Publications by authors named "Magdalini Migkou"

70 Publications

Poor neutralizing antibody responses in 106 patients with WM after vaccination against SARS-CoV-2: a prospective study.

Blood Adv 2021 11;5(21):4398-4405

Department of Clinical Therapeutics, School of Medicine, and.

Immunocompromised patients with hematologic malignancies are more susceptible to COVID-19 and at higher risk of severe complications and worse outcomes compared with the general population. In this context, we evaluated the humoral response by determining the titers of neutralizing antibodies (NAbs) against SARS-CoV-2 in patients with Waldenström macroglobulinemia (WM) after vaccination with the BNT162b2 or AZD1222 vaccine. A US Food and Drug Administration-approved enzyme-linked immunosorbent assay-based methodology was implemented to evaluate NAbs on the day of the first vaccine shot, as well as on days 22 and 50 afterward. A total of 106 patients with WM (43% men; median age, 73 years) and 212 healthy controls (46% men; median age, 66 years) who were vaccinated during the same period at the same center were enrolled in the study (which is registered at www.clinicaltrials.gov as #NCT04743388). Our data indicate that vaccination with either 2 doses of the BNT162b2 or 1 dose of the AZD1222 vaccine leads to lower production of NAbs against SARS-CoV-2 in patients with WM compared with controls on days 22 and 50 (P < .001 for all comparisons). Disease-related immune dysregulation and therapy-related immunosuppression are involved in the low humoral response. Importantly, active treatment with either rituximab or Bruton's tyrosine kinase inhibitors was proven as an independent prognostic factor for suboptimal antibody response after vaccination. In conclusion, patients with WM have low humoral response after COVID-19 vaccination, which underlines the need for timely vaccination ideally during a treatment-free period and for continuous vigilance on infection control measures.
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http://dx.doi.org/10.1182/bloodadvances.2021005444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8450138PMC
November 2021

Myeloma patients with COVID-19 have superior antibody responses compared to patients fully vaccinated with the BNT162b2 vaccine.

Br J Haematol 2021 Sep 16. Epub 2021 Sep 16.

Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, Greece.

Patients with multiple myeloma (MM) have a suboptimal antibody response following vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and lower seroconversion rates following coronavirus disease 2019 (COVID-19) compared with healthy individuals. In this context, we evaluated the development of neutralising antibodies (NAbs) against SARS-CoV-2 in non-vaccinated patients with MM and COVID-19 compared with patients after vaccination with two doses of the BNT162b2 vaccine. Serum was collected either four weeks post confirmed diagnosis or four weeks post a second dose of BNT162b2. NAbs were measured with a Food and Drug Administration-approved enzyme-linked immunosorbent assay methodology. Thirty-five patients with COVID-19 and MM along with 35 matched patients were included. The two groups did not differ in age, sex, body mass index, prior lines of therapy, disease status, lymphocyte count, immunoglobulin levels and comorbidities. Patients with MM and COVID-19 showed a superior humoral response compared with vaccinated patients with MM. The median (interquartile range) NAb titre was 87·6% (71·6-94%) and 58·7% (21·4-91·8%) for COVID-19-positive and vaccinated patients, respectively (P = 0·01).Importantly, there was no difference in NAb production between COVID-19-positive and vaccinated patients who did not receive any treatment (median NAb 85·1% vs 91·7%, P = 0·14). In conclusion, our data indicate that vaccinated patients with MM on treatment without prior COVID-19 should be considered for booster vaccine doses.
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http://dx.doi.org/10.1111/bjh.17841DOI Listing
September 2021

Consolidation with a short course of daratumumab in patients with AL amyloidosis or light chain deposition disease.

Amyloid 2021 Sep 1:1-8. Epub 2021 Sep 1.

Plasma Cell Dyscrasia Unit, Department of Clinical Therapeutics, National and Kapodistrian University of Athens, Athens, Greece.

Daratumumab has major and rapid activity in AL amyloidosis with favourable toxicity. We used as a consolidation a short course of daratumumab in 25 patients with AL amyloidosis or light chain deposition disease (LCDD), who had not achieved a haematologic complete response (hemCR) after standard therapy with bortezomib, cyclophosphamide and dexamethasone (VCD). We evaluated minimal residual disease (MRD) and changes in the bone marrow (BM) microenvironment before and after consolidation using next generation flow cytometry (NGF). At the time of consolidation, 21 patients were in very good partial response (VGPR) and four in partial response (PR); all had detectable MRD. One month after consolidation completion, 8 patients (32%) achieved a hemCR, of whom 5 (20%) became also MRD negative. In the BM, we observed significant changes in B-cell precursors, naïve B-cells, T-cells, CD27+ NK & NKT cells, mast cells and erythroblasts. After a median follow-up of 25 months, none of the patients in hemCR has relapsed and all have achieved an organ response; a haematologic relapse occurred in 6/17 patients that did not achieve hemCR. In conclusion, consolidation with a short course of daratumumab can improve depth of response in patients with AL amyloidosis or LCDD and significantly affects BM environment.
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http://dx.doi.org/10.1080/13506129.2021.1971192DOI Listing
September 2021

Aberrant Plasma Cell Contamination of Peripheral Blood Stem Cell Autografts, Assessed by Next-Generation Flow Cytometry, Is a Negative Predictor for Deep Response Post Autologous Transplantation in Multiple Myeloma; A Prospective Study in 199 Patients.

