ANCHOR: melflufen plus dexamethasone and daratumumab or bortezomib in relapsed/refractory multiple myeloma: final results of a phase I/IIa study.

Melphalan flufenamide (melflufen), a first-in-class, alkylating peptide-drug conjugate, demonstrated clinical benefit in combination with dexamethasone in triple-class refractory multiple myeloma (MM). The phase I/IIa ANCHOR study evaluated melflufen (30 or 40 mg) and dexamethasone (40 mg with daratumumab; 20 mg followed by 40 mg with bortezomib; dose reduced if aged ≥75 years) in triplet combination with daratumumab (16 mg/kg; daratumumab arm) or bortezomib (1.3 mg/m2; bortezomib arm) in patients with relapsed/refractory MM refractory to an immunomodulatory agent and/or a proteasome inhibitor and who had received one to four prior lines of therapy. Primary objectives were to determine the optimal dose of melflufen in triplet combination (phase I) and overall response rate (phase IIa). In total, 33 patients were treated in the daratumumab arm and 23 patients received therapy in the bortezomib arm. No dose-limiting toxicities were reported at either melflufen dose level with either combination. With both triplet regimens, the most common grade ≥3 treatment-emergent adverse events were thrombocytopenia and neutropenia; thrombocytopenia was the most common treatment-emergent adverse event leading to treatment discontinuation. In the daratumumab arm, patients receiving melflufen 30 mg remained on treatment longer than those receiving the 40-mg dose. In the daratumumab arm, the overall response rate was 73% and median progression-free survival was 12.9 months. Notably, in the bortezomib arm, the overall response rate was 78% and median progression-free survival was 14.7 months. Considering the totality of the data, melflufen 30 mg was established as the recommended dose for use with dexamethasone and daratumumab or bortezomib for future studies in relapsed/refractory MM.

Efficacy and safety of melflufen plus daratumumab and dexamethasone in relapsed/refractory multiple myeloma: results from the randomized, open-label, phase III LIGHTHOUSE study.

Melphalan flufenamide (melflufen), a first-in-class alkylating peptide-drug conjugate, plus dexamethasone was approved in Europe for use in patients with triple-class refractory relapsed/refractory multiple myeloma (RRMM) with ≥3 prior lines of therapy and without prior autologous stem cell transplantation (ASCT) or with a time to progression >36 months after prior ASCT. The randomized LIGHTHOUSE study (NCT04649060) assessed melflufen plus daratumumab and dexamethasone (melflufen group) versus daratumumab in patients with RRMM with disease refractory to an immunomodulatory agent and a proteasome inhibitor or who had received ≥3 prior lines of therapy including an immunomodulatory agent and a proteasome inhibitor. A partial clinical hold issued by the US Food and Drug Administration for all melflufen studies led to financial constraints and premature study closure on February 23rd 2022 (data cut-off date). In total, 54 of 240 planned patients were randomized (melflufen group, N=27; daratumumab group, N=27). Median progression-free survival (PFS) was not reached in the melflufen group versus 4.9 months in the daratumumab group (Hazard Ratio: 0.18 [95% Confidence Interval, 0.05-0.65]; P=0.0032) at a median follow-up time of 7.1 and 6.6 months, respectively. Overall response rate (ORR) was 59% in the melflufen group versus 30% in the daratumumab group (P=0.0300). The most common grade ≥3 treatment-emergent adverse events in the melflufen group versus daratumumab group were neutropenia (50% vs. 12%), thrombocytopenia (50% vs. 8%), and anemia (32% vs. 19%). Melflufen plus daratumumab and dexamethasone demonstrated superior PFS and ORR versus daratumumab in RRMM and a safety profile comparable to previously published melflufen studies.

Melflufen in relapsed/refractory multiple myeloma refractory to prior alkylators: A subgroup analysis from the OCEAN study.

