Measurable Residual Disease by Mass Spectrometry and Next-Generation Flow to Assess Treatment Response in Myeloma.

Quantitative immuneprecipitation mass-spectrometry (QIP-MS) allows the identification of the M-protein in patients with multiple myeloma (MM) otherwise in complete response, and could be considered suitable for measurable residual disease (MRD) evaluation in peripheral blood. In the context of the GEM2012MENOS65 and GEM2014MAIN trials, we compared the performance of QIP-MS in serum with next-generation flow (NGF) cytometry in bone marrow to assess MRD in paired samples obtained post-induction, transplant, consolidation and after 24 cycles of maintenance. At each time point, both NGF and QIP-MS were able to segregate two groups of patients with significantly different progression-free survival (PFS); when the evolution of the results obtained with either method was considered, maintaining or converting to MRD negativity was associated with longer survival, significantly better when compared to sustaining or converting to MRD positivity. Of note, reemergence of MRD by QIP-MS was associated with high risk of imminent clinical progression. In conclusion, MRD evaluation by NGF and MS achieve similar prognostic value based in single time point assessments and kinetics. Thus, the minimally-invasive nature of MRD monitoring by MS represents a breakthrough in high-sensitive response assessment in MM. GEM2012MENOS65: #NCT01916252 and EudraCT as #2012-005683-10. GEM2014MAIN: #NCT02406144 and at EudraCT as 2014-00055410.

Serum mass spectrometry for treatment monitoring in patients with multiple myeloma receiving ARI0002h CAR T-cells.

Chimeric antigen receptor (CAR) T-cell therapies have increased the patients with relapsed/refractory multiple myeloma (RRMM) in whom standard electrophoretic techniques fail to detect the M-protein. Quantitative immunoprecipitation mass spectrometry (QIP-MS) can accurately measure serum M-protein with high sensitivity, and identify interferences caused by therapeutic monoclonal antibodies. Here, we investigate the outcome of QIP-MS in 33 patients treated with the academic BCMA-directed CAR T-cell ARI0002h (Cesnicabtagene Autoleucel). QIP-MS offered more detailed insights than serum immunofixation (sIFE), identifying glycosylated M-proteins and minor additional peaks. Moreover, the potential interferences owing to daratumumab or tocilizumab treatments were successfully detected. When analysing different assay platforms during patient's monitoring after ARI0002h administration, we observed that QIP-MS showed a high global concordance (78.8%) with sIFE, whereas it was only moderate (55.6%) with bone marrow (BM)-based next-generation flow cytometry (NGF). Furthermore, QIP-MS consistently demonstrated the lowest negativity rate across the different timepoints (27.3% vs. 60.0% in months 1 and 12, respectively). Patients with QIP-MS(+)/BM-based NGF(-) showed a non-significant shorter median progression free survival than those with QIP-MS(-)/BM-based NGF(-). In summary, we show the first experience to our knowledge demonstrating that QIP-MS could be particularly useful as a non-invasive technique when evaluating response after CAR T-cell treatment in MM.

Immunoparesis recovery in newly diagnosed transplant ineligible multiple myeloma patients, an independent prognostic factor that complements minimal residual disease.

Information on the prognostic value of immunoparesis (IP) recovery in multiple myeloma (MM) patients has been only generated in some observational and retrospective studies. We have evaluated the prognostic impact of IP recovery and its association with minimal residual disease (MRD) in a series of 113 newly diagnosed transplant-ineligible (NDTI) patients, that received fix duration treatment (18 cycles of VMP/lenalidomide-dexamethasone) within the PETHEMA/GEM2010MAS65 trial and who achieved CR or VGPR. Immunoglobulin levels were measured at diagnosis, at the end of treatment (after cycle 18th) and during subsequent follow up whereas MRD was analyzed only at the end of the treatment (after cycle 18th). We found that patients who had IP at diagnosis and recovered it during or after treatment had longer progression free survival (PFS) [p < 0.001; HR 0.32 (0.19-0.52)] and longer overall survival (OS) [p = 0.007; HR 0.40 (0.20-0.80)] compared to those who failed to recover it. When we analyzed IP recovery in MRD negative patients, we found that those cases with IP recovery had longer PFS [p = 0.007; HR 0.31 (0.13-0.76)] and longer OS [p = 0.012; HR 0.21 (0.06-0.80)] as compared to MRD negative patients but without IP recovery. In conclusion, IP recovery confers better prognosis in NDTI-MM patients with fixed duration treatment who achieve CR or VGPR and the prognostic value of MRD can be complemented when combined with IP recovery.

