Individual myeloma‐specific T‐cell clones eliminate tumour cells and correlate with clinical outcomes in patients with multiple myeloma

Despite novel treatment strategies, multiple myeloma (MM) remains an incurable disease with low immunogenicity and multiple immune defects. We developed an ex vivo strategy for inducing myeloma‐specific cytotoxic T lymphocytes (CTLs) and demonstrate the possibility of identification and long‐term in vivo monitoring of individual myeloma‐specific T‐cell clones using the most sensitive clonotypic assay that is able to detect low frequencies of T‐cell clones (1 clonotypic cell in 10⁶ cells). Ten patients with MM were examined for the presence of tumour‐reactive T cells using dendritic cells loaded with autologous tumour cells. All patients had detectable myeloma‐reactive T cells in vitro. Expanded myeloma‐reactive T cells demonstrated specific cytotoxic effects against autologous tumour cells in vitro (median 39·6% at an effector:target ratio of 40:1). The clonality of myeloma‐specific T cells was studied with a clonotypic assay, which demonstrated both oligoclonal and monoclonal populations of myeloma‐specific T cells. CD8⁺ CTLs were the most immunodominant myeloma‐specific T‐cell clones and clinical responses were closely associated with the in vivo expansion and long‐term persistence of individual CD8⁺ T‐cell clones, usually at very low frequencies (10^?3–10^?6). We conclude that the clonotypic assay is the most sensitive tool for immunomonitoring of low‐frequency T cells.     

Intensive chemotherapy with blood progenitor transplantation for primary resistant multiple myeloma

Summary. This study assessed the feasibility and effect of blood progenitors as the only source of haemopoietic support for myeloablative therapy for patients with primary resistant multiple myeloma and markedly infiltrated bone marrow. 17 patients with advanced, primary resistant myeloma received a priming regimen of cyclophosphamide (3 g/m²) and etoposide (900 mg/m²) with GM-CSF. During haematological recovery, at least 2 × 10⁶ CD34⁺ mononuclear cells/kg were collected from each patient with 4-12 leukaphereses. High-dose chemotherapy was then given which consisted of thiotepa (750 mg/m²), busulfan (10 mg/kg) and cyclophosphamide (120 mg/kg) followed by reinfusion of the blood progenitors. Haemopoietic reconstitution was rapid with recovery of granulocytes to >1.0 × 10⁹/1 after a median of 10 d and of platelets to 50 × 10⁹/1 after a median of 29 d. The myeloma responded in 10/17 patients for a projected median duration of at least 12 months. Survival was prolonged significantly in comparison with the outcome of control patients who did not receive intensive treatment. Blood progenitors, assessed from the number of CD34⁺ cells, produced early haemopoietic recovery after myeloablative therapy that induced sustained control of advanced and resistant multiple myeloma.     

Second primary malignancy risk after radiotherapy in rectal cancer survivors

AIM To investigate second primary malignancy(SPM) risk after radiotherapy in rectal cancer survivors METHODS We used Taiwan's National Health Insurance Research Database to identify rectal cancer patients between 1996 and 2011. Surgery-alone, preoperative short course, preoperative long course, and post-operative radiotherapy groups were defined. The overall and sitespecific SPM incidence rates were compared among the radiotherapy groups by multivariate Cox regression, taking chemotherapy and comorbidities into account. Sensitivity tests were performed for attained-year adjustment and long-term survivors analysis. RESULTS A total of 28220 patients were analyzed. The 10-year cumulative SPM incidence was 7.8% [95% confidence interval(CI): 7.2%-8.2%] using a competing risk model. The most common sites of SPM were the lung, liver, and prostate. Radiotherapy was not associated with increased SPM risk in multi-variate Cox model(hazard ratio = 1.05, 95%CI: 0.91-1.21, P = 0.494). The SPM hazard remained unchanged in 10-yearsurvivors. In addition, no SPM risk difference was found between the preoperative radiotherapy and postoperative radiotherapy groups.CONCLUSION In this large population-based cohort study, we demonstrated that radiotherapy had no increase in SPM.     

Autologous haematopoietic cell transplantation in elderly patients with multiple myeloma

High‐dose chemotherapy with melphalan followed by autologous haematopoietic cell transplantation (AHCT) is a standard of care in young patients (<65 years) with multiple myeloma. Most myeloma patients, however, are older than 65 years at the time of diagnosis, and the findings of numerous single‐centre and registry studies provide evidence that AHCT can be a feasible and effective treatment option in these patients. Nevertheless, AHCT is not generally recommended as standard treatment in the elderly, due to the fact that a benefit of AHCT over conventional‐dose therapy has not been demonstrated by prospective randomized trials. Yet, the use of AHCT has increased substantially in older patients in recent years, and an increasing number of reports suggest comparable outcomes for older and younger patients after AHCT. In this review we summarize the results of AHCT for elderly patients with multiple myeloma.     

