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.

Introduction. Autologous haematopoietic stem cell transplantation (auto-HSCT) is a highly effective treatment for multiple myeloma (MM). Auto-HSCT allows a signifi cant improvement of haematological response leading to higher overall survival and quality of life in MM patients. Nonetheless, the majority of patients develop relapse.Aim — a comparison of clinical MM relapses developing at variant terms after auto-HSCT.Patients and methods. A retrospective study enrolled 65 MM patients aged between 39 and 64 years. All patients had auto-HSCT during 2009–2019, all had achieved complete response (CR) or very good partial response (VGPR) and all since developed immunochemical MM relapse in laboratory evidence. Patients were divided in two cohorts by relapse term, the early (within 12 months of auto-HSCT) and late relapse.Results. Early immunochemical relapse was diagnosed in 13 (20 %), late relapse — in 52 (80 %) patients. The dependence between relapse term and depth of post-auto-HSCT antitumour response has been determined. The proportion of CR patients was signifi cantly higher in late than in early relapse (55.8 vs. 23 %). In follow-up, 60 patients (92.3 %) were initiated on antirelapse therapy, all early relapse and 90.3 % late relapse patients. On day +100 of auto-HSCT, CR patients had later relapse vs. VGPR individuals (median 24 vs. 19.9 months, p = 0.08) with signifi cantly weaker paraprotein secretion resembling the clinical course of monoclonal gammopathy of unclear signifi cance (MGUS).Conclusion. Auto-HSCT allows long-term control of the disease. A signifi cant prognostic factor is antitumour response on +100 day of auto-HSCT. Patients attaining CR have later relapse progressing in a MGUS-like manner. Patients with late indolent relapse can be managed long-term without antitumour therapy.

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.

Epidemiological features and clinical variants of inflammatory bowel diseases in St. Petersburg in conditions of outpatient practice are considered. It was established that among patients suffering from ulcerative colitis in the Vyborg and Frunze regions, women predominate in a ratio of 1:2. At the same time, more than 50% of cases of ulcerative colitis and Crohns disease come from the age of 2049 years. The vast majority of patients examined with ulcerative colitis experienced a moderate attack. In more than half of cases, left-sided localization was noted with endoscopic activity of 23 points on the Schroeder scale, rectal lesion was observed in 22% of cases, total colitis was detected in only 14%. In general, the incidence and prevalence of ulcerative colitis in the Vyborg and Frunze regions is higher than Crohns disease. However, more extensive and lengthy studies of the problem are needed, but there are some difficulties associated with the lack of a unified registration base for patients suffering from inflammatory bowel diseases. Given that the incidence of ulcerative colitis and Crohns disease is higher among women and more than 50% of patients are of the most able-bodied age (2049 years), inflammatory bowel disease is a group of highly relevant and socially significant diseases. Lower figures for the incidence and prevalence of inflammatory bowel diseases compared with those of developed countries indicate insufficient detection, diagnostic and clinical features of these diseases, as well as the need to optimize specialized medical care in places of residence of patients suffering from inflammatory bowel diseases. Nevertheless, currently in St. Petersburg and the Leningrad Region a fairly effective system of early detection and dynamic observation of patients suffering from ulcerative colitis has been created, which includes the activities of therapists and gastroenterologists of polyclinics, endoscopists and specialists of centers for the treatment of inflammatory bowel diseases of academic and university clinics.

