Publications by authors named "Maria Roussou"

70 Publications

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

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

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

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

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

Involvement of small nerve fibres and autonomic nervous system in AL amyloidosis: comprehensive characteristics and clinical implications.

Amyloid 2020 Jun 23;27(2):103-110. Epub 2020 Jan 23.

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

Peripheral nerve involvement in immunoglobulin light chain (AL) amyloidosis is common, characterised by severe progressive mixed neuropathy with autonomic dysfunction but there is limited data on the implications and the characteristics of small nerve fibres dysfunction (SNFD). The aim of our prospective study was to evaluate SNFD and its clinical implications in newly diagnosed AL patients. Twenty-three consecutive patients (10 male, mean age 61.78 years) and 21 age- and gender-matched healthy controls (8 male, mean age 61.28 years) underwent clinical evaluation and standard nerve conduction studies (NCS), baroreflex sensitivity (BRS) test, quantitative sensory testing (QST) and skin biopsy at the lower leg for measuring the density of the nerve fibres innervating the epidermis (IENFD). Axonal degeneration of the large nerve fibres was revealed in 15 out of 23 patients while SNFD was indicated by QST and skin biopsy in 56% and 61% of the patients respectively. BRS index significantly correlated with the IENFD and the QST results while low IENFD was associated with significantly poorer survival. Our study provides new insights and also an initial evaluation of new tools for assessment of the involvement of autonomic and small nerve fibres in AL amyloidosis. These findings also appear to have prognostic implications.
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http://dx.doi.org/10.1080/13506129.2020.1713081DOI Listing
June 2020

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

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

Reactive Vasodilation Predicts Mortality in Primary Systemic Light-Chain Amyloidosis.

Circ Res 2019 09 12;125(8):744-758. Epub 2019 Aug 12.

From the Department of Clinical Therapeutics, National and Kapodistrian University of Athens School of Medicine, Greece (K. Stamatelopoulos, G.G., F.A., M.L., M.R., M.G., A.L., G.T., D.D., I.P., C. Pamboukas, E.M., M.K., C. Papamichael, E.T., M.A.D., E.K.).

Cardiac involvement and hypotension dominate the prognosis of light-chain amyloidosis (AL). Evidence suggests that there is also peripheral vascular involvement in AL but its prognostic significance is unknown. To evaluate vascular dysfunction in patients with AL as a potential future area of intervention, we assessed the prognostic utility of flow-mediated dilatation (FMD), a marker of vascular reactivity, which is augmented under conditions of hypotension and autonomic dysfunction. We prospectively evaluated 115 newly diagnosed untreated AL patients in whom FMD was measured. FMD in AL patients was significantly higher than age-, sex- and risk factors-matched controls (4.0% versus 2.32%; =0.006) and comparable with control groups at lower cardiovascular risk (>0.1). Amyloidosis patients presented increased plasma and exhaled markers of the NO pathway while their FMD significantly correlated with augmented sustained vasodilatation after sympathetic stimulation. Increased FMD (≥4.5%) was associated with early mortality (hazard ratio, 4.36; 95% CI, 1.41-13.5; =0.010) and worse survival (hazard ratio, 2.11; 95% CI, 1.17-3.82; =0.013), even after adjustment for Mayo stage, nerve involvement and low systolic blood pressure. This finding was confirmed in a temporal validation AL cohort (n=55; hazard ratio, 4.2; 95% CI, 1.45-12.3; =0.008). FMD provided significant reclassification value over the best prognostic model (continuous Net Reclassification Index, 0.61; =0.001). Finally, better hematologic response was associated with lower posttreatment FMD. FMD is relatively increased in AL and independently associated with inferior survival with substantial reclassification value. Reactive vasodilation merits further investigation as a novel risk biomarker in AL.Visual Overview: An online visual overview is available for this article.
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http://dx.doi.org/10.1161/CIRCRESAHA.119.314862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6784773PMC
September 2019

Pulmonary function abnormalities are common in patients with multiple myeloma and are independently associated with worse outcome.

Ann Hematol 2019 Jun 5;98(6):1427-1434. Epub 2019 Mar 5.

Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, 80 Vasilissis Sofias, 11258, Athens, Greece.