Deep MRD profiling defines outcome and unveils different modes of treatment resistance in standard- and high-risk myeloma.

Patients with multiple myeloma (MM) carrying standard- or high-risk cytogenetic abnormalities (CAs) achieve similar complete response (CR) rates, but the later have inferior progression-free survival (PFS). This questions the legitimacy of CR as a treatment endpoint and represents a biological conundrum regarding the nature of tumor reservoirs that persist after therapy in high-risk MM. We used next-generation flow (NGF) cytometry to evaluate measurable residual disease (MRD) in MM patients with standard- vs high-risk CAs (n = 300 and 90, respectively) enrolled in the PETHEMA/GEM2012MENOS65 trial, and to identify mechanisms that determine MRD resistance in both patient subgroups (n = 40). The 36-month PFS rates were higher than 90% in patients with standard- or high-risk CAs achieving undetectable MRD. Persistent MRD resulted in a median PFS of âˆ¼3 and 2 years in patients with standard- and high-risk CAs, respectively. Further use of NGF to isolate MRD, followed by whole-exome sequencing of paired diagnostic and MRD tumor cells, revealed greater clonal selection in patients with standard-risk CAs, higher genomic instability with acquisition of new mutations in high-risk MM, and no unifying genetic event driving MRD resistance. Conversely, RNA sequencing of diagnostic and MRD tumor cells uncovered the selection of MRD clones with singular transcriptional programs and reactive oxygen species-mediated MRD resistance in high-risk MM. Our study supports undetectable MRD as a treatment endpoint for patients with MM who have high-risk CAs and proposes characterizing MRD clones to understand and overcome MRD resistance. This trial is registered at www.clinicaltrials.gov as #NCT01916252.

Recovery of uninvolved heavy/light chain pair immunoparesis in newly diagnosed transplant-eligible myeloma patients complements the prognostic value of minimal residual disease detection.

Immunoparesis (IP) in multiple myeloma (MM) patients can be measured by classic assessment of immunoglobulin (Ig) levels or by analysis of the uninvolved heavy/light chain pair of the same immunoglobulin (uHLC) by the Hevylite® assay. In this study we evaluate the prognostic value of recovery from IP measured by classic total Ig and uHLC assessment in newly diagnosed MM transplant-eligible (NDMM-TE) patients with intensive treatment and its association with Minimal Residual Disease (MRD). Patients were enrolled and treated in the PETHEMA/GEM2012MENOS65 trial and continued in the PETHEMA/GEM2014MAIN trial. Total Ig (IgG, IgA and IgM) and uHLC were analyzed in a central laboratory at diagnosis, after consolidation treatment and after the first year of maintenance. MRD was analyzed by next generation flow cytometry after consolidation (sensitivity level 2x10-6). We found no differences in progression free survival (PFS) between patients who recovered and patients who didn't recover from IP after consolidation when examining classic total Ig and uHLC. However, after the first year of maintenance, in contrast to patients with classic IP, patients with recovery from uHLC IP had longer PFS than patients without recovery, with hazard ratio of 0.42 (CI95% 0.21-0.81; p=0.008). Multivariate analysis with Cox proportional-hazards regression models confirmed recovery from uHLC IP after the first year of maintenance as an independent prognostic factor for PFS, with an increase in C-statistic of 0.05 (-0.04-0.14; p<0.001) when adding uHLC IP recovery. Moreover, we observed that MRD status and uHLC IP recovery affords complementary information for risk stratification. In conclusion, recovery from uHLC IP after one year of maintenance is an independent prognostic factor for PFS in NDMM-TE patients who receive intensive treatment. Immune reconstitution, measured as recovery from uHLC IP, provides complementary prognostic information to MRD assessment.

Genetic and phenotypic characterisation of HIV-associated aggressive B-cell non-Hodgkin lymphomas, which do not occur specifically in this population: diagnostic and prognostic implications.