Melphalan flufenamide (melflufen), a first-in-class alkylating peptide-drug conjugate, plus dexamethasone demonstrated superior progression-free survival (PFS), but not overall survival (OS), versus pomalidomide plus dexamethasone in relapsed/refractory multiple myeloma in the OCEAN study. Time to progression (TTP) <36 months after a prior autologous stem cell transplantation (ASCT) was a negative prognostic factor for OS with melflufen. This post hoc exploratory analysis evaluated patients refractory to prior alkylators (e.g., cyclophosphamide and melphalan) in OCEAN. In 153 patients refractory to prior alkylators (melflufen, n = 78; pomalidomide, n = 75), the melflufen and pomalidomide arms had similar median PFS (5.6 months [95% CI, 4.2-8.3] vs. 4.7 months [95% CI, 3.1-7.3]; hazard ratio [HR], 0.92 [95% CI, 0.63-1.33]) and OS (23.4 months [95% CI, 14.4-31.7] vs. 20.0 months [95% CI, 12.0-28.7]; HR, 0.92 [95% CI, 0.62-1.38]). Among alkylator-refractory patients with a TTP ≥ 36 months after a prior ASCT or no prior ASCT (melflufen, n = 54; pomalidomide, n = 53), the observed median PFS and OS were longer in the melflufen arm than the pomalidomide arm. The safety profile of melflufen was consistent with previous reports. These results suggest that melflufen is safe and effective in patients with alkylator-refractory disease, suggesting differentiated activity from other alkylators.

Patient-reported outcomes in relapsed/refractory multiple myeloma treated with melflufen plus dexamethasone: analyses from the Phase II HORIZON study.

Relapsed/refractory multiple myeloma (RRMM) is known to have a high burden of disease and complications associated with refractoriness to prior lines of therapy. Severe pain and fatigue symptoms and impairments in physical and emotional functioning have been strongly linked to reduced health-related quality of life (HRQoL) in patients with RRMM. Assessment of patient reported-outcome measures from the pivotal, Phase II HORIZON study (OP-106; NCT02963493) in patients with RRMM (n = 64) demonstrated that melphalan flufenamide (melflufen) plus dexamethasone treatment preserved HRQoL. Patients had clinically meaningful improvements, even after eight treatment cycles, in relevant scales such as global health status/QoL, physical functioning, emotional functioning, pain, and fatigue. Patients with triple-class-refractory disease (n = 50) displayed similar improvements. Patient-reported outcome deterioration was delayed for a substantial amount of time in patients who experienced a response to melflufen plus dexamethasone treatment relative to patients who did not experience a response. These findings support the notion that treatment with melflufen plus dexamethasone may sustain or improve HRQoL over time in patients with RRMM, including in patients with triple-class-refractory disease for whom outcomes are generally worse. The clinical benefits observed in patients from the HORIZON trial are encouraging and supportive of translation into real-world practice.

Impact of Treatment Delay on Outcome in the International Subarachnoid Aneurysm Trial.

Background and Purpose- ISAT (International Subarachnoid Aneurysm Trial) demonstrated that 1 year after aneurysmal subarachnoid hemorrhage, coiling resulted in a significantly better clinical outcome than clipping. After 5 years, this difference did not reach statistical significance, but mortality was still higher in the clipping group. Here, we present additional analyses, reporting outcome after excluding pretreatment deaths. Methods- Outcome measures were death with or without dependency at 1 and 5 years after treatment, after exclusion of all pretreatment deaths. Treatment differences were assessed using relative risks (RRs). With sensitivity and exploratory analyses, the relation between treatment delay and outcome was analyzed. Results- After exclusion of pretreatment deaths, at 1-year follow-up coiling was favorable over clipping for death or dependency (RR, 0.77 [95% CI, 0.67-0.89]) but not for death alone (RR, 0.88 [95% CI, 0.66-1.19]). After 5 years, no significant differences were observed, neither for death or dependency (RR, 0.88 [95% CI, 0.77-1.02]) nor for death alone (RR, 0.82 [95% CI, 0.64-1.05]). Sensitivity analyses showed a similar picture. In good-grade patients, coiling remained favorable over clipping in the long-term. Time between randomization and treatment was significantly longer in the clipping arm (mean 1.7 versus 1.1 days; P<0.0001), during which 17 patients died because of rebleeding versus 6 pretreatment deaths in the endovascular arm (RR, 2.81 [95% CI, 1.11-7.11]). Conclusions- These additional analyses support the conclusion of ISAT that at 1-year follow-up after aneurysmal subarachnoid hemorrhage coiling has a better outcome than clipping. After 5 years, with pretreatment mortality excluded, the difference between coiling and clipping is not significant. The high number of pretreatment deaths in the clipping group highlights the importance of urgent aneurysm treatment to prevent early rebleeding.

