Do Alarmins Have a Role in Multiple Myeloma?

Objective: Calprotectin (CLP), S100A6, and High Mobility Group Nucleosome-Binding Protein 1 (HMGN1), known as alarmins, are involved in the pathogenesis of many tumors. In this study, we aimed to inve stigate the relationship of serum CLP, S100A6, and HMGN1 levels with clinical and laboratory findings in Multiple Myeloma (MM) patients and their role in the pathogenesis of MM. Materials and Methods: We measured serum CLP, S100A6, and HMGN1 levels in 55 newly diagnosed patients and 32 healthy controls (HC). Results: We determined significantly decreased serum CLP, S100A6 ve HMGN1 levels in MM patients compared to HC (p=0.012, p=0.001, p=0.030, respectively). ROC analysis was used to determine a diagnostic cut-off value for serum CLP, S100A6 and HMGN1; the cut off value for CLP was <98 ng/ml (AUC = 0.663, 95% CI 0.554-0.761, p=0.009), S100A6 was <1174.5 pg/ml (AUC = 0.706, 95% CI 0.598-0.799, p=0.001), and HMGN1 was <440.18 pg/ml (AUC = 0.640, 95% CI 0.530-0.740, p:0.03). CLP level was found to be statistically significantly in light chain MM patients ( 91.58±22.57) higher than in heavy chain MM patients (79.42±15.83) (p=0.03). A negative correlation was observed between CLP and M protein, IgG, globulin, and beta 2 microglobulin (correlation coefficient: -0,361; -0,370; -0,279; -0,300, p=0,024, p=006, p=0,04, p=0,0033). Conclusion: In this study, we found that serum CLP, S100A6, and HMGN1 levels were statistically lower in newly diagnosed MM patients compared to HC. These results suggest that CLP may binds to the paraprotein produced by heavy chain MM in the blood and therefore its blood levels are found to be low. Additionally, low levels of HMGN1, which is involved in DNA repair, suggest that HMGN1 may contribute to the complex genetic abnormalities found in MM.

Experience of Daratumumab in Relapsed/Refractory Multiple Myeloma: A Multicenter Study from Türkiye

Objective: This study aimed to evaluate patients with relapsed/refractory multiple myeloma (RRMM) who underwent daratumumab (DARA) therapy. Materials and Methods: This multicenter retrospective study included 134 patients who underwent at least two courses of DARA from February 1, 2018, to April 15, 2022. Epidemiological, disease, and treatment characteristics of patients and treatment-related side effects were evaluated. Survival analysis was performed. Results: The median age at the start of DARA was 60 (range: 35-88), with 56 patients (41.8%) being female and 48 (58.2%) being male. The median time to initiation of DARA and the median follow-up time were 41.2 (5.1-223) and 5.7 (2.1-24.1) months, respectively. The overall response rate after DARA therapy was 75 (55.9%), and very good partial response or better was observed in 48 (35.8%) patients. Overall survival (OS) and progression-free survival (PFS) for all patients were 11.6 (7.8-15.5) and 8.0 (5.1-10.9) months, respectively. OS was higher for patients undergoing treatment with DARA and bortezomib-dexamethasone (DARA-Vd) compared to those undergoing treatment with DARA and lenalidomide-dexamethasone (DARA-Rd) (16.9 vs. 8.3 months; p=0.014). Among patients undergoing DARA-Rd, PFS was higher in those without extramedullary disease compared to those with extramedullary disease (not achieved vs. 3.7 months; odds ratio: 3.4; p<0.001). The median number of prior therapies was 3 (1-8). Initiation of DARA therapy in the early period provided an advantage for OS and PFS, although it was statistically insignificant. Infusion-related reactions were observed in 18 (13.4%) patients. All reactions occurred during the first infusion and most reactions were of grade 1 or 2 (94.5%). The frequency of neutropenia and thrombocytopenia was higher in the DARA-Rd group (61.9% vs. 24.7%, p<0.001 and 42.9% vs. 15.7%, p<0.001). Conclusion: Our study provides real-life data in terms of DARA therapy for patients with RRMM and supports the early initiation of DARA therapy.

Correction to: Efects of AGEs, sRAGE and HMGB1 on Clinical Outcomes in Multiple Myeloma.

