Metabolomic biomarkers of multiple myeloma: A systematiс review.

Multiple myeloma is an incurable malignancy of clonal plasma cells. Various diagnostic methods are used in parallel to accurately determine stage and severity of the disease. Identifying a biomarker or a panel of biomarkers could enhance the quality of medical care that patients receive by adopting a more personalized approach. Metabolomics utilizes high-throughput analytical platforms to examine the levels and quantities of biochemical compounds in biosamples. The aim of this review was to conduct a systematic literature search for potential metabolic biomarkers that may aid in the diagnosis and prognosis of MM. The review was conducted in accordance with PRISMA recommendations and was registered in PROSPERO. The systematic search in PubMed, CINAHL, SciFinder, Scopus, The Cochrane Library and Google Scholar was performed. Studies were limited to those involving people with clinically diagnosed MM and healthy controls as comparators. Articles had to be published in English and had no restrictions on publication date or sample type. The quality of articles was assessed according to QUADOMICS criteria. A total of 709 articles were collected during the literature search. Of these, 436 were excluded based on their abstract, with 26 more removed after a thorough review of the full text. Finally, 16 articles were deemed relevant and were subjected to further analysis of their data. A number of promising candidate biomarkers was discovered. Follow-up studies with large sample sizes are needed to determine their suitability or clinical applications.

Successful Implementation of Combined Treatment Methods for a Rare Recurrence of Waldenstrom Macroglobulinemia With Extramedullary Lesions.

A 67-year-old woman was admitted to the Hematology Department in 2014 with complaints of weakness and a low-grade fever. After conducting various tests, it was confirmed that she had Waldenstrom macroglobulinemia. She underwent several rounds of chemotherapy and maintenance therapy with rituximab, which resulted in a good clinical response. However, in 2019, an abnormal growth in the soft tissues of patient's frontal region was discovered, which was diagnosed as lymphoplasmacytic lymphoma. This later progressed to an intracranial lesion. The patient underwent radiation therapy for both the extramedullary and intracranial growths, which had a positive effect. A year later, she developed a lesion in her lymph nodes and soft tissues of her right leg, which was confirmed to be a recurrence of Waldenstrom disease. She underwent further treatment and is currently in complete remission. This case highlights the rare occurrence of relapse in Waldenstrom disease and the challenges in diagnosing extramedullary lesions. It also demonstrates the success of modern treatment approaches using a combination of therapies.

Improving combination therapies: targeting A2B-adenosine receptor to modulate metabolic tumor microenvironment and immunosuppression.

BACKGROUND: We investigated the role of A2B-adenosine receptor in regulating immunosuppressive metabolic stress in the tumor microenvironment. Novel A2B-adenosine receptor antagonist PBF-1129 was tested for antitumor activity in mice and evaluated for safety and immunologic efficacy in a phase I clinical trial of patients with non-small cell lung cancer. METHODS: The antitumor efficacy of A2B-adenosine receptor antagonists and their impact on the metabolic and immune tumor microenvironment were evaluated in lung, melanoma, colon, breast, and epidermal growth factor receptor-inducible transgenic cancer models. Employing electron paramagnetic resonance, we assessed changes in tumor microenvironment metabolic parameters, including pO2, pH, and inorganic phosphate, during tumor growth and evaluated the immunologic effects of PBF-1129, including its pharmacokinetics, safety, and toxicity, in patients with non-small cell lung cancer. RESULTS: Levels of metabolic stress correlated with tumor growth, metastasis, and immunosuppression. Tumor interstitial inorganic phosphate emerged as a correlative and cumulative measure of tumor microenvironment stress and immunosuppression. A2B-adenosine receptor inhibition alleviated metabolic stress, downregulated expression of adenosine-generating ectonucleotidases, increased expression of adenosine deaminase, decreased tumor growth and metastasis, increased interferon γ production, and enhanced the efficacy of antitumor therapies following combination regimens in animal models (anti-programmed cell death 1 protein vs anti-programmed cell death 1 protein plus PBF-1129 treatment hazard ratio = 11.74 [95% confidence interval = 3.35 to 41.13], n = 10, P < .001, 2-sided F test). In patients with non-small cell lung cancer, PBF-1129 was well tolerated, with no dose-limiting toxicities; demonstrated pharmacologic efficacy; modulated the adenosine generation system; and improved antitumor immunity. CONCLUSIONS: Data identify A2B-adenosine receptor as a valuable therapeutic target to modify metabolic and immune tumor microenvironment to reduce immunosuppression, enhance the efficacy of immunotherapies, and support clinical application of PBF-1129 in combination therapies.

