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In the era of personalized treatment in multiple myeloma, high-risk patients must be accurately identified. The International Myeloma Working Group recommends using the Revised International Staging System (R-ISS) to pick out high-risk patients. The main purpose of our work was to explore the heterogeneity of outcome among R-ISS stage II patients assessing the impact of International Staging System (ISS) stage, chromosomal abnormalities and lactate dehydrogenase level in this subgroup. Data were collected from 1,343 patients up to 65 years old with newly diagnosed myeloma, enrolled in three clinical trials implemented by the Intergroupe Francophone du Myélome. All patients were eligible for intensive treatment. Patients in R-ISS stage II but ISS stage I had 1.6 times higher risk of death than patients in R-ISS stage I (adjusted hazard ratio=1.6; 95% confidence interval: 1.1-2.2; P=0.01) and patients in R-ISS stage II but with ISS stage III had a better overall survival than patients in R-ISS stage III (adjusted hazard ratio=0.7; 95% confidence interval: 0.4-0.9, P=0.02). However, among patients classified in R-ISS II, ISS stage and chromosomal abnormalities (del[17p] and t[4;14]) were still relevant prognostic factors for death. Dividing R-ISS stage II into three subgroups: ISS I with standard-risk chromosomal abnormalities, ISS II or III with standard-risk chromosomal abnormalities and patients with high-risk chromosomal abnormalities, median overall survival times were, respectively, not reached, 112 months and 71 months (P<0.001). In conclusion, stratification of patients in the R-ISS stage II group can be improved by taking into account chromosomal abnormalities and ISS. However, this does not improve predictive performance of survival models.

Cytogenetic abnormalities (CAs) are known to be the preponderant prognostic factor in multiple myeloma. Our team has recently developed a prognostic score based on 6 CAs, with which del(1p32) appears to be the second worst abnormality after del(17p). This study aimed to confirm the adverse effect of 1p32 deletion in patients with newly diagnosed multiple myeloma (NDMM). Among 2551 patients with newly diagnosed multiple myeloma, 11% were harboring del(1p32). Their overall survival (OS) was significantly inferior compared with patients without del(1p32) (median OS: 49 months vs 124 months). Likewise, progression-free survival was significantly shorter. More importantly, biallelic del(1p32) conferred a dramatically poorer prognosis than a monoallelic del(1p32) (median OS: 25 months vs 60 months). As expected, the OS of patients with del(1p32) significantly decreased when this abnormality was associated with other high-risk CAs [del(17p), t(4;14), or gain(1q)]. In the multivariate analysis, del(1p32) appeared as a negative prognostic factor; after adjustment for age and treatment, the risk of progression was 1.3 times higher among patients harboring del(1p32), and the risk of death was 1.9 times higher. At the dawn of risk-adapted treatment strategies, we have confirmed the adverse effect of del(1p32) in multiple myeloma and the relevance of its assessment at diagnosis., (© 2023 by The American Society of Hematology.)

Background: Despite that cytogenetic and molecular analysis of tumor cells can rapidly identify recurring molecular abnormalities, no personalized therapy is currently available in the setting of relapsed/refractory multiple myeloma (r/r MM)., Methods: MM-EP1 is a retrospective study aimed at comparing a personalized molecular-oriented (MO) versus a non-molecular-oriented (no-MO) approach in r/r MM. Actionable molecular targets and their associated therapies were the BRAF V600E mutation and BRAF inhibitors; t(11;14)(q13;q32) and BCL2 inhibitors; and t(4;14)(p16;q32) with FGFR3 fusion/rearrangements and FGFR3 inhibitors., Results: One hundred three highly pretreated r/r MM patients with a median age of 67 years (range 44-85) were included. Seventeen (17%) patients were treated using an MO approach with BRAF inhibitors (vemurafenib or dabrafenib, n = 6), BCL2 inhibitor (venetoclax, n = 9), or FGFR3 inhibitor (erdafitinib, n = 2). Eighty-six (86%) patients received non-MO therapies. Overall response rate was 65% in MO patients versus 58% in the non-MO group ( p = 0.053). Median PFS and OS were 9 and 6 months (HR = 0.96; CI95 = 0.51-1.78; p = 0.88) and 26 and 28 months (HR = 0.98; CI95 = 0.46-2.12; p = 0.98), respectively, in MO and no-MO patients., Conclusion: Despite the low number of patients treated with an MO approach, this study highlights the strengths and weakness of a molecular-targeted approach for the treatment of multiple myeloma. Widespread biomolecular techniques and improvement of precision medicine treatment algorithms could improve selection for precision medicine in myeloma.

