Real-World Evidence of Daratumumab Monotherapy in Relapsed/Refractory Multiple Myeloma Patients and Efficacy on Soft-Tissue Plasmacytomas.

INTRODUCTION: Daratumumab is an anti-CD38 agent that was first investigated as single agent in GEN501 and SIRIUS trials in patients with advanced multiple myeloma (MM). Overall response rate (ORR) was 30% with positive impact on progression-free survival (PFS). However, there is a lack of information regarding plasmacytoma response. MATERIALS AND METHODS: Here, we described a heavily pretreated group of 43 patients who received daratumumab monotherapy after EMA approval and focused on plasmacytoma response. RESULTS: After a median follow-up of 26 months, median time to best response was 2.9 months (range 0.8-13.1), median PFS was 5.2 months (95% CI 2.5 - 8.8) and median OS was 11.2 months (95% CI 6.3 - 17.0). Patients who achieved at least partial response had longer median PFS and OS (12.8 and 20.2 months, respectively) than those who achieved minimal response or stable disease (5.3 and 11.2 months, respectively). Ten patients (23%) had plasmacytomas (70% paraskeletal, 30% extramedullary). The clinical benefit for patients with and without plasmacytomas was 20% versus 42%. A dissociation between serological and plasmacytoma response was observed in 40% of the patients. Thus, 50% of the patients with plasmacytomas achieved at least serological minimal response but only 20% had plasmacytoma response. CONCLUSION: This is the first real-world study of daratumumab monotherapy that focuses on efficacy data regarding soft-tissue plasmacytomas in patients with relapsed/refractory mieloma, showing a limited benefit in this patient population.

Phase II Trial of Allogeneic Transplantation Plus Novel Drugs in Multiple Myeloma: Effect of Intensifying Reduced-Intensity Conditioning with Bortezomib and Adding Maintenance Treatment.

The use of reduced-intensity conditioning (RIC) regimens has decreased the risk of nonrelapse mortality (NRM) after allogeneic stem cell transplantation (alloSCT). In contrast, disease relapse remains the most frequent cause of treatment failure and death. Owing to both their antimyeloma effect and immunomodulatory properties, novel drugs could improve outcomes after alloSCT. This phase II European Myeloma Network trial was designed to evaluate the combination of alloSCT with novel agents. The study was conducted to evaluate the toxicity and efficacy of RIC intensified with bortezomib (Bz) prior to alloSCT for high-risk (HR) multiple myeloma (MM) patients, as well as the efficacy of post-transplantation maintenance with Bz and lenalidomide (Len). Patients received RIC with Bz on days -9 and -2, fludarabine on days -6 to -4, and melphalan on day -3. Patients who were in complete response (CR) or near CR at day +100 post-transplantation received 6 cycles of Bz every 56 days, and the remaining received Bz, Len, and dexamethasone. Len maintenance was started on day +180 at a dose of 5 mg and continued until relapse or toxicity occurred. Of the 24 patients included, 21 were evaluable on day +100, including 12 in CR, 4 in very good partial response, 3 in partial response, and 2 with relapse or progression. The cumulative incidence (CuI) of relapse was 13.6% (95% confidence interval [CI], 3.2% to 31.3%) at 1 year and 28.5% (95% CI, 11.1% to 48.9%) at 2 years. The CuI of NRM was 21.1% (95% CI, 7.4% to 39.4%) at 2 years. With a median follow-up of 39 months (range, 1 to 67 months), the median event-free survival (EFS) was 29 months, and median overall survival (OS) was not reached. EFS and OS at 3 years were 42.5% (95% CI, 21.9% to 61.7%) and 74.01% (95% CI, 50.9% to 87.5%), respectively. The use of Bz within an RIC regimen allows for a high response rate after alloSCT. Maintenance with Bz and Len is feasible and provides remarkable results in terms of EFS and OS in HR MM patients.

Efficacy and Safety of Ruxolitinib in Steroid-Refractory/Dependent Chronic Graft-versus-Host Disease: Real-World Data and Challenges.