[This corrects the article DOI: 10.1007/s12288-022-01574-6.].

Effects of AGEs, sRAGE and HMGB1 on Clinical Outcomes in Multiple Myeloma.

Purpose: The receptor for advanced glycation end products (RAGE) upregulated during the onset and progression of cancer and bone-related pathologies. In this study, we aimed to investigate the role of serum advanced glycation end products (AGEs), soluble RAGE (sRAGE) and high mobility group box 1 (HMGB1), in multiple myeloma (MM). Methods: AGEs, sRAGE and HMGB1 concentrations of 54 newly diagnosed MM patients and 30 healthy volunteers were measured by ELISA. The estimations were done only once at diagnosis. The medical records of the patients were evaluated. Results: There was no significant difference between the AGEs and sRAGE levels between the patient and control groups (p = 0.273, p = 0.313). In ROC analysis, a HMGB1 cutoff value of > 9170 pg/ml accurately discriminated MM patients (AUC = 0.672, 95% CI 0.561-0.77, p = 0.0034). AGEs level was found to be significantly higher in early-stage disease and HMGB1 in advanced disease (p = 0.022, p = 0.026). High HMGB1 levels were detected in patients whose with better first-line treatment response (p = 0.019). At 36 months, 54% of patients with low AGE were alive, compared to 79% of patients with high AGE (p = 0.055). Patients with high HMGB1 levels tended to have a longer PFS (median 43 mo [95% CI; 20.68-65.31] ) compared to patients with low HMGB1 levels (median 25 mo [95% CI; 12.39-37.6], p = 0.054). Conclusion: In this study, a significant elevation of serum HMGB1 level was found in MM patients. In addition, the positive effects of RAGE ligands on treatment response and prognosis were determined.

Long-Term Efficacy of Erythropoiesis-Stimulating Agents in Patients with Low-Risk or Intermediate-1-Risk Myelodysplastic Syndrome: Multicenter Real-Life Data

Objective: This study was undertaken to evaluate the long-term clinical efficacy of epoetin alfa and darbepoetin alfa in patients with myelodysplastic syndrome (MDS) in a real-life setting. Materials and Methods: A total of 204 patients with low-risk or intermediate-1-risk MDS who received epoetin alfa or darbepoetin alfa were included. Hemoglobin levels and transfusion needs were recorded before treatment and at 12 months, 24 months, 36 months, and 48 months of treatment. Results: At the 36-month (p=0.025) and 48-month (p=0.022) visits, epoetin alfa yielded significantly higher hemoglobin levels compared to darbepoetin alfa. Transfusion needs were also significantly lower with epoetin alfa compared to darbepoetin alfa at 24 months (p=0.012) and in the low-risk group compared to the intermediate-risk group at 24 months (p=0.018), 36 months (p=0.025), and 48 months (p<0.001). Treatment response rates at the 24-month, 36-month, and 48-month visits in the epoetin alfa (43.0%, 33.6%, and 27.1%), darbepoetin alfa (29.9%, 22.7%, and 16.5%), low-risk (39.3%, 30.0%, and 26.0%), and intermediate-risk (29.6%, 24.1%, and 11.1%) groups were lower than those obtained at 12 months, and the values differed significantly for the 36-month and 48-month visits with values ranging from p<0.05 to p<0.001. Conclusion: This real-life long-term ESA extension study investigated the clinical efficacy of epoetin alfa and darbepoetin alfa for up to 48 months, revealing that treatment efficacy reached a plateau starting from the 24th month of therapy with a continuing decrease in treatment response rates regardless of treatment type, risk status, or gender. Nonetheless, significantly higher hemoglobin levels and marked improvement in transfusion needs were evident in epoetin-treated patients compared to darbepoetin-treated patients and in the low-risk group compared to the intermediate-risk group.

Programmed Cell Death Ligand 1 Expression Level and Prognostic Significance in Acute Myeloid Leukemia.

