Health-related quality of life in relapsed/refractory multiple myeloma treated with melflufen and dexamethasone: analyses from the phase III OCEAN study.

Not available.

PORT: A Randomized, Cross-Over, Phase 2 Study of Melflufen Peripheral Versus Central Intravenous Administration in Patients With Relapsed/Refractory Multiple Myeloma.

BACKGROUND: Melflufen, a first-in-class alkylating peptide-drug conjugate, rapidly enters tumor cells and metabolizes to melphalan. In previous studies, melflufen was administered via central venous catheter (CVC). However, administration by peripheral venous catheter (PVC) may be preferable. PATIENTS AND METHODS: PORT was a two-period, phase 2 crossover study of CVC versus PVC melflufen administration in patients with relapsed/refractory multiple myeloma. Adults with ≥ 2 prior therapies refractory to/intolerant of an immunomodulatory drug and a proteasome inhibitor were randomized 1:1 to weekly oral dexamethasone plus melflufen (40 mg) via CVC or PVC infusion on day 1 of 28-day cycle 1. In cycle 2, patients continued dexamethasone and crossed over to the other melflufen administration route. In cycle 3, all patients received melflufen until progression; PVC or CVC routes were allowed based upon investigator decision. Pharmacokinetic sampling was performed during and after melflufen infusion. Primary endpoints were melphalan pharmacokinetic parameters (Cmax, AUC(0-t), and AUC(0-∞)) and frequency and severity of PVC-related local reactions. RESULTS: The 90% CIs for adjusted geometric mean ratios for pharmacokinetic parameters following CVC versus PVC administration were within the 0.8-1.25 bioequivalence range (Cmax 0.946 [90% CI: 0.849, 1.053]; AUC(0-t) 0.952 [90% CI: 0.861, 1.053]; AUC(0-∞) 0.955 [90% CI: 0.863, 1.058]). In both arms, adverse events were primarily hematological and similar; no phlebitis or local infusion-related reactions occurred. CONCLUSION: Melflufen PVC and CVC administrations are bioequivalent based on melphalan pharmacokinetic parameters. Melflufen via PVC was well tolerated, with no infusion-related reactions or new safety signals and may represent an alternative route of administration.

Low-burden TP53 mutations represent frequent genetic events in CLL with an increased risk for treatment initiation.

TP53 aberrations predict chemoresistance and represent a contraindication for the use of standard chemoimmunotherapy in chronic lymphocytic leukaemia (CLL). Recent next-generation sequencing (NGS)-based studies have identified frequent low-burden TP53 mutations with variant allele frequencies below 10%, but the clinical impact of these low-burden TP53 mutations is still a matter of debate. In this study, we aimed to scrutinise the subclonal architecture and clinical impact of TP53 mutations using a sensitive, NGS-based mutation analysis in a 'real-world' cohort of 901 patients with CLL. In total, 225 TP53 mutations were identified in 17.5% (158/901) of the patients; 48% of these alterations represented high-burden mutations, while 52% were low-burden TP53 mutations. Low-burden mutations as sole alterations were identified in 39% (62/158) of all mutated cases with 82% (51/62) of these being represented by a single low-burden TP53 mutation. Patients harbouring low-burden TP53 mutations had significantly lower time to first treatment compared to patients with wild-type TP53. Our study has expanded the knowledge on the frequency, clonal architecture, and clinical impact of low-burden TP53 mutations. By demonstrating that patients with sole low-burden TP53 variants represent more than one-third of patients with TP53 mutations and have an increased risk for treatment initiation, our findings strengthen the need to redefine the threshold of TP53 variant reporting to below 10% in the routine diagnostic setting.

[How did the survival of acute myeloid leukemia change over the last ten years in our unit?] / Hogyan változott az akut myeloid leukaemiás betegek túlélése a terápiás lehetoségek bovülésével az elmúlt 10 évben klinikánkon?