Steroid-refractory (SR) chronic graft-versus-host disease (cGVHD) is a major obstacle in recipients of allogeneic stem cell transplantation (HCT). Ruxolitinib is the first agent to demonstrate superior efficacy to the best available therapy, but real-life data are still lacking. Here we describe the results of ruxolitinib compassionate use for the treatment of SR/steroid-dependent cGVHD in a tertiary care university hospital. In this retrospective single-center study, we evaluated the outcomes of 48 patients diagnosed with SR-cGVHD who were treated with ruxolitinib. Forty-seven (98%) had moderate-severe disease, and 27 (56%) had received ≥2 lines of prior therapy (excluding steroids). Results were analyzed using SPSS version 26.0.01 and R version 3.4.3. The overall response rate was 77% (37 of 48), with 15% (7 of 37) in complete remission. The median time to response was 2 months (range, 0.5 to 8 months). Steroid tapering was achieved in 26 patients (54%) and definitive discontinuation was achieved in 10 patients (21%) after a median of 20 months (range, 1.5 to 60 months). Toxicity was predominantly hematologic, including a 33% rate of anemia and a 17% rate of thrombocytopenia. Overall survival at 2 years was significantly higher in responders compared with nonresponders (88% [95% confidence interval (CI), 65% to 96%] versus 49% [95% CI, 12% to 78%]; P = .01). At last follow-up, tapering of ruxolitinib had been started in 8 of 37 responders (22%). Our experience supports the efficacy of ruxolitinib in the treatment of SR-cGVHD, along with its steroid-sparing effect and manageable toxicity. Gradual tapering of ruxolitinib seems feasible without cases of GVHD flare. More studies and longer follow-up are needed to confirm these data, as well as to identify the ideal dose adjustments in cases of toxicity.

Predictors of return to work after autologous stem cell transplantation in patients with multiple myeloma.

Return to work (RTW) is a marker of functional recovery in cancer patients, with quality of life, financial and social implications. We investigated frequency and factors associated with RTW in a cohort of patients younger than 66 years, with newly diagnosed multiple myeloma (MM), uniformly treated with a bortezomib-based induction followed by autologous stem cell transplantation (ASCT). Socio-economic and working status data were collected by a self-administered questionnaire. One hundred and eighty-six patients entered the study. Of whom, 145 (78%) where employed at diagnosis, which was more frequent in younger (median 55 vs. 60 years, p < 0.001), men (59.3% vs. 34.2%, p = 0.004), and with college studies (44.8% vs. 24.4%, p = 0.008). Forty-three (30%) of the 145 patients who had a job at diagnosis, RTW after ASCT in a median of 5 (range 1-27) months. Factors independently associated with RTW were having three or more children (HR 2.87, 95% CI 1.33-6.18), college studies (HR 2.78, 95% CI 1.21-6.41), and a family income >40 × 103€/year (HR 2.31, 95% CI 1.12-4.78). In conclusion, the frequency of RTW herein reported in MM patients seems lower than reported in other malignancies. The risk factors observed may guide the design RTW programs.

Impact of response to treatment in health-related quality of life patient-reported outcomes in elderly patients with relapsed multiple myeloma.

Multiple myeloma (MM) is a recurrent malignancy with a high impact on quality of life. Improved survival relies on the combination of drugs and extended duration of therapy, raising concerns on its toxicity burden in elderly patients. Health-related quality of life measurements attent to capture health aspects relevant to patients other than efficacy. This prospective study aimed to understand the relationship between MM-related symptomatology and other quality of life dimensions using the EORTC QLQ-MY20 questionnaire in individuals with relapsed or refractory MM. Irrespective of treatment modality, over 50% of patients who responded to treatment had significant omprovements of reported scores in all domains. Conversely, disease progression was associated with score deterioration not only in the MM-related symptoms domain but also in all other domains. HRQoL adds valuable information to the established efficacy endpoints but an adequate interpretation of HRQoL outcomes in randomized trials should require stratification according to response.

Low Rate of Invasive Fungal Infections During Induction and Consolidation Chemotherapy for Adults with De Novo Acute Myeloid Leukemia Without Anti-mold Prophylaxis: Single-Center 2002-2018 Empirical/Pre-emptive Approach.

