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Purpose: To introduce a rare case of patient with hyperlipidemic myeloma and ocular manifestation in form of masquerade syndrome with acute elevation of intraocular pressure (IOP) and hyperviscous retinopathy., Results: 55-year-old man with newly diagnosed hyperlipidemic myeloma and hyperviscous syndrome was acutely referred to our glaucoma outpatient clinic due to problems with his left eye: sudden pain, blurred vision, redness of the eye and IOP of 44 mm Hg. We excluded attack of angle closure glaucoma and found presence of whitish material in the anterior chamber and blood obstructing the iridocorneal angle. Glaucoma therapy was initiated and lavage of the anterior chamber of the left eye with sampling of the aqueous humour for biochemical and cytological examination was performed. Identification of trace amount of cryoprotein in the samples of humour proved diagnosis of masquerade syndrome. Finding of the hyperviscous retinopathy and nonperfusion of wide peripheral areas of retina in both eyes was indicated to laser coagulation of these areas. The patient underwent in the meantime three times plasmapheresis, four cycles of biological therapy and autologous stem cell transplantation reaching complete remission of the myeloma. Local and systemic therapy led to significant clinical finding improvement on the anterior segment and fundus of both eyes., Conclusions: Masquerade syndrome can be complicated by acute elevation of IOP. Diagnostic lavage of the anterior chamber, local therapy, systemic therapy and close interdisciplinary cooperation contributed to right diagnosis, IOP normalisation, ocular and general condition improvement.

Proteasome inhibitors are the backbone of multiple myeloma therapy. However, disease progression or early relapse occur due to development of resistance to the therapy. One important cause of resistance to proteasome inhibition is the so-called bounce-back response, a recovery pathway driven by the TCF11/Nrf1 transcription factor, which activates proteasome gene re-synthesis upon impairment of the proteasome function. Thus, inhibiting this recovery pathway potentiates the cytotoxic effect of proteasome inhibitors and could benefit treatment outcomes. DDI2 protease, the 3D structure of which resembles the HIV protease, serves as the key player in TCF11/Nrf1 activation. Previous work found that some HIV protease inhibitors block DDI2 in cell-based experiments. Nelfinavir, an oral anti-HIV drug, inhibits the proteasome and/or pAKT pathway and has shown promise for treatment of relapsed/refractory multiple myeloma. Here, we describe how nelfinavir inhibits the TCF11/Nrf1-driven recovery pathway by a dual mode of action. Nelfinavir decreases the total protein level of TCF11/Nrf1 and inhibits TCF11/Nrf1 proteolytic processing, likely by interfering with the DDI2 protease, and therefore reduces the TCF11/Nrf1 protein level in the nucleus. We propose an overall mechanism that explains nelfinavir's effectiveness in the treatment of multiple myeloma., Competing Interests: The authors declare no conflict of interest.