Pre-existing pulmonary disease may affect treatment choices, toxicity, and survival of patients with multiple myeloma (MM). However, data on the prognostic value of pulmonary function tests (PFTs) in myeloma patients' outcome, at the time of initial assessment of newly diagnosed patients, are scarce. Here, we prospectively performed PFTs in 121 newly diagnosed MM patients, before initiation of treatment, and we evaluated possible associations of lung function with their outcomes. Fifty-four patients (44.63%) had either obstructive or restrictive pulmonary function defects, even among those not reporting a history of lung disease. The survival was significantly worse in those with obstructive pulmonary defect (median OS 32.8 months) vs. those with restrictive (median OS 52.5 months) or normal lung function (median not reached, 3-year survival 76%) (p = 0.013), independently of other myeloma-related factors. Forced vital capacity (FVC) (lt) (p = 0.012), forced expiratory volume in 1 s (FEV1) (lt) (p = 0.018), peak expiratory flow (PEF) (lt/min) (p = 0.008), carbon monoxide diffusion capacity (DLCO) (p = 0.012), and expiratory/inspiratory pressures (Pe) (kPa) (p = 0.032)/(Pi) (kPa) (p = 0.023) were significantly associated with OS. Myeloma-related factors associated with survival included ISS stage (p = 0.008), hypercalcemia (p = 0.064), and high-risk cytogenetics (p = 0.004). In the multivariate analysis, only the presence of high-risk cytogenetics and presence of either or both PEF and DLCO < 65% of predicted were independent prognostic factors. We conclude that PEF and DLCO could be useful in the initial assessment of newly diagnosed MM patients as significant predictors of survival. Further research is needed to evaluate if respiratory screening should be included in the routine initial evaluation of myeloma patients, despite the presence or absence of respiratory symptoms or abnormal clinical respiratory examination.
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http://dx.doi.org/10.1007/s00277-019-03641-xDOI Listing
June 2019

Efficacy of lenalidomide as salvage therapy for patients with AL amyloidosis.

Amyloid 2018 Dec 20;25(4):234-241. Epub 2019 Jan 20.

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

We retrospectively evaluated 55 consecutive patients who received at least one dose of lenalidomide for relapsed/refractory AL amyloidosis. Their median age was 63 years; 72% had heart and 75% kidney involvement and 13% were on dialysis; while 20%, 46% and 34% had Mayo stage -1, -2 and -3 disease, respectively. Median time from start of primary therapy to lenalidomide was 15 months (range 2-100) and median number of prior therapies was 1 (range 1-4); 73% of the patients had prior bortezomib and 42% were bortezomib-refractory. On intent to treat, haematologic response rate was 51% (5.5% CRs, 20% VGPRs) and was 56% versus 40% for patients with and without prior bortezomib and 47% versus 62.5% for bortezomib refractory versus non-refractory patients (p = .351). Organ response was achieved by 16% of evaluable patients (22% renal, 7% liver and 3% cardiac); however, 10 (21%) patients progressed to dialysis. Median survival post lenalidomide was 25 months. Bortezomib-refractory patients had worse outcome (median survival of 10.5 versus 25 months for bortezomib-sensitive patients versus not reached for bortezomib-naive patients, p = .011). Median lenalidomide dose was 10 mg and no patient received the 25 mg dose; however, in 60% a dose reduction was required. Median duration of lenalidomide therapy was 7.2 months and 46% discontinued lenalidomide before completion of planned therapy, mainly due to toxicity (26%) or disease progression/no response (13%). We conclude that although lenalidomide is a major salvage option for patients with relapsed/refractory AL amyloidosis, its toxicity in patients with AL amyloidosis is significant and doses should be adjusted for optimal tolerability.
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http://dx.doi.org/10.1080/13506129.2018.1540410DOI Listing
December 2018

Vulnerability variables among octogenerian myeloma patients: a single-center analysis of 110 patients.

Leuk Lymphoma 2019 03 10;60(3):619-628. Epub 2019 Jan 10.

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

In the era of an aging population, an increasing number of patients are diagnosed with multiple myeloma at an age of ≥80. The frailty of this population as a result of coexisting comorbidities and age-related organ impairment is a significant management challenge. The aim of our study was to analyze the disease characteristics, frailty scores and toxicity profile in relation to patient outcomes. Among 827 consecutive, newly diagnosed, symptomatic patients treated since 01 January 2000, we analyzed the characteristics and outcomes of the 110 who were ≥80. Median survival was 21 months, and early mortality within 2 months from diagnosis was 20%. Several factors were associated with inferior survival, whereas in the multivariate analysis, estimated glomerular filtration rate (eGFR) < 30 ml/min/1.73m and LDH ≥250 IU/L were independently associated with poor overall survival. These patients are a distinct frail subset of the general myeloma population who require individualized approach.
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http://dx.doi.org/10.1080/10428194.2018.1509323DOI Listing
March 2019

Consolidation therapy with the combination of bortezomib and lenalidomide (VR) without dexamethasone in multiple myeloma patients after transplant: Effects on survival and bone outcomes in the absence of bisphosphonates.

