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PURPOSE Proteasome inhibitors are effective in Waldenström's macroglobulinemia (WM) but require parenteral administration and are associated with polyneuropathy. We investigated efficacy and toxicity of the less neurotoxic oral proteasome inhibitor ixazomib combined with rituximab, in patients with relapsed WM. METHODS We conducted a multicenter phase I/II trial with ixazomib, rituximab, and dexamethasone (IRD). Induction consisted of eight cycles IRD wherein rituximab was started in cycle 3, followed by rituximab maintenance. Phase I showed feasibility of 4 mg ixazomib. Primary end point for phase II was overall response rate (ORR [≥ minimal response]) after induction. RESULTS A total of 59 patients were enrolled (median age, 69 years; range, 46-91 years). Median number of prior treatments was 2 (range, 1-7); 70% had an intermediate or high WM-IPSS (International Prognostic Scoring System for WM) score. After eight cycles, ORR was 71% (42 out of 59) (14% very good partial response [PR], 37% PR, and 20% minor response). Depth of response improved until month 12 (best ORR 85% [50 out of 59]: 15% very good PR, 46% PR, and 24% minor response). Median duration of response was 36 months. The average hematocrit level increased significantly (0.33-0.38 L/L) after induction ( P < .001). After two cycles of ixazomib and dexamethasone, immunoglobulin M levels decreased significantly (median 3,700-2,700 mg/dL, P < .0001). Median time to first response was 4 months. Median progression-free survival and overall survival were not reached. After median follow-up of 24 months (range, 7.4-54.3 months), progression-free survival and overall survival were 56% and 88%, respectively. Toxicity included mostly grade 2 or 3 cytopenias, grade 1 or 2 neurotoxicity, and grade 2 or 3 infections. No infusion-related reactions or immunoglobulin M flare occurred with use of subcutaneous rituximab. Quality of life improved significantly after induction. In total, 48 patients (81%) completed at least six cycles of IRD. CONCLUSION Combination of IRD shows promising efficacy with manageable toxicity in patients with relapsed or refractory WM.

Undoubtedly, the development of COVID-19 vaccines displays a critical step towards ending this devastating pandemic, considering their protective benefits in the general population. Yet, data regarding their efficacy and safety in cancer patients are limited. Herein we provide the initial analysis of immune responses after the first dose of vaccination in 21 breast cancer patients receiving cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors. The levels of neutralizing antibodies post vaccination were similar to the matched healthy controls, whereas no safety issues have been raised. Further exploration is needed to reduce the uncertainty of SARS-CoV-2 immunity among cancer patients under treatment.

Comprehensive data on variant transthyretin amyloidosis polyneuropathy (ATTRv-PN) in Greece are lacking. We presently provide an overview of ATTRv-PN in Greece, focusing on unexplored non-endemic regions of the country. In total, we identified 57 cases of ATTRv-PN diagnosed over the past 25 years, including 30 from the island of Crete, an apparent endemic region. Patients carried 10 different TTR mutations (C10R; P24S; V30M; R34G; R34T; I68L; A81T; E89Q; E89K and V94A). Carriers of the common V30M mutation constituted 54.3 % of the cohort. A known founder effect for the V30M mutation was present on the island of Crete. Non-endemic cases identified outside the island of Crete are presently reported in more detail. The age of onset ranged from 25 to 77 years, with a mean of 51.1 years. A mean diagnostic delay of 3.2 years was observed. V30M patients had earlier onset and less cardiac involvement than patients carrying other mutations. Genotype-phenotype correlations were largely consistent with published data. We conclude that, with the exception of the Cretan cluster, ATTRv-PN is not endemic in the Greek population. This makes timely diagnosis more challenging, yet absolutely essential given the availability of therapies that can alter the long-term course of the disease.

In the Phase III ICARIA-MM study (NCT02990338), the addition of the anti-CD38 monoclonal antibody isatuximab to pomalidomide and dexamethasone led to increased progression-free survival and improved response rates in patients with relapsed/refractory multiple myeloma. There is an unmet treatment need, particularly among patients with poor prognoses, including those with high-risk cytogenetics, those who have renal impairment, those who are elderly and those who are refractory to prior lines of treatment. In this review, the subgroup analyses from the ICARIA-MM study, representing subpopulations with poor prognostic factors, are discussed. Overall, the addition of isatuximab to pomalidomide and dexamethasone improved progression-free survival and disease response rates across different subgroups, regardless of prognostic factor.Lay abstract Currently, the majority of patients with multiple myeloma are not cured, and current treatments may not be helpful for patients with poor prognoses, including those with high-risk chromosomal changes, those who have impaired kidney function, those who are elderly and those who are refractory to prior treatments. In this review, we will discuss the benefits of the combination of isatuximab plus pomalidomide and dexamethasone in these difficult-to-treat patients.

Uterine serous carcinoma accounts for 3–10% of endometrial cancers, but it is the most lethal histopathological subtype. The molecular characterization of endometrial carcinomas has allowed novel therapeutic approaches for these patients. We undertook a retrospective analysis of patients with uterine serous carcinomas treated in our hospital within the last two decades to identify possible changes in their management. The patients and their characteristics were evenly distributed across the two decades. Treatment modalities did not change significantly throughout this period. After adjuvant treatment, patients’ median disease-free survival was 42.07 months (95% CI: 20.28–63.85), and it did not differ significantly between the two decades (p = 0.059). The median overall survival was 47.51 months (95% Cl: 32.18–62.83), and it significantly favored the first decade’s patients (p = 0.024). In patients with de novo metastatic or recurrent disease, median progression-free survival was 7.8 months (95% Cl: 5.81–9.93), whereas both the median progression-free survival and the median overall survival of these patients did not show any significant improvement during the examined time period. Overall, the results of our study explore the minor changes in respect of uterine serous carcinoma’s treatment over the last two decades, which are reflected in the survival outcomes of these patients and consequently underline the critical need for therapeutic advances in the near future.

We previously showed that ERCC1 19007 C&gt, T polymorphism was associated with cancer-specific survival (CSS) after platinum-based chemotherapy in patients with advanced urothelial cancer (aUC). We aimed to confirm this association in a different cohort of patients. Genotyping of the 19007C&gt, T polymorphism was carried out by polymerase chain reaction (PCR) amplification and restriction fragment length polymorphism (RFLP) in 98 aUC patients, treated with platinum-based chemotherapy. Median age of the patients was 68.8, 13.3% of them were female, 90.8% had ECOG PS of 0 or 1, and 48% received cisplatin-based chemotherapy. In addition to chemotherapy, 32.7% of the patients received immunotherapy, and 19.4% vinflunine. Eighty-one patients (82.7%) were carriers of the 19007T polymorphic allele: 46 (46.9%) were heterozygotes, and 35 (35.7%) were homozygotes. The ERCC1 polymorphism was not associated with CSS, progression-free (PFS), or overall (OS) survival in the total population. Nevertheless, there was a significant interaction between the prognostic significance of ERCC1 polymorphism and the use of modern immunotherapy: the T allele was associated with worse outcome in patients who received chemotherapy only, while this association was lost in patients who received both chemotherapy and immune checkpoint inhibitors. Our study suggests that novel therapies may influence the significance of ERCC1 polymorphism in patients with aUC. Its determination may be useful in the changing treatment landscape of the disease.

Background: High grade serous ovarian carcinoma (HGSOC) is the most lethal type of epithelial ovarian cancer, with a prevalence of germline BRCA1/2 mutations as high as 20%. Our objective is to determine whether the location of mutations in the different domains of the BRCA1/2 genes affects the clinical outcome of HGSOC patients. Methods: A total of 51 women with BRCA1 or BRCA2 mutated ovarian cancer were identified. Progression-free survival (PFS) and overall survival (OS) were analyzed. Results: In our study cohort, 35 patients were carriers of germline mutations in BRCA1 and 16 in BRCA2. The median PFS time following completion of the primary therapy was 23.8 months (95% CI 20.1–27.5) and the median OS was 92.9 months (95% CI 69.8–116.1) in all BRCA carriers. After multivariate analysis, no significant association among the location or type of BRCA1/2 mutation with PFS or OS was identified. Notably, significant differences in PFS between carriers of identical mutations in the same BRCA gene were detected. Conclusions: Among HGSOC patients, BRCA1/2 carriers with mutations in different locations of the genes show no significant difference in survival outcomes, in terms of PFS and OS, suggesting the potential effect of other genetic abnormalities and co-contributing risk factors.

