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Background: Selinexor combined with dexamethasone has shown activity in patients with heavily pre-treated multiple myeloma. In a phase 1b/2 study, the combination of oral selinexor with bortezomib (a proteasome inhibitor) and dexamethasone induced high response rates with low rates of peripheral neuropathy, the main dose-limiting toxicity of bortezomib. We aimed to evaluate the clinical benefit of weekly selinexor, bortezomib, and dexamethasone versus standard bortezomib and dexamethasone in patients with previously treated multiple myeloma., Methods: This phase 3, randomised, open-label trial was done at 123 sites in 21 countries. Patients aged 18 years or older, who had multiple myeloma, and who had previously been treated with one to three lines of therapy, including proteasome inhibitors, were randomly allocated (1:1) to receive selinexor (100 mg once per week), bortezomib (1·3 mg/m 2 once per week), and dexamethasone (20 mg twice per week), or bortezomib (1·3 mg/m 2 twice per week for the first 24 weeks and once per week thereafter) and dexamethasone (20 mg four times per week for the first 24 weeks and twice per week thereafter). Randomisation was done using interactive response technology and stratified by previous proteasome inhibitor therapy, lines of treatment, and multiple myeloma stage. The primary endpoint was progression-free survival in the intention-to-treat population. Patients who received at least one dose of study treatment were included in the safety population. This trial is registered at ClinicalTrials.gov, NCT03110562. The trial is ongoing, with 55 patients remaining on randomised therapy as of Feb 20, 2020., Findings: Of 457 patients screened for eligibility, 402 were randomly allocated-195 (49%) to the selinexor, bortezomib, and dexamethasone group and 207 (51%) to the bortezomib and dexamethasone group-and the first dose of study medication was given between June 6, 2017, and Feb 5, 2019. Median follow-up durations were 13·2 months [IQR 6·2-19·8] for the selinexor, bortezomib, and dexamethasone group and 16·5 months [9·4-19·8] for the bortezomib and dexamethasone group. Median progression-free survival was 13·93 months (95% CI 11·73-not evaluable) with selinexor, bortezomib, and dexamethasone and 9·46 months (8·11-10·78) with bortezomib and dexamethasone (hazard ratio 0·70 [95% CI 0·53-0·93], p=0·0075). The most frequent grade 3-4 adverse events were thrombocytopenia (77 [39%] of 195 patients in the selinexor, bortezomib, and dexamethasone group vs 35 [17%] of 204 in the bortezomib and dexamethasone group), fatigue (26 [13%] vs two [1%]), anaemia (31 [16%] vs 20 [10%]), and pneumonia (22 [11%] vs 22 [11%]). Peripheral neuropathy of grade 2 or above was less frequent with selinexor, bortezomib, and dexamethasone (41 [21%] patients) than with bortezomib and dexamethasone (70 [34%] patients; odds ratio 0·50 [95% CI 0·32-0·79], p=0·0013). 47 (24%) patients in the selinexor, bortezomib, and dexamethasone group and 62 (30%) in the bortezomib and dexamethasone group died., Interpretation: A once-per-week regimen of selinexor, bortezomib, and dexamethasone is a novel, effective, and convenient treatment option for patients with multiple myeloma who have received one to three previous lines of therapy., Funding: Karyopharm Therapeutics., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Management of beta-thalassemia major (TM) requires life-long hemotransfusions leading to iron overload. Iron elimination is enhanced by the use of modern chelators., Aim: To assess the effect of modern chelation therapy by dynamics of serum ferritin concentration and liver MRI T2*., Patients and Methods: Forty-six patients with TM (male to female ratio =1:1, mean age 33.2±10.9 years) were prospectively studied between 2011 and 2014. Twenty-one patients (45.7%) were treated with deferasirox, 17 (37%) - with deferiprone, and 8 (17.3%) - with deferiprone in combination with deferoxamine. Ferritin was measured by ELISA. MRI T2* was assessed by Siemens Magnetom Avanto 1.5T. The patients were allocated into 3 groups based on their initial ferritin level and liver MRI T2*. Statistical analysis was performed using SPSS v. 18 for Windows. Data were analysed by descriptive analysis, analysis of variance and correlative analysis, means were compared using t-test and one-way ANOVA., Results: In 2011, 9 (19.5%) patients had normal liver MRI T2*; in 2014 they were 17 (37%). The patients with mild grade liver siderosis were 12 (26%) in 2011, and in 2014 they were 14 (30.4%). In 2011, the patients with moderate liver siderosis were 14 (30.4%), and in 2014 - 12 (26.0%). Eleven patients (23.9%) had severe liver siderosis in 2011 and only two patients (4.0%) were diagnosed with the condition in 2014., Conclusion: A reduction of iron overload was found in all studied groups. This positive effect is attributed to the use of modern chelators and the ease of access to accurate monitoring., (This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Chronic myeloid leukemia (CML) arises from the fusion of the BCR and the ABL1 genes. The BCR gene (chromosome 22q11.2) and the ABL1 gene (chromosome 9q34) fuse together due to reciprocal chromosome translocation forming the Philadelphia chromosome (Ph). This fusion gene codes tyrosine kinase which accelerates the cell division and reduces DNA repair. Imatinib mesylate is a selective inhibitor of this tyrosine kinase. It is the first-line treatment for CML-patients. However, it became clear that Philadelphia-positive (Ph+) cells could evolve to elude inhibition due to point mutations within the BCR-ABL kinase domain. To date more than 40 mutations have been identified and their early detection is important for clinical treatment. With the development of the new tyrosine kinase inhibitors (TKIs), associated with these mutations, the resistance problem seems to diminish, as some of the new drugs are less prone to resistance. The aim of this review is to focus on the diff erent mutations leading to resistance.