The 3 main types of cardiac amyloidosis are linked to two protein precursors: AL amyloidosis secondary to free light chain deposits in the context of monoclonal gammopathy (mainly of undetermined significance or myeloma) and transthyretin amyloidosis (ATTR), comprising wild-type transthyretin amyloidosis (ATTRwt for wild type) and hereditary transthyretin amyloidosis (ATTRv for variant). These diseases are underdiagnosed and highly prevalent in common cardiac phenotypes in recent studies (heart failure with preserved ejection fraction, severe aortic stenosis, hypertrophic cardiomyopathy). Myocardial amyloid infiltration affects all cardiac structures and clinically promotes predominantly heart failure, conductive disorders and cardioembolic events. The search for extracardiac signs makes it possible to arouse diagnostic suspicion. Electrocardiogram, echocardiography and cardiac MRI can suspect cardiac amyloidosis. The diagnostic confirmation follows a simple algorithm including a systematic search for monoclonal gammapathy and a disphosphonate scintigraphy. Histological proof is necessary in case of AL or ATTR amyloidosis with concomitant monoclonal gammopathy in order to initiate specific treatment. Due to the late disease onset in ATTRv, genetic testing must be routine in all cases of ATTR. These diseases are no longer perceived as incurable since recent therapeutic innovations. A better knowledge of the disease is more than ever necessary., (Copyright © 2022 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier Masson SAS. All rights reserved.)

The causal protein of amyloid light-chain (AL) amyloidosis is a monoclonal immunoglobulin free light chain (mFLC), which must be quantified in the serum for patient diagnosis and monitoring. Several manufacturers commercialize immunoassays that quantify total kappa (κ) and lambda (λ) FLC, but results can differ greatly between these tests. Here, we compared a recently developed enzyme-linked immunosorbent assay (ELISA) (Sebia) with N-Latex immunonephelometry (Siemens) in 96 patients diagnosed with AL amyloidosis (histologically confirmed) and 48 non-AL patients sent to our referral center for suspicion of cardiac amyloidosis. ELISA free-light chain difference (dFLC) were lower than N-Latex values, and agreement between methods was reduced in the case of involved λ FLC. Diagnosis sensitivity and specificity were >85% with both assays. A receiver operating characteristic analysis indicated that ELISA performances could be improved by using a higher value for the lower limit of the κ/λ ratio. We also assessed Freelite (The Binding Site) in a subgroup of these same AL patients, including 18 cases with normal κ/λ ratio by at least one assay. Only two patients had normal κ/λ ratio with all three assays. Overall, ELISA demonstrated slightly lower sensitivity than N-Latex but may be an alternative to nephelometry/turbidimetry in certain difficult cases., Competing Interests: Sebia (Lisses, France) provided financial support corresponding to the cost of the FLC tests dedicated to the study and performed the ELISAs. T D has received consultant fees and research grants from The Binding Site, AKCEA, ALNYLAM, GSK, PFIZER, PROTHENA and NEURIMMUNE. V A received consulting fees from Addmedica outside of the submitted work., (© 2022 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Heart transplantation in cardiac amyloidosis (CA) patients is possible and generally considered for transplantation if other organs are not affected. In this study, we aimed to describe and assess outcome in patients following heart transplantations at our CA referral center., Methods: We assessed all CA patients that had heart transplantations at our center between 2005 and 2018. Patients with New York Heart Association status 3 out of 4, with poor short-term prognosis due to heart failure, despite treatment, and without multiple myeloma, systemic disease, severe neuropathic/digestive comorbidities, cancer, or worsening infections were eligible for transplantation. Hearts were transplanted by bicaval technique. Standard induction and immunosuppressive therapies were used. Survival outcome of CA patients after transplantation was compared with recipients with nonamyloid pathologies in France., Results: Between 2005 and 2018, 23 CA patients had heart transplants: 17 (74%) had light chain (light chain amyloidosis [AL]) and 6 (26%) had hereditary transthyretin (hereditary transthyretin amyloidosis [ATTRv]) CA. Also, 13 (57%) were male, and the mean age at diagnosis was 56.5 y (range, 47.7-62.8). Among AL patients, 13 had heart-only and 5 had heart-kidney transplantations. Among ATTRv patients, 1 had heart-only and 5 had heart-liver transplantations. The 1-y survival rate after transplantation was 78%, 70% with AL, and 100% with ATTRv. At 2 y, 74% were alive: 65% with AL and 100% with ATTRv., Conclusion: After heart transplantation, French CA and nonamyloid patients have similar survival outcomes. Among CA patients, ATTRv patients have better prognosis than those with AL, possibly due to the combined heart-liver transplantation. Selected CA patients should be considered for heart transplantations., (Copyright © 2022 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