This study used data from the Czech Myeloma Group Registry of Monoclonal Gammopathies to validate the International Myeloma Working Group (IMWG) and revised International Staging System (R-ISS) indices for risk stratification in patients with multiple myeloma (MM) in clinical practice. Patients were included if they had symptomatic MM, complete data allowing R-ISS and IMWG staging (including cytogenetic information regarding t(4;14), t(14;16), and del(17p)), and key parameters for treatment evaluation. Median overall survival (OS) in included patients (n = 550) was 47.7 (95% CI: 39.5-55.9) and 46.2 (95% CI: 38.9-53.5) months from diagnosis and initiation of first-line therapy, respectively. Patients categorized as higher vs lower risk had reduced survival; median OS from diagnosis was 35.4 (95% CI: 30.5-40.3) vs 58.3 (95% CI: 53.8-62.9) months in high-risk vs other patients (IMWG; P = .001) and 34.1 (95% CI: 30.2-38.0) vs 47.2 (95% CI: 43.4-51.0) months in Stage III vs Stage II patients (R-ISS; P < .001). In conclusion, IMWG and R-ISS risk stratification indices are applicable to patients with MM in a real-world setting., (© 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Introduction: Real-world data on patient outcomes and treatment patterns in multiple myeloma (MM) are limited., Materials and Methods: The present noninterventional, observational, retrospective analysis of prospectively collected Czech patient medical record data from the Registry of Monoclonal Gammopathies estimated real-world outcomes in adults with a diagnosis of symptomatic MM made between May 2007 and June 2014., Results: In total, 2446 patients had initiated first-line treatment. The median overall survival since the diagnosis (primary endpoint) was 50.3 months (95% confidence interval, 46.1-54.5 months) and decreased with each successive treatment line. A similar trend was observed for progression-free survival and the depth of response. In line with European guidelines and clinical practice, bortezomib-, thalidomide-, and lenalidomide-based regimens were most commonly used across all treatment lines (42.3%, 28.9%, and 18.4%, respectively). In the first line, bortezomib and thalidomide were used most often, with lenalidomide the most commonly used agent in the relapse setting (second to fourth lines). Exploratory analyses revealed that younger age (≤ 65 years), lower international staging system stage, and previous stem cell transplantation were associated with significant improvements in overall and progression-free survival, especially in the early treatment lines., Conclusion: The present study is the first analysis of Czech data from the Registry of Monoclonal Gammopathies, and it provides important insights into the real-world management of MM for physicians and healthcare providers., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objectives: We conducted an adjusted comparison of progression-free survival (PFS) and overall survival (OS) for daratumumab monotherapy versus standard of care, as observed in a real-world historical cohort of heavily pretreated multiple myeloma patients from Czech Republic., Methods: Using longitudinal chart data from the Registry of Monoclonal Gammopathies (RMG) of the Czech Myeloma Group, patient-level data from the RMG was pooled with pivotal daratumumab monotherapy studies (GEN501 and SIRIUS; 16 mg/kg)., Results: From the RMG database, we identified 972 treatment lines in 463 patients previously treated with both a proteasome inhibitor and an immunomodulatory drug. Treatment initiation dates for RMG patients were between March 2006 and March 2015. The most frequently used treatment regimens were lenalidomide-based regimens (33.4%), chemotherapy (18.1%), bortezomib-based regimens (13.6%), thalidomide-based regimens (8.0%), and bortezomib plus thalidomide (5.3%). Few patients were treated with carfilzomib-based regimens (2.5%) and pomalidomide-based regimens (2.4%). Median observed PFS for daratumumab and the RMG cohort was 4.0 and 5.8 months (unadjusted hazard ratio [HR], 1.14; 95% confidence interval [CI], 0.94-1.39), respectively, and unadjusted median OS was 20.1 and 11.9 months (unadjusted HR, 0.61; 95% CI, 0.48-0.78), respectively. Statistical adjustments for differences in baseline characteristics were made using patient-level data. The adjusted HRs (95% CI) for PFS and OS for daratumumab versus the RMG cohort were 0.79 (0.56-1.12; p = .192) and 0.33 (0.21-0.52; p < .001), respectively., Conclusions: Adjusted comparisons between trial data and historical cohorts can provide useful insights to clinicians and reimbursement decision makers on relative treatment efficacies in the absence of head-to-head comparison studies for daratumumab monotherapy.

Introduction: Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant condition with a risk of malignant conversion., Patients and Methods: With the aim to estimate the cumulative risk MGUS progression to hematologic malignancies, we analyzed a nationwide population-based cohort of 1887 MGUS patients from the Czech Registry of Monoclonal Gammopathies (RMG) between 2007 and 2013., Results: During the follow-up period (median 4 years; range 0.6-34.8), progression to hematologic malignancies was observed in 8.6% (162 of 1887) of patients. Factors associated with progression were as follows: M-protein concentration ≥1.5 g/dL, pathological sFLC (<0.26 or >1.65) ratio, bone marrow plasma cells (BMPCs) in cytology >5%, immunoparesis, age ≥69 years, and the level of serum hemoglobin at baseline <12.0 g/dL. Combining these factors, we propose a new risk model (CMG model). The risk of progression at 10 years was 1.6%, 16.9%, 22.9%, 39.4%, and 52.3%, respectively, if 0 (reference group), one, two, three, or four to five risk factors are present (P<.001) with HR 63 times higher compared to the reference MGUS group., Conclusion: The new CMG model was established with an advantage for better identification of MGUS patients at low risk., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