Purpose: We aimed to evaluate the expression level of programmed death ligand-1 (PD-L1) and its effects on prognosis in acute myeloid leukemia. Methods: The flow cytometry was used to detect PD-L1 expression on leukemic cells of 86 de novo acute myeloid leukemia patients with longitudinal follow-up. Results: Median follow-up was 13 (0-73) months. The mean of expression level was 3.22 ± 0.47 at diagnosis and ranged from 0 to 28%. PD-L1 expression tended to be lower in patients with acute promyelocytic leukemia (2.47 ± 1.08, p = 0.09) but there was no significant difference between neither diagnostic nor cytogenetic subgroups. There was no difference in PD-L1 levels between the patients who achieved complete remission (3.4 ± 0.61) and those who did not (2.91 ± 0.72, p = 0.94). The patients with low PD-L1 at diagnosis (median 25 mo [95% CI; 0-56.7]) had a longer overall survival compared with high PD-L1 (median 13 mo [95% CI; 5.52-25.17], p = 0.079). PD-L1 expression was lower at relapse (2.04 ± 0.79) compared to initial diagnosis (4.52 ± 0.93, p = 0.049). The patients who had overall survival longer than 1 year showed lower PD-L1 expression at relapse (0.66 ± 0.93) compared with who had not (5.06 ± 4.28, p = 0.052). A negative correlation between CD33 and PD-L1 (r = - 0.303, p = 0.005) was detected. Conclusion: Despite its low expression levels, PD-L1 appears to be a clinically important prognostic factor. The negative correlation determined between PD-L1 and CD33 supports the combination approach of PD-L1 inhibitors and CD33 targeted immunotherapies. Supplementary Information: The online version contains supplementary material available at 10.1007/s12288-021-01473-2.

Prognostic Value of Serum Soluble Klotho and Fibroblast Growth Factor-23 in Multiple Myeloma Patients.

Multiple myeloma is the plasma cell malignancy in which bone involvement is common. The Fibroblast growth factor-23 (FGF-23)/Klotho pathway plays a major role in mineral metabolism that FGF-23 is mineralization inhibitory. Klotho also has anti-apoptotic and anti-tumor effects by acting as a tumor suppressor gene. There is a negative correlation between serum FGF-23 and serum soluble Klotho (sKL) levels. As such, there can be considerable interest in investigating sKL and FGF-23 as a biomarker in patients with MM. We used an enzyme-linked immunosorbent assay to measure serum FGF-23 and sKL levels in 55 newly diagnosed MM patients and 23 healthy controls. We determined significantly high serum FGF-23 and low serum sKL levels in MM patients when compared to healthy controls. Serum sKL levels correlated negatively with a p53 positive mutation status, with high ISS, elevated lactate dehydrogenase, C-reactive protein, Beta-2 microglobulin levels. Serum FGF-23 levels are associated negatively with serum phosphorus and positively only light chains and p53 mutation. Patients with high serum FGF-23 levels had significantly shorter median overall survival than those with low serum FGF-23 levels (p = 0.008). Additionally, low sKL levels were related to decreased overall survival, but they didn't reach statistically significant (p = 0.072). There is a significant correlation between low serum sKL, high FGF-23 levels, and known prognostic factors in MM patients. We conclude that low sKL and high FGF-23 levels are a probable prognostic biomarker for poor MM patient outcomes.

The Clinical Efficacy of Epoetin Alfa and Darbepoetin Alfa in Patients with Low-Risk or Intermediate-1-Risk Myelodysplastic Syndrome: Retrospective Multi-center Real-Life Study.

This study aimed to evaluate the clinical efficacy of epoetin alfa and darbepoetin alfa in patients with myelodysplastic syndromes (MDS) in the real-life setting. A total of 204 patients with low-risk or intermediate-1-risk MDS who received epoetin alfa or darbepoetin alfa were included. Hemoglobin levels and transfusion need were recorded before and during 12-month treatment. Hemoglobin levels were significantly higher at each follow up visit when compared to baseline levels in both epoetin alfa (mean ± SD 8.68 ± 1.0 g/dL at baseline vs. 9.83 ± 1.45, 9.99 ± 1.55, 10.24 ± 1.77 and 10.2 ± 1.5 g/dL, respectively) and darbepoetin alfa (8.83 ± 1.09 g/dL at baseline vs. 9.62 ± 1.37, 9.78 ± 1.49, 9.9 ± 1.39 and 10.1 ± 1.5 g/dL, respectively) groups (p < 0.001 for each). Transfusion need significantly decreased from baseline at each study visit in the epoetin alfa group (p < 0.001) and only at the 12th month visit (p < 0.001) in the darbepoetin alfa group. Hemoglobin levels or transfusion need was similar between treatment groups. Overall, 12-month response rate was 58.1% for epoetin alfa and 41.9% for darbepoetin alfa, with no significant difference between treatment groups, whereas higher response rate was noted within the first three months (62.7%) compared to next 9 months (ranged 44.4-60%) of treatment in the epoetin alfa group (p ranged 0.002 to < 0.001). This real-life retrospective study revealed similar efficacy of epoetin alfa and darbepoetin alfa among low risk or intermediate-1 risk MDS patients with no difference in treatment response between treatment groups, whereas a likelihood of earlier treatment response in the epoetin alfa group. Supplementary Information: The online version contains supplementary material available at 10.1007/s12288-021-01458-1.