Cancers (Basel) 2021 Aug 11;13(16). Epub 2021 Aug 11.

Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, 11528 Athens, Greece.

High-dose chemotherapy with autologous stem cell support (ASCT) is the standard of care for eligible newly diagnosed Multiple Myeloma (MM) patients. Stem cell graft contamination by aberrant plasma cells (APCs) has been considered a possible predictive marker of subsequent clinical outcome, but the limited reports to date present unclear conclusions. We prospectively estimated the frequency of graft contamination using highly sensitive next-generation flow cytometry and evaluated its clinical impact in 199 myeloma patients who underwent an ASCT. Contamination (con+) was detected in 79/199 patients at a median level 2 × 10. Its presence and levels were correlated with response to induction treatment, with 94%, 71% and 43% achieving CR, VGPR and PR, respectively. Importantly, con+ grafts conferred 2-fold and 2.8-fold higher patient-risk of not achieving or delaying reaching CR (4 vs. 11 months) and MRD negativity (5 vs. 18 months) post ASCT, respectively. Our data also provide evidence of a potentially skewed bone marrow (BM) reconstitution due to unpurged grafts, since con+ derived BM had significantly higher prevalence of memory B cells. These data, together with the absence of significant associations with baseline clinical features, highlight graft contamination as a potential biomarker with independent prognostic value for deeper responses, including MRD negativity. Longer follow-up will reveal if this corresponds to PFS or OS advantage.
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http://dx.doi.org/10.3390/cancers13164047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8391595PMC
August 2021

The neutralizing antibody response post COVID-19 vaccination in patients with myeloma is highly dependent on the type of anti-myeloma treatment.

Blood Cancer J 2021 08 2;11(8):138. Epub 2021 Aug 2.

Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.

Recent data suggest a suboptimal antibody response to COVID-19 vaccination in patients with hematological malignancies. Neutralizing antibodies (NAbs) against SARS-CoV-2 were evaluated in 276 patients with plasma cell neoplasms after vaccination with either the BNT162b2 or the AZD1222 vaccine, on days 1 (before the first vaccine shot), 22, and 50. Patients with MM (n = 213), SMM (n = 38), and MGUS (n = 25) and 226 healthy controls were enrolled in the study (NCT04743388). Vaccination with either two doses of the BNT162b2 or one dose of the AZD1222 vaccine leads to lower production of NAbs in patients with MM compared with controls both on day 22 and on day 50 (p < 0.001 for all comparisons). Furthermore, MM patients showed an inferior NAb response compared with MGUS on day 22 (p = 0.009) and on day 50 (p = 0.003). Importantly, active treatment with either anti-CD38 monoclonal antibodies (Mabs) or belantamab mafodotin and lymphopenia at the time of vaccination were independent prognostic factors for suboptimal antibody response following vaccination. In conclusion, MM patients have low humoral response following SARS-CoV-2 vaccination, especially under treatment with anti-CD38 or belamaf. This underlines the need for timely vaccination, possibly during a treatment-free period, and for continuous vigilance on infection control measures in non-responders.
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http://dx.doi.org/10.1038/s41408-021-00530-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8327056PMC
August 2021

Low neutralizing antibody responses in WM, CLL and NHL patients after the first dose of the BNT162b2 and AZD1222 vaccine.

Clin Exp Med 2021 Jul 20. Epub 2021 Jul 20.

Department of Clinical Therapeutics, School of Medicine, Alexandra General Hospital, National and Kapodistrian University of Athens, 80 Vas. Sofias Avenue, 11528, Athens, Greece.

Vaccination against SARS-CoV-2 is considered as the most important preventive strategy against COVID-19, but its efficacy in patients with hematological malignancies is largely unknown. We investigated the development of neutralizing antibodies (NAbs) against SARS-CoV-2 in patients with Waldenstrom Macroglobulinemia (WM), Chronic Lymphocytic Leukemia (CLL) and Non-Hodgkin Lymphoma (NHL). After the first dose of the vaccine, on D22, WM/CLL/NHL patients had lower NAb titers compared to controls: the median NAb inhibition titer was 17% (range 0-91%, IQR 8-27%) for WM/CLL/NHL patients versus 32% (range 2-98%, IQR 19-48%) for controls (P < 0.001). Only 8 (14%) patients versus 114 (54%) controls developed NAb titers ≥ 30% on D22 (p < 0.001). Our data indicate that the first dose of both BNT162b2 and AZD1222 leads to lower production of NAbs against SARS-CoV-2 in patients with WM/CLL/NHL compared to controls of similar age and gender and without malignant disease. Even though the response rates were not optimal, vaccination is still considered essential and if possible should be performed before treatment initiation. These patients with suboptimal responses should be considered to be prioritized for booster doses.
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http://dx.doi.org/10.1007/s10238-021-00746-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8290394PMC
July 2021

Ibrutinib plus rituximab for the treatment of adult patients with Waldenström's macroglobulinemia: a safety evaluation.

