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Risk of developing myelodysplastic syndromes (MDS) is significantly increased in both multiple myeloma (MM) and MGUS, suggesting that is therapy independent. However, the incidence and sequelae of dysplastic hematopoiesis at diagnosis are unknown. Here, we used multidimensional flow cytometry (MFC) to prospectively screen for presence of MDS-associated phenotypic alterations (MDS-PA) in the bone marrow of 285 MM patients enrolled in the PETHEMA/GEM2012MENOS65 trial (NCT01916252), and investigated the clinical significance of monocytic MDS-PA in a larger series of 1,252 patients enrolled in four PETHEMA/GEM protocols. At diagnosis, 33/285 (11.6%) cases displayed MDS-PA. Bulk- and single-cell targeted sequencing of MDS recurrently mutated genes in CD34+ progenitors (and dysplastic lineages) from 67 patients unveiled clonal hematopoiesis in 13/26 (50%) cases with MDS-PA versus 9/41 (22%) without MDS-PA; TET2 and NRAS were the most frequently mutated genes. Dynamics of MDS-PA at diagnosis and after autologous transplant were evaluated in 86/285 patients, and showed that in most cases (69/86, 80%) MDS-PA either persisted or remained absent in patients with or without MDS-PA at diagnosis, respectively. Noteworthy, MDS-associated mutations unfrequently emerged after high-dose therapy. Based on MFC profiling, we found that patients with MDS-PA have altered hematopoiesis and Treg distribution in the tumor microenvironment. Importantly, presence of monocytic MDS-PA at diagnosis anticipated greater risk of hematological toxicity and was independently associated with inferior progression-free (HR:1.5, P=.02) and overall survival (HR:1.7, P=.01). This study unveils the biological and clinical significance of dysplastic hematopoiesis in newly-diagnosed MM, which can be screened with moderate sensitivity using cost-effective MFC. Copyright © 2020 American Society of Hematology.

PD1 expression in CD4+ and CD8+ T cells is increased after treatment in multiple myeloma patients with persistent disease. The GEM-Pembresid trial analyzed the efficacy and safety of pembrolizumab as consolidation in patients achieving at least very good partial response but with persistent measurable disease after first- or second-line treatment. Moreover, the characteristics of the immune system were investigated to identify potential biomarkers of response to pembrolizumab. One out of the 17 evaluable patients showed a decrease in the amount of M-protein, although a potential late effect of high-dose melphalan could not be ruled out. Fourteen adverse events were considered related to pembrolizumab, two of which (G3 diarrhea and G2 pneumonitis) prompted treatment discontinuation and all resolving without sequelae. Interestingly, pembrolizumab induced a decrease in the percentage of NK cells at cycle 3, due to the reduction of the circulating and adaptive subsets (0.615 vs. 0.43, p = 0.007, 1.12 vs. 0.86, p = 0.02). In the early progressors, a significantly lower expression of PD1 in CD8+ effector memory T cells (MFI 1327 vs. 926, p = 0.03) was observed. In conclusion, pembrolizumab used as consolidation monotherapy shows an acceptable toxicity profile but did not improve responses in this MM patient population. The trial was registered at clinicaltrials.gov with identifier NCT02636010 and with EUDRACT number 2015-003359-23.

Risk of developing myelodysplastic syndrome (MDS) is significantly increased in both multiple myeloma (MM) and monoclonal gammopathy of undetermined significance, suggesting that it is therapy independent. However, the incidence and sequelae of dys- plastic hematopoiesis at diagnosis are unknown. Here, we used multidimensional flow cytometry (MFC) to prospectively screen for the presence of MDS-associated phenotypic alterations (MDS-PA) in the bone marrow of 285 patients with MM enrolled in the PETHEMA/GEM2012MENOS65 trial (#NCT01916252). We investigated the clinical significance of monocytic MDS-PA in a larger series of 1252 patients enrolled in 4 PETHEMA/GEM protocols. At diagnosis, 33 (11.6%) of 285 cases displayed MDS-PA. Bulk and single-cell-targeted sequencing of MDS recurrently mutated genes in CD34(+) progenitors (and dysplastic lineages) from 67 patients revealed clonal hematopoiesis in 13 (50%) of 26 cases with MDS-PA vs 9 (22%) of 41 without MDS-PA; TET2 and NRAS were the most frequently mutated genes. Dynamics of MDS-PA at diagnosis and after autologous transplant were evaluated in 86 of 285 patients and showed that in most cases (69 of 86 [80%]), MDS-PA either persisted or remained absent in patients with or without MDS-PA at diagnosis, respectively. Noteworthy, MDS-associated mutations infrequently emerged after high-dose therapy. Based on MFC profiling, patients with MDS-PA have altered hematopoiesis and T regulatory cell distribution in the tumor microenvironment. Importantly, the presence of monocytic MDS-PA at diagnosis anticipated greater risk of hematologic toxicity and was independently associated with inferior progression-free survival (hazard ratio, 1.5; P = .02) and overall survival (hazard ratio, 1.7; P = .01). This study reveals the biological and clinical significance of dysplastic hematopoiesis in newly diagnosed MM, which can be screened with moderate sensitivity using cost-effective MFC. (Blood. 2020;135(26):2375-2387)