In recent years, the incidence of osteonecrosis of the jaw (ONJ) as an unknown complication in patients receiving bisphosphonates (BP) has been on the increase. According to literature data it is in the range of 0.83% to 11.9%. ONJ has been mostly reported in patients with malignancies--mainly in multiple myeloma (MM) patients, followed by patients with bone metastases from breast and prostatic cancer. The view that is supported by a growing body of researchers in the discussion on the etiopathogenetic relationship between ONJ and BPs is that ONJ seems to be a class-specific side effect rather than a result of the use of a specific drug. The major risk factor for development of ONJ is not the BP type, but the time of their administration and accumulation in the bone structures. More than 70% of the ONJ patients report preceding dental problems. The immunosuppressive effects of chemo- and radiotherapy, the impaired bone remodeling resulting from corticoid therapy, the antiangiogenetic properties of thalidomide slow down the reparative processes in the oral cavity and appear as a predisposing factor for the development of ONJ. Possibilities for successful treatment are limited; conservative approaches and least surgery, if larger areas are involved, are recommended. Dental prophylaxis is of particular importance. We present a 66-year-old man with multiple myeloma, IgG, BJ(k), II A KC (after Durie and Salmon staging system). ONJ was diagnosed one year after the disease onset, during which the patient received chemotherapy and was administered concurrently 14 cycles of BPs (pamidronate/zolendronate). The diagnosis was based on clinical, radiologic and histological evidence. Surgical removal of the necrotic sequesters and antibiotic treatment produced a clinical improvement. This rare, refractory complication requires the joint efforts of hematologists, oncologists, and maxillofacial surgeons to diagnose, manage prophylactically and treat.

POEMS syndrome (polyneuropathy, organomegaly, M-protein, and skin changes) is a rare plasma cell disease with small tumour mass and multisystem involvement. Since 2003 POEMS syndrome has been a nosological entity with approved diagnostic criteria, though its etiology and pathogenesis are still not clear. Males are more often affected, with peak incidence in the 5th and 6th decades. The major diagnostic problems are difficult detection of plasma cell infiltration in the osteosclerotic lesions and M-gradient most often low concentration IgA (lamda). We present a case of POEMS syndrome in a 47-year-old male patient who initially presented with edema of the lower limbs, moderate lymphadenopathy, hepatosplenomegaly, histological findings of Castleman disease with marked sinusoidal angioproliferation in the lymph nodes and multiple osteosclerotic lesions. Pleural effusion, ascitis, renal failure, progressive lower limbs polyneuropathy with invalidisation of the patient developed later. The attempts to detect lymphoproliferative process by myelogram, trephine biopsy, histological examination of lymph node and the spleen were ineffective and deceptively non-informative, neither did immunoelectrophoresis reveal M-grade. Diagnosis was made after bone biopsy of the largest osteosclerotic lesion and immunofixation (monoclonal IgA, lamda in the serum). The patient underwent treatment with alkylating agents and corticosteroids, radiation of the predominant osteosclerotic lesions and therapy with radioactive strontium. The general condition improved, lymphadenomegaly, skin lesions, pleural effusion and ascitis regressed and renal function was restored. There was a minor improvement of the neurological symptoms. Autollogous stem-cell transplantation is also recommended in literature for patients with generalized bone lesions or progressive and disease-resistant therapy.

Proteasome inhibitors are emerging as a promising class of anti-cancer therapeutic agents. The first of this new class of drugs with a clinical significance, bortezomib (PS 341, Velcade), is a modified dipeptidyl boronic acid. Bortezomib reduces the NF-kappaB translocation / transcription and blocks the drug-related signalling pathways critical to basic vital functions of myeloma cells. Bortezomib induces apoptosis by releasing cytochrome C from mitochondria and by activating caspase-9 and Jun-kinases (JNK) and the Fas-caspase-8-dependent apoptotic pathway. Bortezomib has been reported to down-regulate cytokine-induced expression of VCAM-1, a major ligand on bone marrow stromal cells for VLA-4; it inhibits the heterotypic adherence between the myeloma cells and stromal cells and blocks the signalling pathways of resistance to apoptosis. The drug has been shown experimentally to inhibit the IL-6-induced proliferation of myeloma cells; it demonstrates synergy with dexamethasone and inhibits angiogenesis. Phase II/ III clinical studies with Velcade have shown an overall therapeutic response rate of 35% in refractory, relapsed myeloma patients (Bladé criteria). These surprisingly good results, the drug's good tolerance and controllable side effects provide a solid base for further studies on bortezomib, including studies on the drug used as front line therapy.

Multiple myeloma has recently been found to induce considerable imbalance in the newly identified system of osteoprotegerin (OPG), receptor activator of nuclear factor KB ligand (RANKL) and RANK. The binding of RANKL to RANK on the surface of osteoclastic precursors in the presence of m-CSF activates the signalling pathways for differentiation and proliferation of an osteoclastic line. OPG is a decoy circulating receptor for RANKL which blocks its binding to RANK. There are at least three mechanisms by which myeloma cells affects the OPG/ RANKL/RANK system: 1: The adhesion between the myeloma / stromal cells and the osteoblastic precursors stimulates the system by increasing the production of RANKL. 2: Some myeloma lines produce independently membrane-bound or free RANKL. 3: The normal and mutated plasma cells bind, degrade and block the OPG production from the stromal cells. The OPG/RANKL/RANK system is the latest therapeutic target in the treatment of myeloma bone disease. The first results from the application of a synthetic analogue of OPG, as well as of RANKL antagonists or RANK inhibitors show decrease of the number of osteoclasts, osteolytic lesions and M-gradient.