Broad-spectrum antifungal prophylaxis is currently considered the standard of care for adults with de novo AML for the prevention of invasive fungal infections (IFIs), especially invasive pulmonary aspergillosis (IPA). Because fluconazole has been used in our center as anti-yeast prophylaxis, we sought to analyze in detail the incidence of IFIs over a 17-year period, as well as their impact on outcome. A standardized protocol of patient management, including serum galactomannan screening and thoracic CT-guided diagnostic-driven antifungal therapy, was used in all patients. A total of 214 consecutive adults with de novo AML who were treated in 3 CETLAM (Grupo Cooperativo para el Estudio y Tratamiento de las Leucemias Agudas y Mielodisplasias) protocols from 2002 to 2018 were included. The 90-day incidence of any IFI (including possible cases) was 11% (95% CI 4-15%), most cases occurred during induction chemotherapy (8%, 95% CI 4-12%), and most cases were probable/proven IPA (8%, 95% CI 3-13%). Developing an IFI during induction and consolidation had no impact on 1-year survival. A case-control study with 23 cases of IPA and 69 controls identified induction/re-induction chemotherapy, chronic pulmonary disease and age > 60 years/poor baseline performance status as potential pretreatment risk factors. The current study proves that inpatient induction and consolidation chemotherapy for de novo AML can be given in areas with "a priori" high-burden of airborne molds with fluconazole prophylaxis, while the selective use of anti-mold prophylaxis in patients at very high risk may further reduce the incidence of IFI in this specific clinical scenario.

When an HLA identical donor is not available in adults with hematological neoplasms: single-center comparison of single-unit cord blood transplantation and haploidentical-related PBSC transplantation with PTCy using a standardized conditioning platform (thiotepa-busulfan-fludarabine).

Haploidentical related (Haplo) and umbilical cord blood (UCB) donors are the main "alternative donor" options for allogeneic hematopoietic stem cell transplantation (HCT) for patients without identical donor. At our institution, UCB was the main alternative donor type until 2013, when HaploHCT was introduced as the preferred procedure. A common myeloablative conditioning regimen was used, based on thiotepa, busulfan, and fludarabine. We analyze the outcomes of 47 patients (61%) who received a single UCB transplantation (UCBT) and 30 patients (39%) who received a HaploHCT with post-transplant cyclophosphamide. No differences were found in the rate of neutrophil engraftment, whereas platelet recovery was earlier with HaploHCT. NRM was higher after UCBT at 3 months and 3 years (13% and 13% vs. 23% and 45% in HaploHCT and UCBT, respectively; p < 0.001 for both time points). The 3-year relapse incidence was 35% after HaploHCT vs. 17% after UCBT, respectively (p = 0.13). The 100-day incidence of grade 3-4 acute GVHD (3% vs. 11%) and the 3-year moderate-to-severe chronic GVHD (4% vs. 15%) did not differ between HaploHCT and UCBT, respectively (p > 0.2). There was a trend for higher overall survival at 1 and 3 years in HaploHCT recipients (69% vs. 45% and 64% vs. 38%, respectively; p = 0.055 for both time points). Despite the small sample sizes, multivariate analysis adjusted for patient age and disease status at transplant showed a better 3-year OS in HaploHCT recipients, mostly due to a lower NRM (p < 0.001). Our results support the use of HaploHCT when feasible when an identical donor is not available.

Pomalidomide-dexamethasone for treatment of soft-tissue plasmacytomas in patients with relapsed / refractory multiple myeloma.

OBJECTIVE: The presence of plasmacytomas (Ps) in patients with multiple myeloma (MM) is associated with a poor outcome, both in patients treated conventionally and in patients treated with novel agents. Two types of plasmacytomas have being recognized: paraskeletal plasmacytomas (PPs) and extramedullary plasmacytomas (EMPs), being the incidence of EMPs lower but with worse prognosis. Our aim has been to analyze the efficacy of the pomalidomide-dexamethasone combination in this patient profile. METHOD: In the present study, the efficacy of pomalidomide and dexamethasone in 21 patients from nine hospitals of Catalonia (Spain), with relapsed or refractory MM and Ps, was analyzed. For this purpose, we describe the evolution of paraprotein in serum and urine and the size of plasmacytomas during treatment with pomalidomide-dexamethasone. RESULTS: While 34% of the patients achieved a paraprotein response, only two patients with PPs (9%) responded (RC and PR). There were no responses among patients with EMPs. The median progression-free survival from the start of treatment with pomalidomide/dexamethasone was only 1.7 months and the median overall survival of 4.5 months. CONCLUSION: In conclusion, pomalidomide and dexamethasone has limited efficacy in patients with advanced MM and soft-tissue plasmacytomas.

Prognostic utility of serum free light chain ratios and heavy-light chain ratios in multiple myeloma in three PETHEMA/GEM phase III clinical trials.