Prediction of Outcome After Aneurysmal Subarachnoid Hemorrhage.

Background and Purpose- Early prediction of clinical outcome after aneurysmal subarachnoid hemorrhage (aSAH) is still lacking accuracy. In this observational cohort study, we aimed to develop and validate an accurate bedside prediction model for clinical outcome after aSAH, to aid decision-making at an early stage. Methods- For the development of the prediction model, a prospectively kept single-center cohort of 1215 aSAH patients, admitted between 1998 and 2014, was used. For temporal validation, a prospective cohort of 224 consecutive aSAH patients from the same center, admitted between 2015 and 2017, was used. External validation was performed using the ISAT (International Subarachnoid Aneurysm Trial) database (2143 patients). Primary outcome measure was poor functional outcome 2 months after aSAH, defined as modified Rankin Scale score 4-6. The model was constructed using multivariate regression analyses. Performance of the model was examined in terms of discrimination and calibration. Results- The final model included 4 predictors independently associated with poor outcome after 2 months: age, World Federation of Neurosurgical Societies grade after resuscitation, aneurysm size, and Fisher grade. Temporal validation showed high discrimination (area under the receiver operating characteristic curve, 0.90; 95% CI, 0.85-0.94), external validation showed fair to good discrimination (area under the receiver operating characteristic curve, 0.73; 95% CI, 0.70-0.76). The model showed satisfactory calibration in both validation cohorts. The SAFIRE grading scale was derived from the final model: size of the aneurysm, age, Fisher grade, world federation of neurosurgical societies after resuscitation. Conclusions- The SAFIRE grading scale is an accurate, generalizable, and easily applicable model for early prediction of clinical outcome after aSAH.

ASTRIS: a global real-world study of osimertinib in >3000 patients with EGFR T790M positive non-small-cell lung cancer.

Aim: Osimertinib is a third-generation, irreversible, oral EGFR tyrosine kinase inhibitor. We report real-world effectiveness and safety data. Patients & methods: EGFR T790M positive advanced non-small-cell lung cancer adults, who received ≥1 prior EGFR tyrosine kinase inhibitor, received osimertinib 80 mg daily. Primary effectiveness outcome: overall survival. Secondary effectiveness outcomes included: investigator-assessed clinical response, progression-free survival, time-to-treatment discontinuation. Results: At data cutoff, 3015 patients had enrolled: 57.1% had investigator-assessed response (95% CI: 55.2-58.9). Median progression-free survival: 11.1 months (95% CI: 11.0-12.0) and median time-to-treatment discontinuation: 13.5 months (95% CI: 12.6-13.9). Interstitial lung disease/pneumonitis-like events reported in 28 (1%) patients. Conclusion: Osimertinib demonstrated clinical effectiveness similar to efficacy observed in the clinical trial program with no new safety signals.

Predictive Factors for Rebleeding After Aneurysmal Subarachnoid Hemorrhage: Rebleeding Aneurysmal Subarachnoid Hemorrhage Study.

BACKGROUND AND PURPOSE: Aneurysmal subarachnoid hemorrhage (aSAH) is a devastating type of stroke associated with high morbidity and mortality. One of the most feared complications is an early rebleeding before aneurysm repair. Predictors for such an often fatal rebleeding are largely unknown. We therefore aimed to determine predictors for an early rebleeding after aSAH in relation with time after ictus. METHODS: This observational prospective cohort study included all consecutive patients admitted with aSAH between January 1998 and December 2014 (n=1337) at our University Neurovascular Center. Clinical predictors for rebleeding ≤24 hours were identified using multivariable Cox regression analyses. Kaplan-Meier analyses were applied to evaluate the time of rebleeding ≤72 hours after aSAH. RESULTS: A modified Fisher grade of 3 to 4 was a predictor for an in-hospital rebleeding ≤24 hours after ictus (adjusted hazard ratio, 4.4; 95% confidence interval, 2.1-10.6; P<0.001). The numbers needed to treat to prevent 1 rebleeding ≤24 hours was calculated 15 (95% confidence interval, 10-25). Also, the initiation of external cerebrospinal fluid-drainage (adjusted hazard ratio, 1.9; 95% confidence interval, 1.4-2.5; P<0.001) was independently associated with a rebleeding ≤24 hours. Cumulative in-hospital rebleeding rates were 5.8% ≤24 hours, and 1.2% in the time frame 24-72 hours after ictus. CONCLUSIONS: In our opinion, timing of treatment of aSAH patients, especially those with an modified Fisher grade of 3 or 4 in a good clinical condition, should be reconsidered. These aSAH patients might be regarded a medical emergency, requiring aneurysm repair as soon as possible. In this respect, our findings should provoke the debate on timing of aneurysm repair, especially in patients considered to be at high risk for rebleeding.