Background Neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) is the recommended approach in patients with advanced epithelial ovarian cancer (EOC). However, most patients eventually relapse despite the initial high response rate to chemotherapy. Neutrophil-to-lymphocyte ratio is a well-known biomarker that reflects severe inflammation, critical illness, and mortality in various diseases. Chemotherapy response score (CRS) and neutrophil-to-lymphocyte ratio (NLR) have been identified as potential biomarkers of platinum resistance and disease prognosis. We retrospectively evaluated 132 patients with stage IIIc or IV ovarian/fallopian tube/primary peritoneal cancer who had received NACT followed by IDS from 01/01/2003 to 31/12/2018. CRS was assessed on omental specimens collected from IDS according to ICCR guidelines. Results Median age was 64.57 years (SD: 9.72; range 39.2–87.1). Most ovarian tumors were serous epithelial (90.9%; 120/132). An elevated NLR (defined as > 3) was observed in 72% (95/132) of patients in contrast with 28% (37/132) of patients characterized by low NLR status. Median PFS (mPFS) and median overall survival (mOS) were 13.05 months (95% CI: 11.42–14.67)) and 34.69 months (95% CI: 23.26–46.12) respectively. In univariate analysis, CRS3 score was significantly associated with prolonged mPFS (CRS1/2: 12.79 months vs CRS3: 17.7 months; P = 0.008). CRS score was not associated with mOS (P = 0.876). High NLR was not significantly associated with mPFS (P = 0.128), however it was significantly associated with poor mOS (P = 0.012). In multivariate analysis, only performance of surgery maintained its statistical significance with both PFS (P = 0.001) and OS (P = 0.008). Conclusion NLR could serve as a useful predictor of OS but not PFS in ovarian cancer patients receiving NACT. In accordance with our previous study, CRS score at omentum was found to be associated with PFS but not OS in ovarian cancer patients treated with NACT and IDS., Research highlights Biomarkers that would predict response to neoadjuvant chemotherapy in advanced ovarian cancer patients are eagerly needed: • Neutrophil to Lymphocyte Ratio (NLR) is an indicator of systemic inflammatory response to the malignancy. • NLR was evaluated in 132 patients undergoing Neoadjuvant Chemotherapy for advanced ovarian cancer. • Elevated NLR was associated with worse prognosis. • No association between NLR and response to chemotherapy was noted.

Background Tumor protein 53 (TP53) gene mutations are identified in up to 37% of breast tumors especially in HER-2 positive and basal-like subtype. Previous studies have indicated TP53 mutations as a prognostic biomarker in breast cancer. However, most of these studies performed immunohistochemistry (IHC) for the detection of TP53 mutations. Aim The purpose of our study is to evaluate the role of TP53 somatic mutations detected via next-generation sequencing (NGS) as a potential prognostic marker in patients with breast cancer. Materials and methods 82 female patients with Stage I-III breast cancer underwent NGS in paraffin blocks and blood samples during the period 25/09/2019 through 25/05/2021. 23 cases of somatic TP53 mutations and 23 cases of healthy controls were matched on age at diagnosis, menopausal status, histological subtype, histological grade, ki67 expression and disease stage. Results Mean age at diagnosis was 52.35 (SD; 11.47) years. The somatic TP53 mutation NM_000546.5:c.824G>A p.(Cys275Tyr) was most frequently detected. Co-existence of PIK3CA mutation was a common finding in somatic TP53-mutant tumors (4/23; 17.4%). Disease-free survival was shorter in TP53-mutated cases (16.3 months vs. 62.9 months). TP53 pathogenic somatic mutations were associated with a 8-fold risk of recurrence in the univariate Cox regression analysis (OR = 8.530, 95% CI: 1.81-40.117; p = 0.007). Conclusions Our case-control study suggests that TP53 somatic mutations detected by next-generation sequencing (NGS) are associated with an adverse prognosis in breast cancer.

Overweight, obesity, and metabolic syndrome (MetS) have become epidemic conditions affecting 39%, 13%, and 20% of the population respectively. The aim of this article is to review the literature on the association of obesity and MetS with the risk of cancer. We also explore the effect of lifestyle modifications, such as diet, physical activity, and antidiabetic medications, on cancer incidence. Increased body mass index (BMI) has been associated with a multitude of site-specific cancers, reaching relative risk (RR) 1.54 [95% confidence interval (CI) 1.47-1.61] per 5 unit increase for endometrial cancer, as well as with overall cancer risk (RR 1.03, 95% CI 1.02-1.05). Central adiposity measured by waist circumference or waist-to-hip ratio has been suggested as a stronger predictor than BMI for several cancers, such as colorectal cancer. Metabolic Syndrome has been consistently and positively associated with the risk of very common cancers like colorectal (RR 1.34, 95% CI 1.24-1.44), endometrial (RR 1.62, 95% CI 1.26-2.07) and postmenopausal breast cancer (RR 2.01, 95% CI 1.55-2.60). Hyperglycemia and subsequently T2DM have been also shown to increase the risk of cancer. Nevertheless, these risk factors are modifiable and therefore implementing lifestyle modifications could prevent an important number of cancer cases. Adherence to cancer prevention guidelines, including maintaining a healthy weight, having regular physical exercise (RR 0.58-0.90 for different cite specific cancers) and following a healthy dietary pattern (RR 0.74-0.94 for different cite specific cancers) have a protective effect on the risk of cancer. The strength of this review is the presentation of the best evidence, as the data derive mainly from meta-analyses. Public health policies should focus on the modification of risk factors and future research is needed to reveal the pathophysiological links between these risk factors and cancer to develop more efficient prevention and treatment strategies.

BACKGROUND The utilization and clinical impact of beta-blockers (BBs) in cardiac amyloidosis (CA) is largely unexplored. METHODS We conducted a retrospective, single-center analysis of indications, timing of initiation, types and doses of BB used, reasons to discontinue BB and association between BB tolerance and outcomes in a cohort of patients with immunoglobulin light chain amyloidosis (AL). RESULTS We reviewed 236 patients with AL CA and identified 53 patients taking BB (22.5%). Most patients presented in New York Heart Association Class (NYHA) II or III (74.5%) and 24% presented in Mayo stage IIIB. The most frequent indications for BB initiation were atrial fibrillation (AF) and coronary artery disease (CAD). In most cases (59%) BB was started before the diagnosis of CA. The median duration of BB treatment was 9 months (interquartile range [IQR] 3-24 months). Among patients receiving BB, 28 tolerated BB during follow-up whereas 25 patients discontinued BB. The main causes of BB discontinuation were hypotension and heart failure (HF) exacerbation. Patients intolerant to BB presented with more advanced NYHA class, worse performance status and lower median left ventricular ejection fraction (LVEF) at baseline. At median follow-up duration of 17.7 months, patients who did not tolerate BB had a poor survival. CONCLUSIONS Although some patients with CA may have indications for treatment with BB, their use is uncommon and those with more advanced disease tolerate BB poorly. Intolerance to BB in patients with cardiac AL is an indicator of poorer outcome.

AIMS: SARS-CoV-2 infection may lead to endothelial and vascular dysfunction. We investigated alterations of arterial stiffness, endothelial coronary and myocardial function markers 4 months after COVID-19 infection. METHODS AND RESULTS: In a case-control prospective study, we included 70 patients 4 months after COVID-19 infection, 70 age- and sex-matched untreated hypertensive patients (positive control) and 70 healthy individuals. We measured (i) perfused boundary region (PBR) of the sublingual arterial microvessels (increased PBR indicates reduced endothelial glycocalyx thickness), (ii) flow-mediated dilatation (FMD), (iii) coronary flow reserve (CFR) by Doppler echocardiography, (iv) pulse wave velocity (PWV), (v) global left and right ventricular longitudinal strain (GLS), and (vi) malondialdehyde (MDA), an oxidative stress marker, thrombomodulin and von Willebrand factor as endothelial biomarkers. COVID-19 patients had similar CFR and FMD as hypertensives (2.48 ± 0.41 vs. 2.58 ± 0.88, P = 0.562, and 5.86 ± 2.82% vs. 5.80 ± 2.07%, P = 0.872, respectively) but lower values than controls (3.42 ± 0.65, P = 0.0135, and 9.06 ± 2.11%, P = 0.002, respectively). Compared to controls, both COVID-19 and hypertensives had greater PBR5-25 (2.07 ± 0.15 µm and 2.07 ± 0.26 µm, P = 0.8 vs. 1.89 ± 0.17 µm, P = 0.001), higher PWV (carotid-femoral PWV 12.09 ± 2.50 vs. 11.92 ± 2.94, P = 0.7 vs. 10.04 ± 1.80 m/s, P = 0.036) and impaired left and right ventricular GLS (-19.50 ± 2.56% vs. -19.23 ± 2.67%, P = 0.864 vs. -21.98 ± 1.51%, P = 0.020 and -16.99 ± 3.17% vs. -18.63 ± 3.20%, P = 0.002 vs. -20.51 ± 2.28%, P < 0.001). MDA and thrombomodulin were higher in COVID-19 patients than both hypertensives and controls (10.67 ± 0.32 vs 1.76 ± 0.03, P = 0.003 vs. 1.01 ± 0.05 nmol/L, P = 0.001 and 3716.63 ± 188.36 vs. 3114.46 ± 179.18 pg/mL, P = 0.017 vs. 2590.02 ± 156.51 pg/mL, P < 0.001). Residual cardiovascular symptoms at 4 months were associated with oxidative stress and endothelial dysfunction markers. CONCLUSIONS: SARS-CoV-2 may cause endothelial and vascular dysfunction linked to impaired cardiac performance 4 months after infection.