Expert Opin Drug Saf 2021 Sep 11;20(9):987-995. Epub 2021 Aug 11.

Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.

: Waldenström's macroglobulinemia (WM), an orphan disease, is a rare low-grade B-cell lymphoplasmacytic lymphoma with unique clinical features and monoclonal IgM production. Rituximab remains to this date the backbone of most commonly used treatment combinations. The FDA/EMA approval of Ibrutinib, the first-in-class BTK inhibitor, either as monotherapy or in combination with rituximab, changed the treatment landscape of the disease.: Clinical trial data that demonstrate mode of action, efficacy, and the safety profile of each agent will be covered. A safety analysis of the combination treatment will also be performed to point out its high efficacy and overall favorable toxicity profile. The disadvantages and treatment gaps that still exist in the treatment of WM which relate to the need for long-term ibrutinib administration and the lack of deep remissions and subsequent disease relapse, will also be reviewed.: The ibrutinib-rituximab combination is both effective and safe, in the newly-diagnosed and relapsed-refractory disease setting. The optimal therapeutic approach for WM patients remains however to be established. The question of which combinatory (or synergistic) regimen can allow for a fixed-treatment duration, deep and durable responses with a safe toxicity profile is being addressed in ongoing clinical trials.
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http://dx.doi.org/10.1080/14740338.2021.1945031DOI Listing
September 2021

Continuing Cancer Therapy through the Pandemic While Protecting Our Patients: Results of the Implementation of Preventive Strategies in a Referral Oncology Unit.

Cancers (Basel) 2021 Feb 12;13(4). Epub 2021 Feb 12.

Department of Clinical Therapeutics, National and Kapodistrian University of Athens, Alexandra Hospital, Athens 11528, Greece.

Cancer patients infected with SARS-CoV-2 have worse outcomes, including higher morbidity and mortality than the general population. Protecting this vulnerable group of patients from COVID-19 is of the utmost importance for the continuous operation of an oncology unit. Preventive strategies have been proposed by various societies, and centers around the world have implemented these or modified measures; however, the efficacy of these measures has not been evaluated. In our center, a referral oncology/hematology unit in Athens, Greece, we implemented strict protective measures from the outset of the pandemic in the country and we have prospectively recorded the epidemiological characteristics of COVID-19. Among 11,618 patient visits performed in our unit, 26 patients (case-to-visit ratio of 0.22%) were found positive for SARS-CoV-2, including 4 (1%) among 392 patients that were screened before starting primary systemic treatment. Among patients tested positive for SARS-CoV-2, 22 were symptomatic at the time of diagnosis; subsequently, 12 required hospitalization and 5 died due to COVID-19. Detailed contact tracing indicated that there was no in-unit transmission of the infection. Thus, strict implementation of multilevel protective strategies along with a modestly intense screening program allowed us to continue cancer care in our unit through the pandemic.
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http://dx.doi.org/10.3390/cancers13040763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918613PMC
February 2021

Carfilzomib-induced endothelial dysfunction, recovery of proteasome activity, and prediction of cardiovascular complications: a prospective study.

Leukemia 2021 05 15;35(5):1418-1427. Epub 2021 Feb 15.

Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.

Carfilzomib (CFZ) improves survival in relapsed/refractory multiple myeloma but is associated with cardiovascular adverse events (CVAEs). We prospectively investigated the effect of CFZ on endothelial function and associations with CVAEs. Forty-eight patients treated with Kd (CFZ 20/56 mg/m and dexamethasone) underwent serial endothelial function evaluation, using brachial artery flow-mediated dilatation (FMD) and 26S proteasome activity (PrA) measurement in PBMCs; patients were followed until disease progression or cycle 6 for a median of 10 months. FMD and PrA decreased acutely after the first dose (p < 0.01) and FMD decreased at cycles 3 and 6 compared to baseline (p ≤ 0.05). FMD changes were associated with CFZ-induced PrA changes (p < 0.05) and lower PrA recovery during first cycle was associated with more prominent FMD decrease (p = 0.034 for group interaction). During treatment, 25 patients developed Grade ≥3 CVAEs. Low baseline FMD (HR 2.57 lowest vs. higher tertiles, 95% CI 1.081-6.1) was an independent predictor of CVAEs. During treatment, an acute FMD decrease >40% at the end of first cycle was also independently associated with CVAEs (HR = 3.91, 95% CI 1.29-11.83). Kd treatment impairs endothelial function which is associated with PrA inhibition and recovery. Both pre- and posttreatment FMD predicted CFZ-related CVAEs supporting its role as a possible cardiovascular toxicity biomarker.
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http://dx.doi.org/10.1038/s41375-021-01141-4DOI Listing
May 2021

Carfilzomib-associated renal toxicity is common and unpredictable: a comprehensive analysis of 114 multiple myeloma patients.