The Role of Interim PET/CT on Survival in Diffuse Large B Cell Lymphoma.

BACKGROUND: Diffuse large B cell lymphoma is the most frequent aggressive non-Hodgkin lymphoma. Predicting response and estimating prognosis earlier makes management of this heterogeneous lymphoma more satisfying. Interim PET response is established in Hodgkin Lymphoma to tailor the therapy but results for non-Hodgkin Lymphoma is unconvincing. In the current study evaluation of interim PET and survival outcomes of 103 DLBCL patients is performed. PATIENTS AND METHODS: About 103 Patients with DLBCL followed up in a single center between 2009 and 2019 were enrolled the study. All patients received R-CHOP chemoimmunotherapy at first line. Interim PET was performed after at least one or more cycles. All PET scans were performed with 18F-FDG isotope as PET/CT. PET scoring results were evaluated according to the 5-Point Deauville Scoring system defined in the National Comprehensive Cancer Network clinical guidelines for iPET and eotPET. 5-P DS of scores of 1 to 3 were defined as negative scans, and scores of 4 to 5 were considered to be positive scans. RESULTS: Forty-six (44.7%) Female and 57 (55.3%) male aged between 25 and 83 (median 57) years newly diagnosed DLBCL patients were enrolled in the study. Median PFS was 21 (interquartile range 8.5-53.7) months and median OS was 33.5 (interquartile range 12.5-62.9) months for the total cohort. Positive predictive value of interim PET according to Deauville scoring system was 65.4% and negative predictive value was 77.9%. CONCLUSION: Our study showed that according to Deauville 5 point scale (D 5PS) scoring system, interim PET-positive patients have shorter both PFS and OS than iPET-negative patients.

A Real-life Turkish Experience of Venetoclax Treatment in High-risk Myelodysplastic Syndrome and Acute Myeloid Leukemia.

INTRODUCTION: Venetoclax is a selective B-cell lymphoma 2 (BCL2) inhibitor, which is approved to treat elderly patients with newly diagnosed acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS) in combination with either low-dose cytarabine (ARA-C) or hypomethylating agents. We aimed to collect and share data among the efficacy and safety of venetoclax both as a monotherapy or in combination with other drugs used to treat high-risk MDS or AML. MATERIALS AND METHODS: A total of 60 patients with a median age of 67 (30-83) years from 14 different centers were included in the final analysis. Thirty (50%) of the patients were women; 6 (10%) of the 60 patients were diagnosed with high-risk MDS and the remaining were diagnosed with AML. RESULTS: The best objective response rate (complete remission [CR], complete remission with incomplete hematological recovery (CRi), morphological leukemia-free state [MLFS], partial response [PR]) was 35% in the entire cohort. Best responses achieved during venetoclax per patient number were as follows: 7 CR, 1 CRi, 8 MLFS, 5 PR, and stable disease. Median overall survival achieved with venetoclax was 5 months in patients who relapsed and not achieved in patients who were initially treated with venetoclax. Nearly all patients (86.7%) had experienced a grade 2 or more hematologic toxicity. Some 36.7% of these patients had received granulocyte colony stimulating factor (GCSF) support. Infection, mainly pneumonia (26.7%), was the leading nonhematologic toxicity, and fatigue, diarrhea, and skin reactions were the others reported. CONCLUSION: Our real-life data support the use of venetoclax in patients with both newly diagnosed and relapsed high-risk MDS and AML.