Haematopoietic stem cell transplantation for treatment of primary CNS lymphoma: single‐centre experience and literature review

Primary central nervous system lymphoma (PCNSL) is a rare and malignant tumour type. Established treatment approaches include high‐dose methotrexate (HD‐MTX)‐based chemotherapy and whole‐brain radiotherapy (WBRT). WBRT is associated with significant neurotoxicity and autologous haematopoietic stem cell transplantation (ASCT) has been proposed as an alternative treatment – either in the 1st line setting after HD‐MTX‐based chemotherapy or as salvage treatment for relapsed/refractory PCNSL. We here report our single‐centre experience with five PCNSL patients, who had achieved an objective response after a high‐dose methotrexate‐based induction therapy and consecutively received a high‐dose chemotherapy, consisting of carmustine and thiotepa, followed by ASCT. We also provide a literature review on ASCL for PCNSL. Our data, with three of five patients in continuous complete remission and four of five patients alive after a median follow‐up time of 8 months, as well as previously published results, show that ASCT is a safe treatment option that is able to induce tumour remissions in patients with PCNSL. However, controlled trials are needed to compare the long‐term efficacy and tolerability of ASCT with other treatment approaches and also to establish the optimal sequence of treatment regimens in PCNSL patients.     

Relation between harvest success and outcome after autologous peripheral blood stem cell transplantation in multiple myeloma

We studied the prognostic influence of pretransplant characteristics on response and survival in 104 consecutive patients with multiple myeloma receiving uniform pretransplant treatment consisting of VAD regimen, stem cell mobilisation, harvesting, and conditioning with melphalan 200 mg/m2. At the time of peripheral blood stem cell transplantation (PBSCT), 11% of patients were in complete remission (CR), and 63% in partial remission (PR). We evaluated the influence of age, sex, pretransplant response, number of harvested CD34+ cells, number of infused CD34+ cells, splitting part of the harvest for succeeding transplants on overall (OS) and progression-free survival (PFS) times. Following PBSCT, 31% of the patients were in CR and 57% in PR. Median OS and PFS from transplantation were 67 and 36 months, respectively. Transplant-related mortality was 0%. The number of harvested CD34+ cells was the only variable that was prognostic for OS in univariate and multivariate analyses. None of the variables was prognostic for PFS, although pretransplant response was nearly significant. The procedure of splitting and saving part of the harvest thus reducing the number of cells in the graft had no influence on outcome measured as OS or PFS.     

Outcome of allogeneic transplantation in newly diagnosed and relapsed/refractory multiple myeloma: long‐term follow‐up in a single institution

Allogeneic stem cell transplantation (allo‐SCT) has the potential to induce long‐term remission in multiple myeloma (MM), but the role of allo‐SCT in MM is controversial due to the high rate of treatment‐related mortality (TRM). However, although proteasome inhibitors and immunomodulatory drugs have improved the outcome of patients with MM, high‐risk patients still have a very poor prognosis. This indicates the need for new treatment strategies and identification of patients who might benefit from allo‐SCT. We therefore analyzed the outcome of one hundred and forty‐seven patients with MM who received an allo‐SCT at our institution (58 in first line, 89 in relapsed/refractory setting) after a median follow‐up of 88.8 months. For the first‐line setting, median progression‐free survival (PFS) and overall survival (OS) were remarkably good, with a CR rate of 48.3%, median PFS of 30.2 months, and 10‐yr OS of 51%. We found no difference in outcome for patients with high‐risk metaphase cytogenetics or FISH del(13q14), but efficacy in current standard high‐risk patients could not be determined. The outcome in the relapsed/refractory setting was poor, especially in the subgroup of patients relapsing within 18 months after auto‐SCT. Therefore, if applied at all in these patients, improvement of allo‐SCT is needed, focusing on reduction of TRM and more effective immunotherapy.     

Progress in haematopoietic stem cell transplantation for multiple myeloma

High-dose myeloablative treatment followed by autologous haematopoietic stem cell transplantation has significantly improved survival of patients younger than 65 years of age with multiple myeloma as compared with conventional chemotherapy. However, all patients seem to relapse and molecular remissions are rare. Results of allogeneic transplantation, still hampered by high transplant-related mortality, have improved dramatically over the last 5-6 years and this is an option for patients younger than 50-55 years old. The relapse rate is lower than with autologous transplantation and molecular remissions are frequent. Some patients are still in complete haematological remission more the 10 years following transplantation. Autologous transplantation followed by nonmyeloablative allogeneic transplantation is on trial and may be a way to eventually cure a fraction of younger patients with multiple myeloma.     

Bortezomib‐thalidomide‐dexamethasone versus bortezomib‐cyclophosphamide‐dexamethasone as induction therapy prior to autologous stem cell transplantation in multiple myeloma

‘….Alright, but apart from the sanitation, medicine, education, wine, public order, irrigation, the roads, fresh water and public health………………what have the Romans ever done for us?’ From Monty Python's Life of Brian

An organizational review of the British Society for Haematology (BSH) was started in November 2013 and completed in June 2014. Many members of the Society participated in the surveys and have given their views, including those on the Shape of Training Greenaway report. Members' views were incorporated in the review and these have informed the eight strategic aims agreed at the Board meeting on 10 June 2014. The BSH will aim to realise these strategic aims over the next three to five years.     