Blood Cancer J 2020 11 3;10(11):109. Epub 2020 Nov 3.

Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece.

Carfilzomib (CFZ) is a non-reversible proteasome inhibitor approved for the treatment of patients with relapsed and refractory myeloma (RRMM). Its use has been associated with cardiovascular toxicity but although recently a signal of clinically significant renal complications has also been identified, it is less extensively investigated. We analyzed data of 114 consecutive patients with RRMM who received CFZ-based regimens. Renal complications not related to MM progression were observed in 19 (17%) patients; thrombotic microangiopathy (TMA) was seen in 6 (5%) patients, albuminuria >1 gr/day in 7 patients (6%) and at least grade 3 acute kidney injury (AKI) which could not be otherwise explained in 6 patients (5%). A total of 15 patients discontinued CFZ and dosing was reinitiated at a lower level in one patient with AKI. Albuminuria was associated with focal segmental glomerulosclerosis in the renal biopsy (performed in a total of 6 patients). Renal complications during CFZ therapy are common, occur mostly early and are unpredictable. A potential effect of CFZ on the renal endothelium could be implicated in the pathogenesis of these complications and may also share common pathophysiology with cardiovascular effects of CFZ.
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http://dx.doi.org/10.1038/s41408-020-00381-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642386PMC
November 2020

Emerging treatment strategies for COVID-19 infection.

Clin Exp Med 2021 May 30;21(2):167-179. Epub 2020 Oct 30.

Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, Alexandra General Hospital, 80 Vas. Sofias Avenue, 11528, Athens, Greece.

The new type of coronavirus (COVID-19), SARS-CoV-2 originated from Wuhan, China and has led to a worldwide pandemic. COVID-19 is a novel emerging infectious disease caused by SARS-CoV-2 characterized as atypical pneumonia. As of July 1, 2020, more than 10 million people worldwide had been infected with SARS-CoV-2. The typical manifestations of COVID-19 include fever, sore throat, fatigue, cough, and dyspnoea combined with recent exposure. Most of the patients with COVID-19 have mild or moderate disease, however up to 5-10% present with severe and even life-threatening disease course. The mortality rates are approximately 2%. Therefore, there is an urgent need for effective and specific antiviral treatment. Currently, supportive care measures such as ventilation oxygenation and fluid management remain the standard of care. Several clinical trials are currently trying to identify the most potent drug or combination against the disease, and it is strongly recommended to enroll patients into ongoing trials. Antivirals can be proven as safe and effective only in the context of randomized clinical trials. Currently several agents such as chloroquine, hydroxychloroquine, favipiravir, monoclonal antibodies, antisense RNA, corticosteroids, convalescent plasma and vaccines are being evaluated. The large numbers of therapeutic interventions aim to define the most efficacious regimen. The aim of this article is to describe the treatment strategies that have been used for COVID-19 patients and review all the available literature.
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http://dx.doi.org/10.1007/s10238-020-00671-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7598940PMC
May 2021

Response of an oncology unit in the midst of the COVID-19 outbreak.

J Oncol Pharm Pract 2020 Dec 22;26(8):1947-1952. Epub 2020 Oct 22.

Department of Clinical Therapeutics, Alexandra General Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.

Coronavirus disease 19 (COVID-19) pandemic has caused an emergency in health systems worldwide. Apart from its apparent morbidity and mortality, COVID-19 has also imposed unique challenges in the management of cancer patients. We report here measures taken by a major oncology Unit in Greece to continue operation of the department while ensuring safety of the patients and health care professionals. The efficacy of these measures could serve as guidance for Oncology departments in view of a second wave of COVID-19 cases.
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http://dx.doi.org/10.1177/1078155220967973DOI Listing
December 2020

Circulating Soluble Urokinase-Type Plasminogen Activator Receptor Levels Reflect Renal Function in Newly Diagnosed Patients with Multiple Myeloma Treated with Bortezomib-Based Induction.

J Clin Med 2020 Oct 3;9(10). Epub 2020 Oct 3.

Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, 11528 Athens, Greece.