Amyloid light-chain (AL) amyloidosis is a multisystemic disease. Among its clinical manifestations, vein and arterial thromboembolic events are included. We report the unusual case of a 57-year-old female patient with AL amyloidosis presenting with an ST segment elevation myocardial infarction due to coronary artery embolization (CE). The patient reported a history of exertional dyspnoea along with episodes of haemoptysis for the last few months. Her coronary angiography demonstrated embolization of the distal segment of the left anterior descending artery. The main findings of her cardiac ultrasound included concentric left ventricular hypertrophy, mildly impaired left ventricular systolic function, left atrium enlargement and a restrictive-like filling pattern, while her chest computed tomography (CT) demonstrated bilateral pleural effusions. Cardiac magnetic resonance imaging that was performed afterwards, indicated areas of microvascular infarction, a small apex infarct and findings compatible with possible amyloidosis, a diagnosis that was confirmed later by fat tissue biopsy. Patient was referred for an oncology consultation, started therapy with direct oral anticoagulants, angiotensin converting enzyme inhibitor, statins and anti-plasma cell therapy. She has been improving since then and has been free of cardiovascular events for a follow-up period of 12 months. Cardiologists ought to be aware of amyloidosis as a rare but possible cause of coronary embolization, while close collaboration with oncologists is required for the establishment of the correct diagnosis.

Introduction: Waldenstrom's macroglobulinemia (WM) is a rare lymphoma characterized by the accumulation of IgM-secreting lymphoplasmacytic cells in the bone marrow and other organs. Clinical sequelae relate to direct tissue infiltration by malignant cells but also to the physicochemical and immunological properties of the monoclonal IgM, resulting in a variety of disease-related complications.Areas covered: This narrative review, following a thorough Pubmed search of pertinent published literature, discusses complications secondary to WM, related to direct tumor infiltration, monoclonal IgM circulation, and deposition, as well as other less common ones. The description and pathophysiology of these complications were described together with their specific management strategies and in the context of available treatment options for WM (anti-CD20 monoclonal antibody-based combinations, proteasome inhibitors, BTK inhibitors, and other emerging ones).Expert opinion: The availability of many novel, active and less toxic regimens for the treatment of WM allows the management of the disease with strategies that depend on clinical presentation and disease-related complications, age, toxicity considerations, and presence of comorbidities.

Athanasios Dellis,1 Roubini Zakopoulou,2 Andromahi Kougioumtzopoulou,3 Kimon Tzannis,2 Konstantinos Koutsoukos,2 Charalampos Fragkoulis,4 Efthymios Kostouros,5 Athanasios Papatsoris,6 Ioannis Varkarakis,6 Konstantinos Stravodimos,7 Eleni Boutati,8 Stamata Pagoni,5 Miltiadis Seferlis,9 Michael Chrisofos,10 Vasilios Kouloulias,3 Konstantinos Ntoumas,4 Charalambos Deliveliotis,6 Constantine Constantinides,7 Meletios A Dimopoulos,2 Aristotelis Bamias8 1 2nd Department of Surgery, National & Kapodistrian University of Athens, Aretaieion University Hospital, Athens, Greece; 2Oncology Unit, Department of Clinical Therapeutics, National & Kapodistrian University of Athens, Alexandra Hospital, Athens, Greece; 3Radiotherapy Unit, 2nd Department of Radiology, National & Kapodistrian University of Athens, Attikon University Hospital, Athens, Greece; 4Department of Urology, General Hospital of Athens “G. Gennimatas”, Athens, Greece; 5 3rd Department of Internal Medicine, General Hospital of Athens “G. Gennimatas”, Athens, Greece; 6 2nd Department of Urology, National & Kapodistrian University of Athens, Sismanoglio Hospital, Athens, Greece; 7First Department of Urology, National and Kapodistrian University of Athens, “Laiko” General Hospital, Athens, Greece; 8 2nd Propaedeutic Department of Internal Medicine, National & Kapodistrian University of Athens, Attikon University Hospital, Athens, Greece; 9Department of Urology, Thriasion General Hospital, Athens, Greece; 10 3rd Department of Urology, National & Kapodistrian University of Athens, Attikon University Hospital, Athens, GreeceCorrespondence: Aristotelis Bamias 2nd Propaedeutic Department of Internal Medicine, National & Kapodistrian University of Athens, Attikon University Hospital, Athens, GreeceTel +30 2105831256 Fax +30 210 5326454Email abamias@med.uoa.grBackground: Utilization of neoadjuvant chemotherapy for the treatment of muscle invasive bladder cancer in everyday practice differs from that of clinical trials. We describe the patterns of referral for “neoadjuvant chemotherapy”, treatment and outcomes in a multidisciplinary tumor board.Methods: This was an observational study. Patients referred for neoadjuvant chemotherapy received 4 cycles of dose-dense gemcitabine/cisplatin and were then assessed for definitive local therapy. Patients had a minimum follow-up of 2 years. Primary objective was a 3-year disease-free survival rate.Results: Forty-six patients (clinical stages II: 28, IIIA: 9, IIIB: 4, IVA: 3, missing: 2) were included. Following chemotherapy, 30 underwent radical cystectomy, 8 radiotherapy and 8 no further therapy. Pathological downstaging was observed in 14 (46.6%) of the 30 patients who underwent radical cystectomy; clinical TNM staging was correlated with disease-free survival in the whole population, while clinical and pathological stages, as well as pathological downstaging, were correlated with disease-free survival in patients undergoing radical cystectomy. Three-year disease-free survival rates for the whole cohort and for patients undergoing radical cystectomy were 67.3% (95% confidence interval [CI]: 51– 79.2) and 65.2 (95% CI: 44.9– 79.6), respectively.Conclusion: Real-world muscle invasive bladder cancer patients who receive neoadjuvant chemotherapy are characterized by more advanced diseases and less frequent radical surgery than those included in clinical trials. Nevertheless, outcomes were comparable and, therefore, offering patients with stage II–IVA muscle invasive bladder cancer neoadjuvant chemotherapy after assessment by multidisciplinary tumor boards should be strongly encouraged.Keywords: bladder cancer, neoadjuvant, chemotherapy, cystectomy, radiotherapy

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

The continuous advances in the treatment landscape of multiple myeloma has led to the approval of several novel agents and their combinations that significantly improved patient outcomes. Despite their undoubtful effectiveness in the context of clinical trials, their impact on real-world (RW) clinical practice remains debatable. RW data on the role of novel agents and their combinations among patients with relapsed/refractory multiple myeloma have confirmed the efficacy of proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies. However, the magnitude of the benefit and the safety profile may differ among RW studies and between RW and pivotal clinical trials. Several variables may pertain to these observations and include patient selection, ethnicity, age, comorbidities, disease stage at diagnosis and at relapse, number of prior lines of therapy, disease subtype, presence of renal impairment, extramedullary disease, and cytogenetic abnormalities. All these contribute to a varying degree of disease and patient heterogeneity among the studies that may result in a differential treatment effect. The expertise of each medical center and the treatment setting in terms of availability and drug access are particularly important as well. Interestingly, RW observations may serve as proof of concept for designing novel clinical trials, as is the case with retreatment studies. In conclusion, clinical trial and RW data are complementary, and they should be considered to improve both clinical trial design and clinical practice.

Newer treatments for multiple myeloma (MM) have improved response rates and survival for many patients. However, MM remains challenging to treat due to the propensity for multiple relapses, cumulative and emergent toxicities from prior therapies and increasing genomic complexity that arises due to clonal evolution. In particular, patients with relapsed/refractory MM often require increased complexity of treatment, yet still experience poorer outcomes compared with patients who are newly diagnosed. Additionally, several patient subgroups, including those with extramedullary disease and patients who are frail and/or have multiple comorbidities, have an unfavorable prognosis and remain undertreated. This review (based on an Updates-in-Hematology session at the 25th European Hematology Association Annual Congress 2020) discusses the management of these difficult-to-treat patients with MM.Lay abstract New treatments have extended the lives of many patients with multiple myeloma (MM). Still, MM can sometimes be difficult to control. In some patients, their MM will return after a period of months or years (known as relapse). In others, treatment will need to be stopped or changed due to side effects. Changes to the myeloma cancer cells can sometimes cause a treatment to stop working (known as resistance). Other groups of patients with MM who can be hard to treat are those with a more aggressive type of myeloma called extramedullary disease, and those who are old or frail or have other illnesses. This paper summarizes a meeting of expert doctors at the 25th European Hematology Association Annual Congress 2020. They discussed how to select the best treatment for patients with MM whose condition is difficult to control. They also discussed new medicines that are being tested for the treatment of MM.