We investigated the prognostic impact and clinical utility of serum free light chains (sFLC) and serum heavy-light chains (sHLC) in patients with multiple myeloma treated according to the GEM2005MENOS65, GEM2005MAS65, and GEM2010MAS65 PETHEMA/GEM phase III clinical trials. Serum samples collected at diagnosis were retrospectively analyzed for sFLC (n = 623) and sHLC (n = 183). After induction or autologous transplantation, 309 and 89 samples respectively were available for sFLC and sHLC assays. At diagnosis, a highly abnormal (HA) sFLC ratio (sFLCr) (<0.03 or >32) was not associated with higher risk of progression. After therapy, persistence of involved-sFLC levels >100 mg/L implied worse survival (overall survival [OS], P = 0.03; progression-free survival [PFS], P = 0.007). Among patients that achieved a complete response, sFLCr normalization did not necessarily indicate a higher quality response. We conducted sHLC investigations for IgG and IgA MM. Absolute sHLC values were correlated with monoclonal protein levels measured with serum protein electrophoresis. At diagnosis, HA-sHLCrs (<0.29 or >73) showed a higher risk of progression (P = 0.006). Additionally, involved-sHLC levels >5 g/L after treatment were associated with shorter survival (OS, P = 0.001; PFS, P = 0.018). The HA-sHLCr could have prognostic value at diagnosis; absolute values of involved-sFLC >100 mg/L and involved-sHLC >5 g/L could have prognostic value after treatment.

Chronic Lymphocytic Leukemia: Clinical Stages Maintain Their Prognostic Significance Over the Course of the Disease and Are Surrogates for Response to Therapy.

BACKGROUND: To determine whether in patients with chronic lymphocytic leukemia (CLL), the clinical stage maintains prognostic significance over time and can be considered as a surrogate for the response to therapy. PATIENTS AND METHODS: The data from 229 CLL patients were retrospectively evaluated. The main aims of the study were to describe the changes in clinical stage during the course of CLL as a result of the response to treatment and to determine the time to next therapy (TTNT) and overall survival (OS) according to those changes, in particular, among the heterogeneous International Workshop on CLL (IWCLL) partial response (PR) category. RESULTS: Among the patients in the IWCLL PR category, differences were found in TTNT and OS according to the clinical stage at the response evaluation. With a median follow-up period of 91 months (range, 2-390 months), patients with a PR- Binet A at the response evaluation had significantly longer TTNT and OS compared with those with PR-Binet B/C (median TTNT, 26 vs. 11 months; P = .00; median OS, 63 vs. 43 months; P = .047). CONCLUSION: The results of the present study have shown that for patients with CLL, the Binet clinical stages are good outcome predictors throughout the disease course and also suggest that changes in Binet clinical stage could be useful as response surrogates and to divide the IWCLL PR category into different prognostic subgroups.

FcγRIIb expression in early stage chronic lymphocytic leukemia.

In normal B-cells, B-cell antigen receptor (BCR) signaling can be negatively regulated by the low-affinity receptor FcγRIIb (CD32b). To better understand the role of FcγRIIb in chronic lymphocytic leukemia (CLL), we correlated its expression on 155 samples from newly-diagnosed Binet A patients with clinical characteristics and outcome. FcγRIIb expression was similar in normal B-cells and leukemic cells, this being heterogenous among patients and within CLL clones. FcγRIIb expression did not correlate with well known prognostic markers [disease stage, serum beta-2 microglobulin (B2M), IGHV mutational status, expression of ZAP-70 and CD38, and cytogenetics] except for a weak concordance with CD49d. Moreover, patients with low FcγRIIb expression (69/155, 44.5%) required therapy earlier than those with high FcγRIIb expression (86/155, 55.5%) (median 151.4 months vs. not reached; p=.071). These results encourage further investigation on the role of FcγRIIb in CLL biology and prognostic significance in larger series of patients.

Prognostic impact of circulating plasma cells in patients with multiple myeloma: implications for plasma cell leukemia definition.