The frequency of aggressive subtypes of B-cell non-Hodgkin lymphoma (B-NHL), such as high-grade B-cell lymphomas (HGBL) with MYC and BCL2 and/or BCL6 rearrangement (HGBL-DH/TH) or Burkitt-like lymphoma (BL) with 11q aberration, is not well known in the HIV setting. We aimed to characterise HIV-associated aggressive B-NHL according to the 2017 WHO criteria, and to identify genotypic and phenotypic features with prognostic impact. Seventy-five HIV-associated aggressive B-NHL were studied by immunohistochemistry (CD10, BCL2, BCL6, MUM1, MYC, and CD30), EBV-encoded RNAs (EBERs), and fluorescence in situ hybridisation (FISH) to evaluate the status of the MYC, BCL2, and BCL6 genes and chromosome 11q. The 2017 WHO classification criteria and the Hans algorithm, for the cell-of-origin classification of diffuse large B-cell lymphomas (DLBCL), were applied. In DLBCL cases, the frequencies of MYC and BCL6 rearrangements (14.9 and 27.7%, respectively) were similar to those described in HIV-negative patients, but BCL2 rearrangements were infrequent (4.3%). MYC expression was identified in 23.4% of DLBCL cases, and coexpression of MYC and BCL2 in 13.0%, which was associated with a worse prognosis. As for BL cases, the expression of MUM1 (30.4%) conferred a worse prognosis. Finally, the prevalence of HGBL-DH/TH and BL-like with 11q aberration are reported in the HIV setting. The phenotypic and genotypic characteristics of HIV-associated aggressive B-NHL are similar to those of the general population, except for the low frequency of BCL2 rearrangements in DLBCL. MYC and BCL2 coexpression in DLBCL, and MUM-1 expression in BL, have a negative prognostic impact on HIV-infected individuals.

Response to Novel Drugs before and after Allogeneic Stem Cell Transplantation in Patients with Relapsed Multiple Myeloma.

Multiple myeloma (MM) remains as an incurable disease and, although allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative approach, most patients ultimately relapse, and their treatment remains challenging. Because allo-HSCT can modify not only the biology of the disease, but also the immune system and the microenvironment, it can potentially enhance the response to rescue therapies. Information on the efficacy and safety of novel drugs in patients relapsing after allo-HSCT is lacking, however. The objectives of this study were to evaluate the efficacy and toxicity of rescue therapies in patients with MM who relapsed after allo-HSCT, as well as to compare their efficacy before and after allo-HSCT. This retrospective multicenter study included 126 consecutive patients with MM who underwent allo-HSCT between 2000 and 2013 at 8 Spanish centers. All patients engrafted. The incidence of grade II-IV acute graft-versus-host disease (GVHD) was 47%, and nonrelapse mortality within the first 100 days post-transplantation was 13%. After a median follow-up of 92 months, overall survival (OS) was 51% at 2 years and 43% at 5 years. The median progression-free survival after allo-HSCT was 7 months, whereas the median OS after relapse was 33 months. Patients relapsing in the first 6 months after transplantation had a dismal prognosis compared with those who relapsed later (median OS, 11 months versus 120 months; P < .001). The absence of chronic GVHD was associated with reduced OS after relapse (hazard ratio, 3.44; P < .001). Most patients responded to rescue therapies, including proteasome inhibitors (PIs; 62%) and immunomodulatory drugs (IMiDs; 77%), with a good toxicity profile. An in-depth evaluation, including the type and intensity of PI- and IMiD-based combinations used before and after allo-HSCT, showed that the overall response rate and duration of response after allo-HSCT were similar to those seen in the pretransplantation period. Patients with MM who relapse after allo-HSCT should be considered candidates for therapy with new drugs, which can achieve similar response rates with similar durability as seen in the pretransplantation period. This pattern does not follow the usual course of the disease outside the transplantation setting, where response rates and time to progression decreases with each consecutive line of treatment.

Imaging and bone marrow assessments improve minimal residual disease prediction in multiple myeloma.