In the phase 3 OPTIMISMM trial, pomalidomide, bortezomib, and dexamethasone (PVd) demonstrated superior efficacy vs bortezomib and dexamethasone (Vd) in patients with relapsed or refractory multiple myeloma previously treated with lenalidomide, including those refractory to lenalidomide. This analysis evaluated outcomes in patients at first relapse (N = 226) by lenalidomide-refractory status, prior bortezomib exposure, and prior stem cell transplant (SCT). Second-line PVd significantly improved PFS vs Vd in lenalidomide-refractory (17.8 vs 9.5 months; P = 0.0276) and lenalidomide-nonrefractory patients (22.0 vs 12.0 months; P = 0.0491), patients with prior bortezomib (17.8 vs 12.0 months; P = 0.0068), and patients with (22.0 vs 13.8 months; P = 0.0241) or without (16.5 vs 9.5 months; P = 0.0454) prior SCT. In patients without prior bortezomib, median PFS was 20.7 vs 9.5 months (P = 0.1055). Significant improvement in overall response rate was also observed with PVd vs Vd in lenalidomide-refractory (85.9% vs 50.8%; P P

Background Obesity and high body mass index (BMI) are associated with increased incidence of multiple myeloma (MM). MM usually evolves from a precursor asymptomatic disease, namely monoclonal gammopathy of undetermined significance (MGUS). MGUS progresses to MM at a 1% annual rate; however, risk factors predisposing to MGUS are not completely understood. We conducted a systematic review to assess the relationship between obesity and high BMI with MGUS prevalence and progression to MM. To our knowledge, this is the first systematic review evaluating the role of obesity in MGUS. Patients and Methods We searched the Medline database and ClinicalTrials.gov for studies investigating BMI and obesity association with MGUS incidence and progression. The algorithm consisted of a predefined combination of the words “obesity,” “obese,” “body mass index,” “overweight,” “diet,” “nutrition,” “food,” “dietary,” “adiponectin,” “monoclonal gammopathy,” and “MGUS”. Results Overall, 12 articles were retrieved, including 11 eligible articles and 1 clinical trial. More than 57,068 patients were evaluated in this systematic review. Discrepancies between the identified studies were noted. Multiple studies support the notion that obesity or high BMI are positively linked to MGUS prevalence and transition to MM. In contrast, other studies revealed no such association. Visceral adipose tissue metabolic activity and decreased adiponectin concentrations were identified as biomarkers of MGUS progression to MM. Conclusion Obesity and increased BMI seem to be implicated both in MGUS development and progression to MM. Further studies should be designed to confirm this hypothesis.

Background: In a phase 1b study, intravenous daratumumab plus pomalidomide and dexamethasone induced a very good partial response or better rate of 42% and was well tolerated in patients with heavily pretreated multiple myeloma. We aimed to evaluate whether daratumumab plus pomalidomide and dexamethasone would improve progression-free survival versus pomalidomide and dexamethasone alone in patients with previously treated multiple myeloma. Methods: In this ongoing, open-label, randomised, phase 3 trial (APOLLO) done at 48 academic centres and hospitals across 12 European countries, eligible patients were aged 18 years or older, had relapsed or refractory multiple myeloma with measurable disease, had an Eastern Cooperative Oncology Group performance status of 0–2, had at least one previous line of therapy, including lenalidomide and a proteasome inhibitor, had a partial response or better to one or more previous lines of antimyeloma therapy, and were refractory to lenalidomide if only one previous line of therapy was received. Patients were randomly assigned (1:1) by an interactive web-response system in a random block size of two or four to receive pomalidomide and dexamethasone alone or daratumumab plus pomalidomide and dexamethasone. Randomisation was stratified by number of previous lines of therapy and International Staging System disease stage. All patients received oral pomalidomide (4 mg, once daily on days 1–21) and oral dexamethasone (40 mg once daily on days 1, 8, 15, and 22; 20 mg for those aged 75 years or older) at each 28-day cycle. The daratumumab plus pomalidomide and dexamethasone group received daratumumab (1800 mg subcutaneously or 16 mg/kg intravenously) weekly during cycles 1 and 2, every 2 weeks during cycles 3–6, and every 4 weeks thereafter until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov, NCT03180736. Findings: Between June 22, 2017, and June 13, 2019, 304 patients (median age 67 years [IQR 60–72]; 161 [53%] men and 143 [47%] women) were randomly assigned to the daratumumab plus pomalidomide and dexamethasone group (n=151) or the pomalidomide and dexamethasone group (n=153). At a median follow-up of 16·9 months (IQR 14·4–20·6), the daratumumab plus pomalidomide and dexamethasone group showed improved progression-free survival compared with the pomalidomide and dexamethasone group (median 12·4 months [95% CI 8·3–19·3] vs 6·9 months [5·5–9·3]; hazard ratio 0·63 [95% CI 0·47–0·85], two-sided p=0·0018). The most common grade 3 or 4 adverse events were neutropenia (101 [68%] of 149 patients in the daratumumab plus pomalidomide and dexamethasone group vs 76 [51%] of 150 patients in the pomalidomide and dexamethasone group), anaemia (25 [17%] vs 32 [21%]), and thrombocytopenia (26 [17%] vs 27 [18%]). Serious adverse events occurred in 75 (50%) of 149 patients in the daratumumab plus pomalidomide and dexamethasone group versus 59 (39%) of 150 patients in the pomalidomide and dexamethasone group; pneumonia (23 [15%] vs 12 [8%] patients) and lower respiratory tract infection (18 [12%] vs 14 [9%]) were most common. Treatment-emergent deaths were reported in 11 (7%) patients in the daratumumab plus pomalidomide and dexamethasone group versus 11 (7%) patients in the pomalidomide and dexamethasone group. Interpretation: Among patients with relapsed or refractory multiple myeloma, daratumumab plus pomalidomide and dexamethasone reduced the risk of disease progression or death versus pomalidomide and dexamethasone alone and could be considered a new treatment option in this setting. Funding: European Myeloma Network and Janssen Research and Development., European Myeloma Network and Janssen Research and Development.

In the phase 3 POLLUX trial, daratumumab in combination with lenalidomide and dexamethasone (D-Rd) significantly improved progression-free survival in patients with relapsed/refractory multiple myeloma (RRMM) compared with lenalidomide and dexamethasone (Rd) alone. Here, we present patient-reported outcomes (PROs) from POLLUX, assessed using the validated European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item (EORTC QLQ-C30) and the EuroQol 5-dimensional descriptive system (EQ-5D-5L) questionnaires. Changes from baseline are presented as least-squares mean changes with 95% confidence intervals (CIs) derived from a mixed-effects model. PRO assessment compliance rates were high and similar in both D-Rd and Rd groups through cycle 40 (week 156). In this on-treatment analysis, mean changes from baseline were significantly greater in EORTC QLQ-C30 global health status, physical functioning, and pain scores in the D-Rd group versus the Rd group at multiple time points; however, magnitude of changes was low, suggesting no meaningful impact on health-related quality of life (HRQoL). Subgroup results were similar to those in the overall population. In the POLLUX study, baseline HRQoL was maintained with prolonged D-Rd treatment. These findings complement the sustained and significant improvement in progression-free survival observed with D-Rd and supports its use in patients with RRMM. Clinical trial registration: NCT02076009.

Introduction: The clinical outcome of HER2-positive breast cancer patients changed with the use of anti-Her therapies, though it still remains an aggressive and fatal disease. Implementation of immune checkpoint inhibitors in HER2-positive Breast cancer is a concept supported by the reported biological and preclinical data. Methods: We conducted a systematic review of the current literature involving immune checkpoint inhibitors alone or in combination with targeted therapies or chemotherapy finalized or running in HER2-positive breast cancer. Results: Twelve clinical trials and 2 case reports were identified in our study. Conclusion: The reported clinical trials highlight that checkpoint inhibition seems to be promising in metastatic, neoadjuvant, and adjuvant settings of HER2-positive breast cancer.

Treatment of elderly patients with neoplasia is challenging. Age is a known prognostic factor in ovarian cancer but the optimal treatment of elderly patients has not been determined. We undertook a retrospective analysis to determine clinical practice in advanced-stage ovarian cancer patients older than 70 years of age. Methods: Medical records of women with high-grade serous ovarian cancer, stage III and IV were retrospectively analyzed. Results: A total of 735 patients were identified with a median age of 61.5 years. 22.4% among them were older than 70 years of age at diagnosis. First-line Progression-Free Survival (PFS) and Overall Survival (OS) were significantly worse in elderly patients in comparison to the younger ones [mPFS 11.3 months vs., 14.8 months, (p &lt, 0.001) and mOS 30.2 months vs. 45.6 months (p &lt, 0.001)]. However, elderly patients were characterized by worse ECOG-Performance Status and they were more frequently treated with Neoadjuvant Chemotherapy followed by Interval Debulking Surgery, while often they were more frequently denied debulking surgery compared to patients under 70 years of age. Moreover, elderly patients received more frequently monotherapy with platinum as frontline treatment. In contrast, there was no significant difference in the outcome of the debulking surgery in comparison to the younger patients or the frequency that gBRCA test was performed. Age over 70 years did not retain its significance for either Progression-Free Survival or Overall Survival when adjusted for all other reported prognostic factors. Conclusion: Elderly ovarian cancer patients have a worse prognosis. Comprehensive geriatric assessment should be performed for the optimal treatment of these patients.