BACKGROUND Single-agent ibrutinib has shown substantial activity in patients with relapsed Waldenstrom's macroglobulinemia, a rare form of B-cell lymphoma. We evaluated the effect of adding ibrutinib to rituximab in patients with this disease, both in those who had not received previous treatment and in those with disease recurrence. METHODS We randomly assigned 150 symptomatic patients to receive ibrutinib plus rituximab or placebo plus rituximab. The primary end point was progression-free survival, as assessed by an independent review committee. Key secondary end points were response rates, sustained hematologic improvement from baseline, and safety. The mutational status of MYD88 and CXCR4 was assessed in bone marrow samples. RESULTS At 30 months, the progression-free survival rate was 82% with ibrutinib-rituximab versus 28% with placebo-rituximab (hazard ratio for progression or death, 0.20; P

Autologous hematopoietic cell transplantation (AHCT) is the standard of care for young patients with relapsed/refractory (R/R) Hodgkin's lymphoma (HL). However, there is limited experience of its efficacy and feasibility in older patients. The characteristics and outcomes of 121 patients aged 50 years (42 of them are 60 years old) with R/R HL who underwent AHCT were reviewed. After a median follow-up of 3.1 years, overall survival (OS) and progression-free survival (PFS) at 5 years were 64 and 55 %, respectively, with no differences between 50-59-year-old and 60-year-old patients. Hematological and extra-hematological toxicities after AHCT were comparable between the two groups of age. In univariate analysis, poorer OS and PFS were associated with disease status other than complete remission, hematopoietic cell transplantation comorbidity index (HCT-CI) scores > 1, and Charlson Comorbidity Index (CCI) scores > 1. HCT-CI scores > 1 were also associated with a higher risk of grade 3-4 extrahematologic toxicity. In multivariate analysis, HCT-CI and CCI remained significantly associated with OS and PFS after adjustment for disease status. Our data show that AHCT can be performed in selected patients with R/R HL 50 years with acceptable outcome and toxicity. Comorbidities appear to impact AHCT outcome more than age.

Background In the era of widespread rituximab use for Waldenstrm's macro globulinaemia, new treatment options for patients with rituximab-refractory disease are an important clinical need. Ibrutinib has induced durable responses in previously treated patients with Waldenstrm's macro globulinaemia. We assessed the effi cacy 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 confi rmed Waldenstrm's macro globulinaemia, refractory to rituximab and requiring treatment. Disease refractory to the last rituximab-containing therapy was defi ned 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 signifi cant 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 TherapyAnemia (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 Waldenstrm 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 114 mu g/dL (10.9-12.4) after 4 weeks of ibrutinib treatment and reached 127 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 profi le 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 Waldenstrm's macro globulinaemia.

POEMS syndrome is a rare para-neoplastic syndrome secondary to a plasma cell dyscrasia. Effective treatment can control the disease-related symptom complex. We describe the clinical outcome of autologous stem cell transplantation for patients with POEMS syndrome, determining the impact of patient and disease-specific factors on prognosis. 127 patients underwent an autologous stem cell transplantation between 1997-2010 with a median age of 50 years (range 26-69). The median time from diagnosis to ASCT was 7.5 months with 32% of patients receiving an autologous stem cell transplantation >12 months from diagnosis. Engraftment was seen in 97% patients and engraftment syndrome was documented in 23% of autologous stem cell transplantation recipients. Haematological response was characterized as CR in 48.5%, PR in 20.8%

The diagnosis of Waldenström macroglobulinaemia (WM) can be challenging given the variety of signs and symptoms patients can present. Furthermore, once the diagnosis of WM is established, the initial evaluation should be thorough as well as appropriately directed. During the 8th International Workshop for WM in London, United Kingdom, a multi-institutional task force was formed to develop consensus recommendations for the diagnosis and initial evaluation of patients with WM. In this document, we present the results of the deliberations that took place to address these issues. We provide recommendations for history-taking and physical examination, laboratory studies, bone marrow aspiration and biopsy analysis and imaging studies. We also provide guidance on the initial evaluation of special situations, such as anaemia, hyperviscosity, neuropathy, Bing-Neel syndrome and amyloidosis. We hope these recommendations serve as a practical guidance to clinicians taking care of patients with a suspected or an established diagnosis of WM. © 2016 John Wiley & Sons Ltd

