The impact of cytogenetics on duration of response and overall survival in patients with relapsed multiple myeloma (long-term follow-up results from BSBMT/UKMF Myeloma X Relapse [Intensive]): a randomised, open-label, phase 3 trial.

The Myeloma X trial (ISCRTN60123120) registered patients with relapsed multiple myeloma. Participants were randomised between salvage autologous stem cell transplantation (ASCT) or weekly cyclophosphamide following re-induction therapy. Cytogenetic analysis performed at trial registration defined t(4;14), t(14;16) and del(17p) as high-risk. The effect of cytogenetics on time to progression (TTP) and overall survival was investigated. At 76 months median follow-up, ASCT improved TTP compared to cyclophosphamide (19 months (95% confidence interval [95% CI] 16-26) vs. 11 months (9-12), hazard ratio [HR]: 0·40, 95% CI: 0·29-0·56, P < 0·001), on which the presence of any single high-risk lesion had a detrimental impact [likelihood ratio test (LRT): P = 0·011]. ASCT also improved OS [67 months (95% CI 59-not reached) vs. 55 months (44-67), HR: 0·64, 95% CI: 0·42-0·99, P = 0·0435], with evidence of a detrimental impact with MYC rearrangement (LRT: P = 0·021). Twenty-one (24·7%) cyclophosphamide patients received an ASCT post-trial, median OS was not reached (95% CI: 39-not reached) for these participants compared to 31 months (22-39), in those who did not receive a post-trial ASCT. The analysis further supports the benefit of salvage ASCT, which may still be beneficial after second relapse in surviving patients. There is evidence that this benefit reduces in cytogenetic high-risk patients, highlighting the need for targeted study in this patient group.

Alemtuzumab-based therapy for Secondary Malignant Histiocytosis arising from Pre-B-ALL.

•Secondary Malignant Histiocytosis (SMH) is an exceedingly rare, life-threatening condition that invariably occurs in the presence of an underlying monoclonal hematologic disorder. Prognosis of SMH remains dismal and there is no established treatment. •We report a case of a patient who developed SMH during induction chemotherapy for his underlying pre-B-ALL, that caused persistently high fevers and was only diagnosed by a marrow while cytopenic in phase 2 induction. He was treated with alemtuzumab-based therapy that reduced the histiocytic infiltration of the bone marrow from 80% to 15% and made him eligible to undergo T-cell replete allogeneic stem transplantation from his sibling. •This report is the first to highlight the role of alemtuzumab, an anti-CD52 monoclonal antibody, in clonal disorders originating from transdifferentiation. •The alemtuzumab-based regimen should be reserved only for carefully selected allogeneic transplant patients.

The effect of salvage autologous stem-cell transplantation on overall survival in patients with relapsed multiple myeloma (final results from BSBMT/UKMF Myeloma X Relapse [Intensive]): a randomised, open-label, phase 3 trial.

