Kwee Yong

Guidelines for the diagnosis and management of multiple myeloma 2011.

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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

BACKGROUNDnRelapsed 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.nnnMETHODSnThis 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.nnnFINDINGSnBetween 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).nnnINTERPRETATIONnThis 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.nnnFUNDINGnCancer Research UK.

Cord blood progenitor cells have greater transendothelial migratory activity and increased responses to SDF‐1 and MIP‐3β compared with mobilized adult progenitor cells

When cord blood is used as a source of haemopoietic stem cells for transplantation, fewer cells are required per kg of recipient. This greater engraftment efficiency of cord blood cells may relate to an increased ability to traverse sinusoidal endothelium, a crucial step in the homing of stem cells. We report that freshly isolated cord blood progenitors migrated more efficiently than mobilized adult cells. Cord blood progenitors responded rapidly to growth factor stimulation with an increase in migratory ability within 24u2003h whereas mobilized adult cells responded only after 72u2003h (Pu2003<u20030.01). Cord blood cells also exited G0/G1 rapidly; after 24u2003h of growth factor exposure, 20.2u2003±u20031.2% of cord blood CD34+ cells were in Su2003+u2003G2/M compared to 6.9u2003±u20031.2% of adult CD34+ cells (Pu2003<u20030.01). Proliferating CFC migrated more efficiently (13.3u2003±u20033.4% for GM‐CFC) than non‐proliferating CFC (1.4u2003±u20030.5%, Pu2003<u20030.01) as determined using a 3H‐thymidine suicide assay. Cord blood progenitor cells also demonstrated a greater transmigratory response to chemokine stimulation compared with adult cells; this was manifested as a differential response of freshly isolated cells to SDF‐1, and of growth factor activated cells to MIP‐3β. Finally, cord blood CD34+ cells express higher levels of the chemokine receptor for SDF‐1, CXCR4, when compared with mobilized adult CD34+ cells (Pu2003<u20030.05).

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

BACKGROUNDnThe 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.nnnMETHODSnBSBMT/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.nnnFINDINGSnBetween 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).nnnINTERPRETATIONnSalvage 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.nnnFUNDINGnCancer Research UK, Janssen-Cilag, and Chugai Pharma UK.

Weekly intravenous bortezomib is effective and well tolerated in relapsed/refractory myeloma.

Bortezomib is an effective antimyeloma therapy, but clinical benefits can be limited by neurotoxicity. In newly diagnosed, older patients, modification of the biweekly dosing schedule to weekly regimens improves tolerability whilst maintaining efficacy. There is less information on the efficacy and tolerability of weekly bortezomib regimens in the relapsed/refractory setting. Here, we report our experience of weekly intravenous bortezomib in clinical practice in relapsed/refractory patients.

United Kingdom Myeloma Forum (UKMF) position statement on the use of bendamustine in myeloma.

Bendamustine is a unique bifunctional alkylating agent with promising activity in myeloma. Despite the increasing number of studies demonstrating its efficacy in both the upfront and relapse settings, including patients with renal insufficiency, the optimal use of bendamustine, in terms of dosage, schedule and combination with other agents, has yet to be defined. It is currently licensed for use as frontline treatment with prednisolone for patients with myeloma who are unsuitable for transplantation and who are contraindicated for thalidomide and bortezomib. Studies in relapsed/refractory patients are currently ongoing with other combinations. Given the increasing data to date, the UK Myeloma Forum believes that bendamustine with steroids alone or in combination with a novel agent could be considered for patients with multiply relapsed myeloma. This document provides guidance for the use of bendamustine for patients with myeloma until the results of definitive studies are available.

