therapy use, presence of abnormal nailfold capillaries, and autoantibody profile. Still, it was enhanced in patients with more severe illness and certain clinical manifestations (i.e., pulmonary hypertension, digital ulcers, and cyclophosphamide treatment) and in smokers (current or past). Higher serum CRP, blood eosinophil count, and cellular fibronectin with lower hemoglobin levels were independent determinants of increased HP formation. CONCLUSIONS: Our data indicate a pro-oxidant imbalance in SSc, likely related to systemic inflammation and endothelial injury. However, extensive prospective studies are needed to verify whether it is also associated with clinical disease progression.

Polymorphisms within Autophagy-Related Genes as Susceptibility Biomarkers for Multiple Myeloma: A Meta-Analysis of Three Large Cohorts and Functional Characterization.

Multiple myeloma (MM) arises following malignant proliferation of plasma cells in the bone marrow, that secrete high amounts of specific monoclonal immunoglobulins or light chains, resulting in the massive production of unfolded or misfolded proteins. Autophagy can have a dual role in tumorigenesis, by eliminating these abnormal proteins to avoid cancer development, but also ensuring MM cell survival and promoting resistance to treatments. To date no studies have determined the impact of genetic variation in autophagy-related genes on MM risk. We performed meta-analysis of germline genetic data on 234 autophagy-related genes from three independent study populations including 13,387 subjects of European ancestry (6863 MM patients and 6524 controls) and examined correlations of statistically significant single nucleotide polymorphisms (SNPs; p < 1 × 10-9) with immune responses in whole blood, peripheral blood mononuclear cells (PBMCs), and monocyte-derived macrophages (MDM) from a large population of healthy donors from the Human Functional Genomic Project (HFGP). We identified SNPs in six loci, CD46, IKBKE, PARK2, ULK4, ATG5, and CDKN2A associated with MM risk (p = 4.47 × 10-4-5.79 × 10-14). Mechanistically, we found that the ULK4rs6599175 SNP correlated with circulating concentrations of vitamin D3 (p = 4.0 × 10-4), whereas the IKBKErs17433804 SNP correlated with the number of transitional CD24+CD38+ B cells (p = 4.8 × 10-4) and circulating serum concentrations of Monocyte Chemoattractant Protein (MCP)-2 (p = 3.6 × 10-4). We also found that the CD46rs1142469 SNP correlated with numbers of CD19+ B cells, CD19+CD3- B cells, CD5+IgD- cells, IgM- cells, IgD-IgM- cells, and CD4-CD8- PBMCs (p = 4.9 × 10-4-8.6 × 10-4) and circulating concentrations of interleukin (IL)-20 (p = 0.00082). Finally, we observed that the CDKN2Ars2811710 SNP correlated with levels of CD4+EMCD45RO+CD27- cells (p = 9.3 × 10-4). These results suggest that genetic variants within these six loci influence MM risk through the modulation of specific subsets of immune cells, as well as vitamin D3-, MCP-2-, and IL20-dependent pathways.

POEMS Syndrome-Clinical Picture and Management. Current Knowledge.

POEMS syndrome is a rare form of plasma cell dyscrasia. Difficulties arise already at the stage of making the diagnosis (complex and heterogeneous clinical picture) and continue during the course of treatment (lack of guidelines for therapy, data coming mainly from reports and short series of patients). In this article we review the current state of knowledge on POEMS syndrome diagnostics, clinical characteristics, prognosis, reported treatment outcomes and the emergence of the new therapeutic strategies.

A Stepwise Screening Protocol for Multiple Myeloma.

BACKGROUND: Monoclonal gammopathies and multiple myeloma should be screened in the primary care setting. METHODS: The screening strategy consisted of an initial interview supported with the analysis of basic laboratory test results and the increasing laboratory workload in the following steps was developed based on characteristics of patients with multiple myeloma. RESULTS: The developed 3-step screening protocol includes evaluation of myeloma-related bone disease, two renal function markers, and three hematologic markers. In the second step, the erythrocyte sedimentation rate (ESR) and the level of C-reactive protein (CRP) were cross-tabulated to identify persons qualifying for confirmation of the presence of monoclonal component. Patients with diagnosed monoclonal gammopathy should be referred to a specialized center to confirm the diagnosis. The screening protocol testing identified 900 patients with increased ESR and normal level of CRP and 94 of them (10.4%) had positive immunofixation. CONCLUSIONS: The proposed screening strategy resulted in an efficient diagnosis of monoclonal gammopathy. The stepwise approach rationalized the diagnostic workload and cost of screening. The protocol would support primary care physicians, standardizing the knowledge about the clinical manifestation of multiple myeloma and the method of evaluation of symptoms and diagnostic test results.