(1) Background: Soluble urokinase-type plasminogen activator receptor (suPAR) has been implicated in the pathogenesis of kidney disease in different disease settings. The aim of this study was to investigate a possible link between suPAR circulating levels and renal impairment (RI) in newly diagnosed patients with symptomatic multiple myeloma (NDMM) before and after frontline therapy with bortezomib-based regimens. (2) Methods: We studied 47 NDMM patients (57% males, median age 69.5 years) before the administration of anti-myeloma treatment and at best response to bortezomib-based therapy. suPAR was measured in the serum of all patients and of 24 healthy matched controls, using an immuno-enzymatic assay (ViroGates, Denmark). (3) Results: suPAR levels were elevated in NDMM patients at diagnosis compared to healthy individuals ( < 0.001). suPAR levels strongly correlated with disease stage (-ANOVA < 0.001). suPAR levels both at diagnosis and at best response negatively correlated with estimated glomerular filtration rate (eGFR) values ( < 0.001). Interestingly, no significance changes in suPAR levels were observed at best response compared to baseline values ( = 0.31) among 18 responding patients with baseline eGFR < 50 mL/min/1.73 m. (4) Conclusions: SuPAR levels reflect renal function in NDMM patients treated with bortezomib-based induction. Responders may have elevated circulating suPAR levels, possibly reflecting persistent kidney damage, despite their renal response.
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http://dx.doi.org/10.3390/jcm9103201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600599PMC
October 2020

The Role of Low Dose Whole Body CT in the Detection of Progression of Patients with Smoldering Multiple Myeloma.

Blood Cancer J 2020 09 25;10(9):93. Epub 2020 Sep 25.

1st Department of Radiology, School of Medicine, Aretaieion Hospital, National and Kapodistrian University of Athens, Athens, Greece.

Multiple myeloma (MM) is the second most common hematological malignancy, characterized by plasma cell bone marrow infiltration and end-organ involvement. Smoldering MM (SMM) is an intermediate clinical entity between MGUS and MM, with a risk of progression to symptomatic disease 10% per year. Bone disease is the most frequent symptom of MM, with ~90% of patients developing bone lesions throughout their disease course. Therefore, imaging plays a crucial role in diagnosis and management. Whole-body low-dose CT (WBLDCT) is widely available and has been incorporated in the latest diagnostic criteria of the IMWG. The purpose of this study was to evaluate the role of WBLDCT in the early identification of lesions in patients with SMM who progress solely with bone disease. In total, 100 asymptomatic patients were consecutively assessed with WBLDCT from July 2013 until March 2020 at baseline, 1-year after diagnosis and every 1 year thereafter. Ten percent of patients were identified as progressors with this single imaging modality. This is the first study to evaluate prospectively patients with SMM at different time points to identify early bone lesions related to MM evolution. Serial WBLDCT studies can identify early myeloma evolution and optimize disease monitoring and therapeutic strategies.
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http://dx.doi.org/10.1038/s41408-020-00360-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519647PMC
September 2020

Daratumumab-based therapy for patients with monoclonal gammopathy of renal significance.

Br J Haematol 2021 04 23;193(1):113-118. Epub 2020 Aug 23.

Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece.

Treatment of the plasma cell clone in monoclonal gammopathy of renal significance (MGRS) is necessary in order to reduce toxic immunoglobulin load to the kidneys and salvage renal function. There are limited data on the use of daratumumab in patients with MGRS. We summarize our experience with the use of daratumumab-based therapy in 25 MGRS patients, 12 of whom were previously untreated. The median follow-up of the cohort is 14 months. The best overall haematologic response in evaluable patients was complete response (CR) in five (22%), very good partial response (VGPR) in five (22%) and partial response (PR) in seven (30%) patients for an overall response rate of 74%. Two of five patients in CR and two patients with initially detectable clones, but non-measurable immunoglobulins, had undetectable minimal residual disease (MRD) with next-generation flow cytometry (NGF) after therapy. Haematologic response rate for previously untreated patients was 83% vs. 69% for previously treated and for daratumumab combinations it was 91% vs. 64%, and with CR/VGPR 82% vs. 29%, compared to daratumumab monotherapy. At six months, 12/22 (55%) patients not on dialysis achieved a reduction of proteinuria >30%, of at least 0·5 g/24 h, without an estimated glomerular filtration rate (eGFR) reduction. The toxicity was mild and predictable. In conclusion, daratumumab-based therapy is a new option for patients with MGRS.
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http://dx.doi.org/10.1111/bjh.17052DOI Listing
April 2021

Next generation flow cytometry for MRD detection in patients with AL amyloidosis.

Amyloid 2021 Mar 12;28(1):19-23. Epub 2020 Aug 12.

Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.