BACKGROUND: The Myeloma X trial previously reported improved durability of response (time to disease progression) in patients with relapsed multiple myeloma with salvage autologous stem-cell transplantation (ASCT) compared with oral cyclophosphamide in patients with multiple myeloma relapsing after a first ASCT. We report the final overall survival results of the trial. METHODS: BSBMT/UKMF Myeloma X was a multicentre, randomised, open-label, phase 3 trial done at 51 centres in the UK. Eligible patients with multiple myeloma relapsing after a previous ASCT were re-induced with intravenous bortezomib (1·3 mg/m(2) on days 1, 4, 8, 11), intravenous doxorubicin (9 mg/m(2) per day on days 1-4), and oral dexamethasone (40 mg/day on days 1-4, 8-11, and 15-18 during cycle 1 and days 1-4 during cycles 2-4), with supportive care as per local institutional protocols before randomisation in a 1:1 ratio to either high-dose melphalan (200 mg/m(2)) and salvage ASCT or weekly oral cyclophosphamide (400 mg/m(2) per week for 12 weeks). Randomisation was by permuted blocks stratified by length of first remission and response to re-induction treatment. The primary endpoint was time to disease progression; the study was also powered to detect a difference in the secondary endpoint, overall survival. Further secondary endpoints were the proportion of patients achieving an objective response, progression-free survival, overall survival, toxic effects and safety, pain, and quality of life. Prespecified exploratory endpoints included time to second objective disease progression (PFS2). Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00747877, and the European Clinical Trials Database, number 2006-005890-24, and is now in long-term follow-up. FINDINGS: Between April 16, 2008, and Nov 19, 2012, 297 patients were registered into the study and 174 were randomly assigned to receive either high-dose melphalan and salvage ASCT (n=89) or oral weekly cyclophosphamide (n=85). 173 (58%) of 297 patients relapsed after more than 24 months from first ASCT. 75 (43%) of 174 randomised patients had died at follow-up: salvage ASCT (n=31 [35%]) versus oral weekly cyclophosphamide (n=44 [52%]). Updated time to disease progression shows continued advantage in the salvage ASCT group compared with the weekly cyclophosphamide group (19 months [95% CI 16-26] vs 11 months [9-12]; hazard ratio [HR] 0·45 [95% CI 0·31-0·64] log-rank p<0·0001). Median overall survival was superior in the salvage ASCT group compared with weekly cyclophosphamide group (67 months [95% CI 55-not estimable] vs 52 months [42-60]; log-rank p=0·022; HR 0·56 [0·35-0·90], p=0·0169). Time to second objective disease progression was superior in the salvage ASCT group compared with the weekly cyclophosphamide group (67 months [52-not estimable] vs 35 months [31-43]; HR 0·37 [0·24-0·57], log-rank p<0·0001). During extended follow-up, no further treatment-related or treatment-unrelated adverse events were reported. 15 second primary malignancies were reported in 12 patients (salvage ASCT [n=7] vs oral weekly cyclophosphamide [n=5]). The cumulative incidence of second primary malignancies at 60 months after trial entry was 5·2% (2·1-8·2). INTERPRETATION: Salvage ASCT increases overall survival during consolidation of re-induction treatment in patients with multiple myeloma at first relapse after a first ASCT. The delay of salvage ASCT to third-line treatment or later might not confer the same degree of advantage as seen with salvage ASCT at first relapse. FUNDING: Cancer Research UK, Janssen-Cilag, and Chugai Pharma UK.

Stem Cell Harvesting after Bortezomib-Based Reinduction for Myeloma Relapsing after Autologous Transplantation: Results from the British Society of Blood and Marrow Transplantation/United Kingdom Myeloma Forum Myeloma X (Intensive) Trial.

The phase III British Society of Blood and Marrow Transplantation/United Kingdom Myeloma Forum Myeloma X trial (MMX) demonstrated prospectively, for the first time, superiority of salvage autologous stem cell transplantation over chemotherapy maintenance for multiple myeloma (MM) in first relapse after previous ASCT. However, many patients have stored insufficient stem cells (PBSC) for second ASCT and robust evidence for remobilization after first ASCT is lacking. We report the feasibility, safety, and efficacy of remobilization after bortezomib-doxorubicin-dexamethasone reinduction in MMX and outcomes of second ASCT with these cells. One hundred ten patients underwent ≥1 remobilization with 32 and 4, undergoing second and third attempts, respectively. Toxicities of remobilization were similar to those seen in first-line mobilization. After all attempts, 52% of those with insufficient previously stored PBSC had harvested a sufficient quantity to proceed to second ASCT. Median PBSC doses infused, neutrophil engraftment, and time to discharge after second ASCT were similar regardless of stem cell source, as were the toxicities of second ASCT. No significant differences between PBSC sources were noted in depth of response to ASCT or time to progression. Harvesting after bortezomib-doxorubicin-dexamethasone reinduction for MM at first relapse is safe and feasible and yields a reliable cell product for second ASCT. The study is registered with ClinicalTrials.gov (NCT00747877) and EudraCT (2006-005890-24).

American Society of Blood and Marrow Transplantation, European Society of Blood and Marrow Transplantation, Blood and Marrow Transplant Clinical Trials Network, and International Myeloma Working Group Consensus Conference on Salvage Hematopoietic Cell Transplantation in Patients with Relapsed Multiple Myeloma.

