Summary: Insulin autoimmune syndrome (Hirata’s disease) is a disorder caused by development of autoantibodies to insulin and manifested by hypoglycaemic syndrome. The overwhelming majority of physicians do not include it in the differential diagnosis of hypoglycaemic states because of a misconception of an extremely low prevalence of this condition. This results in unnecessary drug therapy and unjustified surgical interventions in patients that otherwise would be successfully treated conservatively. This disease is strongly associated with certain alleles of the HLA gene. In most cases, this condition develops in predisposed individuals taking drugs containing sulfhydryl groups. Formation of autoantibodies to insulin may be observed in patients with other autoimmune disorders, as well as in those with multiple myeloma or monoclonal gammopathy of undetermined significance. This paper presents the first Russian case report of insulin autoimmune syndrome in an adult patient. Learning points: Insulin autoimmune syndrome, Hirata’s disease, anti-insulin antibodies, and hypoglycaemia.

Background. Multiple myeloma complicated by extramedullary plasmacytoma is an unfavorable variant of the disease. It remains unknown what triggers tumor transformation. The review presents literature data on the pathogenesis of extramedullary disease, as well as a clinical example of a comprehensive study of the tumor substrate.Aim. To study the molecular and biological characteristics of the tumor substrate of the bone marrow and extramedullary plasmacytoma using various research methods.Materials and methods. A 55-year-old patient was admitted to National Medical Research Center for Hematology with a diagnosis of multiple myeloma occurring with extramedullary plasmacytoma of the retroperitoneal space. dNA was isolated from samples of different localization (blood plasma, Cd138+ bone marrow cells, plasmacytoma and buccal epithelial cells). The profile of short tandem dNA repeats (STR) from the obtained samples was studied by multiplex polymerase chain reaction followed by fragment analysis. fluorescent in situ hybridization (fISH) of bone marrow Cd138+ cells was performed using various dNA probes. Comparative genomic hybridization on a microarray (arrayCGH) plasmacytoma dNA was also performed. The mutation profile of the KRAS, NRAS, BRAF genes was studied by Sanger sequencing in tumor samples of various localizations.Results. The induction therapy (vCd (bortezomib + cyclophosphamide + dexamethasone), vRd (bortezomib + lenalidomide + dexamethasone), daratumumab therapy) was ineffective, death occurred 4 months after the first clinical manifestations appeared. Comparison of STR markers of circulating cell-free tumor dNA (cfdNA), Cd138+ bone marrow cells, and plasmacytoma revealed the largest number of involved loci exactly in plasmacytoma’ dNA. A mutation in the NRAS gene was found only in plasmacytoma’ dNA. This indicates the presence of another clone of tumor cells in the extra-medullary plasmacytoma. Molecular karyotyping of plasmacytoma using the arrayCGH method revealed rearrangements of many chromosomes. 1p32.3 bi-allelic deletion, amplification of 1q21, 8q24/MyC rearrangements and del17p13 were confirmed by arrayCGH molecular karyotyping and fISH studies in bone marrow and plasmacytoma.Conclusion. A comprehensive molecular genetic study of the extramedullary plasmacytoma’ substrate is necessary to understand the pathogenesis mechanisms and, on this basis, to develop differentiated therapeutic approaches.

Multiple myeloma (MM) is a disease characterized by spatiotemporal heterogeneity of tumor clones. Different genetic aberrations can be observed simultaneously in tumor cells from different loci, and as the disease progresses, new subclones may appear. The role of liquid biopsy, which is based on the analysis of tumor DNA circulating in the blood plasma, continues to be explored in MM. Here, we present an analysis of the STR profiles and mutation status of the KRAS, NRAS, and BRAF genes, evaluated in plasma free circulating tumor DNA (ctDNA), CD138+ bone marrow cells, and plasmacytomas. The prospective single-center study included 97 patients, with a median age of 55 years. Of these, 94 had newly diagnosed symptomatic MM, and three had primary plasma cell leukemia. It should be noted that if mutations were detected only in ctDNA, “non-classical” codons were more often affected. A variety of adverse laboratory and clinical factors have been associated with the detection of rare KRAS or NRAS gene mutations in bone marrow or ctDNA, suggesting that these mutations may be factors of an unfavorable prognosis for MM. Liquid biopsy studies provide undeniable fundamental information about tumor heterogeneity and clonal evolution in MM. Moreover, we focus on using liquid biopsy to identify new high-risk factors for MM.