The value of minimal residual disease (MRD) status by bone marrow and imaging analysis as independent prognostic factors has been well established in multiple myeloma (MM). Nevertheless data about their potential complementarity for a more accurate assessment are limited. With this aim, we retrospectively analyzed the prediction of outcome with the combination of PET-CT and MRD, assessed by multiparameter flow cytometry (MFC) in 103 patients with newly diagnosed MM. We confirmed the benefit in terms of progression-free survival (PFS), linked to the achievement of negativity by MFC (hazard ratio [HR] 0.53; 95% confidence interval [CI]: 0.28-0.98), and PET-CT (HR 0.18; 95% CI: 0.09-0.36) individually. By combining both techniques, patients who became MRD-/PET-, with a median of PFS 92 months, had significant prolonged median PFS (P < .001). This is compared with MRD+/PET- and PET+ patients (median PFS of 45 and 28 months, respectively). We observed a significant difference (P = .003) in overall survival (OS) outcomes between MRD-/PET- and MRD+/PET- patients (4-year OS 94.2% and 100%, respectively), vs PET+ patients (4-year OS 73.8%). All survival results were confirmed in a conditional landmark analysis. These findings support the potential complementarity between PET-CT and MFC, and highlight their better predictive capability when improving sensitivity.

High dose chemotherapy and autologous stem cell transplantation in nodular lymphocyte-predominant Hodgkin lymphoma: A retrospective study by the European society for blood and marrow transplantation-lymphoma working party.

Whilst autologous stem cell transplantation (auto-SCT) is considered standard of care for relapsed/refractory classical Hodgkin lymphoma, the role of auto-SCT in nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is not well defined due to limited data. We report the first study on auto-SCT for NLPHL with a larger cohort. Eligible for this retrospective registry study were patients reported to the EBMT between 2003 and 2013, aged 18 or older with relapsed/refractory NLPHL who underwent first auto-SCT with disease chemosensitive to salvage therapy. NLPHL transformed to diffuse large B cell lymphoma were excluded. Sixty patients (83% male; median age 40 years) met the eligibility criteria. The median time between diagnosis and transplant was 21 months (IQR 13-58), and the median number of prior treatment lines was 2 (range 1-5), including rituximab in 63% of the patients. At auto-SCT, 62% of the patients were in complete remission (CR) and 38% in partial remission. Seventy-two percent of the patients received BEAM as high-dose therapy. With a median follow-up of 56 months (range 3-105), 5-year progression-free and overall survival (OS) were 66% and 87%, respectively. Univariate comparisons considering age, time from diagnosis to transplant, prior chemotherapy lines, and prior rituximab use failed to identify significant predictors for any survival endpoint except for being in CR at the time of auto-SCT (vs PR, P = .049) for OS. Auto-SCT in patients with relapsed/refractory NLPHL who are sensitive to salvage therapy gives excellent disease control and long-term survival independent of the time interval between diagnosis and transplant.

Autologous Stem Cell Transplantation for Follicular Lymphoma: Favorable Long-Term Survival Irrespective of Pretransplantation Rituximab Exposure.

High-dose chemotherapy supported by autologous stem cell transplantation (HDT/ASCT) has contributed to modify the natural history of follicular lymphoma (FL); however, an overall survival (OS) benefit has been demonstrated at relapse only after a rituximab-free chemotherapy regimen. A total of 655 patients with FL were reported to the Spanish GELTAMO (Grupo Español de Linfomas y Trasplantes de Médula Ósea) registry and underwent first ASCT between 1989 and 2007. A total of 203 patients underwent ASCT in first complete response (CR1), 174 in second complete response (CR2), 28 in third complete response (CR3), 140 in first partial response (PR1), 81 in subsequent PR, and 29 with resistant/refractory disease; 184 patients received rituximab before ASCT. With a median follow-up of 12 years from ASCT, median progression-free survival (PFS) and overall survival (OS) were 9.7 and 21.3 years, respectively. Actuarial 12-year PFS and OS were 63% (95% confidence interval [CI], 58%-68%) and 73% (95% CI, 68%-78%), respectively, for patients in CR (with a plateau in the curve beyond 15.9 years), 25% (95% CI, 19%-28%) and 49% (95% CI 42%-56%), respectively, for patients in PR, and 23% (95% CI, 8%-48%) and 28% (95% CI, 9%-45%), respectively, for patients with resistant/refractory disease (P < .001). In patients who received rituximab before ASCT, the estimated 9-year PFS and OS from ASCT were 59.5% (95% CI, 51%-67%) and 75% (95% CI, 68%-83%), respectively. Interestingly, for patients who underwent transplantation in CR ≥2 or PR ≥2 who had received rituximab before ASCT (n = 90), 9-year PFS and OS were 61% (95% CI, 51%-73%) and 75% (95% CI, 65%-80%), respectively, with no relapses occurring beyond 5.1 years after ASCT. The cumulative incidence of second malignancies in the global series was 6.7% at 5 years and 12.8% at 10 years. This analysis strongly suggests that ASCT is a potentially curative option for eligible patients with FL. In the setting of relapse, it is of especial interest in pretransplantation rituximab-sensitive patients with FL.