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.

Time to redefine Myeloma.

In November 2014 the International Myeloma Working Group (IMWG) revised the definition of multiple myeloma, such that asymptomatic patients with newly diagnosed multiple myeloma without any of the traditional 'CRAB' (hypercalcaemia, renal impairment, anaemia, bone disease) end organ damage criteria but with one of three new criteria would be recommended to start treatment. Previously, the standard of care for such patients was expectant management. These three new criteria are: greater than 60% clonal plasma cells on bone marrow biopsy, a serum free light chain (sFLC) ratio of >100 (the involved sFLC must be >100 mg/l) and greater than one unequivocal focal lesion on advanced imaging (low dose whole body computerized tomography, magnetic resonance imaging, (18) F fluorodeoxyglucose positron emission tomography). Although this would appear to affect a small number of patients, the impact of these changes are broad, leading to an increased use of advanced imaging, a debate around the management of patients previously diagnosed with smouldering myeloma, changed terminology and clinical trial design and an extension of the use of biomarkers. For the first time the philosophy of treatment in myeloma will change from treatment initiation only being triggered by overt end organ damage to an era where sub clinical risk factors will also be taken into account.

Survival for patients with chronic leukemias in the US and Britain: Age-related disparities and changes in the early 21st century.

BACKGROUND: Chronic lymphocytic leukemia (CLL) and chronic myeloid leukemia (CML) are highly treatable conditions occurring primarily in older patients. Lower survival among older people has been reported in both conditions, but newer treatments may change both the overall survival rate and the relative risk associated with aging. Here, we examine survival for patients with CLL and CML in the United States (US) and England. METHODS: Patients with CLL and CML were identified from the Surveillance, Epidemiology, and End Results (US) and National Cancer Registry (England). Five-year relative survival was calculated by major age group. Excess hazard ratios (EHR) by age were calculated for each condition, and multivariable analysis was performed to adjust for the following potential confounders: gender, race or ethnic group (US only), period of diagnosis, and a measure of socioeconomic deprivation (England only). RESULTS: Five-year relative survival increased for both CLL and CML in both England and the US between 1996-2000 and 2006-2010. However, relative age-related disparities persisted. For CLL, the EHR for death was 9.44 (7.84-11.36) in the US and 6.14 (5.65-6.68) in England for ages 85+ compared to ages 55-64. For CML, the EHR was 3.52 (3.17-3.90) in the US and 4.54 (4.13-4.98) in England for ages 75+ compared to ages 45-64. CONCLUSIONS: Survival improved for patients with chronic leukemias in the early 21st century. However, age-related disparities persist, despite clinical trial evidence that treatment in older adults with chronic leukemia can be safe and effective. Further research to determine the reasons for the lower survival in older patients and greater awareness of this problem may improve survival for older patients with chronic leukemia.

High-dose chemotherapy plus autologous stem-cell transplantation as consolidation therapy in patients with relapsed multiple myeloma after previous autologous stem-cell transplantation (NCRI Myeloma X Relapse [Intensive trial]): a randomised, open-label, phase 3 trial.

