In patients with multiple myeloma (MM), risk stratification by chromosomal abnormalities may enable a more rational selection of therapeutic approaches. In the present study, we analyzed the prognostic value of 12 chromosomal abnormalities in a series of 354 MM patients treated within the HOVON-65/GMMG-HD4 trial. Because of the 2-arm design of the study, we were able to analyze the effect of a bortezomib-based treatment before and after autologous stem cell transplantation (arm B) compared with standard treatment without bortezomib (arm A). For all analyzed chromosomal aberrations, progression-free survival (PFS) and overall survival (OS) were at least equal or superior in the bortezomib arm compared with the standard arm. Strikingly, patients with del(17p13) benefited the most from the bortezomib-containing treatment: the median PFS in arm A was 12.0 months and in arm B it was 26.2 months (P ‫؍‬ .024); the 3 year-OS for arm A was 17% and for arm B it was 69% (P ‫؍‬ .028). After multivariate analysis, del(17p13) was an independent predictor for PFS (P < .0001) and OS (P < .0001) in arm A, whereas no statistically significant effect on PFS (P ‫؍‬ .28) or OS (P ‫؍‬ .12) was seen in arm B. In conclusion, the adverse impact of del (17p13)

We recommend use of wb-MRI for risk stratification of patients with asymptomatic multiple myeloma.

Home page: www.blodet.dkThe European Myeloma Network has organized two workshops on fluorescence in situ hybridization in multiple myeloma. The first aimed to identify specific indications and consensus technical approaches of current practice. A second workshop followed a quality control exercise in which 21 laboratories analyzed diagnostic cases of purified plasma cells for recurrent abnormalities. The summary report was discussed at the EHA Myeloma Scientific Working Group Meeting 2010. During the quality control exercise, there was acceptable agreement on more than 1,000 tests. The conclusions from the exercise were that the primary clinical applications for FISH analysis were for newly diagnosed cases of MM or frank relapse cases. A range of technical recommendations included: 1) material should be part of the first draw of the aspirate; 2) samples should be sent at suitable times to allow for the lengthy processing procedure; 3) most importantly, PCs must be purified or specifically identified; 4) positive cut-off levels should be relatively conservative: 10% for fusion or breakapart probes, 20% for numerical abnormalities; 5) informative probes should be combined to best effect; 6) in specialist laboratories, a single experienced analyst is considered adequate; 7) at least 100 PC should be scored; 8) essential abnormalities to test for are t(4;14), t(14;16) and 17p13 deletions; 9) suitable commercial probes should be available for clinically relevant abnormalities; 10) the clinical report should be expressed clearly and must state the percentage of PC involved and the method used for identification; 11) a retrospective European based FISH data bank linked to clinical data should be generated; and 12) prospective analysis should be centralized for upcoming trials based on the recommendations made. The European Myeloma Network aims to build on these recommendations to establish standards for a common European data base to define subgroups with prognostic significance.Key words: myeloma, cytogenetic, interphase FISH, recommendation.Citation: Ross FM, Avet-Loiseau H, Ameye G, Gutiérrez NC, Liebisch P, O´Connor S, Dalva K, Fabris S, Testi AM, Jarosova M, Hodkinson C, Collin A, Kerndrup G, Kuglik P, Ladon D, Bernasconi P, Maes B, Zemanova Z, Michalova K, Michau L, Neben K, Hermansen NEU, Rack K, Rocci A, Protheroe R, Chiecchio L, Poirel HA, Sonneveld P, Nyegaard M, and myeloma and related disorders. Haematologica 2012;97(8):1272-1277. doi:10.3324/haematol.2011 This is an open-access paper. ABSTRACT© F e r r a t a S t o r t i F o u n d a t i o n

BackgroundProliferation of malignant plasma cells is a strong adverse prognostic factor in multiple myeloma and simultaneously targetable by available (e.g. tubulin polymerase inhibitors) and upcoming (e.g. aurora kinase inhibitors) compounds. Design and MethodsWe assessed proliferation using gene expression-based indices in 757 samples including independent cohorts of 298 and 345 samples of CD138-purified myeloma cells from previously untreated patients undergoing high-dose chemotherapy, together with clinical prognostic factors, chromosomal aberrations, and gene expression-based high-risk scores. ResultsIn the two cohorts, 43.3% and 39.4% of the myeloma cell samples showed a proliferation index above the median plus three standard deviations of normal bone marrow plasma cells. Malignant plasma cells of patients in advanced stages or those harboring disease progressionassociated gain of 1q21 or deletion of 13q14.3 showed significantly higher proliferation indices; patients with gain of chromosome 9, 15 or 19 (hyperdiploid samples) had significantly lower proliferation indices. Proliferation correlated with the presence of chromosomal aberrations in metaphase cytogenetics. It was significantly predictive for event-free and overall survival in both cohorts, allowed highly predictive risk stratification (e.g. event-free survival 12.7 versus 26.2 versus 40.6 months, P<0.001) of patients, and was largely independent of clinical prognostic factors, e.g. serum β2-microglobulin, International Staging System stage, associated high-risk chromosomal aberrations, e.g. translocation t(4;14), and gene expression-based high-risk scores. ConclusionsProliferation assessed by gene expression profiling, being independent of serum-β2-microglobulin, International Staging System stage, t(4;14), and gene expression-based risk scores, is a central prognostic factor in multiple myeloma. Surrogating a biological targetable variable, gene expression-based assessment of proliferation allows selection of patients for riskadapted anti-proliferative treatment on the background of conventional and gene expressionbased risk factors.