Analysis of the Adherence of Dental Pulp Stem Cells on Two-Dimensional and Three-Dimensional Silk Fibroin-Based Biomaterials.

Among various biomaterials used as scaffolds in tissue engineering, silk fibroin is a highly attractive material. A scaffold should be biocompatible and nontoxic, with optimal physical features and mechanical properties. For this reason, tissue-engineering approaches in regenerative medicine have focused on investigating the biocompatibility of possible biomaterials by analyzing cell-scaffold interaction properties. The aim of the present study was to examine the biocompatibility of silk fibroin as a film (two-dimensional [2D]) and a scaffold (three-dimensional [3D]) after being cellularized with human dental pulp stem cells (hDPSCs). Human dental pulp stem cells were isolated from healthy patients aged between 18 and 31 years. Further, silk fibroin-based 2D films and 3D scaffolds were prepared. Human dental pulp stem cells were directly seeded onto the biomaterial surfaces and their proliferation, adherence, and cell morphology were analyzed after 24, 120, and 168 hours. Additionally, the characteristics of the silk fibroin 2D films and 3D scaffolds before and after cell seeding were analyzed by scanning electron microscopy. After the initial 24 hours, silk fibroin-based 3D scaffolds displayed more adhered cells with a suitable fibroblastic morphology than those displayed on the 2D films. After longer culture times, hDPSCs proliferated sufficiently to cover the entire surface of the 3D silk fibroin scaffold, whereas the 2D films were only partially covered. Our results indicate the good in vitro biocompatibility of silk fibroin-based biomaterials, especially when 3D scaffolds rather than 2D films are used.

'Management multiple myeloma during pregnancy: a case report and review'.

Multiple myeloma (MM) is a hematologic neoplasm characterized by plasma tumor cell proliferation in the bone marrow. It's a rare malignancy before a 40-year-old and it is extremely uncommon during pregnancy. We report the case of a 37-year-old woman with a newly diagnosed IgG λ MM (Durie-Salmon stage IIIA, International Staging System II and good prognosis cytogenetic) at the 27th week of her pregnancy. Our management during pregnancy, the delivery, and initiation of anti-myeloma treatment with bortezomib, lenalidomide, and dexamethasone are published. There are a few reviews reporting the most common features and management of MM during pregnancy. We perform a comprehensive review of all 32 cases reported between 1965 and 2014 in which a MM was diagnosed during pregnancy including score, cytogenetic results, labor characteristics, and response to therapy. About 53% of pregnant women did not start treatment before partum. Cesarean section was the most common form of delivery (82%). About 88% of newborns were healthy, although most of them were premature (73%). Management of a MM diagnosed during pregnancy should be based on the presence of myeloma-related organ damage to secure survival of the mother without fetal adverse effects related to treatment. Serial fetal ultrasound may be helpful in order to avoid complications. The cesarean section may be preferred depending on maternal and fetus prognosis. Whole-body diffusion-weighted imaging minimal response could be an appropriate technique to discard plasmacytomas during pregnancy in critical situations such as the appearance of symptoms of spinal cord compression. Therapeutic choices should be agreed with the pregnant after a thorough discussion of the prognostic factors of the disease and the potential risk for the fetus and the patient. While awaiting partum, dexamethasone is a non-toxic treatment. Triple therapy including a proteasome inhibitor should be started quickly after delivery. Copyright © 2014 John Wiley & Sons, Ltd.

Long-term prognostic significance of response in multiple myeloma after stem cell transplantation.

For establishing the true effect of different response categories in patients with multiple myeloma (MM) treated with autologous stem cell transplantation, we evaluated, after a median follow-up of 153 months, 344 patients with MM who received a transplant between 1989 and 1998. Overall survival (OS) at 12 years was 35% in complete response (CR) patients, 22% in near complete response (nCR), 16% in very good partial response (VGPR), and 16% in partial response (PR) groups. Significant differences in OS and progression-free survival were found between CR and nCR groups (P = .01 and P = .002, respectively), between CR and VGPR groups (P = .0001 and P = .003), or between CR and PR groups (P = .003 and P = < 10(-5)); no differences were observed between the nCR and VGPR groups (P = .2 and P = .9) or between these groups and the PR group (P = .1 and P = .8). A landmark study found a plateau phase in OS after 11 years; 35% patients in the CR group and 11% in the nCR+VGPR+PR group are alive at 17 years; 2 cases had relapsed in the nCR+VGPR+PR group. In conclusion, MM achieving CR after autologous stem cell transplantation is a central prognostic factor. The relapse rate is low in patients with > 11 years of follow-up, possibly signifying a cure for patients in CR.

