Purpose The clinical outcome of multiple myeloma (MM) is heterogeneous. A simple and reliable tool is needed to stratify MM patients. We combined the International Staging System (ISS) with chromosomal abnormalities (CA) detected by interphase Fluorescence In Situ Hybridization (iFISH) after CD138 plasma cells purification and serum lactate dehydrogenase (LDH) to evaluate their prognostic value in newly diagnosed MM (NDMM). Methods Clinical and laboratory data from 4445 NDMM patients enrolled in eleven international trials were pooled together. The K-adaptive partitioning algorithm was used to define the most appropriate subgroups with homogeneous survival. Results ISS, CA, and LDH data were simultaneously available in 3060/4445 patients. We defined three groups: revised ISS (R-ISS) I (N=871), including ISS I (serum β2-microglobulin level <3.5mg/L and serum albumin level ≥3.5g/dL), no high-risk CA [del(17p) and/or t(4;14) and/or t(14;16)] and normal LDH level (below the upper limit of normal range); R-ISS III (N=295), including ISS III (serum β2-microglobulin level >5.5mg/L) and high-risk CA or high LDH level; R-ISS II (N=1894), including all the other possible combinations. At a median follow-up of 46 months, the 5-year OS was 82% in the R-ISS I, 62% in the R-ISS II, and 40% in the R-ISS III groups; the 5-year PFS was 55%, 36% and 24%, respectively. Conclusions The R-ISS is a simple and powerful prognostic staging system and we recommend its use in future clinical studies to stratify NDMM patients effectively with respect to the relative risk to their survival.

In this study, we compared immunoglobulin heavy-chain-gene-based minimal residual disease (MRD) detection by real-time quantitative PCR (RQ-PCR) and next-generation sequencing (NGS) to assess whether NGS could overcome some limitations of RQ-PCR and further increase sensitivity, specificity, accuracy and reproducibility. In total, 378 samples from 55 patients with acute lymphoblastic leukemia (ALL), mantle cell lymphoma (MCL) or multiple myeloma (MM) were investigated for clonotype identification, clonotype identity and comparability of MRD results. Forty-five clonotypes were identified by RQ-PCR and 49 by NGS. Clonotypes identified by both tools were identical or >97% homologous in 96% of cases. Both tools were able to routinely reach a sensitivity level of 1 × E-05. A good correlation of MRD results was observed (R=0.791, P<0.001), with excellent concordance in 79.6% of cases. Few discordant cases were observed across all disease subtypes. NGS showed at least the same level of sensitivity as allele-specific oligonucleotides-PCR, without the need for patient-specific reagents. We conclude that NGS is an effective tool for MRD monitoring in ALL, MCL and MM. Prospective comparative analysis of unselected cases is required to validate the clinical impact of NGS-based MRD assessment.

PURPOSE We investigated the effect on minimal residual disease, by qualitative and real-time quantitative polymerase chain reaction (RQ-PCR), of a consolidation regimen that included bortezomib, thalidomide, and dexamethasone (VTD) in patients with multiple myeloma (MM) responding to autologous stem-cell transplantation (auto-SCT). PATIENTS AND METHODS Patients achieving at least very good partial response who had an available molecular marker based on the immunoglobulin heavy-chain rearrangement received four courses of treatment every month: four infusions per month of bortezomib at 1.6 mg/m(2), thalidomide at 200 mg/d, and dexamethasone at 20 mg/d on days 1 to 4, 8 to 11, and 15 to 18. Patients were studied with tumor-clone-specific primers by qualitative nested PCR and RQ-PCR. Results Of 39 patients enrolled, 31 received the four VTD courses. Immunofixation complete responses increased from 15% after auto-SCT to 49% after VTD. Molecular remissions (MRs) were 3% after auto-SCT and 18% after VTD. Median time to maximum response was 3.5 months. So far, no patient in MR has relapsed (median follow-up, 42 months). VTD consolidation induced an additional depletion of 4.14 natural logarithms of tumor burden by RQ-PCR. Patients with a tumor load less than the median value after VTD had outcomes better than those who had tumor loads above the median value after VTD (at median follow-up: progression-free survival, 100% v 57%; P < .001). CONCLUSION To the best of our knowledge, this study is the first to document the occurrence of persistent MRs in a proportion of MM patients treated without allogeneic transplantation. Moreover, the major reduction in tumor load recorded by RQ-PCR after VTD suggests that unprecedented levels of tumor cell reduction can be achieved in MM thanks to the new nonchemotherapeutic drugs.