Objectives: COVID-19 patients affected by haematological malignancies have a more severe course of the disease and higher mortality, prompting for effective prophylaxis. The present study aims to evaluate the humoral response after mRNA vaccination as well as the impact of a third vaccine dose in patients with lymphoid malignancies., Methods: We conducted a single-centre study, evaluating the serological responses of mRNA vaccination amongst a cohort of 200 patients affected by lymphoid malignancies after two or three doses using an industrial SARS-CoV-2 serology assay for anti-receptor binding domain (RBD) Spike IgG detection and quantification., Results: Among patients with plasma cell disorders, 59 of 96 (61%) had seroconversion (anti-RBD >50 AU/mL), and recent anti-CD38 therapies were associated with lower serological anti-RBD IgG concentrations (median IgG concentration 137 (IQR 0-512) AU/mL vs. 543 (IQR 35-3496) AU/mL; p < 0.001). Patients with B-cell malignancies had a lower seroconversion rate (20/84, 24%) mainly due to the broad usage of anti-CD20 monoclonal antibodies; only 2 of 53 (4%) patients treated by anti-CD20 antibodies during the last 12 months experienced a seroconversion. A total of 78 patients (44 with plasma cell disorders, 27 with B-cell malignancies, and 7 with other lymphomas) received a third dose of vaccine. The seroconversion rate and antibody concentrations increased significantly, especially in patients with plasma cell disorders, where an increment of anti-RBD IgG concentrations was observed in 31 of 44 (70%) patients, with an anti-RBD concentration median-fold increase of 10.6 (IQR 2.4-25.5). Its benefit in B-cell malignancies is uncertain, with only 2 of 25 (8%) patients having seroconverted after the vaccine booster, without increased median antibody concentration., Discussion: A third mRNA vaccine dose significantly improved humoral responses among patients with plasma cell disorders, whereas the effect was limited among patients with B-cell malignancies., (Copyright © 2022 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

High-dose melphalan (HDM) and transplantation are recommended for eligible patients with multiple myeloma. No other conditioning regimen has proven to be more effective and/or safer. We previously reported in a phase 2 study that bortezomib can safely and effectively be combined with HDM (Bor-HDM), with a 32% complete response (CR) rate after transplantation. These data supported a randomized phase 3 trial. Randomization was stratified according to risk and response to induction: 300 patients were enrolled, and 154 were allocated to the experimental arm (ie, arm A) with bortezomib (1 mg/m2 intravenously [IV]) on days -6, -3, +1, and +4 and melphalan (200 mg/m2 IV) on day -2. The control arm (ie, arm B) consisted of HDM alone (200 mg/m2 IV). There were no differences in stringent CR + CR rates at day 60 posttransplant (primary end point): 22.1% in arm A vs 20.5% in arm B (P = .844). There were also no differences in undetectable minimum residual disease rates: 41.3% vs 39.4% (P = .864). Median progression-free survival was 34.0 months for arm A vs 29.6 months for arm B (adjusted HR, 0.82; 95% CI, 0.61-1.13; P = .244). The estimated 3-year overall survival was 89.5% in both arms (hazard ratio, 1.28; 95% CI, 0.62-2.64; P = .374). Sixty-nine serious adverse events occurred in 18.7% of Bor-HDM-treated patients (vs 13.1% in HDM-treated patients). The proportion of grade 3/4 AEs was similar within the 2 groups (72.0% vs 73.1%), mainly (as expected) blood and gastrointestinal disorders; 4% of patients reported grade 3/4 or painful peripheral neuropathy in arm A (vs 1.5% in arm B). In this randomized phase 3 study, a conditioning regimen with Bor-HDM did not improve efficacy end points or outcomes compared with HDM alone. The original trial was registered at www.clinicaltrials.gov as #NCT02197221., (© 2022 by The American Society of Hematology.)