Cell therapy in bisphosphonate-related osteonecrosis of the jaw.

OBJECTIVE: Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a clinical condition found in patients who have received intravenous or oral bisphosphonate therapy for various diseases related to bone. This report describes a novel treatment of BRONJ using autologous bone marrow stem cells, platelet-rich plasma, beta tricalcium phosphate, and demineralized bone matrix. STUDY DESIGN: We report a 71-year-old woman with history of multiple myeloma treated with intravenous zoledronic acid during 4 years. After a tooth extraction, the patient presented with a painful BRONJ lesion with no healing wound and cortical bone exposure. The patient was surgically managed with a standardized protocol of autologous stem cell therapy combining bone marrow harvest, cell concentration procedures, and intraoral surgery. RESULTS: CT scan performed 6 months later showed improvement of bone and concentric ossification. Cellular therapy might be considered a new strategy to heal BRONJ lesions.

Large T cell clones expressing immune checkpoints increase during multiple myeloma evolution and predict treatment resistance.

Tumor recognition by T cells is essential for antitumor immunity. A comprehensive characterization of T cell diversity may be key to understanding the success of immunomodulatory drugs and failure of PD-1 blockade in tumors such as multiple myeloma (MM). Here, we use single-cell RNA and T cell receptor sequencing to characterize bone marrow T cells from healthy adults (n = 4) and patients with precursor (n = 8) and full-blown MM (n = 10). Large T cell clones from patients with MM expressed multiple immune checkpoints, suggesting a potentially dysfunctional phenotype. Dual targeting of PD-1 + LAG3 or PD-1 + TIGIT partially restored their function in mice with MM. We identify phenotypic hallmarks of large intratumoral T cell clones, and demonstrate that the CD27- and CD27+ T cell ratio, measured by flow cytometry, may serve as a surrogate of clonal T cell expansions and an independent prognostic factor in 543 patients with MM treated with lenalidomide-based treatment combinations.

Mesenchymal dental stem cells in regenerative dentistry.

In the last decade, tissue engineering is a field that has been suffering an enormous expansion in the regenerative medicine and dentistry. The use of cells as mesenchymal dental stem cells of easy access for dentist and oral surgeon, immunosuppressive properties, high proliferation and capacity to differentiate into odontoblasts, cementoblasts, osteoblasts and other cells implicated in the teeth, suppose a good perspective of future in the clinical dentistry. However, is necessary advance in the known of growth factors and signalling molecules implicated in tooth development and regeneration of different structures of teeth. Furthermore, these cells need a fabulous scaffold that facility their integration, differentiation, matrix synthesis and promote multiple specific interactions between cells. In this review, we give a brief description of tooth development and anatomy, definition and classification of stem cells, with special attention of mesenchymal stem cells, commonly used in the cellular therapy for their trasdifferentiation ability, non ethical problems and acceptable results in preliminary clinical trials. In terms of tissue engineering, we provide an overview of different types of mesenchymal stem cells that have been isolated from teeth, including dental pulp stem cells (DPSCs), stem cells from human exfoliated deciduous teeth (SHEDs), periodontal ligament stem cells (PDLSCs), dental follicle progenitor stem cells (DFPCs), and stem cells from apical papilla (SCAPs), growth factors implicated in regeneration teeth and types of scaffolds for dental tissue regeneration.

A randomized phase II study comparing consolidation with a single dose of 90Y ibritumomab tiuxetan vs. maintenance with rituximab for two years in patients with newly diagnosed follicular lymphoma responding to R-CHOP. Long-term follow-up results.

