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In a randomized trial of pomalidomide plus dexamethasone with or without the immunostimulatory monoclonal antibody elotuzumab, the addition of elotuzumab doubled both the response rate and the duration of progression-free survival without increased toxic effects.

The addition of elotuzumab (a monoclonal antibody against SLAMF7) to lenalidomide plus dexamethasone produced a significant increase in progression-free survival as compared with lenalidomide plus dexamethasone alone. Multiple myeloma, a malignant disease of monoclonal plasma cells, has a median overall survival of approximately 5 years. 1 Despite improvements in treatment outcomes with proteasome inhibitors and immunomodulatory drugs, most patients continue to have a relapse, and new treatment approaches are needed. Combination therapy may be key to overcoming drug resistance and improving long-term treatment outcomes. Lenalidomide, an immunomodulatory drug, in combination with dexamethasone is a standard regimen in patients with relapsed or refractory disease. 2 , 3 Three-drug combinations are emerging for patients with previously treated multiple myeloma 3 but may be limited by toxic effects. Agents with new mechanisms of action . . .

RESONATE-2 is a phase 3 study of first-line ibrutinib versus chlorambucil in chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Patients aged ≥65 years (n = 269) were randomized 1:1 to once-daily ibrutinib 420 mg continuously or chlorambucil 0.5–0.8 mg/kg for ≤12 cycles. With a median (range) follow-up of 60 months (0.1–66), progression-free survival (PFS) and overall survival (OS) benefits for ibrutinib versus chlorambucil were sustained (PFS estimates at 5 years: 70% vs 12%; HR [95% CI]: 0.146 [0.098–0.218]; OS estimates at 5 years: 83% vs 68%; HR [95% CI]: 0.450 [0.266–0.761]). Ibrutinib benefit was also consistent in patients with high prognostic risk (TP53 mutation, 11q deletion, and/or unmutated IGHV) (PFS: HR [95% CI]: 0.083 [0.047–0.145]; OS: HR [95% CI]: 0.366 [0.181–0.736]). Investigator-assessed overall response rate was 92% with ibrutinib (complete response, 30%; 11% at primary analysis). Common grade ≥3 adverse events (AEs) included neutropenia (13%), pneumonia (12%), hypertension (8%), anemia (7%), and hyponatremia (6%); occurrence of most events as well as discontinuations due to AEs decreased over time. Fifty-eight percent of patients continue to receive ibrutinib. Single-agent ibrutinib demonstrated sustained PFS and OS benefit versus chlorambucil and increased depth of response over time.

In patients with newly diagnosed multiple myeloma who were ineligible for stem-cell transplantation, the addition of daratumumab to bortezomib, melphalan, and prednisone increased progression-free survival and the response rate at the cost of an increase in infections.