A primary analysis of the ASPIRE study found that the addition of carfilzomib to lenalidomide and dexamethasone (carfilzomib group) significantly improved progression-free survival (PFS) compared with lenalidomide and dexamethasone alone (control group) in patients with relapsed multiple myeloma (RMM). This post hoc analysis examined outcomes from ASPIRE in patients categorised by age. In the carfilzomib group, 103/396 patients were ≥70 years old, and in the control group, 115/396 patients were ≥70 years old. Median PFS for patients <70 years old was 28·6 months for the carfilzomib group versus 17·6 months for the control group [hazard ratio (HR), 0·701]. Median PFS for patients ≥70 years old was 23·8 months for the carfilzomib group versus 16·0 months for the control group (HR, 0·753). For patients <70 years the overall response rate (ORR) was 86·0% (carfilzomib group) and 66·9% (control group); for patients ≥70 years old the ORR was 90·3% (carfilzomib group) and 66·1% (control group). Within the carfilzomib group, grade ≥3 cardiovascular adverse events occurred more frequently among patients ≥70 years old compared with patients <70 years old. Carfilzomib-lenalidomide-dexamethasone has a favourable benefit-risk profile for patients with RMM, including elderly patients ≥70 years old., Trial Registration: clinicaltrials.gov identifier: NCT01080391., (© 2017 The Authors. British Journal of Haematology published by John Wiley & Sons Ltd.)

Purpose To determine the effects of carfilzomib, lenalidomide, and dexamethasone (KRd) versus lenalidomide and dexamethasone (Rd) on health-related quality of life (HR-QoL) in the Carfilzomib, Lenalidomide, and Dexamethasone Versus Lenalidomide and Dexamethasone for the Treatment of Patients With Relapsed Multiple Myeloma (ASPIRE) trial. Methods Patients with relapsed multiple myeloma were randomly assigned to receive KRd or Rd. The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 and myeloma-specific module were administered at baseline; day 1 of cycles 3, 6, 12, and 18; and after treatment. The Global Health Status/Quality of Life (GHS/QoL) scale and seven subscales (fatigue, nausea and vomiting, pain, physical functioning, role functioning, disease symptoms, and adverse effects of treatment) were compared between groups using a mixed model for repeated measures. The percentages of responders with ≥ 5- or 15-point GHS/QoL improvement at each cycle were compared between groups. Results Baseline questionnaire compliance was excellent (94.1% of randomly assigned patients). KRd patients had higher GHS/QoL scores versus Rd patients over 18 treatment cycles (two-sided P < .001). The minimal important difference was met at cycle 12 (5.6 points) and approached at cycle 18 (4.8 points). There was no difference between groups for the other prespecified subscales from ASPIRE. A higher proportion of KRd patients met the GHS/QoL responder definition (≥ 5-point improvement) with statistical differences at cycle 12 (KRd v Rd patients, 25.5% v 17.4%, respectively) and 18 (KRd v Rd patients, 24.2% v 12.9%, respectively). Conclusion KRd improves GHS/QoL without negatively affecting patient-reported symptoms when compared with Rd. These data further support the benefit of KRd in patients with relapsed multiple myeloma.