The presence of circulating plasma cells in patients with multiple myeloma is considered a marker for highly proliferative disease. In the study herein, the impact of circulating plasma cells assessed by cytology on survival of patients with multiple myeloma was analyzed. Wright-Giemsa stained peripheral blood smears of 482 patients with newly diagnosed myeloma or plasma cell leukemia were reviewed and patients were classified into 4 categories according to the percentage of circulating plasma cells: 0%, 1-4%, 5-20%, and plasma cell leukemia with the following frequencies: 382 (79.2%), 83 (17.2%), 12 (2.5%) and 5 (1.0%), respectively. Median overall survival according to the circulating plasma cells group was 47, 50, 6 and 14 months, respectively. At multivariate analysis, the presence of 5 to 20% circulating plasma cells was associated with a worse overall survival (relative risk 4.9, 95% CI 2.6-9.3) independently of age, creatinine, the Durie-Salmon system stage and the International Staging System (ISS) stage. Patients with ≥5% circulating plasma cells had lower platelet counts (median 86×109/L vs 214×109/L, P<0.0001) and higher bone marrow plasma cells (median 53% vs 36%, P=0.004). The presence of ≥5% circulating plasma cells in patients with multiple myeloma has a similar adverse prognostic impact as plasma cell leukemia.

Ibrutinib for patients with rituximab-refractory Waldenström's macroglobulinaemia (iNNOVATE): an open-label substudy of an international, multicentre, phase 3 trial.

BACKGROUND: In the era of widespread rituximab use for Waldenström's macroglobulinaemia, new treatment options for patients with rituximab-refractory disease are an important clinical need. Ibrutinib has induced durable responses in previously treated patients with Waldenström's macroglobulinaemia. We assessed the efficacy and safety of ibrutinib in a population with rituximab-refractory disease. METHODS: This multicentre, open-label substudy was done at 19 sites in seven countries in adults aged 18 years and older with confirmed Waldenström's macroglobulinaemia, refractory to rituximab and requiring treatment. Disease refractory to the last rituximab-containing therapy was defined as either relapse less than 12 months since last dose of rituximab or failure to achieve at least a minor response. Key exclusion criteria included: CNS involvement, a stroke or intracranial haemorrhage less than 12 months before enrolment, clinically significant cardiovascular disease, hepatitis B or hepatitis C viral infection, and a known bleeding disorder. Patients received oral ibrutinib 420 mg once daily until progression or unacceptable toxicity. The substudy was not prospectively powered for statistical comparisons, and as such, all the analyses are descriptive in nature. This study objectives were the proportion of patients with an overall response, progression-free survival, overall survival, haematological improvement measured by haemoglobin, time to next treatment, and patient-reported outcomes according to the Functional Assessment of Cancer Therapy-Anemia (FACT-An) and the Euro Qol 5 Dimension Questionnaire (EQ-5D-5L). All analyses were per protocol. The study is registered at ClinicalTrials.gov, number NCT02165397, and follow-up is ongoing but enrolment is complete. FINDINGS: Between Aug 18, 2014, and Feb 18, 2015, 31 patients were enrolled. Median age was 67 years (IQR 58-74); 13 (42%) of 31 patients had high-risk disease per the International Prognostic Scoring System Waldenström Macroglobulinaemia, median number of previous therapies was four (IQR 2-6), and all were rituximab-refractory. At a median follow-up of 18·1 months (IQR 17·5-18·9), the proportion of patients with an overall response was 28 [90%] of 31 (22 [71%] of patients had a major response), the estimated 18 month progression-free survival rate was 86% (95% CI 66-94), and the estimated 18 month overall survival rate was 97% (95% CI 79-100). Baseline median haemoglobin of 10·3 g/dL (IQR 9·3-11·7) increased to 11·4 g/dL (10·9-12·4) after 4 weeks of ibrutinib treatment and reached 12·7 g/dL (11·8-13·4) at week 49. A clinically meaningful improvement from baseline in FACT-An score, anaemia subscale score, and the EQ-5D-5L were reported at all post-baseline visits. Time to next treatment will be presented at a later date. Common grade 3 or worse adverse events included neutropenia in four patients (13%), hypertension in three patients (10%), and anaemia, thrombocytopenia, and diarrhoea in two patients each (6%). Serious adverse events occurred in ten patients (32%) and were most often infections. Five (16%) patients discontinued ibrutinib: three due to progression and two due to adverse events, while the remaining 26 [84%] of patients are continuing ibrutinib at the time of this report. INTERPRETATION: The sustained responses and median progression-free survival time, combined with a manageable toxicity profile observed with single-agent ibrutinib indicate that this chemotherapy-free approach is a potential new treatment choice for patients who had heavily pretreated, rituximab-refractory Waldenström's macroglobulinaemia. FUNDING: Pharmacyclics LLC, an AbbVie Company.