Most patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma relapse after initial therapy. Bendamustine plus rituximab is often used in the relapsed or refractory setting. We assessed the efficacy and safety of adding ibrutinib, an oral covalent inhibitor of Bruton's tyrosine kinase (BTK), to bendamustine plus rituximab in patients with previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma. The HELIOS trial was an international, double-blind, placebo-controlled, phase 3 study in adult patients (≥18 years of age) who had active chronic lymphocytic leukaemia or small lymphocytic lymphoma with measurable lymph node disease (>1·5 cm) by CT scan, and had relapsed or refractory disease following one or more previous lines of systemic therapy consisting of at least two cycles of a chemotherapy-containing regimen, an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1, and adequate bone marrow, liver, and kidney function. Patients with del(17p) were excluded because of known poor response to bendamustine plus rituximab. Patients who had received previous treatment with ibrutinib or other BTK inhibitors, refractory disease or relapse within 24 months with a previous bendamustine-containing regimen, or haemopoietic stem-cell transplant were also excluded. Patients were randomly assigned (1:1) by a web-based system to receive bendamustine plus rituximab given in cycles of 4 weeks' duration (bendamustine: 70 mg/m2 intravenously on days 2–3 in cycle 1, and days 1–2 in cycles 2–6; rituximab: 375 mg/m2 on day 1 of cycle 1, and 500 mg/m2 on day 1 of cycles 2–6 for a maximum of six cycles) with either ibrutinib (420 mg daily orally) or placebo until disease progression or unacceptable toxicity. Patients were stratified according to whether they were refractory to purine analogues and by number of previous lines of therapy. The primary endpoint was independent review committee (IRC)-assessed progression-free survival. Crossover to ibrutinib was permitted for patients in the placebo group with IRC-confirmed disease progression. Analysis was by intention-to-treat and is continuing for further long-term follow-up. The trial is registered with ClinicalTrials.gov, number NCT01611090. Between Sept 19, 2012, and Jan 21, 2014, 578 eligible patients were randomly assigned to ibrutinib or placebo in combination with bendamustine plus rituximab (289 in each group). The primary endpoint was met at the preplanned interim analysis (March 10, 2015). At a median follow-up of 17 months (IQR 13·7–20·7), progression-free survival was significantly improved in the ibrutinib group compared with the placebo group (not reached in the ibrutinib group (95% CI not evaluable) vs 13·3 months (11·3–13·9) in the placebo group (hazard ratio [HR] 0·203, 95% CI 0·150–0·276; p<0·0001). IRC-assessed progression-free survival at 18 months was 79% (95% CI 73–83) in the ibrutinib group and 24% (18–31) in the placebo group (HR 0·203, 95% CI 0·150–0·276; p<0·0001). The most frequent all-grade adverse events were neutropenia and nausea. 222 (77%) of 287 patients in the ibrutinib group and 212 (74%) of 287 patients in the placebo group reported grade 3–4 events; the most common grade 3–4 adverse events in both groups were neutropenia (154 [54%] in the ibrutinib group vs 145 [51%] in the placebo group) and thrombocytopenia (43 [15%] in each group). A safety profile similar to that previously reported with ibrutinib and bendamustine plus rituximab individually was noted. In patients eligible for bendamustine plus rituximab, the addition of ibrutinib to this regimen results in significant improvements in outcome with no new safety signals identified from the combination and a manageable safety profile. Janssen Research & Development.

Prolonging overall survival (OS) remains an unmet need in relapsed or refractory multiple myeloma (RRMM). In ELOQUENT-2 (NCT01239797), elotuzumab plus lenalidomide/dexamethasone (ERd) significantly improved progression-free survival (PFS) versus lenalidomide/dexamethasone (Rd) in patients with RRMM and 1–3 prior lines of therapy (LoTs). We report results from the pre-planned final OS analysis after a minimum follow-up of 70.6 months, the longest reported for an antibody-based triplet in RRMM. Overall, 646 patients with RRMM and 1–3 prior LoTs were randomized 1:1 to ERd or Rd. PFS and overall response rate were co-primary endpoints. OS was a key secondary endpoint, with the final analysis planned after 427 deaths. ERd demonstrated a statistically significant 8.7-month improvement in OS versus Rd (median, 48.3 vs 39.6 months; hazard ratio, 0.82 [95.4% Cl, 0.68–1.00]; P = 0.0408 [less than allotted α of 0.046]), which was consistently observed across key predefined subgroups. No additional safety signals with ERd at extended follow-up were reported. ERd is the first antibody-based triplet regimen shown to significantly prolong OS in patients with RRMM and 1–3 prior LoTs. The magnitude of OS benefit was greatest among patients with adverse prognostic factors, including older age, ISS stage III, IMWG high-risk disease, and 2–3 prior LoTs.

