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Genome-wide association studies (GWAS) have transformed our understanding of susceptibility to multiple myeloma (MM), but much of the heritability remains unexplained. We report a new GWAS, a meta-analysis with previous GWAS and a replication series, totalling 9974 MM cases and 247,556 controls of European ancestry. Collectively, these data provide evidence for six new MM risk loci, bringing the total number to 23. Integration of information from gene expression, epigenetic profiling and in situ Hi-C data for the 23 risk loci implicate disruption of developmental transcriptional regulators as a basis of MM susceptibility, compatible with altered B-cell differentiation as a key mechanism. Dysregulation of autophagy/apoptosis and cell cycle signalling feature as recurrently perturbed pathways. Our findings provide further insight into the biological basis of MM.

Until recently, only retrospective studies had been published on salvage high-dose melphalan (HDM) with autologous stem cell 'transplantation' (ASCT). In a prospective, nonrandomized phase-2 study, we treated 53 bortezomib-naïve patients with bortezomib-dexamethasone as induction and bortezomib included in the conditioning regimen along with the HDM. Median progression-free survival (PFS), time to next treatment (TNT) and overall survival (OS) after start of reinduction therapy were 21.6, 22.8 and 46.6 months, respectively. For 49 patients who completed salvage bortezomib-HDM(II) with ASCT, there was no significant difference of PFS and TNT after HDM (II) compared with after the initial HDM(I), and thus patients were their own controls (PFS (I: 20.1 vs II: 19.3 months (P=0.8)) or TNT (I: 24.4 vs II: 20.7 months (P=0.8)). No significant differences in the response rates after salvage ASCT compared with the initial ASCT. Bortezomib-HDM conditioning combo was feasible, and toxicity was as expected for patients treated with bortezomib and ASCT. In conclusion, in bortezomib-naïve patients treated at first relapse with salvage ASCT including bortezomib, PSF and TNT did not differ significantly from initial ASCT and median OS was almost 5.5 years with acceptable toxicity. A recent prospective randomized study confirms salvage ASCT to be an effective treatment.Bone Marrow Transplantation advance online publication, 29 June 2015; doi:10.1038/bmt.2015.125.

PMCID: PMC4112539.-- International Myeloma Working Group: et al., Plasma cell leukemia (PCL) is a rare and aggressive variant of myeloma characterized by the presence of circulating plasma cells. It is classified as either primary PCL occurring at diagnosis or as secondary PCL in patients with relapsed/refractory myeloma. Primary PCL is a distinct clinic-pathological entity with different cytogenetic and molecular findings. The clinical course is aggressive with short remissions and survival duration. The diagnosis is based upon the percentage (≥20%) and absolute number (≥2 × 10 9/l) of plasma cells in the peripheral blood. It is proposed that the thresholds for diagnosis be re-examined and consensus recommendations are made for diagnosis, as well as, response and progression criteria. Induction therapy needs to begin promptly and have high clinical activity leading to rapid disease control in an effort to minimize the risk of early death. Intensive chemotherapy regimens and bortezomib-based regimens are recommended followed by high-dose therapy with autologous stem cell transplantation if feasible. Allogeneic transplantation can be considered in younger patients. Prospective multicenter studies are required to provide revised definitions and better understanding of the pathogenesis of PCL., This work has been supported in part by “Josep Font” Grant from Hospital Clínic de Barcelona and RD06/0020/0005 from Instituto de Salud Carlos III, Spain.

During the last few years, several new drugs have been introduced for treatment of patients with multiple myeloma, which have significantly improved treatment outcome. All of these novel substances differ at least in part in their mode of action from similar drugs of the same drug class, or are representatives of new drugs classes, and as such present with very specific side effect profiles. In this review, we summarize these adverse events, provide information on their prevention, and give practical guidance for monitoring of patients and for management of adverse events.Leukemia accepted article preview online, 18 December 2017. doi:10.1038/leu.2017.353.