Am J Hematol 2019 04 10;94(4):400-407. Epub 2019 Jan 10.

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

Optimizing consolidation treatment in transplant-eligible newly diagnosed multiple myeloma patients in order to improve efficacy and bone-related outcomes is intriguing. We conducted an open-label, prospective study evaluating the efficacy and safety of bortezomib and lenalidomide (VR) consolidation after ASCT, in the absence of dexamethasone and bisphosphonates. Fifty-nine patients, who received bortezomib-based induction, were given 4 cycles of VR starting on day 100 post-ASCT. After ASCT, 58% of patients improved their response status, while following VR consolidation 39% further deepened their response; stringent complete response rates increased to 51% after VR from 24% post-ASCT. VR consolidation resulted in a significant reduction of soluble receptor activator of nuclear factor-κB ligand/osteoprotegerin ratio and sclerostin circulating levels, which was more pronounced among patients achieving very good partial response or better. After a median follow-up of 62 months, no skeletal-related events (SREs) were observed, despite the lack of bisphosphonates administration. The median TTP after ASCT was 37 months, while median overall survival (OS) has not been reached yet; the probability of 4- and 5-year OS was 81% and 64%, respectively. In conclusion, VR consolidation is an effective, dexamethasone- and bisphosphonate-free approach, which offers long OS with improvements on bone metabolism and no SREs.
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http://dx.doi.org/10.1002/ajh.25392DOI Listing
April 2019

Elevated vWF Antigen Serum Levels Are Associated With Poor Prognosis, and Decreased Circulating ADAMTS-13 Antigen Levels Are Associated With Increased IgM Levels and Features of WM but not Increased vWF Levels in Patients With Symptomatic WM.

Clin Lymphoma Myeloma Leuk 2019 01 23;19(1):23-28. Epub 2018 Aug 23.

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

Background: Waldenström's macroglobulinemia (WM) is a rare malignancy characterized by bone marrow infiltration by lymphoplasmacytic cells and the presence of a monoclonal IgM paraprotein. The interactions of lymphoplasmacytic cells with other cells in their microenvironment, including mast cells and endothelial cells, support their survival and proliferation and can induce resistance to therapy. von Willebrand factor (vWF) plays a key role in primary hemostasis but is also a marker of endothelial "stimulation." High levels of vWF have been associated with an adverse prognosis in patients with symptomatic WM and might reflect the interactions between lymphoplasmacytic cells and other cells of their microenvironment.

Materials And Methods: Considering vWF and ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) as markers of endothelial dysfunction and activation, we evaluated the prognostic importance of vWF and ADAMTS-13 antigen levels in the serum of patients with previously untreated symptomatic WM to validate vWF as a possible prognostic marker for progression-free and overall survival. We also validated the measurement of vWF in the serum instead of citrated plasma and investigated the possible correlations of ADAMTS-13 antigen levels with disease characteristics. The analysis included 42 patients with symptomatic WM and 19 matched healthy controls.

Results: The serum levels of vWF antigen provided significant prognostic information, and patients with levels ≥ 200 IU/dL had a very poor prognosis compared with patients with lower levels. The ADAMTS-13 antigen levels were decreased in WM patients and correlated with the IgM levels, β-microglobulin, and extent of bone marrow infiltration.

Conclusion: vWF levels measured in the serum could become an important prognostic marker in patients with WM and requires further investigation.
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http://dx.doi.org/10.1016/j.clml.2018.07.294DOI Listing
January 2019

Bortezomib-based therapy for relapsed/refractory multiple myeloma in real-world medical practice.

Eur J Haematol 2018 Oct 5;101(4):556-565. Epub 2018 Sep 5.

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

Objective: The efficacy and safety of bortezomib-based therapy for relapsed/refractory multiple myeloma (RRMM) in clinical trials may differ from the oncology practice experience. The electronic VELCADE OBservational Study was designed to prospectively evaluate bortezomib for multiple myeloma (MM) in real-world medical practice.

Method: Patients scheduled to receive intravenous bortezomib for MM were eligible. The primary objective was to evaluate clinical outcomes, including response, time to response, time to next therapy, treatment-free interval, progression-free survival (PFS), and overall survival (OS). Secondary objectives included safety and healthcare resource utilization.