Introduction. Despite the availability of results from several studies that evaluated the role of magnetic resonance imaging (MRI) in the diagnosis of multiple myeloma (MM), data on the value of MRI after antineoplastic treatment, in particular after autologous hematopoietic stem cell transplantation (auto-HSCT), are limited. Objective. To study changes in bone marrow lesions using MRI in MM patients before and after auto-HSCT. Materials and methods. Forty patients with MM (15 male and 25 female) aged 36 to 66 years (median age 56 years) were enrolled in a prospective study. MRI of the spine and pelvic bones was performed before and 100 days after auto-HSCT to track bone marrow changes after transplantation. MRI was carried out with a GE Signa Profile system without contrast enhancement. The nature of the lesions was determined, and the bone marrow infiltration lesions (>= 5 mm) were counted. Results. MR images showed a decrease in the number of foci after auto-HSCT in 17 (52%) patients, and a reduction in the volume of the tumors in 29 (88%) patients. In most patients, even when a complete response (CR) was achieved, MRI revealed residual tumor load in the bone marrow, which decreased after auto-HSCT (by 1.4 times in the number of detectable lesions, and by 2.4 times in the tumor volume). Conclusion. By making it possible to evaluate the residual tumor load, whole-body bone marrow MRI can be used as an additional non-invasive method for assessing response to antitumor therapy in MM patients.

Daratumumab, the first therapeutic monoclonal antibody that binds to CD38, is used for treatment of patients with multiple myeloma. The CD38 transmembrane protein is highly expressed on the surface of malignant myeloma cells, but also, to a lesser extent, is expressed by many other types of cells, including red blood cells (RBCs). When daratumumab binds to CD38 expressed on RBCs, this may result in positive indirect antiglobulin tests (IAT) performed to identify immunological compatibility before RBC transfusions. Anti-CD38-specific agglutination may also variably affect autocontrol, direct antiglobulin test (DAT), and eluate tests. The aim of the study was to develop a protocol for preventing CD38-specific agglutination in antiglobulin tests by treatment of RBCs with dithiothreitol (DTT). Materials and methods. Between July 2016 and April 2017, 9 multiple myeloma patients undergoing daratumumab treatment were tested using routine methods in the Immunohematology Laboratory of the National Hematological Research Center in Moscow. The tests included ABO and Rh typing, extended phenotype matching, DAT, and IAT in LISS/Coombs gel cards. Tests were performed before and after treatment of RBCs with DTT. Results. No daratumumab interference was observed in ABO, Rh, Kell, MNS or Fy typing with IgM antibodies. DAT and auto control were also negative in all patients. On the other hand, all patients showed daratumumabmediated positive IAT, which was resolved by treatment of RBCs with DTT. Conclusions. Anti-CD38 antibodies interfere with serological tests. This interference can be resolved by treating RBCs with DTT. Blood banks and immunohematological laboratories should be informed that a patient is receiving treatment with anti-CD38.

Introduction. Computed tomography (CT) is a powerful method of medical imaging that can reveal in skeletal bones foci of destruction, soft tissue masses and pathological fractures characteristic of multiple myeloma (MM). It has a number of valuable advantages over conventional plain film radiography, which has traditionally been used in the diagnosis of MM. The absence of a significant difference in the radiation load between a plain radiography and a low dose CT makes the latter the method of choice for screening for presence and extent of osteolytic lesions. Objective. To explore the potential of low-dose computed tomography in the diagnosis of MM and to describe characteristic structural changes of bones during treatment. Materials and methods. One hundred and eighty-eight whole-body low-dose CT scans were performed in patients with newly diagnosed MM followed by monitoring of changes in the areas of interest according to the standard protocol. Results. Osteolytic changes were observed in 91% of patients; 49.6% of patients showed soft-tissue masses spreading beyond the affected bones. Based on the follow-up CT scans according to the standard scanning protocol, we established radiological criteria of a positive response to antitumor therapy. The method has been included in the Russian multiple myeloma clinical guidelines.

AIM:To investigate the nature of mutations in exons 4 and 5 of the uromodulin (UM) gene, including in the area encoding the domain of 8 cysteines (D8C), in patients with multiple myeloma (MM) with the secretion of monoclonal light chains (LC) in cast nephropathy (CN) and without kidney injury.SUBJECTS AND METHODS:The investigation enrolled 24 patients in MM remission, who were observed to have monoclonal LC secretion at onset. Group 1 included 14 patients with CN; Group 2 consisted of 10 patients with normal renal function (a comparison group). The compared groups did not differ in the number of serum and urinary monoclonal LCs. Genomic DNA was extracted from the peripheral blood samples of patients. The nucleotide sequence of exons 4 and 5 of the UM gene was determined by the Sanger method.RESULTS:No differences were found in the frequency of polymorphisms depending on the severity of kidney injury. The missense mutation p.142R>R/Q in the UM gene, which had not been previously described, was discovered.CONCLUSION:The patients with MM were not found to have statistically significant differences in the frequency and nature of polymorphisms of exons 4 and 5 in the UM gene, including in the area encoding D8C, in CN without kidney injury.