Cytomegalovirus infection and non-neutropenic fever after autologous stem cell transplantation: high rates of reactivation in patients with multiple myeloma and lymphoma

In a retrospective study, we examined the association between cytomegalovirus (CMV) infection and non-neutropenic fever immediately following autologous peripheral blood stem cell transplantation for a variety of haematological malignancies and solid tumours. Sixty non-neutropenic febrile episodes (41 in CMV-seropositive and 19 in CMV-seronegative patients) were evaluated. CMV reactivation, documented by CMV antigenaemia, was detected in 16 out of 41 (39%) seropositive patients compared with 0 out of 19 seronegative patients. In 12 of these 16 patients, CMV infection was considered the sole cause of fever. Thirteen patients had maximum antigenaemia levels > 5 cells/slide. Specific antiviral treatment led to the resolution of the fever in all, but two, patients, who developed fatal CMV pneumonia. Patients with multiple myeloma and lymphoma, possibly owing to a combination of disease-related characteristics and prior immunosuppressive treatment, had high rates of CMV reactivation and may require more frequent diagnostic evaluation and prompt therapeutic intervention.     

Risk of skin cancer in multiple myeloma patients: a retrospective cohort study

Immunosuppressed patients are known to have an increased incidence of skin cancer. Patients with multiple myeloma (MM) show impaired immune function. In the past, because of poor survival, the incidence of specific secondary primary malignancies such as skin cancer among these patients was difficult to establish. With more effective MM therapies that have emerged in recent years, these patients are living markedly longer, and therefore, it becomes of increasing importance to determine whether their risk of developing other medical problems such as skin cancer is increased. We performed a retrospective cohort study of 205 myeloma patients and 193 age‐, race‐, and gender‐matched control subjects to assess the incidence of skin cancers among patients with MM and determine the specific types of and risk factors for skin cancer. We found that there is an increased occurrence of skin cancer among patients with MM compared to control subjects (26.8% vs. 16.1% in controls; P = 0.009). Among specific types of skin cancer, the proportion of patients with squamous cell carcinoma (SCC) was higher than controls (P = 0.016). In addition to MM diagnosis, older age and Caucasian ethnicity were predictors of skin cancer of any type. Furthermore, older age was also a predictor of SCC.     

Real‐world use of pomalidomide and dexamethasone in double refractory multiple myeloma suggests benefit in renal impairment and adverse genetics: a multi‐centre UK experience

Myeloma patients who become refractory to immunomodulatory agents (IMiDs) and bortezomib have poor survival, with limited therapeutic options. Pomalidomide has shown improved survival and good tolerability in this patient cohort in clinical trials, but real world data are scarce. We retrospectively analysed all patients treated with pomalidomide at five UK centres between 2013 and 2016. Of 85 patients identified, 70 had sufficient information for response assessments. Median age was 66 years [40–89], 96·5% were refractory to IMiDs, 72·9% were refractory to both an IMiD and bortezomib and 92·9% were refractory to their last treatment. Of 45 patients with fluorescence in situ hybridization results 64% had adverse risk, 19 patients (22·4%) had an estimated glomerular filtration rate <45 ml/min. Grade ≥3 non‐haematological toxicities occurred in 42·4%, and grade ≥3 neutropenia and thrombocytopenia in 38% and 24% respectively, but only 18·8% had dose reductions. The overall response rate was 52·9%. At a median follow‐up of 13·2 months, median progression‐free survival was 5·2 months [95% confidence interval (CI) 4·150–6·238], and median overall survival was 13·7 months (95% CI 11·775–15·707). No significant difference was seen in response, survival or tolerability by renal function, age or cytogenetic risk. This real‐world data support the results seen in published clinical trials.     

Risk of second primary malignancy in patients with sinonasal tumors: a population‐based cohort study

Background

The 5‐year overall survival rate for patients with sinonasal cancers has remained around 50% for the last 3 decades. Prior studies on head and neck cancers have suggested that 1 reason for poor survival is the frequent development of second primary malignancies (SPMs). The purpose of this study is to assess overall and site‐specific risks of SPM following treatment of sinonasal malignancy.

Methods

A retrospective, population‐based cohort study was performed on 2614 patients in the Surveillance, Epidemiology, and End Results (SEER) database who were diagnosed with primary sinonasal malignancy between 1973 and 2014. Standardized incidence ratios (SIRs) and absolute excess risks (AERs) were calculated to assess risk of SPM relative to incidence in the general population.

Results

A total of 422 (16.1%) patients with primary sinonasal malignancies developed a total of 480 SPMs. This cohort had a significantly higher frequency of SPMs than expected in the general population (SIR 1.32; 95% confidence interval [CI], 1.20 to 1.44; AER 53.41). Site‐specific analyses of SIRs suggested highest risk of malignancy in the sinonasal tract (SIR 75.64; 95% CI, 53.53 to 103.83; AER 17.22), followed by bone, eye and orbit, oral cavity and pharynx, and lung and mediastinum.

Conclusion

Patients with history of sinonasal cancer are at significantly increased risk of developing an SPM. Careful monitoring for development of additional tumors may be warranted.