Objective: To determine the optimal 2-[ 18 F]FDG-PET/MRI imaging protocol for the initial staging of patients with suspected or confirmed multiple myeloma., Methods: Radiologists and nuclear medicine specialists reviewed all PET/MRI exams of 104 patients with a monoclonal gammopathy (MG). The presence of focal and diffuse bone marrow involvement (BMI) was assessed using 4 different image datasets: WB-MRI, PET, WB-PET/MRI, and WB-DCE-PET/MRI. A reference standard was established by a panel review of all baseline and follow-up imaging, and biological and pathological information. The diagnostic performance for each image dataset to detect BMI was evaluated and compared (Fisher's exact test)., Results: Sensitivity, specificity, and accuracy for focal BMI of WB-MRI was 87%, 97%, and 92%; of PET was 78%, 97%, and 95%; of WB-PET/MRI was 93%, 97%, and 95%; and of WB-DCE-PET/MRI was 93%, 97%, and 95%, respectively. WB-PET/MRI and WB-DCE-PET/MRI were statistically superior to PET (p = 0.036) without decreasing specificity. The sensitivity, specificity, and accuracy of WB-MRI for diffuse BMI detection was 91%, 80%, and 85%; of 3DT1-PET was 53%, 89%, and 74%; of WB-PET/MRI was 98%, 66%, and 79%; and of WB-DCE-PET/MRI was 98%, 59%, and 75%, respectively. PET lacked sensitivity compared to all other dataset studies (p < 0.0001). WB-MRI had the best accuracy without reaching statistical significance when compared to the other datasets., Conclusion: The WB-PET/MRI dataset including T1 and T2 Dixon, WB-DWI, and PET images provides optimal diagnostic performance to detect both focal lesions and diffuse BMI, with limited added value of WB-DCE for baseline staging of patients with MG. Key Points • The combination of morphological and functional MRI sequences and metabolic (2-[ 18 F]FDG-PET) images increases the diagnostic performance of PET/MRI to detect focal bone lesions. • The adjunction of dynamic contrast-enhanced sequences did not improve diagnostic performance., (© 2021. The Author(s), under exclusive licence to European Society of Radiology.)

Primary plasma cell leukemia (pPCL) is an aggressive form of multiple myeloma (MM) that has not benefited from recent therapeutic advances in the field. Because it is very rare and heterogeneous, it remains poorly understood at the molecular level. To address this issue, we performed DNA and RNA sequencing of sorted plasma cells from a large cohort of 90 newly diagnosed pPCL and compared with MM. We observed that pPCL presents a specific genomic landscape with a high prevalence of t(11;14) (about half) and high-risk genomic features such as del(17p), gain 1q, and del(1p32). In addition, pPCL displays a specific transcriptome when compared with MM. We then wanted to characterize specifically pPCL with t(11;14). We observed that this subentity displayed significantly fewer adverse cytogenetic abnormalities. This translated into better overall survival when compared with pPCL without t(11;14) (39.2 months vs 17.9 months, P = .002). Finally, pPCL with t(11;14) displayed a specific transcriptome, including differential expression of BCL2 family members. This study is the largest series of patients with pPCL reported so far., (© 2022 by The American Society of Hematology.)