In this Policy Review, the Bone Working Group of the International Myeloma Working Group updates its clinical practice recommendations for the management of multiple myeloma-related bone disease. After assessing the available literature and grading recommendations using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) method, experts from the working group recommend zoledronic acid as the preferred bone-targeted agent for patients with newly diagnosed multiple myeloma, with or without multiple myeloma-related bone disease. Once patients achieve a very good partial response or better, after receiving monthly zoledronic acid for at least 12 months, the treating physician can consider decreasing the frequency of or discontinuing zoledronic acid treatment. Denosumab can also be considered for the treatment of multiple myeloma-related bone disease, particularly in patients with renal impairment. Denosumab might prolong progression-free survival in patients with newly diagnosed multiple myeloma who have multiple myeloma-related bone disease and who are eligible for autologous stem-cell transplantation. Denosumab discontinuation is challenging due to the rebound effect. The Bone Working Group of the International Myeloma Working Group also found cement augmentation to be effective for painful vertebral compression fractures. Radiotherapy is recommended for uncontrolled pain, impeding or symptomatic spinal cord compression, or pathological fractures. Surgery should be used for the prevention and restoration of long-bone pathological fractures, vertebral column instability, and spinal cord compression with bone fragments within the spinal route.

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/m2 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 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.

Summary Background Improved therapeutic options are needed for patients with relapsed or relapsed and refractory multiple myeloma. Subcutaneous bortezomib has replaced intravenous bortezomib as it is associated with a more favourable toxicity profile. We investigated the activity and safety of three different dosing regimens of oral panobinostat in combination with subcutaneous bortezomib and oral dexamethasone for this indication. Methods PANORAMA 3 is an open-label, randomised, phase 2 study being done at 71 sites (hospitals and medical centres) across 21 countries. Patients aged 18 years or older with relapsed or relapsed and refractory multiple myeloma (as per International Myeloma Working Group 2014 criteria), who had received one to four previous lines of therapy (including an immunomodulatory agent), and had an Eastern Cooperative Oncology Group performance status of 2 or lower, were randomly assigned (1:1:1) to receive oral panobinostat 20 mg three times weekly, 20 mg twice weekly, or 10 mg three times weekly, plus subcutaneous bortezomib and oral dexamethasone. All study drugs were administered in 21-day cycles. Randomisation was done by an interactive response technology provider, and stratified by number of previous treatment lines and age. The primary endpoint was overall response rate after up to eight treatment cycles (analysed in all randomly assigned patients by intention to treat). Safety analyses included all patients who received at least one dose of any study drug. No statistical comparisons between groups were planned. This trial is ongoing and registered with ClinicalTrials.gov , NCT02654990 . Findings Between April 27, 2016, and Jan 17, 2019, 248 patients were randomly assigned (82 to panobinostat 20 mg three times weekly, 83 to panobinostat 20 mg twice weekly, and 83 to 10 mg panobinostat three times weekly). Median duration of follow-up across all treatment groups was 14·7 months (IQR 7·8–24·1). The overall response rate after up to eight treatment cycles was 62·2% (95% CI 50·8–72·7; 51 of 82 patients) for the 20 mg three times weekly group, 65·1% (53·8–75·2; 54 of 83 patients) for the 20 mg twice weekly group, and 50·6% (39·4–61·8; 42 of 83 patients) for the 10 mg three times weekly group. Grade 3–4 adverse events occurred in 71 (91%) of 78 patients in the 20 mg three times weekly group, 69 (83%) of 83 patients in the 20 mg twice weekly group, and 60 (75%) of 80 patients in the 10 mg three times weekly group; the most common (≥20% patients in any group) grade 3–4 adverse events were thrombocytopenia (33 [42%] of 78, 26 [31%] of 83, and 19 [24%] of 83 patients) and neutropenia (18 [23%], 13 [16%], and six [8%]). Serious adverse events occurred in 42 (54%) of 78 patients in the 20 mg three times weekly group, 40 (48%) of 83 patients in the 20 mg twice weekly group, and 35 (44%) of 83 patients in the 10 mg three times weekly group; the most common serious adverse event (≥10% patients in any group) was pneumonia (nine [12%] of 78, ten [12%] of 83, and nine [11%] of 80 patients). There were 14 deaths during the study (five [6%] of 78 patients in the 20 mg three times weekly group, three [4%] of 83 in the 20 mg twice weekly group, and six [8%] of 80 in the 10 mg three times weekly group); none of these deaths was deemed treatment related. Interpretation The safety profile of panobinostat 20 mg three times weekly was more favourable than in previous trials of this regimen with intravenous bortezomib, suggesting that subcutaneous bortezomib improves the tolerability of the panobinostat plus bortezomib plus dexamethasone regimen. The overall response rate was highest in the 20 mg three times weekly and 20 mg twice weekly groups, with 10 mg three times weekly best tolerated. Funding Novartis Pharmaceuticals and Secura Bio.

Waldenström macroglobulinaemia is an indolent B-cell lymphoma with clearly defined criteria for diagnosis, initiation of therapy, and response, which was established by consensus panels at previous International Workshops for Waldenström Macroglobulinaemia (IWWM). The treatment options for Waldenström macroglobulinaemia continued to be researched after the publication of the eighth IWWM consensus recommendations in 2016, and at the tenth IWWM in New York, USA (October, 2018) an international consensus panel was formed to update treatment recommendations. Participants were selected as members of the consensus panel based on their expertise on Waldenström macroglobulinaemia. The initial live discussion took place during the tenth IWWM meeting and two separate teleconferences were held in June, 2019, and January, 2020, to refine recommendations. No external or financial support was received for the elaboration of these recommendations. According to these updated consensus recommendations, alkylating drugs (bendamustine, cyclophosphamide) and proteasome inhibitors (bortezomib, carfilzomib, ixazomib), both in combination with rituximab, as well as BTK inhibitors (ibrutinib), alone or in combination with rituximab, are preferred first-line therapy options for symptomatic patients with Waldenström macroglobulinaemia. In previously treated patients with Waldenström macroglobulinaemia who had an initial durable response, reuse of a previous regimen or another primary therapy regimen are acceptable options. Novel BTK inhibitors (acalabrutinib, zanubrutinib, tirabrutinib) and the BCL2 antagonist venetoclax appear safe and active, and represent emerging options for the treatment of Waldenström macroglobulinaemia. The choice of therapy should be guided by the patient's clinical profile, genomic features, and drug availability.

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.

Introduction: The phase3 ALCYONE study demonstrated significantly longer progression-free and overall survival (PFS/OS) and higher overall response rates (ORR) with daratumumab plus bortezomib, melphalan, and prednisone (D-VMP) versus VMP alone in transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM). In Latin America, bortezomib- or thalidomide-based regimens remain standard of care (SoC) for this population. No head-to-head trials have compared D-VMP with SoC regimens used in Latin America. Methods: Propensity score matching (PSM) was used to control for baseline differences between patient populations and compare outcomes for D-VMP versus SoC regimens used in Latin America. Data for the D-VMP cohort were from the D-VMP arm of the ALCYONE trial (n = 350). Data for the SoC cohort were from the retrospective, observational Hemato-Oncology Latin America (HOLA) study, which included patients with NDMM who did not receive a transplant (n = 729). Propensity scores were estimated using logistic regression. Exact, optimal, and nearest-neighbor PSM were applied to pick the best-performing method. Doubly robust estimation was the base case, since some baseline imbalances persisted. Results: All 350 patients from the D-VMP arm of ALCYONE were included in OS/PFS analyses and 338 in ORR analysis; 478 and 324 patients, respectively, from HOLA were included in these analyses. Naïve comparison revealed important differences in baseline characteristics (age, chronic kidney disease, hypercalcemia, and International Staging System [ISS] stage). After nearest-neighbor matching, baseline characteristics, except ISS stage, were well balanced; comparisons favored D-VMP over SoC for OS (hazard ratio = 0.41; 95% confidence interval [CI] 0.25–0.66; P = 0.002) and PFS (hazard ratio = 0.48; 95% CI 0.35–0.67; P < 0.001). After exact matching, imbalances remained in age and ISS stage; comparisons favored D-VMP over SoC for ORR (odds ratio = 5.44; 95% CI 2.65–11.82; P < 0.001). Conclusion: In transplant-ineligible patients with NDMM, D-VMP showed superior effectiveness versus bortezomib- and thalidomide-based regimens, supporting adoption of daratumumab-containing regimens in Latin America.

Introduction Lenalidomide plus dexamethasone is effective and well tolerated in relapsed/refractory multiple myeloma (RRMM). In this observational, noninterventional European post-authorization safety study, the safety profile of lenalidomide plus dexamethasone was investigated and compared with that of other agents in the treatment of RRMM in a real-world setting. Patients and Methods Patients had received ≥ 1 prior antimyeloma therapy; prior lenalidomide was excluded. Treatment was per investigator’s routine practice. Adverse events were analyzed by incidence rates per 100 person-years to account for differences in observation length and treatment duration. Results In total, 2150 patients initiated lenalidomide, and 1479 initiated any other antimyeloma therapy, predominately bortezomib (80.3%), which was primarily administered intravenously (74.3%). The incidence rate of neuropathy was lower with lenalidomide (10.5) than with bortezomib (78.9) or thalidomide (38.7). Lenalidomide also had a lower incidence rate of infections (68.7) versus bortezomib (95.9) and thalidomide (76.0). Conversely, the incidence rate of neutropenia was higher with lenalidomide (38.0) than with bortezomib (18.2) or thalidomide (25.7). The incidence rates of thrombocytopenia were 24.4, 40.4, and 14.4 with lenalidomide, bortezomib, and thalidomide, respectively. Conclusion No new safety signals for lenalidomide were identified in this study, which is the largest prospective real-world European study of lenalidomide in patients with RRMM to date. These results confirm that the safety profile of lenalidomide plus dexamethasone in RRMM in a real-world setting is comparable to that reported in clinical trials.