Case Report: AL Amyloidosis Severe Restrictive Cardiomyopathy Associated With Multiple Myeloma-Diagnostic Difficulties.

Background: Cardiac AL amyloidosis as a complication of multiple myeloma (MM) is a formidable life-threatening condition. The first-line therapy for both MM and systemic AL amyloidosis is proteasome inhibitors (PIs). Unfortunately, the use of PIs may lead to cardiovascular toxicity development, which requires specific cardio-oncology supervision. Case Report: A 57-year-old woman was admitted to a university hospital with clinical manifestation of progressive chronic heart failure. The patient had hypertension and no history of diabetes mellitus, myocardial infarction (MI), stroke, and arrhythmias. After a series of laboratory and instrumental examination methods, MM complicated by cardiac AL amyloidosis was proved. Upon specific cardio-oncology examination (NT-proBNP 4,274 pg/ml), ECHO showed systolic dysfunction, motion abnormalities in LV basal and middle segments, and a typical depositional myocardium pattern ("luminescence"); cardiac MRI revealed restrictive cardiomyopathy and specific hyperenhancement of the ventricles and atria; 24-h ECG showed QS-pattern in leads V1-V3 and unstable ventricular tachycardia (VT) paroxysms. Cardio-oncology consultation showed baseline cardiovascular risk was very high (≥20%), and cardioprotective therapy [iACE/ARBs, beta-blockers (BB), statins] was administered. The patient underwent VCD (bortezomib; cyclophosphamide; dexamethasone) chemotherapy (CMT) program. By the time of publication, the patient had received four CMT courses with a positive oncohematological and cardiovascular effect. Conclusion: In this clinical case, we described a complication of MM, which was rare according to the severity and manifestation with restrictive cardiomyopathy due to secondary cardiac amyloidosis. The case's features were difficulties in verifying the underlying disease and its own complication, and the complexity of patient management according to modern principles of cardio-oncology.

Angiotensin-Converting Enzyme Inhibitor Therapy Effects in Patients With Heart Failure With Preserved and Mid-Range Ejection Fraction.

BACKGROUND: There is hypothesis that endothelial function enhancement is strongly associated with better outcome and functional class improvement in heart failure with preserved ejection fraction (HFpEF) and heart failure with mid-range ejection fraction (HFmrEF) patients. Perindopril is the only angiotensin-converting enzyme inhibitor (ACEI) drug with proven positive effect on the endothelium in coronary artery disease (CAD) patients. In patients with HFpEF and HFmrEF, its impact is still unknown. The aim of this study was to assess perindopril's influence on endothelial dysfunction markers in these groups of patients. METHODS: We included 60 patients with HFpEF and HFmrEF. At the baseline, endothelial dysfunction biomarkers were measured by IFA and echocardiographic parameters (left atrial volume index (LAVI), ejection fraction (EF), left ventricular mass index (LVMI), left ventricular end-diastolic diameter (LVEDD), and left ventricular end-diastolic volume (LVEDV)) were studied. In patients with no history of previous ACEI or angiotensin II receptor blockers (ARBs) therapy, perindopril was prescribed for 12 months. If patient was treated with ARB or ACEI drug other than perindopril before the study, after 48-h withdrawal period, previous drug was replaced by perindopril. RESULTS: After 12-month therapy with perindopril, E-selectin decreased from 57.25 to 46.05 ng/mL and from 56.55 to 47.6 ng/mL in HFpEF and HFmrEF patients, respectively (P < 0.05). Significant reductions from 0.99 to 0.76 pg/mL (P < 0.05) and from 1.08 to 0.97 pg/mL (P < 0.05) in endothelin-1 level were shown in patients with HFpEF and HFmrEF. CONCLUSION: The 12-month therapy with perindopril leads to LAVI reduction in HFmrEF patients and potential endothelial dysfunction markers decrease in HFpEF and HFmrEF patients.