The Current State of Knowledge About Evolution of Multiple Myeloma to Plasma Cell Leukemia.

Plasma cell leukemia is a rare form of multiple myeloma (MM). In contrast to de novo primary plasma cell leukemia (pPCL), which is very uncommon presentation of MM, there is increasing frequency of transformation to secondary plasma cell leukemia (sPCL) with increasing survival of patients (MM). The molecular basis of sPCL remains poorly understood sPCL is particularly aggressive and is associated with an extremely poor prognosis, constituting a major unmet medical need. High-quality data in sPCL regarding presentation, treatment and outcomes is limited. Herein we review the current state of knowledge on sPCL diagnostics, molecular biology, clinical characteristics, prognosis and reported treatment outcomes and the emergence of the new therapeutic strategies.

More Than 2% of Circulating Tumor Plasma Cells Defines Plasma Cell Leukemia-Like Multiple Myeloma.

PURPOSE: Primary plasma cell leukemia (PCL) is the most aggressive monoclonal gammopathy. It was formerly characterized by ≥ 20% circulating plasma cells (CTCs) until 2021, when this threshold was decreased to ≥ 5%. We hypothesized that primary PCL is not a separate clinical entity, but rather that it represents ultra-high-risk multiple myeloma (MM) characterized by elevated CTC levels. METHODS: We assessed the levels of CTCs by multiparameter flow cytometry in 395 patients with newly diagnosed transplant-ineligible MM to establish a cutoff for CTCs that identifies the patients with ultra-high-risk PCL-like MM. We tested the cutoff on 185 transplant-eligible patients with MM and further validated on an independent cohort of 280 transplant-ineligible patients treated in the GEM-CLARIDEX trial. The largest published real-world cohort of patients with primary PCL was used for comparison of survival. Finally, we challenged the current 5% threshold for primary PCL diagnosis. RESULTS: Newly diagnosed transplant-ineligible patients with MM with 2%-20% CTCs had significantly shorter progression-free survival (3.1 v 15.6 months; P < .001) and overall survival (14.6 v 33.6 months; P = .023) than patients with < 2%. The 2% cutoff proved to be applicable also in transplant-eligible patients with MM and was successfully validated on an independent cohort of patients from the GEM-CLARIDEX trial. Most importantly, patients with 2%-20% CTCs had comparable dismal outcomes with primary PCL. Moreover, after revealing a low mean difference between flow cytometric and morphologic evaluation of CTCs, we showed that patients with 2%-5% CTCs have similar outcomes as those with 5%-20% CTCs. CONCLUSION: Our study uncovers that ≥ 2% CTCs is a biomarker of hidden primary PCL and supports the assessment of CTCs by flow cytometry during the diagnostic workup of MM.

A pleiotropic variant in DNAJB4 is associated with multiple myeloma risk.

Pleiotropy, which consists of a single gene or allelic variant affecting multiple unrelated traits, is common across cancers, with evidence for genome-wide significant loci shared across cancer and noncancer traits. This feature is particularly relevant in multiple myeloma (MM) because several susceptibility loci that have been identified to date are pleiotropic. Therefore, the aim of this study was to identify novel pleiotropic variants involved in MM risk using 28 684 independent single nucleotide polymorphisms (SNPs) from GWAS Catalog that reached a significant association (P < 5 × 10-8 ) with their respective trait. The selected SNPs were analyzed in 2434 MM cases and 3446 controls from the International Lymphoma Epidemiology Consortium (InterLymph). The 10 SNPs showing the strongest associations with MM risk in InterLymph were selected for replication in an independent set of 1955 MM cases and 1549 controls from the International Multiple Myeloma rESEarch (IMMEnSE) consortium and 418 MM cases and 147 282 controls from the FinnGen project. The combined analysis of the three studies identified an association between DNAJB4-rs34517439-A and an increased risk of developing MM (OR = 1.22, 95%CI 1.13-1.32, P = 4.81 × 10-7 ). rs34517439-A is associated with a modified expression of the FUBP1 gene, which encodes a multifunctional DNA and RNA-binding protein that it was observed to influence the regulation of various genes involved in cell cycle regulation, among which various oncogenes and oncosuppressors. In conclusion, with a pleiotropic scan approach we identified DNAJB4-rs34517439 as a potentially novel MM risk locus.