In contrast to the upfront setting in which the role of high-dose therapy with autologous hematopoietic cell transplantation (HCT) as consolidation of a first remission in patients with multiple myeloma (MM) is well established, the role of high-dose therapy with autologous or allogeneic HCT has not been extensively studied in MM patients relapsing after primary therapy. The International Myeloma Working Group together with the Blood and Marrow Transplant Clinical Trials Network, the American Society of Blood and Marrow Transplantation, and the European Society of Blood and Marrow Transplantation convened a meeting of MM experts to: (1) summarize current knowledge regarding the role of autologous or allogeneic HCT in MM patients progressing after primary therapy, (2) propose guidelines for the use of salvage HCT in MM, (3) identify knowledge gaps, (4) propose a research agenda, and (5) develop a collaborative initiative to move the research agenda forward. After reviewing the available data, the expert committee came to the following consensus statement for salvage autologous HCT: (1) In transplantation-eligible patients relapsing after primary therapy that did NOT include an autologous HCT, high-dose therapy with HCT as part of salvage therapy should be considered standard; (2) High-dose therapy and autologous HCT should be considered appropriate therapy for any patients relapsing after primary therapy that includes an autologous HCT with initial remission duration of more than 18 months; (3) High-dose therapy and autologous HCT can be used as a bridging strategy to allogeneic HCT; (4) The role of postsalvage HCT maintenance needs to be explored in the context of well-designed prospective trials that should include new agents, such as monoclonal antibodies, immune-modulating agents, and oral proteasome inhibitors; (5) Autologous HCT consolidation should be explored as a strategy to develop novel conditioning regimens or post-HCT strategies in patients with short (less than 18 months remissions) after primary therapy; and (6) Prospective randomized trials need to be performed to define the role of salvage autologous HCT in patients with MM relapsing after primary therapy comparing it to "best non-HCT" therapy. The expert committee also underscored the importance of collecting enough hematopoietic stem cells to perform 2 transplantations early in the course of the disease. Regarding allogeneic HCT, the expert committee agreed on the following consensus statements: (1) Allogeneic HCT should be considered appropriate therapy for any eligible patient with early relapse (less than 24 months) after primary therapy that included an autologous HCT and/or high-risk features (ie, cytogenetics, extramedullary disease, plasma cell leukemia, or high lactate dehydrogenase); (2) Allogeneic HCT should be performed in the context of a clinical trial if possible; (3) The role of postallogeneic HCT maintenance therapy needs to be explored in the context of well-designed prospective trials; and (4) Prospective randomized trials need to be performed to define the role salvage allogeneic HCT in patients with MM relapsing after primary therapy. © 2015 American Society for Blood and Marrow Transplantation.

This report represents a further update of the consensus panel criteria for the assessment of clinical response in patients with Waldenström macroglobulinaemia (WM). These criteria have been updated in light of further data demonstrating an improvement in categorical responses with new drug regimens as well as acknowledgement of the fact that such responses are predictive of overall outcome. A number of key changes are proposed but challenges do however remain and these include the variability in kinetics of immunoglobulin M (IgM) reduction with different treatment modalities and the apparent discrepancy between IgM and bone marrow/tissue response noted with some regimens. Planned sequential bone marrow assessments are encouraged in clinical trials. © 2012 Blackwell Publishing Ltd.

Multiple myeloma (MM) is a hematological neoplasm that arises from a single clone of malignant plasma cells in the bone marrow. In Europe, 4.6/100 000 males and 3.2/100 000 females every year develop MM, with a median age at diagnosis around 60 years., Polish Ministry of Science and Higher Education (Lodz, Poland) - NN40217833, Fondo de Investigaciones Sanitarias (Madrid, Spain) - PI081051, Consejería de Salud de la Junta de Andalucia (Sevilla, Spain) - P08-CVI-4116

Design and methods: An interdisciplinary, expert panel of specialists on MM and myeloma-related bone disease convened for a face-to-face meeting to review and assess the evidence and develop the recommendations. The panel reviewed and graded the evidence available from randomized clinical trials, clinical practice guidelines, and the body of published literature. Where published data were weak or unavailable, the panel used their own clinical experience to put forward recommendations based solely on their expert opinions. Results: The panel recommends the use of BPs in MM patients suffering from lytic bone disease or severe osteoporosis. Intravenous administration may be preferable; however, oral administration can be considered for patients unable to make hospital visits. Dosing should follow approved indications with adjustments if necessary. In general, BPs are well tolerated, but preventive steps should be taken to avoid renal impairment and osteonecrosis of the jaw (ONJ). The panel agrees that BPs should be given for 2 years, but this may be extended if there is evidence of active myeloma bone disease. Initial therapy of ONJ should include discontinuation of BPs until healing occurs. BPs should be restarted if there is disease progression. Conclusions: BPs are an essential component of MM therapy for minimizing skeletal morbidity. Recent retrospective data indicate that a modified dosing regimen and preventive measures can greatly reduce the incidence of ONJ.