The treatment of AL amyloidosis aims to eradicate the plasma cell clone and eliminate toxic free light chain production. Only in a minority of patients the plasma cell clone is completely eradicated; residual light chain production may still exist while clonal relapse may occur. We used sensitive next-generation flow cytometry (NGF) to detect minimal residual disease (MRD) in AL amyloidosis patients at complete haematologic response. MRD evaluation was feasible in 51 of 52 (98%) tested patients and at a median sensitivity of 2.3 × 10 MRD was undetectable in 23 (45%). An organ response occurred in 86% of MRDneg vs 77% in MRDpos; renal response in 15/17(88%) of MRDneg vs in 14/16(87.5%) of MRDpos and cardiac response in 10/10(100%) of MRDneg vs 11/15(73%) of MRDpos patients. After a median follow-up of 24 months post MRD testing, no MRDneg patient had a haematologic relapse vs 6/28(21%) MRDpos ( = .029). Pooling haematologic and organ progressions, 9 (32%) MRDpos patients had disease progression vs only 1 (4%) MRDneg patient ( = .026). In conclusion, MRD detection using NGF has profound clinical implications, so that AL patients with undetectable MRD have a very high probability of organ response and a very low probability of haematologic relapse.
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http://dx.doi.org/10.1080/13506129.2020.1802713DOI Listing
March 2021

Timing and impact of a deep response in the outcome of patients with systemic light chain (AL) amyloidosis.

Amyloid 2021 Mar 27;28(1):3-11. Epub 2020 Jul 27.

Department of Clinical Therapeutics, National and Kapodistrian University of Athens, Athens, Greece.

A rapid and deep haematologic response is fundamental in order to improve outcomes of patients with AL amyloidosis. We evaluated the impact of timing and depth of haematologic response at early time points (at 1 and 3 months from the start of therapy) in 227 consecutive previously untreated AL patients, who received bortezomib-based primary therapy. After 1 month of therapy, 30.5% had ≥VGPR, 28% PR and 36% no response (NR), with 11% having iFLC <20 mg/L and 15% dFLC <10 mg/L. Deep haematologic response at 1 month (either ≥VGPR or iFLC <20 mg/L or dFLC <10 mg/L), was associated with a high organ response rate. The survival of patients with ≥VGPR was significantly better than those with PR and NR at 1-month landmark ( < .001) but this benefit was mainly driven by those with iFLC <20 mg/L. The depth of haematologic response at 1 month was significant across all Mayo stages. At 3 months, 46% of the patients had not significantly improved the depth of their response but even patients that improved their response from an iFLC ≥20 mg/L at 1 month to iFLC <20 mg/L at 3 months still had inferior outcome to those with an early deep response. Thus, in patients with AL amyloidosis, a very rapid and deep response is crucial, especially for those at high risk, targeting very low FLC levels within the first month of therapy.
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http://dx.doi.org/10.1080/13506129.2020.1798224DOI Listing
March 2021

Long PFS of more than 7 years is achieved in 9% of myeloma patients in the era of conventional chemotherapy and of first-generation novel anti-myeloma agents: a single-center experience over 20-year period.

Ann Hematol 2020 Jun 7;99(6):1257-1264. Epub 2020 May 7.

Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Alexandra General Hospital, 80 Vas. Sofias Avenue, 11528, Athens, Greece.

Advances in the management of multiple myeloma (MM) have led to a significant prolongation of both progression-free (PFS) and overall survival (OS). Herein, we evaluated the characteristics of patients who achieved a PFS of at least 7 years following frontline therapy, as compared with all other patients who were treated in a single center during the same time period. Thirty-six (8.8%) patients achieved a PFS of at least 7 years (long PFS group) after frontline treatment. Long PFS patients were younger (p < 0.001) and had lower ECOG performance status (p = 0.014), higher hemoglobin (p = 0.001), and higher creatinine clearance (p < 0.001) compared with the others. More patients in the long PFS group had ISS-1 or ISS-2 disease (p = 0.002) and normal pattern of marrow infiltration (p = 0.035). No patient in the long PFS group had high-risk cytogenetics at diagnosis. Long PFS patients had received more often autologous stem cell transplantation (p = 0.001) and had achieved deeper responses. The probability of achieving long PFS (≥ 7 years) for patients who managed to be progression-free at 2, 3, and 4 years was 11.6%, 13.2%, and 15.3%, respectively. Median OS in the long PFS group has not been reached yet, while in all other patients, the median OS was 4.3 years. In conclusion, our study in an unselected patient group showed that 9% of patients with newly diagnosed myeloma experience prolonged PFS of more than 7 years in the era of conventional chemotherapy or first-generation novel agents. We anticipate that novel treatment approaches will increase the probability of achieving a prolonged relapse-free status.
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http://dx.doi.org/10.1007/s00277-020-04060-zDOI Listing
June 2020

Clinical characteristics and outcomes of oligosecretory and non-secretory multiple myeloma.

Ann Hematol 2020 Jun 19;99(6):1251-1255. Epub 2020 Apr 19.

Department of Clinical Therapeutics, Alexandra Hospital, National and Kapodistrian University of Athens, Vasilissis Sofias 80, 11528, Athens, Greece.