Feasibility of immediate placement of single-tooth implants in the aesthetic zone: a 1-year randomized controlled trial.

AIM: To assess whether outcome of immediate implant placement and immediate provisionalization after 1 year was non-inferior to immediate implant placement and delayed provisionalization regarding Marginal Bone Level (MBL). MATERIALS AND METHODS: Forty patients with a failing tooth in the aesthetic zone were randomly assigned for immediate implant placement with immediate (n = 20) or delayed (n = 20) provisionalization. Follow-up was at 1 month and after 1 year. The study was powered to detect a difference in MBL of <0.9 mm. Apart from MBL, soft tissue peri-implant parameters, aesthetic indexes and patient satisfaction were assessed. RESULTS: After 1 year, MBL changes were -0.75 ± 0.69 mesially and -0.68 ± 0.65 distally mm for the immediate group and -0.70 ± 0.64 and -0.68 ± 0.64 mm for the delayed group respectively (NS). Regarding differences in means, non-inferiority was observed after 1 year (mesially: Group A versus B: difference in mean 0.08 mm (95% CI -0.38 to 0.53, p = 0.71 distally: Group A versus B: difference in mean 0.09 mm (95% CI -0.37 to 0.56 mm, p = 0.66).No significant differences in the other outcome variables were observed. CONCLUSIONS: This study showed that immediate placement and immediate provisionalization was non-inferior to immediate placement with delayed provisionalization. In addition, although not powered for these outcome variables, no clinically relevant differences in other outcomes were observed (www.isrtcn.com: ISRCTN57251089).

Appreciation of CT-negative, lumbar puncture-positive subarachnoid haemorrhage: risk factors for presence of aneurysms and diagnostic yield of imaging.

OBJECTIVE: Patients without a subarachnoid haemorrhage (SAH) on brain CT scan (CT-negative), but a lumbar puncture (LP)-proven SAH, are a challenging patient category. The optimal diagnostic approach is still a matter of debate. Also, there is little knowledge on the probability of finding an underlying vascular lesion. DESIGN: In this observational study, a consecutive cohort of 94 patients with CT-negative, LP-positive SAH was prospectively collected between 1998 and 2013. The yield of diagnostic modalities as well as patient outcome was studied. In addition, risk factors for the presence of a vascular lesion were analysed. RESULTS: In 40 patients (43%), an intracranial vascular abnormality was detected: 37 aneurysms and three arterial dissections. Female gender was significantly associated with detection of a vascular lesion. Time between ictus and diagnosis of SAH was not associated with the presence of vascular pathology. Overall, 99% of patients had a modified Rankin Score of 0-2 after a median follow-up of 72 months. The yield of additional digital subtraction angiography in patients with a negative CT angiography was zero. CONCLUSIONS: In this study, the chance of finding a vascular lesion in a patient with CT-negative, LP-positive SAH was 43%, underlining the need for an adequate diagnostic workup. In general, the patient outcome was favourable. Female gender was found to be predictive for detecting a vascular lesion. In contrast with previous reports, the interval between ictus and LP was not associated with the presence of an aneurysm.

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

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

Benefit Versus Risk Assessment of Melflufen and Dexamethasone in Relapsed/Refractory Multiple Myeloma: Analyses From Longer Follow-up of the OCEAN and HORIZON Studies.