Zoledronic acid as compared with observation in multiple myeloma patients at biochemical relapse: results of the randomized AZABACHE Spanish trial.

This study analyzed the anti-myeloma effect of zoledronic acid monotherapy by investigating patients at the time of asymptomatic biochemical relapse. One hundred patients were randomized to receive either zoledronic acid (4 mg iv/4 weeks, 12 doses) (n=51) or not (n=49). Experimental and control groups were well balanced for disease and prognostic features. Zoledronic acid did not show an antitumor effect according to changes in M-component. However, there were fewer symptomatic progressions in the experimental group than in the control group (34 versus 41, respectively; P=0.05) resulting in a median time to symptoms of 16 versus 10 months (P=0.161). The median time to next therapy was also slightly longer for the treated group than the untreated, control group (13.4 versus 10.1 months), although the difference was not statistically significant (P=0.360). The pattern of relapses was different for treated versus control patients: progressive bone disease (8 versus 20), anemia (24 versus 18), renal dysfunction (1 versus 2), and plasmacytomas (1 versus 1, respectively). This concurred with fewer skeletal-related events in the treated group than in the control group (2 versus 14), with a projected 4-year event proportion of 6% versus 40% (P<0.001). In summary, zoledronic acid monotherapy does not show an antitumor effect on biochemical relapses in multiple myeloma, but does reduce the risk of progression with symptomatic bone disease and skeletal complications. This trial was registered in the ClinicalTrials.gov database with code NCT01087008.

A phase II trial of lenalidomide, dexamethasone and cyclophosphamide for newly diagnosed patients with systemic immunoglobulin light chain amyloidosis.

Immunomodulatory drugs have been shown to be of benefit in relapsed/refractory immunoglobulin light-chain (AL) amyloidosis. We designed a prospective, multicentre phase II trial of lenalidomide, dexamethasone and cyclophosphamide for newly diagnosed patients with AL amyloidosis not eligible for autologous stem-cell transplantation. Twenty-eight patients were included in the study. Cardiac involvement was present in 23 patients; 14 of them had cardiac stage III. The overall haematological response rate was 46%, including complete and very good partial responses in 25% and 18% of patients respectively. Haematological response was mainly associated with absence of cardiac stage III and lower tumour burden. Organ response was observed in 46% of patients. After a median follow-up of 24 months, median progression-free and overall survival have not been reached, both being significantly longer in responders (P < 0·001 and P = 0·001 respectively). Seventeen patients have discontinued treatment, mostly due to amyloid-related death, disease progression or lack of response. Only 14% of the patients discontinued treatment due to therapy-related adverse events. Our results support the efficacy of this regimen, with high quality responses and prolonged survival, as well as its tolerability, in patients with AL amyloidosis not eligible for stem cell transplant and without advanced cardiac involvement (clinicaltrials.gov identifier: NCT01194791).

GEM2005 trial update comparing VMP/VTP as induction in elderly multiple myeloma patients: do we still need alkylators?

Melphalan (M), in combination with prednisone (MP), has been the backbone of new combinations, including bortezomib plus MP (VMP). However, new alkylator-free schemes, such as lenalidomide plus low-dose dexamethasone, are challenging the role of alkylators in myeloma treatment of elderly patients. Here we have updated, after a long follow-up (median 6 years), the results of the GEM2005 study that addressed this question by comparing VMP with bortezomib plus thalidomide and prednisone (VTP) as induction. Between April 2005 and October 2008, 260 patients were randomized to receive 6 cycles of VMP or VTP as induction. The median progression-free survival was 32 months for the VMP and 23 months for the VTP arms (P 5 .09). VMP significantly prolonged the overall survival (OS) compared with VTP (median of 63 and 43 months, respectively; hazard ratio [HR]: 0.67, P 5 .01). Achieving immunophenotypic complete response was associated with a significantly longer OS, especially in the VMP arm (66%remain alive after 8 years). Melphalan, plus bortezomib, should be maintained as standard care for the treatment of elderly multiple myeloma patients. This trial was registered at www.clinicaltrials.gov as #NCT00443235.

Impact of cyclosporine levels on the development of acute graft versus host disease after reduced intensity conditioning allogeneic stem cell transplantation.