AIM To determine the efficiency of maintenance therapy with bortezomib in patients with multiple myeloma (MM) who have achieved complete remission (CR) after autologous hematopoietic stem cell (auto-HSCT), depending on the presence of minimal residual disease (MRD). SUBJECTS AND METHODS In January 2014 to February 2016, fifty-two MM patients (19 men and 33 women) aged 24 to 66 years (median 54 years), who had achieved CR after auto-HSCT, were randomized to perform maintenance therapy with bortezomib during a year. On day 100 after auto-HSCT, all the patients underwent immunophenotyping of bone marrow plasma cells by 6-color flow cytometry to detect MRD. Relapse-free survival (RFS) was chosen as a criterion for evaluating the efficiency of maintenance therapy. RESULTS After auto-HSCT, MRD-negative patients had a statistically significantly higher 2-year RFS rate than MRD-positive patients: 52.9% (95% confidence interval (CI), 35.5 to 70.5%) versus 37.2% (95% CI, 25.4 to 49.3%) (p=0.05). The presence of MRD statistically significantly increased the risk of relapse (odds ratio 1.7; 95% CI, 1.2 to 3.4; p=0.05). Two-year cumulative risk of relapse (using the Kaplan-Meier) after auto-HSCT did not statistically significantly differ in MRD-negative patients receiving (n=15) and not receiving (n=10) maintenance therapy with bortezomib (p=0.58). After completion of maintenance treatment, 42% of the MRD-positive patients achieved a negative status. In the MRD-positive patients who had received maintenance therapy, the average time to recurrence was 5 months longer than that in the naïve patients: 17.3 versus 12.3 months. CONCLUSION The MRD status determined in MM patients who have achieved CR after auto-HSCT is an important factor for deciding on the use of maintenance therapy.

Aim. To determine the prevalence of amp1q21 and its relationship to the clinical manifestations of multiple myeloma (MM). Subjects and methods. In December 2009 to March 2016, a total 134 patients aged 30 to 81 years (median 57 years) underwent a pretreatment FISH-study of bone marrow (BM) with centromeric and locus-specific DNA probes to identify amp1q21, t(11;14), t(4;14), t(14;16), t(14;20), t(6;14), trisomies of chromosomes 5, 9, 15, del13q14, del17p13/TP53, and t(8q24)/cMYC. Induction therapy with bortezomib-containing cycles was performed. Autologous stem cell transplantation was carried out in 48 patients. The median follow-up of patients was 19.3 months (3.2—77.4 months). Disease progression was diagnosed in 69 (51.5%) patients; 12 patients also underwent FISH study during disease progression. Results. At the onset of MM, amp1q21 was detected in 53 (39.6%) patients. The overall 5-year survival rate in patients with amp1q21 was almost 2 times lower than that in those without amp1q21 (43.5 and 79.4%, respectively; p=0.07). The overall 5-year survival rate in patients with one extra copy of 1q21 (only 3 copies) was 67.3%, that in those with 2 or more extra copies of 1q21 (only 4—7 copies) was 20.9% (p=0.0016). Nine (75%) of the 12 patients examined during disease progression were found to have amp1q21: 2 cases were detected in the period of progression to have amp1q21 in its absence at disease onset; 7 cases had amp1q21 both at MM onset and progression; however, the number of copies of 1q21 was unchanged. Conclusion. Аmp1q21 is one of the most common chromosomal abnormalities in patients with new-onset MM and may appear in the course of disease progression. The presence of аmp1q21 is an important prognostic factor and must have to be included in the diagnostic study both at disease onset and progression.