Lenalidomide and dexamethasone with or without clarithromycin in patients with multiple myeloma ineligible for autologous transplant: a randomized trial

Mieloma; Assajos controlats aleatorisMieloma; Ensayos controlados aleatoriosMyeloma; Randomized controlled trialsAlthough case-control analyses have suggested an additive value with the association of clarithromycin to continuous lenalidomide and dexamethasone (Rd), there are not phase III trials confirming these results. In this phase III trial, 286 patients with MM ineligible for ASCT received Rd with or without clarithromycin until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). With a median follow-up of 19 months (range, 0–54), no significant differences in the median PFS were observed between the two arms (C-Rd 23 months, Rd 29 months; HR 0.783, p = 0.14), despite a higher rate of complete response (CR) or better in the C-Rd group (22.6% vs 14.4%, p = 0.048). The most common G3–4 adverse events were neutropenia [12% vs 19%] and infections [30% vs 25%], similar between the two arms; however, the percentage of toxic deaths was higher in the C-Rd group (36/50 [72%] vs 22/40 [55%], p = 0.09). The addition of clarithromycin to Rd in untreated transplant ineligible MM patients does not improve PFS despite increasing the ≥CR rate due to the higher number of toxic deaths in the C-Rd arm. Side effects related to overexposure to steroids due to its delayed clearance induced by clarithromycin in this elderly population could explain these results. The trial was registered in clinicaltrials.gov with the name GEM-CLARIDEX: Ld vs BiRd and with the following identifier NCT02575144. The full trial protocol can be accessed from ClinicalTrials.gov. This study received financial support from BMS/Celgene

Geriatric assessment in hematology scale predicts treatment tolerability in older patients diagnosed with hematological malignancies: The RETROGAH study

Chemotherapy; Geriatric assessment; ToxicityQuimioterapia; Evaluación geriátrica; ToxicidadQuimioteràpia; Avaluació geriàtrica; ToxicitatIntroduction The GAH (Geriatric Assessment in Hematology) scale is a psychometrically valid tool aimed at identifying older patients with hematological malignancies at higher risk of treatment-related toxicity. Our objective in this study was to determine the weights for each dimension of the GAH scale and the cut-off point to reliably predict treatment tolerability in this population, estimated by a weighted receiver operating characteristic (ROC) analysis and quantified by the area under the curve (AUC). Material and Methods The RETROGAH was a retrospective cohort study including 126 patients who had previously participated in the GAH study. Patients were ≥ 65 years old with newly diagnosed myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML), multiple myeloma (MM), or chronic lymphoid leukemia (CLL) and treated with standard front-line therapy within three months after having completed the GAH scale. Results The optimal cut-off value of the GAH total score to discriminate patients at higher risk of treatment toxicity was 42, with 68.5% sensitivity and 55.8% specificity. Using this value, 66.1% of patients evaluated were found to develop some type of toxicity. The AUC was 0.6259 (95% CI: 0.512–0.739; p = 0.035). Discussion The GAH scale not only would enable clinicians to individualize therapy based on individual risk of toxicity but also discriminate patients that will benefit most from intensive treatments from those requiring an adapted approach. While futures studies in clinical practice may improve the model and overcome its limitations, the GAH scale should not be used alone when making treatment decisions.This study was supported by Celgene España S.L

Neurosurgery in a patient with severe hemophilia B: an experience using eftrenonacog alfa as perioperative management

Anesthesia; Haemophilia B; NeurosurgeryAnestesia; Hemofilia B; NeurocirugíaAnestèsia; Hemofília B; NeurocirurgiaExtended half-life FIX (EHL-FIX) concentrates have been developed with the purpose of reducing the frequency of infusions in patients with severe or moderate hemophilia B. We describe the case of a 63-year-old patient with severe hemophilia B (sHB) treated with FIX-Fc fusion protein (rFIXFc) who underwent neurosurgery

Predicting long-term disease control in transplant-ineligible patients with multiple myeloma: impact of an MGUS-like signature

