As compared with MPT, continuous lenalidomide-dexamethasone given until disease progression was associated with a significant improvement in progression-free survival, with an overall survival benefit at the interim analysis, among patients with newly diagnosed multiple myeloma who were ineligible for stem-cell transplantation. (Funded by Intergroupe, Francophone du Myélome and Celgene; FIRST ClinicalTrials.gov number, NCT00689936; European Union Drug Regulating Authorities Clinical Trials number, 2007-004823-39.).

Key Points Rd continuous significantly extended OS compared with MPT and resulted in comparable OS to that with Rd18 in patients with multiple myeloma. Patients achieving complete or very good partial response with Rd benefited greatly from continuous vs fixed treatment in terms of PFS.

Autologous haematopoietic SCT with PBSCs is regularly used to restore BM function in patients with multiple myeloma or lymphoma after myeloablative chemotherapy. Twenty-eight experts from the European Group for Blood and Marrow Transplantation developed a position statement on the best approaches to mobilising PBSCs and on possibilities of optimising graft yields in patients who mobilise poorly. Choosing the appropriate mobilisation regimen, based on patients' disease stage and condition, and optimising the apheresis protocol can improve mobilisation outcomes. Several factors may influence mobilisation outcomes, including older age, a more advanced disease stage, the type of prior chemotherapy (e.g., fludarabine or melphalan), prior irradiation or a higher number of prior treatment lines. The most robust predictive factor for poor PBSC collection is the CD34(+) cell count in PB before apheresis. Determination of the CD34(+) cell count in PB before apheresis helps to identify patients at risk of poor PBSC collection and allows pre-emptive intervention to rescue mobilisation in these patients. Such a proactive approach might help to overcome deficiencies in stem cell mobilisation and offers a rationale for the use of novel mobilisation agents.

Several solution properties of complexes formed between the trivalent lanthanide ions (LnIII) and the macrocyclic ligand DOTP8-, including stability constants, protonation equilibria, and interactions of the LnDOTP5- complexes with alkali metal ions, have been examined by spectrophotometry, potentiometry, osmometry, and 1H, 31P, and 23Na NMR spectroscopy. Spectrophotometric competition experiments between DOTP and arsenazo III for complexation with the LnIII ions at pH 4 indicate that the thermodynamic stability constants (log K ML) of LnDOTP5- range from 27.6 to 29.6 from LaIII to LuIII. The value for LaDOTP5- obtained by colorimetry (27.6) was supported by a competition experiment between DOTP and EDTA monitored by 1H NMR (27.1) and by a potentiometric competition titration between DTPA and DOTP (27.4). Potentiometric titrations of several LnDOTP5- complexes indicated that four protonation steps occur between pH 10 and 2; the protonation constants determined by potentiometry were consistent with 31P shift titrations of the LnDOTP5- complexes. Dissection of the 31P shifts of the heavy LnDOTP5- complexes (Tb → Tm) into contact and pseudocontact contributions showed that the latter dominated at all pH values. The smaller 31P shifts observed at lower pH for TmDOTP5- were partially due to relaxation of the chelate structure which occurred upon protonation. The 31P shifts of other LnDOTP5- complexes (Ln = Pr, Nd, Eu) showed a different pH-dependent behavior, with a change in chemical shift direction occurring after two protonation steps. This behavior was traced to a pH-dependent alteration of the contact shift at the phosphorus nuclei as these complexes were protonated. 23Na NMR studies of the interactions of TmDOTP5- with alkali and ammonium cations showed that Et4N+ and Me4N+ did not compete effectively with Na+ for the binding sites on TmDOTP5-, while K+ and NH4 + competed more effectively and Cs+ and Li+ less effectively. A 23Na shift of more than 400 ppm was observed at low Na+/TmDOTP5- ratios and high pH, indicating that Na+ was bound near the 4-fold symmetry axis of TmDOTP5- under these conditions. Osmolality measurements of chelate samples containing various amounts of Na+ indicated that at high Na+/TmDOTP5- ratios at least three Na+ ions were bound to TmDOTP5-. These ions showed a significantly smaller 23Na-bound shift, indicating they must bind to the chelate at sites further away from the 4-fold symmetry axis. Fully bound 23Na shifts and relaxation rate enhancements and binding constants for all Na x H y TmDOTP species were obtained by fitting the observed 23Na shift and relaxation data and the osmometric data, using a spreadsheet approach. This model successfully explained the 23Na shift and osmolality observed for the commercial reagent Na4HTmDOTP·3NaOAc (at 80 mM at pH 7.4).