We analyze the impact of cyclosporine (CsA) levels in the development of acute graft-versus-host disease (aGVHD) after reduced intensity conditioning allogeneic hematopoietic transplantation (allo-RIC). We retrospectively evaluated 156 consecutive patients who underwent HLA-identical sibling allo-RIC at our institution. CsA median blood levels in the 1st, 2nd, 3rd and 4th weeks after allo-RIC were 134 (range: 10-444), 219 (54-656), 253 (53-910) and 224 (30-699) ng/mL; 60%, 16%, 11% and 17% of the patients had median CsA blood levels below 150 ng/mL during these weeks. 53 patients developed grade 2-4 aGVHD for a cumulative incidence of 45% (95% CI 34-50%) at a median of 42 days. Low CsA levels on the 3rd week and sex-mismatch were associated with the development of GVHD. Risk factors for 1-year NRM and OS were advanced disease status (HR: 2.2, P = 0.02) and development of grade 2-4 aGVHD (HR: 2.5, P < 0.01), while there was a trend for higher NRM in patients with a low median CsA concentration on the 3rd week (P = 0.06). These results emphasize the relevance of sustaining adequate levels of blood CsA by close monitoring and dose adjustments, particularly when engraftment becomes evident. CsA adequate management will impact on long-term outcomes in the allo-RIC setting.

Recidiva endobronquial de linfoma difuso de células grandes B. Diagnóstico con criosonda / Recurrent Endobronchial Diffuse Large B-cell Lymphoma. Diagnosed by Cryoprobe

La localización endobronquial del linfoma difuso de células grandes tipo B (LDCGB) es infrecuente. El diagnóstico histológico se realiza mediante la obtención de muestras de tejido pulmonar. En estos casos, la necesidad de realizar estudios inmunohistoquímicos para establecer el diagnóstico requiere la obtención de muestras de un tamaño y calidad adecuados, lo que, en ocasiones, implica la repetición de la exploración endoscópica y la realización de biopsias adicionales. Presentamos el primer caso de un paciente diagnosticado de recidiva de LDCGB endobronquial mediante biopsia bronquial realizada con criosonda (AU)

The bronchial involvement of diffuse large B-cell lymphoma (DLBCL) is an exceptional finding. Histological diagnosis is done with lung tissue samples. In these cases, the need for immunohistochemistry studies in order to establish the diagnosis requires obtaining tissue samples of adequate size and quality. Sometimes, endoscopic explorations may be repeated to obtain further biopsies. We present the first documented case of recurrent endobronchial DLBCL that was diagnosed from a bronchial biopsy taken with a cryoprobe (AU)

Recurrent endobronchial diffuse large B-cell lymphoma. Diagnosed by cryoprobe.

The bronchial involvement of diffuse large B-cell lymphoma (DLBCL) is an exceptional finding. Histological diagnosis is done with lung tissue samples. In these cases, the need for immunohistochemistry studies in order to establish the diagnosis requires obtaining tissue samples of adequate size and quality. Sometimes, endoscopic explorations may be repeated to obtain further biopsies. We present the first documented case of recurrent endobronchial DLBCL that was diagnosed from a bronchial biopsy taken with a cryoprobe.

Updated experience with inolimomab as treatment for corticosteroid-refractory acute graft-versus-host disease.

Refractory acute graft-versus-host disease (aGVHD) remains an important cause of mortality after allogeneic stem cell transplantation. No standard therapy exists once steroids fail to obtain a good response. In 2006, our group published a series of patients who received inolimomab, an anti-interleukin-2 receptor monoclonal antibody, as salvage therapy with initial encouraging results. In this update, we analyzed a larger group of patients with prolonged follow-up. Ninety-two consecutive patients were treated with inolimomab at our center between April 1999 and December 2011. Overall response rate was 42% (complete response in 14%) on day +30. Predictors of failure to respond in the multivariate analysis were overall aGVHD grade IV, instauration of inolimomab before day 15 of aGVHD diagnosis, and severe lymphopenia. Patients without gastrointestinal involvement appeared to do better, with a 70% response rate compared with 39% in patients with gastrointestinal involvement (P = .06). However, the 2-year overall survival rate was of 18% for the entire cohort (95% confidence interval, 10% to 26%) and 33% for day 30 responders (95% confidence interval, 25% to 40%) and Acute GVHD was the main cause of death (49%) followed by opportunistic infections (27%). Results of this update show that although inolimomab is a well-tolerated drug with a moderate number of short-term responses, it is associated with long-term survival in only one-third of responding patients. These data highlight the need to investigate new rescue treatments with sustained effect and the importance of reporting long-term outcomes in GVHD studies.