The presence of certain high-risk cytogenetic abnormalities, such as translocations (4;14) and (14;16) and deletion (17p), are known to have a negative impact on survival in multiple myeloma (MM). The phase 3 study ASPIRE (N = 792) demonstrated that progression-free survival (PFS) was significantly improved with carfilzomib, lenalidomide, and dexamethasone (KRd), compared with lenalidomide and dexamethasone (Rd) in relapsed MM. This preplanned subgroup analysis of ASPIRE was conducted to evaluate KRd vs Rd by baseline cytogenetics according to fluorescence in situ hybridization. Of 417 patients with known cytogenetic risk status, 100 patients (24%) were categorized with high-risk cytogenetics (KRd, n = 48; Rd, n = 52) and 317 (76%) were categorized with standard-risk cytogenetics (KRd, n = 147; Rd, n = 170). For patients with high-risk cytogenetics, treatment with KRd resulted in a median PFS of 23.1 months, a 9-month improvement relative to treatment with Rd. For patients with standard-risk cytogenetics, treatment with KRd led to a 10-month improvement in median PFS vs Rd. The overall response rates for KRd vs Rd were 79.2% vs 59.6% (high-risk cytogenetics) and 91.2% vs 73.5% (standard-risk cytogenetics); approximately fivefold as many patients with high- or standard-risk cytogenetics achieved a complete response or better with KRd vs Rd (29.2% vs 5.8% and 38.1% vs 6.5%, respectively). KRd improved but did not abrogate the poor prognosis associated with high-risk cytogenetics. This regimen had a favorable benefit-risk profile in patients with relapsed MM, irrespective of cytogenetic risk status, and should be considered a standard of care in these patients. This trial was registered at www.clinicaltrials.gov as #NCT01080391., (© 2016 by The American Society of Hematology.)

Introduction: The normalization of free light chain ratio (FLCr) has been introduced as a marker of stringent complete remission (CR) of multiple myeloma (MM). There is currently a lack of literature assessing the role of FLCr on MM disease progression and remission status., Patients and Methods: A multicentered retrospective review of 125 patients with MM in CR and various FLCr values was completed. Parameters of interest included patient demographics, FLCr values, complete remission (CR)/relapse status, and time to progression (TTP). The FLCr values were recorded to provide time-dependent findings on the role of FLCr on progression-free survival and overall survival (OS)., Results: The mean follow-up time of 125 patients from five hospitals in the Czech Republic was 31 months. A total of 47.2% of patients relapsed (54 of 125) during the follow-up period. The median TTP of patients with normal FLCr (n = 66) was 54.4 and 40.2 months for patients with abnormal FLCr (n = 59) (P = 0.217). None of the patients reached median overall survival regardless of FLCr values (P = 0.821). In the subgroup of newly diagnosed patients after upfront autologous stem cell transplantation (ASCT), there were 55.6% of patients (35 of 63) with normal FLCr and 44.4% (28 of 64) with abnormal FLCr. A total of 34.9% of patients (22 of 63) relapsed in this subgroup. Within the abnormal FLCr patients, a median TTP was 56.3 months, but no median TTP was reached among the normal FLCr patients (P = 0.746). Median OS in patients with normal (nFLCr) and abnormal FLCr (aFLCr) was not reached (P = 0.787)., Conclusion: We did not observe any benefit from FLCr normalization in CR in myeloma patients in terms of progression-free survival or overall survival., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: A new interleukin-6 (IL-6)-dependent plasma cell leukemia cell line UHKT-944 was established from bone marrow cells derived from a 55-yr-old man with plasma cell leukemia., Results: The cell line possesses phenotypic characteristics of plasma cells including the production of a monoclonal immunoglobulin IgA1-kappa. VH3-9 region of IgVH genes was rearranged and somatically hypermutated. The UHKT-944 cells were found to be negative for most of tested B-cell, T-cell, and myeloid markers. According to cytogenetic analysis, the cells were classified as near tetraploid with several numerical and structural abnormalities including the t(14;20) involving IgH locus., Conclusion: The established permanent plasma cell leukemia cell line is a suitable model for the study of cellular and molecular mechanisms of pathogenesis of this rare malignant disease., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Lenalidomide plus dexamethasone is a reference treatment for relapsed multiple myeloma. The combination of the proteasome inhibitor carfilzomib with lenalidomide and dexamethasone has shown efficacy in a phase 1 and 2 study in relapsed multiple myeloma., Methods: We randomly assigned 792 patients with relapsed multiple myeloma to carfilzomib with lenalidomide and dexamethasone (carfilzomib group) or lenalidomide and dexamethasone alone (control group). The primary end point was progression-free survival., Results: Progression-free survival was significantly improved with carfilzomib (median, 26.3 months, vs. 17.6 months in the control group; hazard ratio for progression or death, 0.69; 95% confidence interval [CI], 0.57 to 0.83; P=0.0001). The median overall survival was not reached in either group at the interim analysis. The Kaplan-Meier 24-month overall survival rates were 73.3% and 65.0% in the carfilzomib and control groups, respectively (hazard ratio for death, 0.79; 95% CI, 0.63 to 0.99; P=0.04). The rates of overall response (partial response or better) were 87.1% and 66.7% in the carfilzomib and control groups, respectively (P<0.001; 31.8% and 9.3% of patients in the respective groups had a complete response or better; 14.1% and 4.3% had a stringent complete response). Adverse events of grade 3 or higher were reported in 83.7% and 80.7% of patients in the carfilzomib and control groups, respectively; 15.3% and 17.7% of patients discontinued treatment owing to adverse events. Patients in the carfilzomib group reported superior health-related quality of life., Conclusions: In patients with relapsed multiple myeloma, the addition of carfilzomib to lenalidomide and dexamethasone resulted in significantly improved progression-free survival at the interim analysis and had a favorable risk-benefit profile. (Funded by Onyx Pharmaceuticals; ClinicalTrials.gov number, NCT01080391.).