Secretion of monoclonal immunoglobulins (MIg) detected in the serum and/or urine is one of the typical features of multiple myeloma (MM). However, some patients secrete MIg in quantities below "measurable" (termed oligosecretory MM) and others have no detectable MIgs by standard serum and urine immunofixation (termed non-secretory MM). In a cohort of 852 consecutive patients with active myeloma, we identified 100 (11.7%) patients with oligo/non-secretory MM, including 20 (2.3%) with non-secretory MM. Compared to patients with secretory MM, these were younger, less anemic, and had less often renal dysfunction and less extensive bone marrow infiltration. Presence and extent of bone disease were similar, however, hypercalcemia was less common and more often is ISS (International Staging System)-1 and, in those with available FISH (Fluoresense In Situ Hybridization) , high-risk cytogenetics were less common. FLCs (Free Light Chains) were available in 17 patients with non-secretory MM: only 3 had normal FLC ratio; the others had abnormal ratio and 9/14 had involved FLC ≥ 100 mg/L. The 4-year OS for patients with oligo/non-secretory disease was 64% vs 58% for secretory MM. In multivariate analysis, oligo/non-secretory disease was not an independent prognostic factor per se. Thus, 12% of MM patients present with oligo/non-secretory disease at diagnosis and have different biologic characteristics but similar outcome to other MM patients.
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http://dx.doi.org/10.1007/s00277-020-03984-wDOI Listing
June 2020

Early Relapse After Autologous Transplant Is Associated With Very Poor Survival and Identifies an Ultra-High-Risk Group of Patients With Myeloma.

Clin Lymphoma Myeloma Leuk 2020 07 4;20(7):445-452. Epub 2020 Feb 4.

Department of Clinical Therapeutics, National and Kapodistrian University of Athens, Athens, Greece. Electronic address:

Introduction: Patients relapsing early after autologous stem cell transplantation (ASCT) are a particular therapeutic challenge.

Methods: This was a retrospective, single center study that included 297 consecutive patients that received first-line ASCT RESULTS: We identified 43 (14.5%) patients that relapsed within <12 months. At diagnosis, these patients had more often elevated lactate dehydrogenase, lower estimated glomerular filtration rate, hypercalcemia, and high-risk cytogenetics; the International Staging System stage distribution was similar. Consolidation and maintenance were associated with lower rates of early relapses. Progression-free survival to second-line therapy was 5 months versus 19 months for those with an early versus late relapse (P < .001), the median PFS to second-line therapy was 15.5 months versus >5 years (P < .001) and the median post-ASCT survival was 18 months versus >6 years. The survival after an early relapse has not improved significantly over time. In multivariate analysis, early relapse (hazard ratio, 14; P < .001) was the most important prognostic factor for poor survival after ASCT.

Conclusion: Patients relapsing <12 months after ASCT comprise an ultra-high-risk group, with poor outcomes even with the application of the more recent combinations, that urgently needs more effective therapies.
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http://dx.doi.org/10.1016/j.clml.2019.10.014DOI Listing
July 2020

Impact of Minimal Residual Disease Detection by Next-Generation Flow Cytometry in Multiple Myeloma Patients with Sustained Complete Remission after Frontline Therapy.

Hemasphere 2019 Dec 1;3(6):e300. Epub 2019 Oct 1.

Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece.

Minimal residual disease (MRD) was monitored in 52 patients with sustained CR (≥2 years) after frontline therapy using next-generation flow (NGF) cytometry. 25% of patients initially MRD- reversed to MRD+. 56% of patients in sustained CR were MRD+; 45% at the level of 10; 17% at 10. All patients who relapsed during follow-up were MRD+ at the latest MRD assessment, including those with ultra-low tumor burden. MRD persistence was associated with specific phenotypic profiles: higher erythroblasts' and tumor-associated monocytes/macrophages' predominance in the bone marrow niche. NGF emerges as a suitable method for periodic, reproducible, highly-sensitive MRD-detection at the level of 10.
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http://dx.doi.org/10.1097/HS9.0000000000000300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6924563PMC
December 2019

Impact of last lenalidomide dose, duration, and IMiD-free interval in patients with myeloma treated with pomalidomide/dexamethasone.

Blood Adv 2019 12;3(23):4095-4103

Department of Clinical Therapeutics.

To gain insights into the characteristics of clinical resistance to lenalidomide, we evaluated the outcomes of 147 consecutive patients with multiple myeloma (MM) homogeneously treated with immunomodulatory imide drugs (IMiDs) pomalidomide and dexamethasone (Pd) for relapsed and/or refractory MM (median, 3 prior lines of treatment). We focused our analysis on the effect of the lenalidomide dose at which resistance was developed, the duration of lenalidomide exposure, and lenalidomide-free interval. On intent to treat, 33% of patients achieved ≥partial remission (PR) with Pd. When Pd was given immediately after lenalidomide, ≥PR was 32% (vs 37% after bortezomib). The response rates were similar for patients that received 5 to 15 mg vs 25 mg of lenalidomide (38.5% vs 30.5%, P = .329). Response rates were higher for patients that had received at least 12 months of lenalidomide (44% vs 27%) and for those with ≥18 months from last lenalidomide dose to pomalidomide dose (65% vs 23%). Median progression-free survival (PFS) and overall survival (OS) were 5 and 12.1 months, respectively, which was similar for patients who received lenalidomide, bortezomib or other regimens just before Pd and similar for patients who were receiving different doses of lenalidomide. IMiD-free interval ≥18 months was associated with longer PFS (10.3 vs 3.9 months, P = .003) and OS (27.1 vs 9.3, P = .008) as well as duration of last lenalidomide therapy ≥12 months (PFS: 7.8 vs 3.2, P = .023; OS: 16.5 vs 7.9, P = .005) even after adjustment for the number of prior therapies, duration of disease, and last lenalidomide dose.
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http://dx.doi.org/10.1182/bloodadvances.2019000539DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6963239PMC
December 2019

Treatment of Bing-Neel syndrome with first line sequential chemoimmunotherapy: A case report.