INTRODUCTION: Melphalan flufenamide (melflufen), a first-in-class alkylating peptide-drug conjugate, plus dexamethasone demonstrated superior progression-free survival (PFS) but directionally different overall survival (OS) favoring pomalidomide (hazard ratio [HR], 1.10) in OCEAN. METHODS: These analyses further investigated prognostic subgroups impacting survival in updated data from the randomized, phase 3 OCEAN study (NCT03151811; date: February 3, 2022) and the phase 2 HORIZON study (NCT02963493; date: February 2, 2022). RESULTS: In OCEAN, subgroups prognostic for OS were age (P = .011; <65 years favored pomalidomide) and no previous autologous stem cell transplant (ASCT) or progression >36 months after ASCT (P = .001; favored melflufen). Overall, 245 of 495 (49%) patients randomized had received a previous ASCT, of which 202 (82%) had progressed within 36 months following their ASCT. When excluding patients who had progressed <36 months post-ASCT (melflufen group, n = 145; pomalidomide group, n = 148), median OS was 23.6 months with melflufen and 19.8 months with pomalidomide (HR, 0.83 [95% CI, 0.62-1.12]; P = .22). Among patients with triple-class refractory disease in HORIZON, patients who had progressed <36 months post-ASCT (n = 58) had a lower response rate and shorter duration of response and PFS than the remaining patients (n = 52). Safety was consistent with previous reports. CONCLUSION: These analyses demonstrate a consistent benefit for melflufen and dexamethasone in patients with relapsed/refractory multiple myeloma who have not received an ASCT or progressed >36 months after receiving an ASCT (ClinicalTrials.gov identifier: NCT03151811).

Posterior transdural discectomy: a new approach for the removal of a central thoracic disc herniation.

BACKGROUND: The optimal surgical approach for thoracic disc herniation remains a matter of debate, especially for central disc herniation. In this paper, we present a new technique to remove central thoracic disc herniation, the posterior transdural approach, and report a series of 13 cases operated on in this way at our institute. METHODS: Between September 2004 and October 2010, 13 patients with symptomatic central thoracic disc herniation were operated on, utilising this posterior transdural approach. All patients underwent magnetic resonance imaging (MRI) of the thoracic spine before surgery. All patients were followed at our outpatient department for at least 3 months. In addition, all patients were interviewed in April 2009 and February 2011 to evaluate the final results. A seven-point Likert scale was applied and the Frankel score was determined preoperatively and postoperatively. Additionally, a postoperative MRI was obtained for all but two patients. RESULTS: The most frequently involved levels were T10-11 and T12-L1. Median operative time was 210 min (range 140-360). Three patients experienced reversible complications. No patient required spinal fixation. The median duration of hospitalisation was 6 days (range 4-20 days). With a median follow-up of 18 months, symptoms improved in 12 patients (92%), including the three patients with complications. One patient was unchanged (8%), while none of the patients experienced worsening of symptoms. CONCLUSIONS: The posterior transdural approach is well tolerated by the patient and has a relatively high success rate. It is a relatively simple and safe procedure, suitable for the operative treatment of almost all types of thoracic disc herniation, but especially the centrally located disc herniation.

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

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

Melflufen and Dexamethasone in Heavily Pretreated Relapsed and Refractory Multiple Myeloma.

PURPOSE: Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and rapidly and selectively releases alkylating agents into tumor cells. The phase II HORIZON trial evaluated the efficacy of melflufen plus dexamethasone in relapsed and refractory multiple myeloma (RRMM), a population with an important unmet medical need. PATIENTS AND METHODS: Patients with RRMM refractory to pomalidomide and/or an anti-CD38 monoclonal antibody received melflufen 40 mg intravenously on day 1 of each 28-day cycle plus once weekly oral dexamethasone at a dose of 40 mg (20 mg in patients older than 75 years). The primary end point was overall response rate (partial response or better) assessed by the investigator and confirmed by independent review. Secondary end points included duration of response, progression-free survival, overall survival, and safety. The primary analysis is complete with long-term follow-up ongoing. RESULTS: Of 157 patients (median age 65 years; median five prior lines of therapy) enrolled and treated, 119 patients (76%) had triple-class-refractory disease, 55 (35%) had extramedullary disease, and 92 (59%) were refractory to previous alkylator therapy. The overall response rate was 29% in the all-treated population, with 26% in the triple-class-refractory population. In the all-treated population, median duration of response was 5.5 months, median progression-free survival was 4.2 months, and median overall survival was 11.6 months at a median follow-up of 14 months. Grade ≥ 3 treatment-emergent adverse events occurred in 96% of patients, most commonly neutropenia (79%), thrombocytopenia (76%), and anemia (43%). Pneumonia (10%) was the most common grade 3/4 nonhematologic event. Thrombocytopenia and bleeding (both grade 3/4 but fully reversible) occurred concomitantly in four patients. GI events, reported in 97 patients (62%), were predominantly grade 1/2 (93%); none were grade 4. CONCLUSION: Melflufen plus dexamethasone showed clinically meaningful efficacy and a manageable safety profile in patients with heavily pretreated RRMM, including those with triple-class-refractory and extramedullary disease.