Results: In total, 873 patients with a median of two therapy lines prior to initiating bortezomib were included. The overall response rate (≥partial response) was 69%, including 37% complete response/near-complete response. Median time to response was 1.8 months, median time to next therapy was 9.7 months, and median treatment-free interval was 7.9 months. After 22.6 months' median follow-up, median PFS was 12.0 months and median OS was 36.1 months. The most common adverse events (AEs) were neuropathy not otherwise specified (19%), diarrhea NOS, and thrombocytopenia (each 17%); 230 (26%) patients discontinued bortezomib due to AEs. Of 689 (79%) patients without baseline peripheral neuropathy (PN), the rate of new-onset any-grade PN increased to 51% (12% grade 3/4) by cycle 8. Overall, 244 (28%) patients were hospitalized, 372 (43%) attended an outpatient visit, and 341 (39%) underwent a diagnostic/therapeutic procedure during bortezomib treatment.

Conclusion: These prospective real-world data demonstrate the effectiveness and safety of bortezomib-based therapy for RRMM and confirm high response rates and long OS for this population.
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http://dx.doi.org/10.1111/ejh.13147DOI Listing
October 2018

Detection of MYD88 and CXCR4 mutations in cell-free DNA of patients with IgM monoclonal gammopathies.

Leukemia 2018 12 19;32(12):2617-2625. Epub 2018 Jul 19.

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

Liquid biopsyis being integrated into cancer diagnostics with profound therapeutic implications. However, its role in Waldenström's Macroglobulinemia (WM) and IgM monoclonal gammopathies is still unclear. In this study, we evaluated the role of peripheral blood (PB) cell-free DNA (cfDNA) in characterizing the mutational status of MYD88 and CXCR4 of patients with IgM monoclonal gammopathies. Paired bone marrow (BM) tumor DNA (tDNA) and PB cfDNA samples from 98 patients (9 MGUS, 45 with WM in remission, 44 with smoldering WM, newly diagnosed or relapsed WM) and 10 controls with non-IgM monoclonal gammopathies were analyzed. Regarding MYD88 mutation, 76 patients had paired tDNA and cfDNA informative samples. Among patients with WM in remission, 65% harbored the MYD88 mutation, whereas the corresponding percentage among smoldering/newly diagnosed or relapsed WM was 92%. The overall concordance rate was 94% (72/76). For CXCR4 mutations, 65 patients had paired informative tDNA and cfDNA samples. The overall concordance rate was 90% (59/65). All controls had wild-type MYD88 and CXCR4. In conclusion, PB cfDNA is a useful, minimally invasive, cost-effective, and time-effective tool for the identification of the presence of MYD88 and CXCR4 mutations in patients with IgM monoclonal gammopathies avoiding unnecessary BM assessment.
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http://dx.doi.org/10.1038/s41375-018-0197-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6286389PMC
December 2018

Circulating Soluble Receptor Activator of Nuclear Factor Kappa B Ligand and C-C Motif Ligand 3 Correlate With Survival in Patients With Waldenström Macroglobulinemia.

Clin Lymphoma Myeloma Leuk 2018 06 31;18(6):431-437. Epub 2018 Mar 31.

Department of Clinical Therapeutics, University of Athens School of Medicine, Athens, Greece. Electronic address:

Background: Serum receptor activator of nuclear factor κB ligand (sRANKL) and chemokine (C-C) motif ligand 3 (CCL-3) have been reported to be elevated in Waldenström macroglobulinemia (WM) patients. However, there are no published data regarding the prognostic value of these molecules in WM regarding progression-free and overall survival.

Methods: To evaluate the effect of these markers of bone remodeling on survival parameters, we prospectively evaluated serum cytokines and biological markers in 55 patients with symptomatic WM before they received any kind of treatment. Serum levels of CCL-3 and bone remodeling markers were also evaluated in asymptomatic WM and IgM monoclonal gammopathy of undetermined significance. Furthermore, we assessed bone marrow biopsy samples from newly diagnosed WM patients for CCL-3 and RANKL expression.

Results: High circulating sRANKL values predicted shorter median overall survival (46 months vs. not reached, P = .025). High serum levels of CCL-3 predicted shorter median progression-free survival (27 months vs. not reached, P = .048). At bone marrow biopsy evaluation, the whole number of the neoplastic cells revealed strong cytoplasmic positivity for CCL-3, while the neoplastic clone did not express RANKL.

Conclusion: We conclude that WM cells produce CCL-3 and possibly enhance the production of RANKL in the bone microenvironment. The correlation of sRANKL and CCL-3 with survival reveals the importance of these cytokines in disease biology and highlights the significance of the interactions between WM and stromal cells for the development of WM. Finally, these findings provide the rationale for the use of anti-RANKL and anti-CCL-3 drugs in animal models of WM before their clinical evaluation.
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http://dx.doi.org/10.1016/j.clml.2018.03.010DOI Listing
June 2018
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