Effect of a 6-Week Cycle of Nordic Walking Training on Vitamin 25(OH)D3, Calcium-Phosphate Metabolism and Muscle Damage in Multiple Myeloma Patients-Randomized Controlled Trial.

Introduction: Multiple myeloma (MM) is a hematological malignancy affecting older adults. One of the most common myeloma-defining events is the development of symptomatic lytic bone disease. The serum concentrations of calcium (Ca), inorganic phosphorus (P), and vitamin 25(OH)D3 in the serum reflect bone metabolism. An enzyme lactate dehydrogenase (LDH) is a marker of muscle damage, but its serum activity also has an important prognostic value in MM. Myoglobin (Mb) is a small protein present in muscles; its serum level increases when myocytes are damaged. Objectives: In this study, the impact of a 6-week Nordic walking (NW) exercise program on blood parameters related to calcium-phosphate metabolism and damage of skeletal muscles was assessed. Patients and methods: A total of 33 patients with MM in the remission stage, without cytostatic treatment, were allocated and randomly assigned to one of two groups: 17 in the training group (NW) and 16 in the control group (CG). All patients were supplemented per os with vitamin D3 and calcium carbonate daily and received zoledronic acid every 4 weeks (intravenous). Nordic walking training sessions took place 3 times a week for 6 weeks, 1 h each. Blood samples were drawn before and after the 6 weeks of training sessions to assess the serum concentrations of vitamin 25(OH)D3, P, Ca, Mb, and LDH. Results: Patients from the NW group showed a statistically significant decrease in mean serum myoglobin concentration (p = 0.018) and an increase in 25(OH)D3 (p < 0.001) and total Ca (p = 0.001) concentrations. There were no statistically significant changes in the results obtained in CG. Between groups, after 6 weeks, Mb serum concentration was significantly lower in NW (p = 0.041), and 25(OH)D3 was higher (p < 0.001) compared to CG. There was a correlation between the changes in myoglobin, phosphorus, 25(OH)D3, and Ca concentrations after 6 weeks. Conclusions: NW training is a safe and beneficial form of physical exercise for patients with MM without inducing muscle damage. NW performed outside improves serum vitamin 25(OH)D3 concentration.

Does a Multiple Myeloma Polygenic Risk Score Predict Overall Survival of Patients with Myeloma?

BACKGROUND: Genome-wide association studies (GWAS) of multiple myeloma in populations of European ancestry (EA) identified and confirmed 24 susceptibility loci. For other cancers (e.g., colorectum and melanoma), risk loci have also been associated with patient survival. METHODS: We explored the possible association of all the known risk variants and their polygenic risk score (PRS) with multiple myeloma overall survival (OS) in multiple populations of EA [the International Multiple Myeloma rESEarch (IMMEnSE) consortium, the International Lymphoma Epidemiology consortium, CoMMpass, and the German GWAS] for a total of 3,748 multiple myeloma cases. Cox proportional hazards regression was used to assess the association between each risk SNP with OS under the allelic and codominant models of inheritance. All analyses were adjusted for age, sex, country of origin (for IMMEnSE) or principal components (for the others) and disease stage (ISS). SNP associations were meta-analyzed. RESULTS: SNP associations were meta-analyzed. From the meta-analysis, two multiple myeloma risk SNPs were associated with OS (P < 0.05), specifically POT1-AS1-rs2170352 [HR = 1.37; 95% confidence interval (CI) = 1.09-1.73; P = 0.007] and TNFRSF13B-rs4273077 (HR = 1.19; 95% CI = 1.01-1.41; P = 0.04). The association between the combined 24 SNP MM-PRS and OS, however, was not significant. CONCLUSIONS: Overall, our results did not support an association between the majority of multiple myeloma risk SNPs and OS. IMPACT: This is the first study to investigate the association between multiple myeloma PRS and OS in multiple myeloma.