Disease control; Multiple myeloma; BiomarkersControl de la malaltia; Mieloma múltiple; BiomarcadorsControl de la enfermedad; Mieloma múltiple; BiomarcadoresDisease control at 5 years would be a desirable endpoint for elderly multiple myeloma (MM) patients, but biomarkers predicting this are not defined. Therefore, to gain further insights in this endpoint, a population of 498 newly diagnosed transplant-ineligible patients enrolled in two Spanish trials (GEM2005MAS65 and GEM2010MAS65), has been analyzed. Among the 435 patients included in this post-hoc study, 18.6% remained alive and progression free after 5 years of treatment initiation. In these patients, overall survival (OS) rate at 10 years was 60.8% as compared with 11.8% for those progressing within the first 5 years. Hemoglobin (Hb) ≥ 12 g/dl (OR 2.74, p = 0.001) and MGUS-like profile (OR 4.18, p = 0.005) were the two baseline variables associated with long-term disease-free survival. Upon including depth of response (and MRD), Hb ≥ 12 g/dl (OR 2.27) and MGUS-like signature (OR 7.48) retained their predictive value along with MRD negativity (OR 5.18). This study shows that despite the use of novel agents, the probability of disease control at 5 years is still restricted to a small fraction (18.6%) of elderly MM patients. Since this endpoint is associated with higher rates of OS, this study provides important information about diagnostic and post-treatment biomarkers helpful in predicting the likelihood of disease control at 5 years

ICO-ICS Praxis para el tratamiento médico y con irradiación del mieloma múltiple

Tractament mèdic; Tractament amb irradiació; Mieloma múltipleMedical treatment; Irradiation treatment; Multiple myelomaTratamiento médico; Tratamiento con irradiación; Mieloma múltipleEl mieloma múltiple (MM) és una neoplàsia de cèl·lules plasmàtiques que representa al voltant de l’1% del total de neoplàsies i el 10% de les neoplàsies hematològiques. Té una incidència aproximada de 4-5 nous casos/100.000 habitants/any i presenta una incidència màxima entre els 70 i 75 anys d’edat. Un 35% dels afectats té menys de 65 anys. Els objectius d'aquesta guia són: desenvolupar i difondre la ICO-ICSPraxi per al tractament del mieloma múltiple; disminuir la variabilitat terapèutica entre els pacients tractats en els diferents centres d’aquesta institució; implementar i avaluar els resultats de la terapèutica en els pacients amb mieloma múltiple tractats d’acord amb les recomanacions d’aquesta guia

Molecular profiling of immunoglobulin heavy-chain gene rearrangements unveils new potential prognostic markers for multiple myeloma patients

Investigació genètica; MielomaInvestigación genética; MielomaGenetics research; MyelomaMultiple myeloma is a heterogeneous disease whose pathogenesis has not been completely elucidated. Although B-cell receptors play a crucial role in myeloma pathogenesis, the impact of clonal immunoglobulin heavy-chain features in the outcome has not been extensively explored. Here we present the characterization of complete heavy-chain gene rearrangements in 413 myeloma patients treated in Spanish trials, including 113 patients characterized by next-generation sequencing. Compared to the normal B-cell repertoire, gene selection was biased in myeloma, with significant overrepresentation of IGHV3, IGHD2 and IGHD3, as well as IGHJ4 gene groups. Hypermutation was high in our patients (median: 8.8%). Interestingly, regarding patients who are not candidates for transplantation, a high hypermutation rate (≥7%) and the use of IGHD2 and IGHD3 groups were associated with improved prognostic features and longer survival rates in the univariate analyses. Multivariate analysis revealed prolonged progression-free survival rates for patients using IGHD2/IGHD3 groups (HR: 0.552, 95% CI: 0.361−0.845, p = 0.006), as well as prolonged overall survival rates for patients with hypermutation ≥7% (HR: 0.291, 95% CI: 0.137−0.618, p = 0.001). Our results provide new insights into the molecular characterization of multiple myeloma, highlighting the need to evaluate some of these clonal rearrangement characteristics as new potential prognostic markers.This work was partially supported by the Instituto de Salud Carlos III (ISCIII), Spanish Ministry of Economy and Competitiveness PI15/01956, CIBERONC-CB16/12/00233, and “Una manera de hacer Europa” (Innocampus; CEI-2010-1-0010)”. M.G.-A., I.P.-C., and C.J. are supported by the Fundación Española de Hematología y Hemoterapia (FEHH, co-funded by Fundación Cris in the latter case), A.M. by the European Social Fund and the Spanish Education Council through the University of Salamanca, and M.E.S. by the ISCIII (CPII18/00028). All Spanish funding is co-sponsored by the European Union FEDER program. The authors wish to thank José Pérez, Alicia Antón, Montserrat Hernández-Ruano, Estrella Arnés, Rebeca Maldonado, Mercedes Jiménez, Alejandra Martín, Isabel Sánchez, Rocío Corral and Francisco Boix (University Hospital of Salamanca, Spain) for their technical support, as well as the Spanish Multiple Myeloma “GEM-PETHEMA” group for providing clinical data. The authors are also very grateful to the patients who participated in this study