Evaluation of a Generic Bortezomib Molecule in Newly Diagnosed Multiple Myeloma Patients

Objective: Constantly increasing health expenditures lead to the use of generic molecules and generic versions of bortezomib have been used for a long time. The aim of this study is to retrospectively examine the effectiveness, side effects, and reliability of generic bortezomib in newly diagnosed multiple myeloma (MM) patients. Materials and Methods: The data of 95 patients who received four cycles of bortezomib as first- or second-line therapy in a single center were retrospectively recorded. Treatment responses, side effects, and progression-free survival (PFS) rates were calculated and compared. Results: Of the 95 patients, 42 used the original and 53 used the generic molecule. Epidemiological data, MM types, genetic risk groups, laboratory values at diagnosis, and bortezomib treatment lines (as a first line or second) were evaluated and there was no statistical difference between the two groups. When the response rates were evaluated according to International Myeloma Working Group criteria, there was no significant difference (p=0.42). Rates of partial response and higher responses were similar (81% vs. 79.2%, p=0.84). PFS rates were 42.8 months with the original and 37.8 months with the generic molecule (p=0.68). Side effects were seen in 44.2% of all patients, and the most common side effects were neuropathy, cytopenia, and infection. These rates were similar in the two groups (p=0.55). Conclusion: Although this retrospective study is limited in scope, it is the first study comparing the original molecule of bortezomib with a generic version. There were no statistical differences between the two groups in terms of treatment responses, PFS, or side effects. However, large-scale evaluations will help obtain more data on this subject.

Serum calprotectin (S100A8/A9) levels as a new potential biomarker of treatment response in Hodgkin lymphoma.

INTRODUCTION: Hodgkin lymphoma (HL) is unusual among malignancies, with inflammation playing such a prominent role in its pathogenesis. S100A8/A9 (calprotectin) is a heterodimeric protein, which has a role in the inflammatory response and oncogenesis. In this study in HL patients, the correlation between serum S100A8/A9 levels and treatment responses was investigated along with whether this marker is correlated with other inflammatory markers. MATERIALS AND METHODS: Thirty-three HL patients and 20 healthy volunteers were included. Demographic and clinical characteristics were recorded. Calprotectin levels were measured with Human S100A8/A9 Heterodimer Quantikine ELISA kit. Calprotectin levels were measured twice in patients, before and after treatment, and once in the control group. Treatment responses were evaluated with positron emission tomography-computed tomography (PET-CT). RESULTS: The mean age of patients was 44.3 ± 18.1 (66.3% male). The median (IQR) values of S100A8/A9 before and after treatment in the patient group were 4.98 (2.6-7.8) and 1.87 (1.1-4.8)µg/mL. Median (IQR) S100A8/A9 concentration in the control group was 1.41 (0.98-2.73)µg/mL. In patients, pretreatment values were significantly higher than in controls (P < .001). However, median values of patients after treatment and controls were similar. Patient median S100A8/A9 levels were significantly lower post-treatment compared with pretreatment values (P = .001). When inflammatory markers were examined within groups, no relationship was found between markers. In ROC analysis, a S100A8/A9 cutoff value of ≥3.31µg/mL accurately discriminated end-of-treatment PET positivity (AUC = 0.78; 95% CI 0.58-0.98; accuracy = 76.2%). CONCLUSION: S100A8/A9 may be a potential biomarker for treatment response in HL independent of inflammation. This is the first study to investigate and show this finding. However, further large-scale studies are still required.

Carfilzomib-induced tumor lysis syndrome in relapsed multiple myeloma: a report of two cases.

BACKGROUND: Tumor lysis syndrome (TLS) is a potentially fatal complication of cancer therapy characterized by severe electrolyte and metabolic abnormalities such as hyperphosphatemia, hyperkalemia, and hypocalcaemia. TLS usually occurs in aggressive hematologic malignancies such as Burkitt lymphoma and acute leukemia. TLS has rarely been observed in multiple myeloma (MM). CASE REPORT: We present 2 patients with relapsed MM who developed TLS after the first cycle of carfilzomib treatment. CONCLUSION: Carfilzomib is a next-generation proteasome inhibitor with proven efficacy in relapsed/refractory MM. Recently, increasing frequency of TLS has been reported in MM, especially after treatment with proteasome inhibitors. The potential complications of TLS should be considered especially during the first cycle of carfilzomib treatment.