INTRODUCTION: Acute myeloid leukemia (AML) is a hematological malignancy with high mortality rate. The treatment is especially challenging in patients older than 65 years, which is the large majority of those. For patients unfit for intensive chemotherapy regimens, only palliative cytoreduction and basic supportive care used to be the options in our unit. However, from 2018, the azacitidine-venetoclax combination has been a new therapeutic alternative. This treatment resulted in marked survival benefit in clinical trials, however, its impact on the daily clinical practice and the entire patient population is unclear. OBJECTIVE: Our goal was to evaluate how the application of azacitidine-venetoclax changed the treatment and survival of AML patients in our practice. METHOD: We retrospectively analyzed the available clinical data of all AML patients treated consecutively between January 1, 2011 and December 31, 2021 at the 3rd Department of Internal Medicine (from 2020 onward called Department of Internal Medicine and Hematology), examining their treatment depending on the time period of therapy (2011-2017 and 2018-2021). Patients with acute promyelocytic leukemia were excluded. RESULTS: 423 patients were diagnosed during this period. The number of cases showed a marked increase: in the first 7 years of our study, 184 patients were diagnosed, while this rose to 239 during the subsequent 4 years. The median age of patients was 67.6 years, with more than 60% of patients aged over 65. An improving trend can be observed in the overall survival: between 2011 and 2017, the median overall survival was 4.8 ± 0.9 months, while between 2018 and 2021, it was 8.3 ± 1.4 months (p = 0.051). Moreover, in the case of patients over 65 there was a significant overall survival improvement: 3.1 ± 0.5 vs. 4.9 ± 0.6 months (p = 0,01). The main factor behind this improvement could be that a large proportion of over 65 patients previously only fit for supportive care could now be treated with azacitidine-venetoclax: the percentage of actively treated patients grew from 57.1% to 75.3% in the second period. CONCLUSION: The survival of patients unfit for curative therapy and older than 65 showed a steady increase which can be attributed to the introduction of new therapeutic alternatives. Orv Hetil. 2023; 164(45): 1787-1794.

Efficacy and safety of single-agent belantamab mafodotin versus pomalidomide plus low-dose dexamethasone in patients with relapsed or refractory multiple myeloma (DREAMM-3): a phase 3, open-label, randomised study.

BACKGROUND: Multiple myeloma remains incurable, and heavily pretreated patients with relapsed or refractory disease have few good treatment options. Belantamab mafodotin showed promising results in a phase 2 study of patients with relapsed or refractory multiple myeloma at second or later relapse and a manageable adverse event profile. We aimed to assess the safety and efficacy of belantamab mafodotin in a phase 3 setting. METHODS: In the DREAMM-3 open-label phase 3 study, conducted at 108 sites across 18 countries, adult patients were enrolled who had confirmed multiple myeloma (International Myeloma Working Group criteria), ECOG performance status of 0-2, had received two or more previous lines of therapy, including two or more consecutive cycles of both lenalidomide and a proteasome inhibitor, and progressed on, or within, 60 days of completion of the previous treatment. Participants were randomly allocated using a central interactive response technology system (2:1) to receive belantamab mafodotin 2·5 mg/kg intravenously every 21 days, or oral pomalidomide 4·0 mg daily (days 1-21) and dexamethasone 40·0 mg (20·0 mg if >75 years) weekly in a 28-day cycle. Randomisation was stratified by previous anti-CD38 therapy, International Staging System stage, and number of previous therapies. The primary endpoint was progression-free survival in all patients who were randomly allocated. The safety population included all randomly allocated patients who received one or more doses of study treatment. This trial is registered with ClinicalTrials.gov, NCT04162210, and is ongoing. Data cutoff for this analysis was Sept 12, 2022. FINDINGS: Patients were recruited between April 2, 2020, and April 18, 2022. As of September, 2022, 325 patients were randomly allocated (218 to the belantamab mafodotin group and 107 to the pomalidomide-dexamethasone group); 184 (57%) of 325 were male and 141 (43%) of 325 were female, 246 (78%) of 316 were White. Median age was 68 years (IQR 60-74). Median follow-up was 11·5 months (5·5-17·6) for belantamab mafodotin and 10·8 months (5·6-17·1) for pomalidomide-dexamethasone. Median progression-free survival was 11·2 months (95% CI 6·4-14·5) for belantamab mafodotin and 7·0 months (4·6-10·6) for pomalidomide-dexamethasone (hazard ratio 1·03 [0·72-1·47]; p=0·56). Most common grade 3-4 adverse events were thrombocytopenia (49 [23%] of 217) and anaemia (35 [16%]) for belantamab mafodotin, and neutropenia (34 [33%] of 102) and anaemia (18[18%]) for pomalidomide-dexamethasone. Serious adverse events occurred in 94 (43%) of 217 and 40 (39%) of 102 patients, respectively. There were no treatment-related deaths in the belantamab mafodotin group and one (1%) in the pomalidomide-dexamethasone group due to sepsis. INTERPRETATION: Belantamab mafodotin was not associated with statistically improved progression-free survival compared with standard-of-care, but there were no new safety signals associated with its use. Belantamab mafodotin is being tested in combination regimens for relapsed or refractory multiple myeloma. FUNDING: GSK (study number 207495).

[Venetoclax-based salvage in multiple myeloma with (11;14) translocation after suboptimal response to first-line therapy]. / Venetoclaxalapú mentokezelés (11;14)-transzlokációs myeloma multiplexben az elso vonalbeli kezelésre adott nem megfelelo válasz esetén.