Introduction: Multiple myeloma (MM) is the second most common haematological malignancy and is characterized by bone marrow infiltration of monoclonal plasma cells and end-organ involvement. Smoldering MM (SMM) is an intermediate clinical entity between MGUS and MM, with a risk of progression to symptomatic disease at 10% per year. Bone disease is the most frequent related symptom of MM, with approximately 90% of patients developing bone lesions throughout their disease course. Therefore, imaging plays a crucial role in diagnosis and management of these patients. Conventional radiography was traditionally considered as the standard of care, however the limited sensitivity in detecting osteolytic bone lesions has led to more advanced imaging modalities. Imaging also is of high importance to discriminate MM from smoldering disease, since the presence of bone lesions establishes the diagnosis of active disease and requires treatment initiation. Computed tomography (CT) was found to be the most sensitive modality in detecting small osteolytic bone lesions less than 5 mm. Ionizing radiation exposure was one of the main limitations of this technique. Technological advances have made possible low dose assessment of the entire skeleton with effective radiation doses comparable to those of a whole-body plain radiographic skeletal survey. Furthermore, the low dose CT is widely available and has a very short scan time. Therefore, whole-body low dose CT (WBLDCT) 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 patients with asymptomatic MM who progress with bone disease only and who require immediate antimyeloma treatment. Patients and Methods: Our study was approved by the local IRB and all patients provided informed consent. All patients diagnosed with SMM based on the 2003 International Myeloma Working Group (IMWG) definition of SMM were serially assessed with WBLDCT from July 2013 until March 2020 as part of our institutional workup. The assessments were performed at baseline, 1-year post diagnosis and every 1 year thereafter. The patients enrolled in the study were those who had at least 2 consecutive CT assessments at the above described time points. All WBLDCT exams were performed with a 16-detector CT scanner. The CTs were evaluated by two experienced radiologists, blinded to the clinical and laboratory data. RESULTS We prospectively evaluated 100 patients with SMM (median age at diagnosis 61 years, range 40-86 years, 52 female /48 male) who underwent WBLDCT at the above described time points. Median number of WBLDCTs exams performed was 2.5 (range 2-5). Totally, 31 patients progressed (either with CRAB criteria and/or at least one myeloma defining event). During a median follow up of 57 months 31 patients have progressed (with either CRAB criteria and/or at least one myeloma defininf event). Importantly, 10 of 31 patients progressed only with bone lesions that were identified on the scheduled WBLDCT as per protocol. Median time to progression from asymptomatic to symptomatic disease for all patients has not been reached, while median time for those who actually progressed was 22 months (95% CI:15,6-28,4). For the subgroup of patients who progressed with bone lesions only the median time was also 22 months (95%CI:3,4-40,6). Median time to progression was not statistically different between the two progressor subgroups. All patients were initiated with antimyeloma treatment immediately post evolution to symptomatic disease. PFS for all 31 patients at first line treatment was 52 months (95%CI:34,5-69,5) and median PFS for bone progressors has not yet been reached. Among the patients who progressed 29 were alive at the time of the analysis. The 2 deaths that occurred were one related (progressive disease) and one unrelated to multiple myeloma (cardiovascular event). Neither had progressed with isolated bone involvement. Conclusion: In conclusion, our strategy allowed early detection of bone lesions in 10% of our patients and these patients were immediately initiated with antimyeloma treatment to avoid further myeloma-related complications. Consecutive low-dose WBLDCT studies can identify early myeloma evolution to symptomatic disease and optimize the disease monitoring along with our therapeutic strategy. Disclosures Gavriatopoulou: Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Genesis Pharma: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Kastritis:Amgen: Consultancy, Honoraria, Research Funding; Genesis Pharma: Consultancy, Honoraria, Other: Travel/accommodations/expenses; Janssen: Consultancy, Honoraria, Other: Travel/accommodations/expenses, Research Funding; Pfizer: Consultancy; Takeda: Consultancy, Honoraria, Other: Travel/accommodations/expenses. Terpos:Janssen: Honoraria, Other: travel expenses , Research Funding; Takeda: Honoraria, Other: travel expenses , Research Funding; Celgene: Honoraria; Medison: Honoraria; Amgen: Honoraria, Research Funding; Genesis: Honoraria, Other: travel expenses , Research Funding. Dimopoulos:Celgene: Honoraria; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria; Beigene: Honoraria; Amgen: Honoraria; Takeda: Honoraria.

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.

The increasing lifespan of the world population and the novel therapeutic combinations for the treatment of multiple myeloma (MM), which are more efficacious and safer, make the question of how to manage the older patient with MM increasingly relevant. Clinical trial data come mostly from subgroup analysis, as no clinical trials have been designed for elderly patients with MM, particularly the octogenarian population. Age has been traditionally used as a surrogate marker of physiological decline but does not accurately reflect frailty on its own. Validated frailty assessment tools that accurately and sensitively risk-stratify older MM patients are needed. Such tools are being increasingly incorporated into clinical trial design. We should aim to use them to offer a tailored therapeutic approach to this heterogeneous subgroup of the MM population. Risk stratification based on disease-specific and patient-specific characteristics helps set the relevant outcome measures and therapeutic goals that will allow the right choice of treatment. The treatment goal for all patients should be to prolong survival and preserve quality of life. In the fit old MM patient, good responses can be achieved by carefully selecting candidates for autologous stem cell transplant and novel triplet or quadruplet combinations. At the other end of the spectrum, quality-of-life outcome measures and toxicity minimization with dose adaptation should be the focus.

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

PURPOSE Smoldering multiple myeloma (SMM) is a precursor condition of multiple myeloma (MM) with a 10% annual risk of progression. Various prognostic models exist for risk stratification; however, those are based on solely clinical metrics. The discovery of genomic alterations that underlie disease progression to MM could improve current risk models. METHODS We used next-generation sequencing to study 214 patients with SMM. We performed whole-exome sequencing on 166 tumors, including 5 with serial samples, and deep targeted sequencing on 48 tumors. RESULTS We observed that most of the genetic alterations necessary for progression have already been acquired by the diagnosis of SMM. Particularly, we found that alterations of the mitogen-activated protein kinase pathway ( KRAS and NRAS single nucleotide variants [SNVs]), the DNA repair pathway (deletion 17p, TP53, and ATM SNVs), and MYC (translocations or copy number variations) were all independent risk factors of progression after accounting for clinical risk staging. We validated these findings in an external SMM cohort by showing that patients who have any of these three features have a higher risk of progressing to MM. Moreover, APOBEC associated mutations were enriched in patients who progressed and were associated with a shorter time to progression in our cohort. CONCLUSION SMM is a genetically mature entity whereby most driver genetic alterations have already occurred, which suggests the existence of a right-skewed model of genetic evolution from monoclonal gammopathy of undetermined significance to MM. We identified and externally validated genomic predictors of progression that could distinguish patients at high risk of progression to MM and, thus, improve on the precision of current clinical models.

This study aimed to predict long-term progression-free survival (PFS) using early M-protein dynamic measurements in patients with relapsed/refractory multiple myeloma (MM). The PFS was modeled based on dynamic M-protein data from two phase III studies, POLLUX and CASTOR, which included 569 and 498 patients with relapsed/refractory MM, respectively. Both studies compared active controls (lenalidomide and dexamethasone, and bortezomib and dexamethasone, respectively) alone vs. in combination with daratumumab. Three M-protein dynamic features from the longitudinal M-protein data were evaluated up to different time cutoffs (1, 2, 3, and 6 months). The abilities of early M-protein dynamic measurements to predict the PFS were evaluated using Cox proportional hazards survival models. Both univariate and multivariable analyses suggest that maximum reduction of M-protein (i.e., depth of response) was the most predictive of PFS. Despite the statistical significance, the baseline covariates provided very limited predictive value regarding the treatment effect of daratumumab. However, M-protein dynamic features obtained within the first 2 months reasonably predicted PFS and the associated treatment effect of daratumumab. Specifically, the areas under the time-varying receiver operating characteristic curves for the model with the first 2 months of M-protein dynamic data were ~ 0.8 and 0.85 for POLLUX and CASTOR, respectively. Early M-protein data within the first 2 months can provide a prospective and reasonable prediction of future long-term clinical benefit for patients with MM.