Smoldering multiple myeloma (SMM) is an asymptomatic precursor state of multiple myeloma (MM). Recently, MM was redefined to include biomarkers predicting a high risk of progression from SMM, thus necessitating a redefinition of SMM and its risk stratification. We assembled a large cohort of SMM patients meeting the revised IMWG criteria to develop a new risk stratification system. We included 1996 patients, and using stepwise selection and multivariable analysis, we identified three independent factors predicting progression risk at 2 years: serum M-protein >2 g/dL (HR: 2.1), involved to uninvolved free light-chain ratio >20 (HR: 2.7), and marrow plasma cell infiltration >20% (HR: 2.4). This translates into 3 categories with increasing 2-year progression risk: 6% for low risk (38%; no risk factors, HR: 1); 18% for intermediate risk (33%; 1 factor; HR: 3.0), and 44% for high risk (29%; 2–3 factors). Addition of cytogenetic abnormalities (t(4;14), t(14;16), +1q, and/or del13q) allowed separation into 4 groups (low risk with 0, low intermediate risk with 1, intermediate risk with 2, and high risk with ≥3 risk factors) with 6, 23, 46, and 63% risk of progression in 2 years, respectively. The 2/20/20 risk stratification model can be easily implemented to identify high-risk SMM for clinical research and routine practice and will be widely applicable.

The effectiveness of the novel hematopoietic stem cell mobilizing agent plerixafor was evaluated in nationwide compassionate use programs in 13 European countries. A total of 580 poor mobilizers with non-Hodgkin's lymphoma (NHL), Hodgkin's lymphoma (HL) and multiple myeloma (MM) were enrolled. All patients received plerixafor plus granulocyte CSF with or without chemotherapy. Overall, the collection yield was significantly higher in MM patients (42.0 Â 10 6 CD34 þ cells/kg: 81.6%; 45.0 Â 10 6 CD34 þ cells/kg: 32.0%) than in NHL patients (42.0 Â 10 6 CD34 þ cells/kg: 64.8%; 45.0 Â 10 6 CD34 þ cells/kg: 12.6%; Po0.0001) and also significantly higher in HL patients (42.0 Â 10 6 CD34 þ cells/kg: 81.5%; 45.0 Â 10 6 CD34 þ cells/kg: 22.2%) than in NHL patients (P ¼ 0.013). In a subgroup analysis, there were no significant differences in mobilization success comparing patients with diffuse large B-cell lymphoma, follicular lymphoma and mantle cell lymphoma. Our data emphasize the role of plerixafor in poor mobilizers, but further strategies to improve the apheresis yield especially in patients with NHL are required.

The introduction of new agents and management strategies over the past decade has resulted in a major step change in treatment outcomes with deepening responses and increased survival for patients with multiple myeloma. In daily clinical practice, healthcare professionals are now faced with challenges including, optimal treatment sequencing and changing treatment goals. In light of this, a group of experts met to discuss diagnostic and treatment guidelines, examine current clinical practice, and consider how new clinical trial data may be integrated into the management of multiple myeloma in the future.

A systematic literature review and network meta-analysis of treatments for patients with untreated multiple myeloma not eligible for stem cell transplantation, Leukemia & Lymphoma, 58:1, 153-161, DOI: 10.1080/10428194.2016 In newly diagnosed multiple myeloma (MM), patients ineligible for front-line autologous stem cell transplantation (ASCT), melphalan and prednisone (MP) with thalidomide (MPT) or bortezomib (VMP) are standard first-line therapeutic options. Despite new treatment regimens incorporating bortezomib or lenalidomide, MM remains incurable. The FIRST study demonstrated significant improvement in progression-free survival (PFS) and overall survival (OS) for the combination of lenalidomide and low-dose dexamethasone (Rd) until progression vs. MPT in transplant-ineligible ndMM patients. However, to date no head-to-head randomized controlled trials (RCTs) have compared Rd or MPT versus VMP. We conducted a network meta-analysis using RCTs identified through a systematic literature review to evaluate the relative efficacy of Rd versus other regimens on survival endpoints in previously untreated MM patients ineligible for ASCT. In this analysis, Rd was associated with a significant PFS and survival advantage versus other first-line treatments (VMP, MPT, MP), challenging the role of alkylators in this setting. ARTICLE HISTORY