Comparison of next-generation sequencing (NGS) and next-generation flow (NGF) for minimal residual disease (MRD) assessment in multiple myeloma

Mieloma; Factors de riscMieloma; Factores de riesgoMyeloma; Risk factorsDetecting persistent minimal residual disease (MRD) allows the identification of patients with an increased risk of relapse and death. In this study, we have evaluated MRD 3 months after transplantation in 106 myeloma patients using a commercial next-generation sequencing (NGS) strategy (LymphoTrack®), and compared the results with next-generation flow (NGF, EuroFlow). The use of different marrow pulls and the need of concentrating samples for NGS biased the applicability for MRD evaluation and favored NGF. Despite that, correlation between NGS and NGF was high (R2 = 0.905). The 3-year progression-free survival (PFS) rates by NGS and NGF were longer for undetectable vs. positive patients (NGS: 88.7% vs. 56.6%; NGF: 91.4% vs. 50%; p < 0.001 for both comparisons), which resulted in a 3-year overall survival (OS) advantage (NGS: 96.2% vs. 77.3%; NGF: 96.6% vs. 74.9%, p < 0.01 for both comparisons). In the Cox regression model, NGS and NGF negativity had similar results but favoring the latter in PFS (HR: 0.20, 95% CI: 0.09–0.45, p < 0.001) and OS (HR: 0.21, 95% CI: 0.06–0.75, p = 0.02). All these results reinforce the role of MRD detection by different strategies in patient prognosis and highlight the use of MRD as an endpoint for multiple myeloma treatment

Portal vein thrombosis in a patient with severe hemophilia B: A challenging balanced management

Key Clinical Message The increased life expectancy in patients with hemophilia (PwH) over the last years has raised the incidence of comorbidities, including thromboembolic events. Thromboembolic events are rare in PwH and most of them occur in the presence of exogenous risk factors. There is still scarce scientific evidence on the optimal antithrombotic treatment and management approach in this population. Abstract In the hemophilic population thromboembolic events are rare. Most of them are often multifactorial and occur in the presence of both exogenous (orthopedic surgery, intensive replacement therapy, use of central venous catheters…) and endogenous (cardiovascular diseases) risk factors. We describe the case of a 43‐year‐old patient with severe hemophilia B (sHB) receiving prophylaxis with eftrenonacog alfa (rFIXFc) and antithrombotic treatment due to portal vein thrombosis. The patient was treated with extended half‐ life factor IX (EHL‐FIX) prophylaxis maintaining higher trough levels to avoid new bleeding episodes associated to the underlying disease and the use of antithrombotic therapy with low molecular weight heparin. EHL‐FIX concentrates allow prolonged intervals between intravenous infusions and higher hemostatic protection thanks to increased factor trough levels. This current case report provides clinical evidence in antithrombotic management in a patient with severe hemophilia B

Multiple myeloma and SARS-CoV-2 infection: clinical characteristics and prognostic factors of inpatient mortality

Malalties infeccioses; Mieloma; PronòsticEnfermedades infecciosas; Mieloma; PronósticoInfectious diseases; Myeloma; PrognosisThere is limited information on the characteristics, prognostic factors, and outcomes of patients with multiple myeloma (MM) hospitalized with COVID-19. This retrospective case series investigated 167 patients reported from 73 hospitals within the Spanish Myeloma Collaborative Group network in March and April, 2020. Outcomes were compared with 167 randomly selected, contemporary, age-/sex-matched noncancer patients with COVID-19 admitted at six participating hospitals. Among MM and noncancer patients, median age was 71 years, and 57% of patients were male; 75 and 77% of patients, respectively, had at least one comorbidity. COVID-19 clinical severity was moderate–severe in 77 and 89% of patients and critical in 8 and 4%, respectively. Supplemental oxygen was required by 47 and 55% of MM and noncancer patients, respectively, and 21%/9% vs 8%/6% required noninvasive/invasive ventilation. Inpatient mortality was 34 and 23% in MM and noncancer patients, respectively. Among MM patients, inpatient mortality was 41% in males, 42% in patients aged >65 years, 49% in patients with active/progressive MM at hospitalization, and 59% in patients with comorbid renal disease at hospitalization, which were independent prognostic factors on adjusted multivariate analysis. This case series demonstrates the increased risk and identifies predictors of inpatient mortality among MM patients hospitalized with COVID-19