Feasibility of magnetic resonance angiography (MRA) follow-up as the primary imaging modality after coiling of intracranial aneurysms.

BACKGROUND: Digital subtraction angiography (DSA) is still regarded as the gold standard for detecting residual flow in treated aneurysms. Recent reports have also shown excellent results from magnetic resonance angiography (MRA) imaging. This is an important observation, since DSA is associated with a risk of medical complications, is time consuming, and is more expensive. PURPOSE: To determine whether MRA could replace conventional DSA and serve as the primary postinterventional imaging modality in patients with coiled intracranial aneurysms. MATERIAL AND METHODS: We studied a prospectively enrolled cohort of 190 patients treated endovascularly for a first-ruptured and/or unruptured intracranial aneurysm between January 2004 and December 2008. The imaging protocol included a 1.5T time-of-flight (TOF) MRA and a DSA at 3 months (on the same day) and, depending on comparability, a 1.5T TOF-MRA or DSA 1 year after treatment. All images were evaluated by a multidisciplinary panel. RESULTS: In 141/190 patients, both an MRA and DSA were performed after 3-month follow-up. In 2/141 patients (1.4%), (small) neck remnants gave false-negative MRA results. In one patient (0.7%), this led to additional neurosurgical clipping of the aneurysm. In 25/141 patients, future follow-up (>3 months) consisted of DSA because of various reasons. In 24/25 of these patients, primary MRA images alone would invariably have led to additional DSA imaging. CONCLUSION: The present study shows that 1.5T TOF-MRA is a feasible primary follow-up modality after coiling of intracranial aneurysms. Given our data, we now suggest that, in every patient with a coiled intracranial aneurysm, the first follow-up, 3 months after coiling, should be an MRA study. Only when this MRA is inconclusive (e.g., because of coil artifacts), or in the case of suspicion of recanalization, should DSA be performed additionally.

Epstein-Barr virus-DNA load monitoring late after lung transplantation: a surrogate marker of the degree of immunosuppression and a safe guide to reduce immunosuppression.

BACKGROUND: Posttransplant lymphoproliferative disease (PTLD) is a serious complication after lung transplantation and its relation with Epstein-Barr virus (EBV) is well recognized. It has been postulated that preemptive reduction of immunosuppression guided by EBV-DNA load may lead to a significantly lower incidence of PTLD, because of the reconstitution of T-cell control. In this report, we describe the feasibility of this approach in terms of safety with regard to the risk of acute as well as chronic allograft rejection in 75 lung transplant recipients transplanted between 1990 and 2001 and followed for this study from June 1, 2001 until January 1, 2006. METHODS: From all patients visiting our outpatient clinic, EBV-DNA load was measured at least twice a year during the study period. In patients with positive results, measurements were repeated every two to four weeks. EBV reactivation was defined as two consecutive EBV-DNA load measurements with a rising trend; with the last measurement exceeding 10.000 copies/mL under stable immunosuppression. In such case, immunosuppression was reduced. RESULTS: EBV reactivation was observed in 26/75 patients (35%). One (1.5%) of these patients developed PTLD during the study period. Acute rejection, acceleration of chronic allograft rejection, or worse survival were not observed after reduction of immunosuppression. CONCLUSIONS: Preemptive reduction of immunosuppression after lung transplantation guided by EBV-DNA load appears to be a safe approach for the prevention of PTLD in lung transplant recipients late after transplantation.