We compared the safety and efficacy of siltuximab (S), an anti-interleukin-6 chimeric monoclonal antibody, plus bortezomib (B) with placebo (plc) + B in patients with relapsed/refractory multiple myeloma in a randomized phase 2 study. Siltuximab was given by 6 mg/kg IV every 2 weeks. On progression, B was discontinued and high-dose dexamethasone could be added to S/plc. Response and progression-free survival (PFS) were analyzed pre-dexamethasone by European Group for Blood and Marrow Transplantation (EBMT) criteria. For the 281 randomized patients, median PFS for S + B and plc + B was 8.0 and 7.6 months (HR 0.869, P = 0.345), overall response rate was 55 versus 47% (P = 0.213), complete response rate was 11 versus 7%, and median overall survival (OS) was 30.8 versus 36.8 months (HR 1.353, P = 0.103). Sustained suppression of C-reactive protein, a marker reflective of inhibition of interleukin-6 activity, was seen with S + B. Siltuximab did not affect B pharmacokinetics. Siltuximab/placebo discontinuation (75 versus 66%), grade ≥3 neutropenia (49 versus 29%), thrombocytopenia (48 versus 34%), and all-grade infections (62 versus 49%) occurred more frequently with S + B. The addition of siltuximab to bortezomib did not appear to improve PFS or OS despite a numerical increase in response rate in patients with relapsed or refractory multiple myeloma., (© 2014 Wiley Periodicals, Inc.)

Multiple myeloma is one of the most common hematological malignancies with increasing prevalence. Not until the introduction of 1 or 2 cycles of highdose therapy with the support of hematopoietic cells meant a certain progress in the prognosis of patients. The radical change in the therapy efficiency was not made possible until the so-called new or targeting drugs -  thalidomide, bortezomib and lenalidomide. The 2 latter preparations have particularly changed the approach to the disease itself from one of the least prognostically favourable hematological tumours to a longterm controllable malignancy with a potential to treat at least some of the patients. Currently, 3 ways of further progress towards more efficient treatment methods are under investigation: a) maintenance or consolidation treatment aimed at further intensification of therapeutic response, b) combination of targeting drugs and c) efficiency of the "second generation" targeting drugs.