As of June 10th 2020 about 7.2 million individuals have tested positive for, and more than 410,000 have died due to COVID-19. In this review we outline the pathophysiology that underpins the potential use of anti-rheumatic therapies for severe COVID-19 infection and summarize the current evidence regarding the risk and outcome of COVID-19 in patients with systemic autoimmune diseases. Thus far there is no convincing evidence that any disease-modifying anti-rheumatic drug (conventional synthetic, biologic or targeted synthetic) including hydroxychloroquine, may protect against severe COVID-19 infection; answers about their possible usefulness in the management of the cytokine storm associated with severe COVID-9 infection will only arise from ongoing randomized controlled trials. Evidence on COVID-19 risk and outcome in patients with systemic autoimmune diseases is extremely limited; thus, any conclusions would be unsafe and should be seen with great caution. At present, the risk and severity (hospitalization, intensive care unit admission and death) of COVID-19 infection in people with autoimmune diseases do not appear particularly dissimilar to the general population, with the possible exception of hospitalization in patients exposed to high glucocorticoid doses. At this stage it is impossible to draw any conclusions for differences in COVID-19 risk and outcome between different autoimmune diseases and between the various immunomodulatory therapies used for them. More research in the field is obviously required, including as a minimum careful and systematic epidemiology and appropriately controlled clinical trials.

Introduction Bortezomib, melphalan, and prednisone (VMP) is the standard of care for transplant-ineligible newly diagnosed multiple myeloma. The phase III VISTA trial established the bortezomib dosing schedule for VMP. To mitigate bortezomib-associated toxicity, the phase III ALCYONE study of daratumumab plus VMP (D-VMP) versus VMP used modified bortezomib dosing. D-VMP demonstrated improved progression-free survival and overall response rate. Propensity score matching enables indirect comparisons by controlling for differences in baseline covariates. Patients and Methods The efficacy and safety of both arms of ALCYONE were compared with VISTA VMP using propensity score matching. ALCYONE D-VMP and VMP patients were matched on selected baseline characteristics to VISTA VMP patients, reducing or eliminating systematic differences between treatment groups. Results After matching, median progression-free survival and overall response rate were comparable for ALCYONE VMP and VISTA VMP, and were significantly improved with ALCYONE D-VMP versus VISTA VMP. Rates of grade 3/4 peripheral sensory neuropathy were significantly lower for both arms of ALCYONE versus VISTA VMP, with or without matching. Conclusion This propensity score matching analysis demonstrates significant improvements in efficacy with ALCYONE D-VMP versus VISTA VMP and a significantly lower incidence of peripheral sensory neuropathy in both arms of ALCYONE versus VISTA VMP, although safety improvements may be due to different bortezomib administration routes (ALCYONE, subcutaneous; VISTA, intravenous).

Patients relapsing early after autologous stem cell transplantation (ASCT) are a particular therapeutic challenge.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 within12 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 versus5 years (P .001) and the median post-ASCT survival was 18 months versus6 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.Patients relapsing12 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.

The phase 3, double-blind, placebo-controlled TOURMALINE-MM3 study (NCT02181413) demonstrated improved progression-free survival with ixazomib maintenance versus placebo post autologous stem cell transplant (ASCT) in multiple myeloma patients. We report additional safety data from TOURMALINE-MM3 to inform adverse event (AE) management recommendations. Patients were randomized 3:2 to receive ixazomib (n = 395) or placebo (n = 261) on days 1, 8, and 15 of 28-day cycles for ~ 2 years or until progressive disease/toxicity. The initial 3-mg ixazomib dose was escalated to 4 mg in cycle 5, if tolerated in cycles 1–4. Safety was a secondary endpoint assessed in all treated patients; AEs were graded using Common Terminology Criteria for AEs v4.03. The rate of grade ≥ 3 AEs was higher in the ixazomib arm (19%) than in the placebo arm (5%), but the rate of discontinuation due to AEs was similar (7% vs. 5%). For AEs of clinical interest, rates were higher with ixazomib versus placebo: nausea 39% versus 15%, vomiting 27% versus 11%, diarrhea 35% versus 24%, thrombocytopenia 13% versus 3%, and peripheral neuropathy 19% versus 15%. However, the majority of events were low-grade, manageable with supportive therapy or dose reduction, and reversible, and did not result in discontinuation. There was no evidence of cumulative, long-term, or late-onset toxicity with ixazomib maintenance. Ixazomib is an efficacious and tolerable option for post-ASCT maintenance. AEs associated with ixazomib maintenance can be managed in the context of routine post-ASCT supportive care due to the limited additional toxicity. ClinicalTrials.gov NCT02181413

Summary Background Lenalidomide and bortezomib frontline exposure has raised a growing need for novel treatments for patients with relapsed or refractory multiple myeloma. Carfilzomib in combination with daratumumab has shown substantial efficacy with tolerable safety in relapsed or refractory multiple myeloma in a phase 1 study. In this study, we aimed to compare the efficacy and safety of carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma. Methods In this randomised, multicentre, open-label, phase 3 study, 466 patients recruited from 102 sites across North America, Europe, Australia, and Asia with relapsed or refractory multiple myeloma were randomly assigned 2:1 to carfilzomib, dexamethasone, and daratumumab (KdD) or carfilzomib and dexamethasone (Kd). All patients received twice per week carfilzomib at 56 mg/m2 (20 mg/m2; days 1 and 2 during cycle 1). Daratumumab (8 mg/kg) was administered intravenously on days 1 and 2 of cycle 1 and at 16 mg/kg weekly for the remaining doses of the first two cycles, then every 2 weeks for four cycles (cycles 3–6), and every 4 weeks thereafter. Patients received 40 mg dexamethasone weekly (20 mg for patients ≥75 years old starting on the second week). The primary endpoint was progression-free survival assessed by intention to treat. Adverse events were assessed in the safety population. This trial (NCT03158688) is registered with ClinicalTrials.gov, and is active but not recruiting. Findings Between June 13, 2017, and June 25, 2018, 466 patients of 569 assessed for eligibility were enrolled. After median follow-up of approximately 17 months, median progression-free survival was not reached in the KdD group versus 15·8 months in the Kd group (hazard ratio 0·63; 95% CI 0·46–0·85; p=0·0027). Median treatment duration was longer in the KdD versus the Kd group (70·1 vs 40·3 weeks). Grade 3 or higher adverse events were reported in 253 (82%) patients in the KdD group and 113 (74%) patients in the Kd group. The frequency of adverse events leading to treatment discontinuation was similar in both groups (KdD, 69 [22%]; Kd, 38 [25%]). Interpretation KdD significantly prolonged progression-free survival versus Kd in patients with relapsed or refractory multiple myeloma and was associated with a favourable benefit–risk profile. Funding Amgen.

Background Cabazitaxel is a novel taxane that might be active in breast cancer resistant to first-generation taxanes. Methods The purpose of the current multicentre phase II trial was to evaluate the activity and safety of cabazitaxel, as second-line treatment, in patients with human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC) previously treated with taxanes. The primary endpoint was objective response rate (ORR). Results Eighty-four patients were enrolled between October 2012 and November 2016. Taxane resistance to previous treatment was detected in 43 cases. The ORR was 22.6% in the intent-to-treat population, 23.3% in taxane-resistant and 20.5% in taxane-non-resistant cases. At a median follow-up of 39.6 months, the median progression-free survival and overall survival were 3.7 months (95% CI 2.2–4.4) and 15.2 months (95% CI 11.3–19.4), respectively. Regarding toxicity, grade 3–4 neutropenia was reported in 22.6% and febrile neutropenia in 6% of the patients, respectively. Two fatal events (one febrile neutropenia and one sepsis) were reported as being related to study treatment. Conclusions This phase II trial suggests that cabazitaxel is active as second-line treatment in taxane-pretreated patients with HER2-negative MBC, with manageable toxicity.