Background: We recently reported the results of the phase III randomized HOVON87/NMSG18 study showing comparable efficacy of treatment with melphalan, prednisolone and thalidomide following by thalidomide maintenance (MPT-T) versus melphalan, prednisolone and lenalidomide followed by lenalidomide maintenance (MPR-R) (Zweegman S et al. Blood 2016;127(9):1109- 1116). As not only efficacy but also potential toxicity affecting quality of life (QoL) guides the choice of treatment, health-related (HR) QoL is important. Aims: To evaluate the HRQoL results of the HOVON87/NMSG18 study. Methods: Two validated HRQoL instruments (EORTC QLQ-C30 and MY20) were obtained at baseline, after 3 and 9 induction cycles (3ID and 9ID) and after 6 and 12 months of maintenance therapy (6MT and 12MT). The subscales global QoL, physical functioning, pain, fatigue, constipation, diarrhea, nausea/vomiting, insomnia, disease symptoms, side effects of treatment and neuropathy were analysed. Change in HRQoL score over time between treatment arms was assessed by linear mixed models. Independent sample t-tests were used to determine changes from baseline. Minimal important difference (MID) within arms was defined as a difference in score of >=1 standard error of measurement (SEM) or, if a subscale consisted of one parameter only, MIDlevels described in previous literature were used. To determine clinically relevant superiority of one arm, a difference in score of >=5 was used and in addition significance level was calculated. Results: From 553 (90.2%) of the 613 patients who participated in the HRQoL part of the study a baseline questionnaire was available. Forty (15%) of patients randomized to MPT-T versus 68 (24%) of patients randomized to MPR-R completed therapy until 12 months of maintenance therapy. Change in HRQoL between arms over time: in MPT-T improvement of HRQoL over time as compared to MPR-R was found for the subscales diarrhea and insomnia. In contrast, MPR-R showed improvement over time for the subscales pain, constipation, side effects of treatment and neuropathy, as compared to MPT-T. Change in HRQoL per arm: In MPT-T MID was reached for the following subscales; global QoL increased after 9ID until 12MT (MID range 7-13), pain decreased at every time point (MID range -21 to -23), disease symptoms deceased after 9ID (MID -12), fatigue decreased during MT (MID 12) and insomnia decreased at each time point (MID range -11 to -21). In MPR-R the MID was reached for the following subscales; global QoL increased after 9ID until 12MT (MID range 8-14), physical functioning increased at 12MT (MID 13), pain decreased at every time point (MID range -14 to -26) and insomnia decreased at 6MT (MID -10). Difference between MPT-T and MPR-R: In the MPT-T arm significantly (p=5 points) less pain and disease symptoms at 3ID, less fatigue at 3ID and 9ID, less diarrhea and less insomnia at all time points were observed. In contrast, patients on MPRR reported better global QoL, better physical functioning and less pain at 12MT, in general less side effects of treatment, and less constipation and neuropathy separately, at all time points than patients treated with MPT-T. (Table Presented) Summary/Conclusions: Both treatment with MPT-T and MPR-R controlled pain and resulted in an improvement in global QoL as compared to baseline after 9ID and during maintenance. Treatment with thalidomide initially resulted in less pain and disease symptoms. At all treatment stages thalidomide caused less diarrhea, fatigue and insomnia as compared to treatment with lenalidomide. In contrast, therapy with lenalidomide resulted in less side effects of treatment, less constipation and less neuropathy as compared to thalidomide at all stages of treatment. In addition, long term maintenance therapy with lenalidomide resulted in better global QoL, better physical functioning and less pain.

High-dose melphalan and autologous stem cell transplantation (HDM/ASCT) is widely used in immunoglobulin light chain (AL) amyloidosis, but the benefit is debated mainly because of the high treatment-related mortality (24% in a randomised study comparing HDM/ASCT with oral melphalan/dexamethasone). We report here on the long-term outcome of all patients treated with HDM/ASCT for AL amyloidosis in Sweden between 1994 and 2009. Seventy-two patients were treated at eight Swedish centres. Median follow-up was 67.5 months. At least partial response (organ or haematological) was seen in 64% of the patients. Median overall survival was 98 months or 8.2 years, with 5-year survival 63.9% and 10-year survival 43.4%. In patients with cardiac involvement or multiple organ involvement, survival was significantly shorter, median overall survival 49 and 56 months, respectively. All mortality within 100 days from ASCT was 12.5% for all patients and 17.2% in the patients with cardiac involvement. For patients treated in the earlier time period (1994-2001), 100-day mortality was 23.8% compared with 7.8% in the later period (2002-2009). In conclusion, long survival times can be achieved in patients with AL amyloidosis treated with HDM/ASCT, also in smaller centres. Early mortality is high, but with a decreasing trend over time.

The prognosis for patients multiple myeloma (MM) has improved substantially over the past decade with the development of new, more effective chemotherapeutic agents and regimens that possess a high level of anti-tumor activity. In spite of this important progress, however, nearly all MM patients ultimately relapse, even those who experience a complete response to initial therapy. Management of relapsed MM thus represents a vital aspect of the overall care for patients with MM and a critical area of ongoing scientific and clinical research. This comprehensive manuscript from the International Myeloma Working Group provides detailed recommendations on management of relapsed disease, with sections dedicated to diagnostic evaluation, determinants of therapy, and general approach to patients with specific disease characteristics. In addition, the manuscript provides a summary of evidence from clinical trials that have significantly impacted the field, including those evaluating conventional dose therapies, as well as both autologous and allogeneic stem cell transplantation. Specific recommendations are offered for management of first and second relapse, relapsed and refractory disease, and both autologous and allogeneic transplant. Finally, perspective is provided regarding new agents and promising directions in management of relapsed MM.Leukemia accepted article preview online, 29 December 2015. doi:10.1038/leu.2015.356.

An expert panel convened to reach a consensus regarding the optimal use of lenalidomide in combination with dexamethasone (Len/Dex) in patients with relapsed or refractory multiple myeloma (RRMM). On the basis of the available evidence, the panel agreed that Len/Dex is a valid and effective treatment option for most patients with RRMM. As with other therapies, using Len/Dex at first relapse is more effective regarding response rate and durability than using it after multiple salvage therapies. Len/Dex may be beneficial regardless of patient age, disease stage and renal function, although the starting dose of lenalidomide should be adjusted for renal impairment and cytopenias. Long-term treatment until there is evidence of disease progression may be recommended at the best-tolerated doses of both lenalidomide and dexamethasone. Recommendations regarding the prevention and management of adverse events, particularly venous thromboembolism and myelosuppression, were provided on the basis of the available evidence and practical experience of panel members. Ongoing trials will provide more insight into the effects of continuous lenalidomide-based therapy in myeloma. © 2011 Macmillan Publishers Limited All rights reserved.