This study presents the results of experimental studies on the thermal conductivity of specimens made from selected pure polymer filaments manufactured with the use of FFF 3D-printing technology. The tested samples were made of polylactic acid (PLA), polyethylene terephthalate glycol (PET-G), and acrylonitrile butadiene styrene (ABS). In particular, the effects of the infill patterns and infill density on the tested samples were examined in order to characterize the influence of these parameters on the materials’ effective thermal conductivity. Honeycomb and grid infill patterns of the tested samples with infill densities of 40%, 60%, 80%, and 100% were examined. The influence of temperature on thermal conductivity was studied as well. Thermal conductivity was measured using the guarded heat flow method, according to the ASTM E1530 standard within the defined temperature ranges of 20–60 °C for ABS and PET-G and 20–50 °C for PLA material. Samples of the tested materials were manufactured with the use of the Fused Filament Fabrication method (FFF), and filaments with a uniform black color were used. The obtained results were analyzed in terms of thermal conductivity variation after samples’ infill pattern and infill density modifications, which provides extended thermal property characterization of the polymeric filaments adopted for 3D printing.

Treatment for patients with chronic lymphocytic leukaemia who are elderly or who have comorbidities is challenging because fludarabine-based chemoimmunotherapies are mostly not suitable. Chlorambucil remains the standard of care in many countries. We aimed to investigate whether the addition of ofatumumab to chlorambucil could lead to better clinical outcomes than does treatment with chlorambucil alone, while also being tolerable for patients who have few treatment options. We carried out a randomised, open-label, phase 3 trial for treatment-naive patients with chronic lymphocytic leukaemia in 109 centres in 16 countries. We included patients who had active disease needing treatment, but in whom fludarabine-based treatment was not possible. We randomly assigned patients (1:1) to receive oral chlorambucil (10 mg/m2) on days 1–7 of a 28 day treatment course or to receive chlorambucil by this schedule plus intravenous ofatumumab (cycle 1: 300 mg on day 1 and 1000 mg on day 8; subsequent cycles: 1000 mg on day 1) for three to 12 cycles. Assignment was done with a randomisation list that was computer generated at GlaxoSmithKline, and was stratified, in a block size of two, by age, disease stage, and performance status. The primary endpoint was progression-free survival in the intention-to-treat population and assessment was done by an independent review committee that was masked to group assignment. The study is registered with ClinicalTrials.gov, number NCT00748189. We enrolled 447 patients, median age 69 years (range 35–92). Between Dec 22, 2008, and May 26, 2011, we randomly assigned 221 patients to chlorambucil plus ofatumumab and 226 patients to chlorambucil alone. Median progression-free survival was 22·4 months (95% CI 19·0–25·2) in the group assigned to chlorambucil plus ofatumumab compared with 13·1 months (10·6–13·8) in the group assigned to chlorambucil only (hazard ratio 0·57, 95% CI 0·45–0·72; p<0·0001). Grade 3 or greater adverse events were more common in the chlorambucil plus ofatumumab group (109 [50%] patients; vs 98 [43%] given chlorambucil alone), with neutropenia being the most common event (56 [26%] vs 32 [14%]). Grade 3 or greater infections had similar frequency in both groups. Grade 3 or greater infusion-related adverse events were reported in 22 (10%) patients given chlorambucil plus ofatumumab. Five (2%) patients died during treatment in each group. Addition of ofatumumab to chlorambucil led to clinically important improvements with a manageable side-effect profile in treatment-naive patients with chronic lymphocytic leukaemia who were elderly or had comorbidities. Chlorambucil plus ofatumumab is therefore an important treatment option for these patients who cannot tolerate more intensive therapy. GlaxoSmithKline, Genmab A/S.