BACKGROUND: Relapsed multiple myeloma has no standard treatment, and the role of autologous stem-cell transplantation (ASCT) has not been fully defined. We aimed to compare high-dose melphalan plus salvage ASCT with cyclophosphamide in patients with relapsed multiple myeloma who had previously undergone ASCT. METHODS: This multicentre, randomised, open-label, phase 3 study recruited patients aged at least 18 years with multiple myeloma who needed treatment for first progressive or relapsed disease at least 18 months after a previous ASCT from 51 centres across the UK. Before randomisation, eligible patients received bortezomib, doxorubicin, and dexamethasone (PAD) induction therapy and then underwent peripheral blood stem-cell mobilisation and harvesting if applicable. Eligible patients (with adequate stem-cell harvest) were randomly assigned (1:1), using an automated telephone randomisation line, to either high-dose melphalan 200 mg/m(2) plus salvage ASCT or oral cyclophosphamide (400mg/m(2) per week for 12 weeks). Randomisation was stratified by length of first remission or plateau and response to PAD re-induction therapy. The primary endpoint was time to disease progression, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00747877, and EudraCT, number 2006-005890-24. FINDINGS: Between April 16, 2008, and Nov 19, 2012, 297 patients were registered, of whom 293 received PAD re-induction therapy. Between Aug 26, 2008, and Nov 16, 2012, 174 patients with sufficient PBSCs were randomised to salvage ASCT (n=89) or cyclophosphamide (n=85). After a median follow-up of 31 months (IQR 19-42), median time to progression was significantly longer in the salvage ASCT than in the cyclophosphamide group (19 months [95% CI 16-25] vs 11 months [9-12]; hazard ratio 0·36 [95% CI 0·25-0·53]; p<0·0001). Frequently reported (in >10% of patients) grade 3-4 adverse events with PAD induction, salvage ASCT, and cyclophosphamide were: neutropenia (125 [43%] of 293 patients after PAD, and 63 [76%] of 83 patients in the salvage ASCT group vs 11 [13%] of 84 patients in the cyclophosphamide group), thrombocytopenia (150 [51%] after PAD, and 60 [72%] vs four [5%], respectively), and peripheral neuropathy (35 [12%] after PAD, and none vs none, respectively). INTERPRETATION: This study provides evidence for the improved efficacy of high-dose melphalan plus salvage ASCT when compared with cyclophosphamide in patients with relapsed multiple myeloma eligible for intensive therapy, which might help to guide clinical decisions regarding the management of such patients. FUNDING: Cancer Research UK.

Age disparities in survival from lymphoma and myeloma: a comparison between US and England.

Population-level survival in older patients with lymphoma is significantly lower than in younger patients. In this study, data were obtained from cancer registries in England and the United States (US) for patients diagnosed with Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL) and myeloma. Five-year relative survival was calculated using period analysis. Generalised linear models were used to determine excess hazard ratios (EHR) for older compared to younger patients. Five-year relative survival was lower for older patients diagnosed with HL, NHL and myeloma in both countries. The greatest age-related survival inequality was observed for patients with HL: in 2006-10 the EHR comparing patients aged 75 + years with those aged 15-24 years was 14·02 in the US and 15·69 in England. For NHL, the EHR was 1·91 in the US and 3·81 in England. For myeloma, comparing patients aged 75 + years with those aged 25-44 years, the EHR was 2·79 in the US and 3·60 in England. Survival of patients with lymphoma is lower for older patients in both the US and England but the discrepancy is less in the US. Physicians should be encouraged to evaluate patients' frailty and co-morbidities as well as their age when considering treatment options for patients with lymphoma and myeloma.

Race and outcomes of autologous hematopoietic cell transplantation for multiple myeloma.

Blacks are twice as likely to develop and die from multiple myeloma (MM), and are less likely to receive an autologous hematopoietic-cell transplant (AHCT) for MM compared to Whites. The influence of race on outcomes of AHCT for MM is not well described. We compared the probability of overall survival (OS), progression-free survival (PFS), disease progression, and nonrelapse mortality (NRM) among Black (N=303) and White (N=1892) recipients of AHCT for MM, who were reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) from 1995 to 2005. The Black cohort was more likely to be female, and had better Karnofsky performance scores, but lower hemoglobin and albumin levels at diagnosis. Black recipients were younger and more likely to be transplanted later in their disease course. Disease stage and treatment characteristics prior to AHCT were similar between the 2 groups. Black and White recipients had similar probabilities of 5-year OS (52% versus 47%, P=.19) and PFS (19% versus 21%, P=.64) as well as cumulative incidences of disease progression (72% versus 72%, P=.97) and NRM (9% versus 8%, P=.52). In multivariate analyses, race was not associated with any of these endpoints. Black recipients of AHCT for MM have similar outcomes compared to Whites, suggesting that the reasons underlying lower rates of AHCT in Blacks need to be studied further to ensure equal access to effective therapy.