INTRODUCTION: Multiple myeloma is one of the most common hematologic malignancies, with approximately 400 patients diagnosed in Hungary annually. Novel therapies emerging in the last decade have made a great impact on most patients' survival, however, those responding poorly to standard first-line therapy and failing to proceed to stem cell transplantation face a dire prognosis. Venetoclax, a selective Bcl-2 inhibitor has been shown very effective in the treatment of relapsed/refractory t(11;14) patients, but there are only a few studies about its safety and efficacy when used as salvage in the second line. OBJECTIVE: The aim of our study was to analyze the data of t(11;14) patients treated with venetoclax salvage at our clinic and to evaluate its efficacy. METHOD: Between 2017 and 2021, 13 patients received venetoclax therapy at our clinic after suboptimal response to frontline treatment, whose data we analyzed retrospectively. RESULTS: Adverse prognostic markers were very prevalent in our group, 4 of our patients had del(17p), 5 had amp(1q21) and 6 had stage 3. Nevertheless, all 13 patients responded well to venetoclax therapy, with 6 reaching very good partial response and 7 complete response. All eligible patients (10) could proceed to transplantation. After median 38 months follow up, neither median progression-free, nor median overall survival was reached, since only 3 patients progressed and 1 died. CONCLUSION: We have shown that when salvage is needed for t(11;14) patients who respond suboptimally to standard frontline therapy, venetoclax is a remarkably good option. Orv Hetil. 2023; 164(23): 894-899.

Soluble B-cell maturation antigen as a monitoring marker for multiple myeloma.

Objective: Response to treatment in multiple myeloma (MM) is routinely measured by serum and urine M-protein and free light chain (FLC), as described by the International Myeloma Working Group (IMWG) consensus statement. A non-negligible subgroup of patients however present without measurable biomarkers, others become oligo or non-secretory during recurrent relapses. The aim of our research was to evaluate soluble B-cell maturation antigen (sBCMA) as a monitoring marker measured concurrent with the standard monitoring in MM patients at diagnosis, at relapse and during follow up, in order to establish its potential usefulness in oligo and non-secretory disease. Method: sBCMA levels were measured in 149 patients treated for plasma cell dyscrasia (3 monoclonal gammopathy of unknown significance, 5 smoldering myeloma, 7 plasmacytoma, 8 AL amyloidosis and 126 MM) and 16 control subjects using a commercial ELISA kit. In 43 newly diagnosed patients sBCMA levels were measured at multiple timepoints during treatment, and compared to conventional IMWG response and progression free survival (PFS). Results: sBCMA levels among control subjects were significantly lower than among newly diagnosed or relapsed MM patients [20.8 (14.7-38.7) ng/mL vs. 676 (89.5-1,650) and 264 (20.7-1,603) ng/mL, respectively]. Significant correlations were found between sBCMA and the degree of bone marrow plasma cell infiltration. Out of the 37 newly diagnosed patients who have reached partial response or better per IMWG criteria, 33 (89%) have had at least a 50% drop in sBCMA level by therapy week 4. Cohorts made similarly to IMWG response criteria-achieving a 50% or 90% drop in sBCMA levels compared to level at diagnosis-had statistically significant differences in PFS. Conclusion: Our results confirmed that sBCMA levels are prognostic at important decision points in myeloma, and the percentage of BCMA change is predictive for PFS. This highlights the great potential use of sBCMA in oligo- and non-secretory myeloma.

Landscape of BCL2 Resistance Mutations in a Real-World Cohort of Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia Treated with Venetoclax.

The oral, highly selective Bcl2 inhibitor venetoclax has substantially improved the therapeutic landscape of chronic lymphocytic leukemia (CLL). Despite the remarkable response rates in patients with relapsed/refractory (R/R) disease, acquired resistance is the leading cause of treatment failure, with somatic BCL2 mutations being the predominant genetic drivers underpinning venetoclax resistance. To assess the correlation between disease progression and the most common BCL2 mutations G101V and D103Y, sensitive (10-4) screening for the most common BCL2 mutations G101V and D103Y was performed in 67 R/R CLL patients during venetoclax single-agent or venetoclax-rituximab combination therapy. With a median follow-up time of 23 months, BCL2 G101V and D103Y were detected in 10.4% (7/67) and 11.9% (8/67) of the cases, respectively, with four patients harboring both resistance mutations. Ten out of eleven patients carrying BCL2 G101V and/or D103Y experienced relapse during the follow-up period, representing 43.5% of the cases (10/23) showing clinical signs of disease progression. All BCL2 G101V or D103Y variants were detected in patients receiving venetoclax as a continuous single-agent treatment while these mutations were not observed during or after fixed-duration venetoclax therapy. Targeted ultra-deep sequencing of BCL2 uncovered three additional variants in four patient samples obtained at relapse, suggesting convergent evolution and implying a cooperating role of BCL2 mutations in driving venetoclax resistance. This cohort is the largest R/R CLL patient population reported to date in which BCL2 resistance mutations were investigated. Our study demonstrates the feasibility and clinical value of sensitive screening for BCL2 resistance mutations in R/R CLL.