Whole-body MRI quantitative biomarkers are associated significantly with treatment response in patients with newly diagnosed symptomatic multiple myeloma following bortezomib induction

AbstractObjectivesTo evaluate whole-body MRI (WB-MRI) parameters significantly associated with treatment response in multiple myeloma (MM).MethodsTwenty-one MM patients underwent WB-MRI at diagnosis and after two cycles of chemotherapy. Scans acquired at 3.0xa0T included T2, diffusion-weighted-imaging (DWI) and mDixon pre- and post-contrast. Twenty focal lesions (FLs) matched on DWI and post-contrast mDixon were selected for each time point. Estimated tumour volume (eTV), apparent diffusion coefficient (ADC), enhancement ratio (ER) and signal fat fraction (sFF) were derived. Clinical treatment response to chemotherapy was assessed using conventional criteria. Significance of temporal parameter change was assessed by the paired t test and receiver operating characteristics/area under the curve (AUC) analysis was performed. Parameter repeatability was assessed by interclass correlation (ICC) and Bland–Altman analysis of 10 healthy volunteers scanned at two time points.ResultsFifteen of 21 patients responded to treatment. Of 254 FLs analysed, sFF (pu2009<u20090.0001) and ADC (pu2009=u20090.001) significantly increased in responders but not non-responders. eTV significantly decreased in 19/21 cases. Focal lesion sFF was the best discriminator of treatment response (AUC 1.0). Bone sFF repeatability was excellent (ICC 0.98) and better than bone ADC (ICC 0.47).ConclusionWB-MRI derived focal lesion sFF shows promise as an imaging biomarker of treatment response in newly diagnosed MM.Key Points• Bone signal fat fraction using mDixon is a robust quantifiable parametern • Fat fraction and ADC significantly increase in myeloma lesions responding to treatmentn • Bone lesion fat fraction is the best discriminator of myeloma treatment response

Myeloma presenting during pregnancy

Multiple myeloma predominantly affects the elderly with only 2% of cases presenting under the age of 40 years [1]. Therefore, myeloma presenting in pregnancy is rare with just 16 cases reported [1–4], of which only four received anti-myeloma therapy during pregnancy [1–3]. Because of the rarity of this condition, there are no published recommendations for management, nor is it known if pregnancy has any prognostic relevance. We describe three cases of myeloma presenting in pregnancy. One has previously been reported [5] and we are updating the outcome. In doing so, we suggest a practical approach to treating myeloma presenting during pregnancy that optimizes outcomes for both the mother and baby.

Patient perceptions of second transplants in myeloma: impact on recruitment in the British Society of Blood and Marrow Transplantation/UK Myeloma Forum Myeloma X Relapse (Intensive) Trial

Xu Huang Deepti P. Wilks Shayne Atkinson Tim C. P. Somervaille Cancer Research UK Leukaemia Biology Laboratory, Paterson Institute for Cancer Research, The University of Manchester, Manchester Cancer Research Centre Biobank, Paterson Institute for Cancer Research, The University of Manchester, and Cytogenetics Laboratory, The Christie NHS Foundation Trust, Manchester, UK E-mail: tsomervaille@picr.man.ac.uk

The start of a new wave: Developments in proteasome inhibition in multiple myeloma

Multiple myeloma (MM) accounts for 10% of hematological cancers. Stem cell transplantation remains the cornerstone of first‐line treatment for eligible patients, but historically, pharmaceutical treatment options for MM have been limited. The proteasome was identified as a target for MM therapy in the early 2000s and, in 2004, the boronic acid proteasome inhibitor bortezomib gained European approval. Bortezomib now plays a major role in MM treatment, but the duration of its use can be limited by toxicities such as peripheral neuropathy and the development of resistance. A new generation of proteasome inhibitors has since entered the treatment landscape: carfilzomib, an epoxyketone‐based agent with a distinct mode of action, high clinical efficacy, and lower levels of peripheral neuropathy compared with bortezomib, received approval in 2015 for use in patients with relapsed and/or refractory MM (RRMM). Ixazomib, a second‐generation, orally administered, boronic acid proteasome inhibitor, has also been approved for use in patients with RRMM. In just over a decade, proteasome inhibitor‐based regimens have become an integral component of MM treatment; with more proteasome inhibitors in development, this remains a vibrant research area with potential to improve the lives of patients with MM in the years to come.