We identified CDK6 as a novel molecular marker that can be determined by immunohistochemistry on routinely processed tissue specimens and may facilitate the prognostic assessment of medulloblastoma patients. Furthermore, increased protein-levels of PPM1D and CDK6 may link the TP53 and RB1 tumor suppressor pathways to medulloblastoma pathomechanisms.

To identify variants for multiple myeloma risk, we conducted a genome-wide association study with validation in additional series totaling 4,692 cases and 10,990 controls. We identified four risk loci at 3q26.2 (rs10936599, P=8.70x10-14), 6p21.33 (rs2285803, PSORS1C2; P= 9.67x10-11), 17p11.2 (rs4273077, TNFRSF13B; P=7.67x10-9) and 22q13.1 (rs877529, CBX7; P=7.63x10-16). These data provide further evidence for genetic susceptibility to this B-cell hematological malignancy and insight into the biological basis of predisposition.

In multiple myeloma, there has been little progress in the specifi c therapeutic targeting of oncogenic mutations. Whole-genome sequencing data have recently revealed that a subset of patients carry an activating mutation (V600E) in the BRAF kinase. To uncover the clinical relevance of this mutation in multiple myeloma, we correlated the mutation status in primary tumor samples from 379 patients with myeloma with disease outcome. We found a signifi cantly higher incidence of extramedullary disease and a shorter overall survival in mutation carriers when compared with controls. Most importantly, we report on a patient with confi rmed BRAF V600E mutation and relapsed myeloma with extensive extramedullary disease, refractory to all approved therapeutic options, who has rapidly and durably responded to low doses of the mutation-specifi c BRAF inhibitor vermurafenib. Collectively, we provide evidence for the development of the BRAF V600E mutation in the context of clonal evolution and describe the prognostic and therapeutic relevance of this targetable mutation.SIGNIFICANCE: This is the fi rst evidence of the clinical and therapeutic relevance of BRAF V600E mutations in multiple myeloma, proving the principle of specifi c inhibition of driver mutations in this disease. Cancer Discov; 3(8);

As more efficient agents for stem cell mobilization are being developed, there is an urgent need to define which patient population might benefit from these novel drugs. For a precise and prospective definition of "poor mobilization" (PM), we have analyzed the efficiency of mobilization in patients intended to receive autologous transplantation at our center in the past 6 years. Between January 2003, and December 2008, 840 patients with the following diagnoses were scheduled to undergo leukapheresis: multiple myeloma (MM, n = 602) and non-Hodgkin lymphoma (NHL, n= 238). Most patients mobilized readily: close to 85% of the patients had a level of 20/microL to >500/microL of CD34(+) cells at the peak of stimulation. Of the 840 patients, 129 (15.3%) were considered to be PMs, defined as patients who had a peak concentration of <20/microL of CD34(+) cells upon stimulation with granulocyte-colony stimulating factor (G-CSF) subsequent to induction chemotherapy appropriate for the respective disease. Among them, 38 (4.5%) patients had CD34(+) levels between 11 and 19/microL at maximum stimulation, defined as "borderline" PM, 49 (5.8%) patients had CD34(+) levels between 6 and 10/microL, defined as "relative" PM, and 42 patients (5%) with levels of <5/microL, defined as "absolute" PM. There was no difference in the incidence of PM between patients with MM versus those with NHL. Sex, age, body weight (b.w.) and previous irradiation therapy did not make any significant difference. Only the total number of cycles of previous chemotherapy (P = .0034), and previous treatment with melphalan (Mel; P = .0078) had a significant impact on the ability to mobilize. For the good mobilizers, the median time to recovery of the white blood cells (WBCs) to 1.0/nL or more was 13 days with a range of 7 to 22 days, whereas for the PM group it was 14 days with a range of 8 to 37 days. This difference was statistically not significant. The median time to recovery of the platelets counts to an unmaintained level of >20/nL was 11 days with a range of 6 to 17 days for the good mobilizers, whereas for the PM it was 11 days with a range of 7 to 32 days. Again, this difference was not significant. The majority of the patients today intended for autologous transplantations were able to mobilize readily. As long as > or =2.0 x 10(6) of CD34(+) cells/kg b.w. have been collected, PM was not associated with inferior engraftment.