[Impact of the type of hematopoietic stem-cell transplant on quality of life and psychopathology]. / A haematopoeticus ossejt-transzplantáció hatása az életminoségre és a pszichés tünetekre.

Background and purpose:

Despite the decrease in transplant-related mortality, patients who receive hematopoietic stem-cell transplants often suffer from short-and long-term morbidities, poorer quality of life, and psychosocial functioning deficits. Several studies have compared the quality of life and affective symptoms of patients after undergoing autologous and allogeneic hematopoietic stem-cell transplants. Some studies have reported similar or greater quality of life impairments in allogeneic hematopoietic stem-cell recipients, but the findings have been inconsistent. Our purpose was to examine the influence of the type of hematopoietic stem-cell transplantation on the quality of life and affective symptoms of patients.

The study sample comprised 121 patients with various hematological diseases who underwent hematopoietic stem-cell transplantation at St. István and St. László Hospitals, Budapest. The study had a cross-sectional design. Quality of life was evaluated using the Hungarian version of the Functional Assessment of Cancer Therapy–Bone Marrow Transplant scale (FACT-BMT). Anxiety and depressive symptoms were assessed using Spielberger’s State and Trait Anxiety Inventory (STAI) and the Beck Dep­ression Inventory (BDI), respectively. Basic sociodemographic and clinical variables were also recorded. Comparisons between autologous and allogeneic recipients were analyzed using a t-test when the variables were normally distributed and a Mann–Whitney U test otherwise. A stepwise multiple linear regression analysis was performed to identify the risk factors that contributed to the quality of life and the affective symptoms in each group.

Quality of life (p=0.83) and affective symptoms (pBDI=0.24; pSSTAI=0.63) were similar between the autologous and allogeneic transplant groups. The BDI scores of allogeneic transplant patients indicated mild depression, but their STAI scores were similar to those of the general population. Allogeneic transplant patients with symptoms of graft-versus-host disease (GVHD) experienced more severe clinical conditions (p=0.01), poorer functional status (p<0.01) and received more immunosuppressive treatment (p<0.01) than those without graft versus host disease. Patients suffering from graft versus host disease experienced more severe depression (p=0.01), and constant anxiety (p=0.03) than those without graft versus host disease. Quality of life was affected by depressive and anxiety symptoms and psychiatric comorbidity in both the alloge­neic and autologous groups.

Graft versus host disease-related severe somatic complaints seemed to influence the allogeneic transplant patients’ quality of life by inducing depressive and anxiety symptoms.

Overall Survival With Daratumumab, Bortezomib, and Dexamethasone in Previously Treated Multiple Myeloma (CASTOR): A Randomized, Open-Label, Phase III Trial.

PURPOSE: At the primary analysis of CASTOR (median follow-up, 7.4 months), daratumumab plus bortezomib and dexamethasone (D-Vd) significantly prolonged progression-free survival versus bortezomib and dexamethasone (Vd) alone in relapsed or refractory multiple myeloma (RRMM). We report updated efficacy and safety results at the final analysis for overall survival (OS). METHODS: CASTOR was a multicenter, randomized, open-label, phase III study during which eligible patients with ≥ 1 line of prior therapy were randomly assigned to Vd (up to eight cycles) with or without daratumumab (until disease progression). After positive primary analysis and protocol amendment, patients receiving Vd were offered daratumumab monotherapy after disease progression. RESULTS: At a median (range) follow-up of 72.6 months (0.0-79.8), significant OS benefit was observed with D-Vd (hazard ratio, 0.74; 95% CI, 0.59 to 0.92; P = .0075). Median OS was 49.6 months with D-Vd versus 38.5 months with Vd. Prespecified subgroup analyses demonstrated an OS advantage with D-Vd versus Vd for most subgroups, including patients age ≥ 65 years and patients with one or two prior lines of therapy, International Staging System stage III disease, high-risk cytogenetic abnormalities, and prior bortezomib treatment. The most common (≥ 10%) grade 3/4 treatment-emergent adverse events with D-Vd versus Vd were thrombocytopenia (46.1% v 32.9%), anemia (16.0% v 16.0%), neutropenia (13.6% v 4.6%), lymphopenia (10.3% v 2.5%), and pneumonia (10.7% v 10.1%). CONCLUSION: D-Vd significantly prolonged OS in patients with RRMM, with the greatest OS benefit observed in patients with one prior line of therapy. To our knowledge, our results, together with the OS benefit observed with daratumumab plus lenalidomide and dexamethasone in the phase III POLLUX study, demonstrate for the first time an OS benefit with daratumumab-containing regimens in RRMM (ClinicalTrials.gov identifier: NCT02136134 [CASTOR]).

Cardiac Amyloidosis with Normal Wall Thickness: Prevalence, Clinical Characteristics and Outcome in a Retrospective Analysis.