Medicine (Baltimore) 2019 Nov;98(44):e17794

Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Alexandra General Hospital.

Rationale: Bing-Neel syndrome (BNS) is a rare manifestation of Waldenström macroglobulinemia (WM) with <200 cases reported in the literature. Herein, we describe a case of newly diagnosed BNS treated with a novel therapeutic strategy.

Patient Concerns: A 67-year-old woman diagnosed with asymptomatic WM 3 years ago presented with gradual vision deterioration the past 3 months. Ophthalmologic examination revealed bilateral reduction in visual acuity (7/10) and bilateral optic disc swelling which was more prominent in the left eye.

Diagnoses: Brain imaging revealed bilateral swelling of optic nerves extending from the retina to the optic chiasm and swelling of the left optic tract. Patchy enhancement of optic nerves was also shown upon intravenous contrast administration. Flow cytometry of the cerebrospinal fluid (CSF) revealed the presence of κ-light chain restricted, monoclonal B-lymphocytes. CSF protein electrophoresis showed a monoclonal band in the gamma region and immunofixation was positive for immunoglobulin M and kappa light chain. Thus, the diagnosis of BNS was established.

Interventions: The patient was initially treated with intrathecal methotrexate and systemic chemotherapy. Following 2 intrathecal methotrexate infusions, CSF flow cytometry did not detect any cells, whereas the patient reported improvement in visual acuity. Therefore, we opted to start maintenance treatment with IV rituximab and per os ibrutinib.

Outcomes: Following 1 year posttreatment initiation, visual problems have resolved completely and the patient remains on hematologic and imaging complete response.

Lessons: We propose a novel sequential chemoimmunotherapy approach for BNS treatment aiming both at rapid disease control and deep and durable remission with minimization of induced toxicity.
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http://dx.doi.org/10.1097/MD.0000000000017794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946242PMC
November 2019

Primary treatment of light-chain amyloidosis with bortezomib, lenalidomide, and dexamethasone.

Blood Adv 2019 10;3(20):3002-3009

Department of Clinical Therapeutics, National and Kapodistrian University of Athens, Athens, Greece.

Bortezomib and dexamethasone with cyclophosphamide (CyBorD) or melphalan (BMDex) are commonly used primary treatments for light-chain (AL) amyloidosis, but limited data exist on bortezomib with immunomodulatory drug combinations. We report our experience with primary therapy with a bortezomib, lenalidomide, and dexamethasone (VRD) "light" regimen in 34 consecutive patients with AL amyloidosis. The majority (79%) had cardiac involvement, 15% and 23% were Mayo stage 3A and 3B, respectively, and 54% had renal involvement. After the first VRD cycle, 71% of patients achieved a hematologic response (44% at least very good partial response [VGPR]). On intent to treat, 11 (32%) achieved a complete response (of whom 5 of 11 were minimal residual disease [MRD] negative at 10-5), 17 (50%) a VGPR, and 2 (7%) a partial response. The 12-month survival was 73%. Starting lenalidomide dose was 5 mg in 86% of patients. Hematologic toxicity was mild; nonhematologic toxicities included rash (grade 3/4 [16%]), infections (grade ≥3 [12%]), constipation (grade ≥3 [9%]), and peripheral neuropathy (grade 2 [20%]); 37.5% of patients required lenalidomide dose reduction, 27% discontinued lenalidomide, 38% required bortezomib dose reduction, and 12% discontinued bortezomib. We compared VRD to CyBorD in 68 patients matched for Mayo stage and baseline difference between involved minus uninvolved serum free light chain levels, and observed a trend for deeper response at 3 and 6 months with VRD. In conclusion, VRD can be an active regimen for newly diagnosed patients with AL amyloidosis able to induce very deep hematologic responses at the expense of increased toxicity.
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http://dx.doi.org/10.1182/bloodadvances.2019000147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6849948PMC
October 2019

Screening for Gaucher disease among patients with plasma cell dyscrasias.

Leuk Lymphoma 2021 03 30;62(3):761-763. Epub 2019 Sep 30.

Department of Clinical Therapeutics, Alexandra General Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece.

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http://dx.doi.org/10.1080/10428194.2019.1672059DOI Listing
March 2021
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