Dasatinib-induced immune mediated-thrombotic thrombocytopenic purpura.

Most commonly seen side effects with Tyrosine kinase inhibitors (TKI's) are hematologic toxicities. Besides, with dasatinib autoimmune side effects can be seen. Thrombotic thrombocytopenic purpura (TTP) is a life- threatening disease that can be related to various causes mainly autoimmune disorders or antineoplastic drugs. Few cases of TKI associated secondary thrombotic microangiopathies (TMA) have been reported in literature. Most of cases were diagnosed as hemolytic uremic syndrome (HUS) rather than TTP. Herein, we describe a 37-year-old CML patient who was diagnosed as immune-mediated TTP related to dasatinib.

Isolated Breast Relapse of Acute Lymphoblastic Leukemia After Allogeneic Hematopoietic Stem Cell Transplantation.

Isolated breast relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is less often seen. Chronic graft-versus-host disease (cGVHD) is effective in preventing marrow relapse, but cGVHD seems not to be effective extramedullary relapse (EMR). We report the case of isolated breast relapse after first allo-HSCT for acute lymphoblastic leukemia (ALL). A 47-year-old female was diagnosed with ALL achieved complete remission with salvage chemotherapy and underwent allo-HSCT from an HLA-matched sibling male donor. At 17 months post-transplant, she presented with a bilateral breast masses that confirmed the diagnosis lymphoblast involvement. She had no evidence of leukemia in her marrow that determined 100 % full-donor chimerism when she was relapsed in her both breasts.

Azacitidine versus decitabine in patients with refractory anemia with excess blast-Results of multicenter study.

The present study aimed to compare the efficacy and safety of azacitidine and decitabine in patients with myelodysplastic syndrome (MDS). A total of 88 patients diagnosed with refractory anemia with excess blast (RAEB) treated with azacitidine (n=57) or decitabine (n=31) were evaluated. Comparisons between azacitidine and decitabine groups were performed in the whole cohort, and in a 1:1 propensity score-matched cohort in order to reduce the simple selection bias. Patients who received azacitidine or decitabine had comparable overall response rates in both the unmatched (49.1% vs. 64.5%, p=0.166) and the propensity-matched cohorts (52% vs. 68%, p=0.248). The cumulative incidence of AML transformation at one year was comparable between azacitidine and decitabine in the unmatched (24.0% vs. 31.3%, p=0.26) and in the propensity-matched cohorts (18.7% vs. 31.5%, p=0.11). There was no difference in terms of transfusion requirement, febrile neutropenia episodes or the need for antifungal use during the treatment cycles in the propensity-matched cohort. The median overall survival was 20.4 months for azacitidine and 16.8 months for decitabine (p=0.59). Finally, we found that at least a four-cycle treatment with any HMA was a favorable factor. In conclusion, both azacitidine and decitabine have similar efficacy and toxicity profiles in the treatment of MDS-RAEB.

Soluble Programmed Death 1 (PD-1) Is Decreased in Patients With Immune Thrombocytopenia (ITP): Potential Involvement of PD-1 Pathway in ITP Immunopathogenesis.

Immune thrombocytopenia (ITP) is an autoimmune disease characterized by dysregulation of T cells. Programmed death (PD) 1 and programmed death 1 ligand 1 (PD-L1) are cosignaling molecules, and the major role of the PD-1 pathway is the inhibition of self-reactive T cells and to protect against autoimmune diseases. We measured levels of serum soluble PD 1 (sPD-1) and serum soluble PD-L1 (sPD-L1) in 67 patients with ITP (24 newly diagnosed ITP [ndITP], 43 chronic ITP [cITP]) and 21 healthy controls (HCs). We determined decreased serum sPD-1 levels both in patients with ndITP and in patients with cITP when compared to HC. Moreover, there was a positive correlation between sPD-1 levels and platelet counts. The sPD-L1 levels were decreased in patients with ndITP when compared to patients with cITP. This is the first study investigating PD-1 signaling pathway in ITP. Decreased sPD-1 levels may have a role in ITP pathogenesis as without the inhibitory regulation of PD-1, sustained activation of T cells may cause inflammatory responses which is the case in ITP.