Background: Cardiac amyloidosis (CA) is a rare, progressive, infiltrative cardiac disease. Light chain (AL) and transthyretin (ATTR) amyloidosis are in the background in almost all cases. New, easily available diagnostic tools and recently introduced novel therapies for both types of CA put this disease into the field of interest. Increased left ventricular wall thickness (IWT) detected by echocardiography is generally thought to be a necessary part of the diagnosis. We aimed to determine the proportion of CA patients without IWT, and to define the clinical characteristics of this cohort. Methods: In an academic tertiary center for CA, we identified patients diagnosed and treated for CA between January 2009 and February 2022. In a retrospective analysis we defined the proportion of patients with (≥12 mm) and without (<12 mm) IWT, and described their clinical features. Results: We identified 98 patients suitable for the analysis. In total, 70 had AL and 27 ATTR CA; 89 patients had CA with IWT and 9 patients (9%) had CA without IWT. All non-IWT patients had AL type CA. Both group of patients had clinically significant disease, which is supported by the relevant elevation in cardiac biomarker levels. There was no difference between the outcome of the two groups. Conclusion: Patients without IWT form a relevant subgroup among those with CA. Our results suggest that diagnostic algorithms and criteria should take these individuals into consideration, and, therefore, give them access to effective treatments.

Serum fetuin-A level is independent of Helicobacter pylori postinfection status in systemic lupus erythematosus.

Helicobacter pylori is a common pathogen causing gastric inflammation and malignancy. Fetuin-A is a multifunctional protein that is involved in the regulation of calcification, insulin resistance and inflammation. Reports on serum levels of fetuin-A in acute H. pylori infection are contradictory. We intended to see whether H. pylori post-infection status has a long-term effect on serum fetuin-A levels in a well-characterized series of systemic lupus erythematosus cases. In this cross-sectional study 117 patients with systemic lupus erythematosus were enrolled. Helicobacter infection status and serum fetuin-A concentration were determined by ELISA and radial immunodiffusion, respectively. H. pylori positive patients had higher serum fetuin-A concentration than negative ones: 517 (456-603) vs. 476 (408-544) mg L-1, median (25-75% percentiles), P = 0.020. No other parameters differed between these groups. During univariate regression analysis fetuin-A levels were associated with Erythrocyte sedimentation rate (ESR), White blood cell count (WBC), C-reactive protein (CRP), serum total protein, albumin, and the SLEDAI index at the time of diagnosis but only serum albumin remained a significant determinant in multivariate regression study.

Targeted Venetoclax Therapy in t(11;14) Multiple Myeloma: Real World Data From Seven Hungarian Centers.

Despite the introduction of novel agents, multiple myeloma remains incurable for most patients, necessitating further therapeutic options. Venetoclax, a selective BCL-2 inhibitor, had shown promising results in patients with translocation t(11;14), but questions remain open about its optimal use. We have contacted all Hungarian haematology centers for their experience treating t(11;14) myeloma patients with venetoclax. 58 patients were reported. 37 received venetoclax in the relapsed/refractory setting with few or no other therapeutic options available. 21 patients started venetoclax as salvage after failing to achieve satisfactory response to first line therapy. In the relapsed/refractory setting objective response rate (ORR) was 94%, median progression-free survival (PFS) 10.0 months and median overall survival (OS) 14.6 months. In reinduction patients, ORR was 100%, median PFS and OS were not reached. Importantly, we found no adverse effect of high risk features such as deletion 17p or renal failure, in fact renal failure ameliorated in 42% of the cases, including three patients who became dialysis independent. Our study also reports the highest number of plasma cell leukemia cases successfully treated with venetoclax published in literature, with refractory plasma cell leukemia patients achieving a median PFS of 10.0 and a median OS of 12.2 months.

Decreased circulating dipeptidyl peptidase-4 enzyme activity is prognostic for severe outcomes in COVID-19 inpatients.

Aim: To investigate the serum circulating DPP4 activity in patients with COVID-19 disease. Materials & methods: Serum samples from 102 hospitalized COVID-19 patients and 43 post-COVID-19 plasma donors and 39 SARS-CoV-2 naive controls and their medical data were used. Circulating DPP4 activities according to different COVID-19 disease peak severity (WHO) groups at sampling and at peak were assessed. Results: A significant decrease (p < 0.0001) in serum DPP4 activity was found in study groups of higher disease severity. When the circulating DPP4 activity was assessed as a prognostic marker, the logistic regression (p = 0.0023) indicated that the enzyme activity is a predictor of mortality (median 9.5 days before death) with receiver operating characteristic area under the curves of 73.33% (p[area = 0.5] < 0.0001) as single predictor and 83.45% (p[area = 0.5] < 0.0001) in combination with age among hospitalized patients with COVID-19. Conclusion: Decreased circulating DPP4 activity is associated with severe COVID-19 disease and is a strong prognostic biomarker of mortality.