Complete response (CR) was an uncommon event in elderly myeloma patients until novel agents were combined with standard oral melphalan-prednisone. This analysis assesses the impact of treatment response on progression-free survival (PFS) and overall survival (OS). We retrospectively analyzed 1175 newly diagnosed myeloma patients, enrolled in 3 multicenter trials, treated with melphalanprednisone alone (n ‫؍‬ 332), melphalan-prednisone-thalidomide (n ‫؍‬ 332), melphalanprednisone-bortezomib (n ‫؍‬ 257), or melphalan-prednisone-bortezomib-thalidomide (n ‫؍‬ 254). After a median follow-up of 29 months, the 3-year PFS and OS were 67% and 27% (hazard ratio ‫؍‬ 0.16; P < .001), and 91% and 70% (hazard ratio ‫؍‬ 0.15; P < .001) in patients who obtained CR and in those who achieved very good partial response, respectively. Similar results were observed in patients older than 75 years. Multivariate analysis confirmed that the achievement of CR was an independent predictor of longer PFS and OS, regardless of age, International Staging System stage, and treatment. These findings highlight a significant association between the achievement of CR and long-term outcome, and support the use of novel agents to achieve maximal response in elderly patients, including those more than 75 years. This trial was registered at www.clinicaltrials.gov as #NCT00232934, #ISRCTN 90692740, and #NCT01063179. (Blood. 2011;117(11):3025-3031)

Our findings indicate that the two treatment strategies are equivalent. No difference in oncologic outcome was found at a median follow-up of 36 months. The significantly lower stoma rate noted in the SBTS group argues in favour of the SBTS procedure when performed in expert hands.

In this randomized multicenter study of 136 patients, 6 courses of CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone) followed by rituximab (CHOP-R) were compared with rituximabsupplemented high-dose sequential chemotherapy with autografting (R-HDS) to assess the value of intensified chemotherapy as a first-line treatment for highrisk follicular lymphoma (FL) after the introduction of monoclonal antibodies. The analysis was intention to treat with event-free survival (EFS) as the primary endpoint. Complete remission (CR) was 62% with CHOP-R and 85% with R-HDS (P < .001). At a median follow-up (MFU) of 51 months, the 4-year EFS was 28% and 61%, respectively (P < .001), with no difference in overall survival (OS). Molecular remission (MR) was achieved in 44% of CHOP-R and 80% of R-HDS patients (P < .001), and was the strongest independent outcome predictor. Patients relapsing after CHOP-R underwent salvage R-HDS in 71% of cases. Salvage R-HDS had an 85% CR rate and a 68% 3-year EFS (MFU, 30 months). We conclude that (1) achieving MR is critical for effective disease control, regardless of which treatment is used; IntroductionIn the last 15 years, our approach to treatment of follicular lymphoma (FL) has evolved considerably, chiefly due to 3 major achievements. First, new agents, particularly rituximab, have improved overall outcome in patients with FL. 1,2 Second, a subset of patients with a rapid and progressive course has been recognized. [3][4][5] The International Prognostic Index (IPI), the age-adjusted IPI (aaIPI), and more recent FL-specific scores such as the Intergruppo Italiano Linfomi (IIL) score and Follicular Lymphoma International Prognostic Index (FLIPI) now allow simple and effective identification of these high-risk patients, whose management is currently far from satisfactory. 4,5 Finally, many phase 2 studies have demonstrated that the achievement of molecular remission (MR) as determined by polymerase chain reaction (PCR) is associated with a better outcome in the context of a wide array of different treatments. [6][7][8][9][10][11] In this rapidly evolving field, the place for intensified regimens with autologous stem cell transplantation (ASCT) is poorly defined. Most data arise from pre-rituximab studies. [12][13][14][15][16] ASCT improves overall survival (OS) in relapsed patients, 7,12 while data at diagnosis are less clear. The 3 phase 3 studies published so far The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. For personal use only. on May 7, 2018. by guest www.bloodjournal.org From have been based on total body irradiation (TBI)-containing regimens, did not select patients according to validated prognostic scores, and did not include molecular analysis. [13][14][15] Two of these trials showed that intensive therapy ensures better progression-free survi...

Role of interim-PET (I-PET) in diffuse large

Bortezomib and thalidomide significantly improved OS in multiple myeloma patients not eligible for transplantation.