Background The emergence of highly active novel agents has led some to question the role of autologous haematopoietic stem-cell transplantation (HSCT) and subsequent consolidation therapy in newly diagnosed multiple myeloma. We therefore compared autologous HSCT with bortezomib-melphalan-prednisone (VMP) as intensification therapy, and bortezomib-lenalidomide-dexamethasone (VRD) consolidation therapy with no consolidation.Methods In this randomised, open-label, phase 3 study we recruited previously untreated patients with multiple myeloma at 172 academic and community practice centres of the European Myeloma Network. Eligible patients were aged 18-65 years, had symptomatic multiple myeloma stage 1-3 according to the International Staging System (I S S), measurable disease (serum M protein >10 g/L or urine M protein >200 mg in 24 h or abnormal free light chain [FLC] ratio with involved FLC >100 mg/L, or proven plasmacytoma by biopsy), and WHO performance status grade 0-2 (grade 3 was allowed if secondary to myeloma). Patients were first randomly assigned (1:1) to receive either four 42-day cycles of bortezomib (1.3 mg/m 2 administered intravenously or subcutaneously on days 1, 4, 8, 11, 22, 25, 29, and 32) combined with melphalan (9 mg/m(2) administered orally on days 1-4) and prednisone (60 mg/m(2) administered orally on days 1-4) or autologous HSCT after high-dose melphalan (200 mg/m(2)), stratified by site and ISS disease stage. In centres with a double HS CT policy, the first randomisation (1:1:1) was to VMP or single or double HSCT. Afterwards, a second randomisation assigned patients to receive two 28-day cycles of consolidation therapy with bortezomib (1.3 mg/m(2)either intravenously or subcutaneously on days 1, 4, 8, and 11), lenalidomide (25 mg orally on days 1-21), and dexamethasone (20 mg orally on days 1, 2, 4, 5, 8, 9, 11, and 12) or no consolidation; both groups received lenalidomide maintenance therapy (10 mg orally on days 1-21 of a 28-day cycle). The primary outcomes were progression-free survival from the first and second randomisations, analysed in the intention-to-treat population, which included all patients who underwent each randomisation. All patients who received at least one dose of study drugs were included in the safety analyses. This study is registered with the EU Clinical Trials Register (EudraCT 2009-017903-28) and ClinicalTrials.gov (NCT01208766), and has completed recruitment.Findings Between Feb 25, 2011, and April 3, 2014, 1503 patients were enrolled. 1197 patients were eligible for the first randomisation, of whom 702 were assigned to autologous HSCT and 495 to VMP; 877 patients who were eligible for the first randomisation underwent the second randomisation to VRD consolidation (n=449) or no consolidation (n=428). The data cutoff date for the current analysis was Nov 26, 2018. At a median follow-up of 60.3 months (IQR 52. 2-67. 6), median progression-free survival was significantly improved with autologous HSCT compared with VMP (56.7 months [95% CI 49.3-64.5] vs 41.9 months [37.5-46.9]; hazard ratio [HR] 0.73, 0.62-0.85; p=0.0001). For the second randomisation, the number of events of progression or death at data cutoff was lower than that preplanned for the final analysis; therefore, the results from the second protocol-specified interim analysis, when 66% of events were reached, are reported (data cutoff Jan 18, 2018). At a median follow-up of 42.1 months (IQR 32.3-49.2), consolidation therapy with VRD significantly improved median progression-free survival compared with no consolidation (58.9 months [54.0-not estimable] vs 45.5 months [39.5-58.4]; HR 0.77, 0.63-0.95; p=0.014). The most common grade >= 3 adverse events in the autologous HSCT group compared to the VMP group included neutropenia (513 [79%] of 652 patients vs 137 [29%] of 472 patients), thrombocytopenia (541 [83%] vs 74 [16%]), gastrointestinal disorders (80 [12%] vs 25 [5%]), and infections (192 [30%] vs 18 [4%]). 239 (34%) of 702 patients in the autologous HSCT group and 135 (27%) of 495 in the VMP group had at least one serious adverse event. Infection was the most common serious adverse event in each of the treatment groups (206 [56%] of 368 and 70 [37%] of 189). 38 (12%) of 311 deaths from first randomisation were likely to be treatment related: 26 (68%) in the autologous HSCT group and 12 (32%) in the VMP group, most frequently due to infections (eight [21%]), cardiac events (six [16%]), and second primary malignancies (20 [53%]).Interpretation This study supports the use of autologous HSCT as intensification therapy and the use of consolidation therapy in patients with newly diagnosed multiple myeloma, even in the era of novel agents. The role of high-dose chemotherapy needs to be reassessed in future studies, in particular in patients with undetectable minimal residual disease after four-drug induction regimens including a monoclonal antiboby combined with an immunomodulatory agent and a proteasome inhibitor plus dexamethasone. Copyright (C) 2020 Elsevier Ltd. All rights reserved.

International audience; COVID-19 is a systemic infection with a significant impact on the hematopoietic system and hemostasis. Lymphopenia may be considered as a cardinal laboratory finding, with prognostic potential. Neutrophil/lymphocyte ratio and peak platelet/lymphocyte ratio may also have prognostic value in determining severe cases. During the disease course, longitudinal evaluation of lymphocyte count dynamics and inflammatory indices, including LDH, CRP and IL-6 may help to identify cases with dismal prognosis and prompt intervention in order to improve outcomes. Biomarkers, such high serum procalcitonin and ferritin have also emerged as poor prognostic factors. Furthermore, blood hypercoagulability is common among hospitalized COVID-19 patients. Elevated D-Dimer levels are consistently reported, whereas their gradual increase during disease course is particularly associated with disease worsening. Other coagulation abnormalities such as PT and aPTT prolongation, fibrin degradation products increase, with severe thrombocytopenia lead to life-threatening disseminated intravascular coagulation (DIC), which necessitates continuous vigilance and prompt intervention. So, COVID-19 infected patients, whether hospitalized or ambulatory, are at high risk for venous thromboembolism, and an early and prolonged pharmacological thromboprophylaxis with low molecular weight heparin is highly recommended. Last but not least, the need for assuring blood donations during the pandemic is also highlighted.

COVID-19 has caused unprecedented societal turmoil, triggering a rapid, still ongoing, transformation of healthcare provision on a global level. In this new landscape, it is highly important to acknowledge the challenges this pandemic poses on the care of the particularly vulnerable cancer patients and the subsequent psychosocial impact on them. We have outlined our clinical experience in managing patients with gastrointestinal, hematological, gynaecological, dermatological, neurological, thyroid, lung and paediatric cancers in the COVID-19 era and have reviewed the emerging literature around barriers to care of oncology patients and how this crisis affects them. Moreover, evolving treatment strategies and novel ways of addressing the needs of oncology patients in the new context of the pandemic are discussed.

Treatment personalisation plays a key role in the current management of patients with cancer. Several biomarkers have shown clinical utility and may guide therapeutic decisions. Amongst patients with lung cancer, the level of expression of programmed death ligand 1 (PD-L1) has both prognostic and predictive values in terms of response to the inhibition of programmed cell death protein 1 (PD-1). Depending on the clinical setting, the expression of PD-L1 ≥1% or ≥50% has been associated with improved outcomes amongst patients receiving pembrolizumab. Regarding patients with colorectal carcinoma, mutations in the KRAS oncogene predict the responsiveness to the inhibition of epidermal growth factor receptor (EGFR). Only patients with wild-type KRAS tumours derive benefit from cetuximab and panitumumab in terms of response and survival. In conclusion, future research should aim in the optimisation of the use of biomarker in the clinical practice in order to provide the optimal drug combination to each individual patient.

Combination of carfilzomib with dexamethasone (Kd) is approved for use in relapsed and/or refractory multiple myeloma (RRMM), with carfilzomib administered twice weekly at 56 mg/m2 (Kd56 BIW) or once weekly at 70 mg/m2 (Kd70 QW). Post hoc cross-trial comparisons were performed to compare efficacy and safety profiles of Kd70 QW vs Kd56 BIW dosing schedules using data from three trials of patients with RRMM: A.R.R.O.W., CHAMPION-1, and ENDEAVOR. To select for comparable patient populations, side-by-side efficacy and safety comparisons were performed in subgroups of patients with 2-3 prior lines of therapy who were not refractory to bortezomib. The overall response rate (ORR) was 69.9% (95% confidence interval [CI], 61.7-77.2) for Kd70 QW and 72.4% (95% CI, 65.9-78.2) for Kd56 BIW. Median progression-free survival (PFS) was 12.1 months (95% CI, 8.4-14.3) for Kd70 QW and 14.5 months (95% CI, 10.2-not evaluable) for Kd56 BIW. Frequency of grade ≥ 3 adverse events (AEs) was 67.6% for Kd70 QW and 85.3% for Kd56 BIW. Regression analyses (adjusting for prognostic factors) of all patients in the trials who received Kd70 QW vs Kd56 BIW estimated a PFS hazard ratio of 0.91 (95% CI, 0.69-1.19; P = .47) and an ORR odds ratio of 1.12 (95% CI, 0.74-1.69; P = .61). These results suggest that Kd70 QW has a comparable efficacy profile compared with Kd56 BIW and represents a convenient and well-tolerated treatment for patients with RRMM.

Epithelioid hemangioendothelioma (EHE) is a rare vascular malignant tumor with indolent course. Liver transplantation for local disease is the treatment of choice. In the metastatic setting there is no consensus regarding the appropriate systemic treatment. We present two cases of metastatic hepatic epithelioid hemangioendothelioma (hEHE) treated with the combination of Doxorubicin and Olaratumab. Both patients showed Stable Disease (SD) as a response, after the completion of six cycles of this combination therapy.

Selinexor is an oral, small molecule inhibitor of the nuclear export protein exportin 1 with demonstrated activity in hematologic and solid malignancies. Side effects associated with selinexor include nausea, vomiting, fatigue, diarrhea, decreased appetite, weight loss, thrombocytopenia, neutropenia, and hyponatremia. We reviewed 437 patients with multiple myeloma treated with selinexor and assessed the kinetics of adverse events and impact of supportive care measures. Selinexor reduced both platelets and neutrophils over the first cycle of treatment and reached a nadir between 28 and 42 days. Platelet transfusions and thrombopoietin receptor agonists were effective at treating thrombocytopenia, and granulocyte colony stimulating factors were effective at resolving neutropenia. The onset of gastrointestinal side effects (nausea, vomiting, and diarrhea) was most common during the first 1–2 weeks of treatment. Nausea could be mitigated with 5-HT3 antagonists and either neurokinin 1 receptor antagonists, olanzapine, or cannbainoids. Loperamide and bismuth subsalicylate ameliorated diarrhea. The primary constitutional side effects of fatigue and decreased appetite could be managed with methylphenidate, megestrol, cannabinoids or olanzapine, respectively. Hyponatremia was highly responsive to sodium replacement. Selinexor has well-established adverse effects that mainly occur within the first 8 weeks of treatment, are reversible, and respond to supportive care.