Melflufen or pomalidomide plus dexamethasone for patients with multiple myeloma refractory to lenalidomide (OCEAN): a randomised, head-to-head, open-label, phase 3 study.

BACKGROUND: Melphalan flufenamide (melflufen), an alkylating peptide-drug conjugate, plus dexamethasone showed clinical activity and manageable safety in the phase 2 HORIZON study. We aimed to determine whether melflufen plus dexamethasone would provide a progression-free survival benefit compared with pomalidomide plus dexamethasone in patients with previously treated multiple myeloma. METHODS: In this randomised, open-label, head-to-head, phase 3 study (OCEAN), adult patients (aged ≥18 years) were recruited from 108 university hospitals, specialist hospitals, and community-based centres in 21 countries across Europe, North America, and Asia. Eligible patients had an ECOG performance status of 0-2; must have had relapsed or refractory multiple myeloma, refractory to lenalidomide (within 18 months of randomisation) and to the last line of therapy; and have received two to four previous lines of therapy (including lenalidomide and a proteasome inhibitor). Patients were randomly assigned (1:1), stratified by age, number of previous lines of therapy, and International Staging System score, to either 28-day cycles of melflufen and dexamethasone (melflufen group) or pomalidomide and dexamethasone (pomalidomide group). All patients received dexamethasone 40 mg orally on days 1, 8, 15, and 22 of each cycle. In the melflufen group, patients received melflufen 40 mg intravenously over 30 min on day 1 of each cycle and in the pomalidomide group, patients received pomalidomide 4 mg orally daily on days 1 to 21 of each cycle. The primary endpoint was progression-free survival assessed by an independent review committee in the intention-to-treat (ITT) population. Safety was assessed in patients who received at least one dose of study medication. This study is registered with ClinicalTrials.gov, NCT03151811, and is ongoing. FINDINGS: Between June 12, 2017, and Sept 3, 2020, 246 patients were randomly assigned to the melflufen group (median age 68 years [IQR 60-72]; 107 [43%] were female) and 249 to the pomalidomide group (median age 68 years [IQR 61-72]; 109 [44%] were female). 474 patients received at least one dose of study drug (melflufen group n=228; pomalidomide group n=246; safety population). Data cutoff was Feb 3, 2021. Median progression-free survival was 6·8 months (95% CI 5·0-8·5; 165 [67%] of 246 patients had an event) in the melflufen group and 4·9 months (4·2-5·7; 190 [76%] of 249 patients had an event) in the pomalidomide group (hazard ratio [HR] 0·79, [95% CI 0·64-0·98]; p=0·032), at a median follow-up of 15·5 months (IQR 9·4-22·8) in the melflufen group and 16·3 months (10·1-23·2) in the pomalidomide group. Median overall survival was 19·8 months (95% CI 15·1-25·6) at a median follow-up of 19·8 months (IQR 12·0-25·0) in the melflufen group and 25·0 months (95% CI 18·1-31·9) in the pomalidomide group at a median follow-up of 18·6 months (IQR 11·8-23·7; HR 1·10 [95% CI 0·85-1·44]; p=0·47). The most common grade 3 or 4 treatment-emergent adverse events were thrombocytopenia (143 [63%] of 228 in the melflufen group vs 26 [11%] of 246 in the pomalidomide group), neutropenia (123 [54%] vs 102 [41%]), and anaemia (97 [43%] vs 44 [18%]). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]). 27 [12%] patients in the melflufen group and 32 [13%] in the pomalidomide group had fatal treatment-emergent adverse events. Fatal treatment-emergent adverse events were considered possibly treatment related in two patients in the melflufen group (one with acute myeloid leukaemia, one with pancytopenia and acute cardiac failure) and four patients in the pomalidomide group (two patients with pneumonia, one with myelodysplastic syndromes, one with COVID-19 pneumonia). INTERPRETATION: Melflufen plus dexamethasone showed superior progression-free survival than pomalidomide plus dexamethasone in patients with relapsed or refractory multiple myeloma. FUNDING: Oncopeptides AB.

Impact of venetoclax monotherapy on the quality of life of patients with relapsed or refractory chronic lymphocytic leukemia: results from the phase 3b VENICE II trial.

Venetoclax, a potent B-cell lymphoma-2 (BCL-2) inhibitor, has demonstrated clinical efficacy in chronic lymphocytic leukemia (CLL). VENICE II is an open-label, single-arm, phase 3b study (NCT02980731) evaluating the impact of venetoclax monotherapy (400 mg once daily) for ≤2 years on health-related quality of life (HRQoL) of patients with relapsed/refractory CLL. The primary endpoint was mean change in the global health status (GHS)/quality of life (QoL) subscale of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) from baseline to Week 48. Overall, 210 patients received ≥1 dose of venetoclax; median treatment duration was 67.4 weeks. The primary endpoint was met with mean improvement of +9.3 points (n = 156, 95% confidence interval 6.1-12.5; p=.004) in GHS/QoL. At Week 48, clinically meaningful improvements were observed for role functioning, fatigue, and insomnia domains of EORTC QLQ-C30, suggesting venetoclax monotherapy has a positive impact on HRQoL. No new safety signals were reported.