Intravenous injection is the standard administration route of bortezomib; however, subcutaneous administration is an important alternative. We compared the efficacy and safety of subcutaneous versus intravenous bortezomib at the approved 1·3 mg/m 2 dose and twice per week schedule in patients with relapsed multiple myeloma. This randomised, phase 3 study was undertaken at 53 centres in ten countries in Europe, Asia, and South America. Patients aged 18 years and older with relapsed multiple myeloma after one to three previous lines of therapy were randomly assigned to receive up to eight 21-day cycles of bortezomib 1·3 mg/m 2, on days 1, 4, 8, and 11, by subcutaneous injection or intravenous infusion. Randomisation was by an interactive voice response system based on a computer-generated randomisation schedule, stratified by number of previous lines and disease stage. Patients and treating physicians were not masked to treatment allocation. The primary objective was to show non-inferiority of subcutaneous versus intravenous bortezomib in terms of overall response rate (ORR) after four cycles in all patients with a diagnosis of measurable, secretory multiple myeloma who received one or more dose of drug (response-evaluable population). Non-inferiority was defined as retaining 60% of the intravenous treatment effect. This study is registered with ClinicalTrials.gov, number NCT00722566, and is ongoing for long-term follow-up. 222 patients were randomly assigned to receive subcutaneous (n=148) or intravenous (n=74) bortezomib. The response-evaluable population consisted of 145 patients in the subcutaneous group and 73 in the intravenous group. Patients received a median of eight cycles (range one to ten) in both groups. ORR after four cycles was 42% in both groups (61 patients in subcutaneous group and 31 in intravenous group; ORR difference −0·4%, 95% CI −14·3 to 13·5), showing non-inferiority (p=0·002). After a median follow-up of 11·8 months (IQR 7·9–16·8) in the subcutaneous group and 12·0 months (8·1–15·6) in the intravenous group, there were no significant differences in time to progression (median 10·4 months, 95% CI 8·5–11·7, vs 9·4 months, 7·6–10·6; p=0·387) and 1-year overall survival (72·6%, 95% CI 63·1–80·0, vs 76·7%, 64·1–85·4; p=0·504) with subcutaneous versus intravenous bortezomib. Grade 3 or worse adverse events were reported in 84 (57%) patients in the subcutaneous group versus 52 (70%) in the intravenous group; the most common were thrombocytopenia (19 [13%] vs 14 [19%]), neutropenia (26 [18%] vs 13 [18%]), and anaemia (18 [12%] vs six [8%]). Peripheral neuropathy of any grade (56 [38%] vs 39 [53%]; p=0·044), grade 2 or worse (35 [24%] vs 30 [41%]; p=0·012), and grade 3 or worse (nine [6%] vs 12 [16%]; p=0·026) was significantly less common with subcutaneous than with intravenous administration. Subcutaneous administration was locally well tolerated. Subcutaneous bortezomib offers non-inferior efficacy to standard intravenous administration, with an improved safety profile. Johnson & Johnson Pharmaceutical Research and Development, and Millennium Pharmaceuticals.

Background and Clinical Significance: Waldenström macroglobulinemia (WM) is a rare, indolent B-cell non-Hodgkin lymphoma, characterised by the presence of monoclonal immunoglobulin M (IgM) and lymphoplasmacytic infiltration of the bone marrow. It is often associated with various haematological and systemic disorders, including previous cold agglutinin disease (CAD), a condition where cold-sensitive antibodies lead to haemolysis. Case Presentation: A 55-year-old male patient was admitted to the Internal Diseases Ward with symptoms of weakness, reduced effort tolerance, and weight loss, along with life-threatening normoblastic anaemia (haemoglobin [Hb]: 3.90 g/dL). Initial blood tests raised suspicion of CAD due to the presence of multiple blood clots, as well as a decrease in lymphocyte and neutrophil counts. CAD was then confirmed by a cold agglutinin titre of 1:2000 and direct antiglobulin test ([DAT] 4+). Two weeks later, upon transfer to the Haematological Diseases Ward, further investigation revealed elevated IgM levels (up to 31.55 g/L). Additional diagnostic tests, including serum protein electrophoresis, imaging, multiparametric flow cytometry, and bone marrow biopsy, confirmed the diagnosis of WM. The L265P MYD88 mutation test was positive. Treatment with intravenous rituximab was initiated, followed by bendamustine/rituximab (BR) therapy protocol as first-line treatment. After two cycles, the patient’s clinical condition and laboratory results significantly improved, with a marked reduction in IgM (<0.4 g/L). Hb levels steadily rose to 12.60 g/dL, eliminating the need for further blood transfusions. Conclusions: This case highlights the importance of recognising the coexistence of CAD and WM, which may present with overlapping clinical features, including life-threatening anaemia. Extensive diagnostics and prompt treatment with combination therapy can lead to effective clinical improvement.