This is a randomized phase-2 trial aimed to compare consolidation vs. maintenance in untreated patients with follicular lymphoma (FL) responding to induction. 146 patients were enrolled from 25 Spanish institutions (ZAR2007; ClinicalTrials.gov #NCT00662948). Patients in PR or CR/CR[u] after R-CHOP were randomized 1:1 to 90Y-ibritumomab-tiuxetan 0.4 mCi/kg (arm A) vs. rituximab 375 mg/m2 every 8 weeks for 2 years (arm B). After a median follow-up of 10.55 years, 53 patients eventually progressed with a 10-year PFS of 50% vs. 56% for patients in arm A and B, respectively (HR = 1.42; p > 0.1). No significant differences were seen in OS (10-year OS 78% vs. 84.5%; HR = 1.39, p > .1). Patients receiving 90Y-ibritumomab-tiuxetan showed higher incidence of second neoplasms than those in arm B (10-year cumulative incidence 18.5 vs. 2%, respectively; p = .038). In conclusion, in FL patients responding to R-CHOP, no significant differences were found between consolidation and maintenance, although with higher late toxicity for consolidation.

Mass spectrometry vs immunofixation for treatment monitoring in multiple myeloma.

Monitoring of the monoclonal protein (M-protein) by electrophoresis and/or immunofixation (IFE) has long been used to assess treatment response in multiple myeloma (MM). However, with the use of highly effective therapies, the M-protein becomes frequently undetectable, and more sensitive methods had to be explored. We applied IFE and mass spectrometry (EXENT&FLC-MS) in serum samples from newly diagnosed MM patients enrolled in the PETHEMA/GEM2012MENOS65 obtained at baseline (n = 223), and after induction (n = 183), autologous stem cell transplantation (n = 173), and consolidation (n = 173). At baseline, the isotypes identified with both methods fully matched in 82.1% of samples; in the rest but 2 cases, EXENT&FLC-MS provided additional information to IFE with regards to the M-protein(s). Overall, the results of EXENT&FLC-MS and IFE were concordant in >80% of cases, being most discordances due to EXENT&FLC-MS+ but IFE- cases. After consolidation, IFE was not able to discriminate 2 cohorts with different median progression-free survival (PFS), but EXENT&FLC-MS did so; furthermore, among IFE- patients, EXENT&FLC-MS identified 2 groups with significantly different median PFS (P = .0008). In conclusion, compared with IFE, EXENT&FLC-MS is more sensitive to detect the M-protein of patients with MM, both at baseline and during treatment, and provides a more accurate prediction of patients' outcome. This trial was registered at www.clinicaltrials.gov as #NCT01916252.

R-COMP versus R-CHOP as first-line therapy for diffuse large B-cell lymphoma in patients ≥60 years: Results of a randomized phase 2 study from the Spanish GELTAMO group.

The use of non-pegylated liposomal doxorubicin (Myocet® ) in diffuse large B-cell lymphoma (DLBCL) has been investigated in retrospective and single-arm prospective studies. This was a prospective phase 2 trial of DLBCL patients ≥60 years old with left ventricular ejection fraction (LVEF) ≥55% randomized to standard R-CHOP or investigational R-COMP (with Myocet® instead of conventional doxorubicin). The primary end point was to evaluate the differences in subclinical cardiotoxicity, defined as decrease in LVEF to <55% at the end of treatment. Secondary objectives were efficacy, safety, and variations of troponin and N-terminal pro-B-type natriuretic peptide (NT-proBNP) and LVEF along follow-up. Ninety patients were included, 45 in each group. No differences were observed in the percentage of patients with LVEF <55% at end of treatment (11% in R-CHOP arm vs. 7% in R-COMP arm, p = 0.697) or at 4 months (10% vs. 6%, respectively, p = 0.667) and 12 months (8% vs. 7%, respectively, p = 1). However, a higher percentage of R-CHOP compared with R-COMP patients showed increased troponin levels in cycle 6 (100% vs. 63%, p = 0.001) and at 1 month after treatment (88% vs. 56%, respectively, p = 0.015). Cardiovascular adverse events were seen in five R-CHOP patients (nine episodes, four grade ≥3) and in four R-COMP patients (five episodes, all grade 1-2). No significant differences in efficacy were observed. In conclusion, R-COMP is a feasible immunochemotherapy schedule for DLBCL patients ≥60 years, with similar efficacy to R-CHOP. However, the use of non-pegylated doxorubicin instead of conventional doxorubicin was not associated with less early cardiotoxicity, although some reduced cardiac safety signals were observed. Trial registration: ClinicalTrials.gov Identifier: NCT02012088.