Long-time progression-free survival in relapsed, refractory multiple myeloma with the oral ixazomib-lenalidomide-dexamethasone regime / Hosszú távú progressziómentes túlélés relabált, refrakter myeloma multiplex tisztán orális ixazomib-lenalidomid-dexametazon kezelésével.

Összefoglaló. Bevezetés: A myeloma multiplex mindmáig alapvetoen gyógyíthatatlan betegség, ezért nagy klinikai jelentoségük van az eredményes mento kezeléseknek. A szájon át adható elso proteaszómagátlóval, az ixazomibbal kiegészített lenalidomid-dexametazon terápia jól tolerálható, csak orális szerekbol álló kombináció, mely hazánkban 2015 áprilisától kezdodoen a "Named Patient Program" keretén belül vált elérhetové relabált, refrakter myeloma multiplexes betegek kezelésére. Célkituzés: Kutatásunk célja az ixazomib-lenalidomid-dexametazon kezelés mellett a hosszú távon progressziómentes túlélok célzott vizsgálata. Módszer: A program keretében összesen 7 centrumban 80 visszaeso beteg részesült e triplet kezelésben, adataikat retrospektíven elemeztük. Leíró statisztikai és Kaplan-Meier-analízist végeztünk. Eredmények: A betegek nagyobb hányada reagált: 63,75%-os válaszarány mellett 14 (17,5%) betegnél nem volt terápiás válasz/stabil betegség alakult ki, és 15-nél (18,75%) a betegség a kezelés mellett is progrediált. A progressziómentes túlélés a teljes betegcsoportban 10,6 hónapnak adódott, ugyanakkor 16 beteg (18,75%) két éven túl progressziómentesnek bizonyult, sot közülük 11-nél a betegség még 3 év után sem progrediált. Tanulmányunkban a fenti, hosszú távú túlélo betegcsoport tulajdonságait tárjuk fel. Megbeszélés: A folyamatos terápia a myeloma multiplex kezelésében meghatározóvá vált. Ezért fontos ismernünk, hogy kik lehetnek azok a betegek, akik különösen sokat profitálnak egy bizonyos terápiából. A hosszú távon progressziómentes túlélok között az immunglobulin-nehézláncot érinto transzlokációk vagy triszómiák közül (trend szintjén) az utóbbiak kedvezobb progressziómentes túléléssel bírtak, de progressziómentes platót mindkét betegcsoportban észleltünk. A betegség tumortömegét méro nemzetközi stádiumbeosztás (ISS) nem jelezte elore a hosszú túlélést. Gyógyszerelhagyáshoz vezeto mellékhatást a hosszú távú túlélo csoportban egyet sem regisztráltunk; az észlelt mellékhatások nagy része enyhe volt. Következtetések: Munkánk során az ixazomib-lenalidomid-dexametazon kombinációt effektívnek és biztonságosnak találtuk relabált, refrakter myeloma multiplex kezelésére, mely a betegek mintegy hatodánál több éven át eredményesen alkalmazható. Cikkünkkel a hazai beteganyagon szerzett tapasztalatainkat szeretnénk megosztani a COVID-19-világjárvány alatt különösen aktuálissá vált, tisztán orális terápiás lehetoségrol. Orv Hetil. 2021; 162(36): 1451-1458. INTRODUCTION: Despite great advances in therapy, multiple myeloma is still a largely incurable disease, therefore the importance of salvage therapies is paramount. The first oral proteasome inhibitor ixazomib in combination with lenalidomide-dexamethasone is a tolerable, orally administered regime, which has become available for Hungarian relapsed, refractory multiple myeloma patients from April 2015 in the Named Patient Program. OBJECTIVE: Our goal was to investigate the long-time progression-free surviving patient population treated with the ixazomib-lenalidomide-dexamethasone triplet. METHOD: We retrospectively studied a total of 80 patients from 7 centers who received the triplet combination. Survival analyses were performed. RESULTS: Two-third of the patients responded: the overall response rate was 63.75%. 14 patients (17.5%) did not respond/had stable disease and 15 patients (18.75%) outright progressed upon therapy. Although progression-free survival was only 10.6 months for the entire patient cohort, the disease in a subgroup of 16 patients did not progress within two years. In fact, 11 of them were still in sustained remission after 3 years of therapy. Our goal was to analyze the characteristics of this subgroup. DISCUSSION: The idea of long-term therapy of multiple myeloma is gaining widespread acceptance. Therefore it is important to know which patients may benefit the most from certain therapies. Among these 16 long-term responder patients, reciprocal translocation of the immunoglobulin heavy chain seemed to lack an adverse impact on progression-free survival; comparable to trisomies, both curves had a progression-free plateau. The International Staging System (ISS) score at the start of therapy did not predict long-term survivorship. Most of the side effects in this subgroup were mild, manageable, none led to therapy discontinuation. CONCLUSION: Ixazomib-lenalidomide-dexamethasone was confirmed to be an effective and safe combination for relapsed, refractory multiple myeloma, and one-sixth of the treated patients were able to receive it for several years, effectively. This fully oral therapeutic option is at its best during the present COVID-19 pandemic. Orv Hetil. 2021; 162(36): 1451-1458.