Proteasome inhibitors and immunomodulators (IMiDs), primarily bortezomib and lenalidomide, are essential components of treatment for both newly diagnosed and relapsed/refractory multiple myeloma (MM), producing high response rates and resulting in improved overall survival. However, bortezomib often induces a dose-limiting toxicity in the form of peripheral neuropathy (PN). Neurotoxicity often affects patient’s quality of life and requires dose modification or withdrawal of therapy, with a possible effect on the overall response. A prompt recognition of predisposing factors (such as diabetes mellitus, vitamin B12 deficiencies, or viral infections) and appearance of signs and symptoms, through a periodic neurological assessment with appropriate scales, is extremely important. Usually, bortezomib-induced PN is a sensory axonopathy characterized by numbness, tingling, and severe neuropathic pain in stocking and glove distribution while motor neuropathy is less frequently observed. Dose adjustment of bortezomib could be necessary during treatment. Anticonvulsants (pregabalin, gabapentin, carbamazepine, etc.) and tricyclic antidepressants (amitriptyline) are most often used to relieve neurological pain. In this review we focus on the clinical manifestations of bortezomibinduced PN, current understanding of the pathophysiological mechanisms as well as clinical and pharmacological aspects of prevention and management this complication. New proteasome inhibitors such as ixazomib and carfilzomib do not have the neurotoxicity of bortezomib. An early switch within the class of proteasome inhibitors from bortezomib to oral ixazomib appears to be an important approach to prevent severe PN. Our own clinical case of an early switch from bortezomib-based induction to IRd triplet (ixazomib, lenalidomide, dexamethasone) is cited as an illustration of the success of this approach.

Supportive therapy is becoming increasingly important for the state-of-the-art algorithm of multiple myeloma (MM) treatment. The introduction of innovative drugs and transplantation methods into clinical practice considerably improved the disease-free and overall survival rates. However, in the vast majority of cases, MM still remains an incurable malignant plasma cell tumor. It is often treated on a continuous basis with a succession of targeted drugs and integration of glucocorticosteroids and conventional cytostatic agents into the program therapy. All of these together with immunodeficiency, bone lesions, and myeloma nephropathy lead to a high risk of adverse events and cumulative toxicity of treatment. At the same time, one of the main goals at all MM therapy stages is to maintain quality of life. The characteristics of clinical symptoms, the nuances of targeted therapy and chemotherapy-associated adverse events justify the need for further development of supportive MM therapy algorithms which remain to be a matter of current concern. They should be mainly aimed at preventing the therapy complications, reducing the rate of adverse events and clinical manifestations of side effects as well as developing a treatment strategy for cumulative toxicity. In the state-of-the-art algorithm of program MM treatment, supportive therapy-related knowledge is of no less value than the information on antitumor drugs and their efficacy. This paper reports the personal experience and provides recommendations mostly based on the results of clinical studies or views of expert panels. It also offers practical recommendations for supportive therapy in symptomatic MM which include prevention of skeletal complications, thromboses, and infections, nausea and vomiting management, vaccination, pre-medication and the algorithm of monoclonal antibody administration, anesthesia, peripheral polyneuropathy treatment, correction of secondary immunodeficiency, nutritional support, fatigue assessment and countermeasures.

The article Hypoglycemic syndrome in patients with monoclonal gammopathy published by Solovyev MV, Yukina MY, Troshina EA in Problems of Endocrinology 2020;65(6) (doi: 10.14341/probl12266) contains wrong data in Conflict of interests section. Correct information is: Manuscript preparation and publication was supported by the Russian Science Foundation (project No. 17-75-30035). The information given in the article about the sources of funding should not have any significant effect on the perception of information by readers and / or interpretation of the data presented. The authors regret the incorrect information in a previously published article.