Variant Transthyretin Amyloidosis (ATTRv) in Hungary: First Data on Epidemiology and Clinical Features.

BACKGROUND: Variant transthyretin amyloidosis (ATTRv) is an autosomal dominant inherited disease, where the mutation of the transthyretin gene (TTR) results in the deposition of pathogenic protein fibrils in various tissues. The mutation type influences the clinical course. Until now, no data were available on the genotype, phenotype, and prevalence of Hungarian ATTRv patients. The aim of our study was to assess the prevalence, regional distribution, genotypes, and phenotypes of Hungarian patients with ATTRv. METHODS: With the collaboration of Hungarian regional and university centers, we identified patients diagnosed with ATTRv. We also searched prior publications for case studies of Hungarian ATTRv patients. RESULTS: 40 individuals in 23 families with ATTRv were identified within the borders of Hungary. At the time of the diagnosis, 24 of them were symptomatic. The two most common mutations were ATTRHis88Arg (nine families) and ATTRIle107Val (8 families). ATTRVal30Met was demonstrated in 2 families, and ATTRVal122del, ATTRPhe33Leu, ATTRIle84Ser, and ATTRAsp18Gly in one family each. The median age of the symptomatic patients at the time of clinical diagnosis was 65 years. The most common clinically significant organ involvement was restrictive cardiomyopathy, found in 24 patients. Polyneuropathy was diagnosed in 20 patients. A total of 19 patients showed a mixed phenotype. The leading symptom was heart failure in 8 cases (3 of them had only cardiac symptoms), polyneuropathy in 11 cases (all of them also had cardiac symptoms), and equally severe cardiac and neuropathy symptoms were present in 3 cases. Out of 24 symptomatic patients, 10 received targeted pharmacological therapy. The follow-up period ranged from 1 to 195 months. At the time of the retrospective analysis, 12 patients had already died, and 1 patient underwent heart transplantation. CONCLUSIONS: As TTR genotype influences the phenotype and clinical course of ATTRv, it is important to know the regional data. In Hungary, ATTRHis88Arg and ATTRIle107Val are the most common mutations in ATTRv, both presenting with mixed phenotype, but the median age at the time of the diagnosis is 9 years lower in patients with ATTRHis88Arg than in patients with ATTRIle107Val.

Beneficial Effect of Lenalidomide-Dexamethason Treatment in Relapsed/Refractory Multiple Myeloma Patients: Results of Real-Life Data From 11 Hungarian Centers.

In Hungary, the cost of lenalidomide-based therapy is covered only for relapsed multiple myeloma (MM) patients, therefore lenalidomide is typically used in the second-line either as part of a triplet with proteasome inhibitors or as a doublet. Lenalidomide-dexamethasone is a standard treatment approach for relapsed/refractory MM, and according to recent large randomized clinical trials (RCT, the standard arm of POLLUX, ASPIRE, TOURMALINE), the progression-free survival (PFS) is expected to be approximately 18 months. We surveyed ten Hungarian centers treating MM and collected data of 278 patients treated predominantly after 2016. The median age was 65 years, and patients were distributed roughly equally over the 3 international staging system groups, but patients with high risk cytogenetics were underrepresented. 15.8% of the patients reached complete response, 21.6% very good partial response, 40.6% partial response, 10.8% stable disease, and 2.5% progressed on treatment. The median PFS was unexpectedly long, 24 months, however only 9 months in those with high risk cytogenetics. We found interesting differences between centers regarding corticosteroid type (prednisolone, methylprednisolone or dexamethasone) and dosing, and also regarding the choice of anticoagulation, but the outcome of the various centers were not different. Although the higher equivalent steroid dose resulted in more complete responses, the median PFS of those having lower corticosteroid dose and methylprednisolone were not inferior compared to the ones with higher dose dexamethasone. On multivariate analysis high risk cytogenetics and the number of prior lines remained significant independent prognostic factors regarding PFS (p < 0.001 and p = 0.005). Our results show that in well-selected patients Lenalidomide-dexamethasone can be a very effective treatment with real-world results that may even outperform those reported in the recent RCTs. This real world information may be more valuable than outdated RCT data when treatment options are discussed with patients.