Background: CASSIOPEIA part 1 showed superior depth of response and significantly improved progression-free survival with daratumumab, bortezomib, thalidomide, and dexamethasone (D-VTd) versus bortezomib, thalidomide, and dexamethasone (VTd) as induction and consolidation in patients with autologous stem-cell transplant (ASCT)-eligible newly diagnosed multiple myeloma. In part 2, we compared daratumumab maintenance versus observation only., Methods: CASSIOPEIA is a two-part, open-label, randomised, phase 3 trial of patients aged 18-65 years with newly diagnosed multiple myeloma and Eastern Cooperative Oncology Group performance status 0-2, done in 111 European academic and community practice centres. In part 1, patients were randomly assigned (1:1) to induction and consolidation with D-VTd or VTd. Patients still on study who had a partial response or better were randomly assigned (1:1) by an interactive web-response system to daratumumab 16 mg/kg intravenously every 8 weeks (a reduced frequency compared with standard daratumumab long-term dosing) or observation only for up to 2 years. Stratification factors were induction treatment and depth of response in part 1. The part 2 primary endpoint was progression-free survival from second randomisation. This preplanned interim analysis of progression-free survival was done after 281 events and shall be considered the primary analysis of progression-free survival. Sponsor personnel and designees who were involved in the analysis were masked to treatment group until the independent data monitoring committee recommended that the preplanned interim analysis be considered the main analysis of progression-free survival in part 2. Otherwise, treatment assignments were unmasked. The interaction between induction and consolidation and maintenance was tested at a two-sided significance level of 0·05 by a stratified Cox regression model that included the interaction term between maintenance treatment and induction and consolidation treatment. Efficacy analyses were done in the maintenance-specific intention-to-treat population, which comprised all patients who underwent second randomisation. Safety was analysed in all patients in the daratumumab group who received at least one dose and all patients randomly assigned to observation only. This trial is registered with ClinicalTrials.gov, NCT02541383. Long-term follow-up is ongoing and the trial is closed to new participants., Findings: Between May 30, 2016, and June 18, 2018, 886 patients (458 [84%] of 543 in the D-VTd group and 428 [79%] of 542 in the VTd group) were randomly assigned to daratumumab maintenance (n=442) or observation only (n=444). At a median follow-up of 35·4 months (IQR 30·2-39·9) from second randomisation, median progression-free survival was not reached (95% CI not evaluable [NE]-NE) with daratumumab versus 46·7 months (40·0-NE) with observation only (hazard ratio 0·53, 95% CI 0·42-0·68, p<0·0001). A prespecified analysis of progression-free survival results showed a significant interaction between maintenance and induction and consolidation therapy (p<0·0001). The most common grade 3 or 4 adverse events were lymphopenia (16 [4%] of 440 patients in the daratumumab group vs eight [2%] of 444 patients in the observation-only group), hypertension (13 [3%] vs seven [2%]), and neutropenia (nine [2%] vs ten [2%]). Serious adverse events occurred in 100 (23%) patients in the daratumumab group and 84 (19%) patients in the observation-only group. In the daratumumab group, two adverse events led to death (septic shock and natural killer-cell lymphoblastic lymphoma); both were related to treatment., Interpretation: Daratumumab maintenance every 8 weeks for 2 years significantly reduced the risk of disease progression or death compared with observation only. Longer follow-up and other ongoing studies will shed further light on the optimal daratumumab-containing post-ASCT maintenance treatment strategy., Funding: Janssen Research & Development, the Intergroupe Francophone du Myélome, and the Dutch-Belgian Cooperative Trial Group for Hematology Oncology., Competing Interests: Declaration of interests PM reports personal fees from Celgene, Amgen, Takeda, Janssen, and AbbVie, outside the submitted work. CH reports personal fees from Janssen, AbbVie, Amgen, and Celgene, outside the submitted work. AP reports personal fees from Celgene, Amgen, Janssen, Sanofi, and Takeda, outside the submitted work. BA reports grants from Amgen, Celgene, Sanofi, and Janssen, during the conduct of the study; personal fees from Amgen, Celgene/Bristol Myers Squibb, Sanofi, GlaxoSmithKline, Takeda, and Janssen, outside the submitted work; and advisory board participation from Amgen, Celgene/Bristol Myers Squibb, Sanofi, GlaxoSmithKline, and Janssen, outside the submitted work. KB reports grants from Celgene outside the submitted work; personal fees from Celgene, Janssen, Takeda, and Amgen, outside the submitted work; and non-financial support from Celgene, AbbVie, and Takeda, outside the submitted work. SZ reports grants from Celgene, Janssen, and Takeda, during the conduct of the study. MD reports grants from Celgene and Janssen during the conduct of the study; participation on an advisory board for Celgene, Takeda, Janssen, Sanofi, and Oncopeptides, outside the submitted work. TD reports grants from Celgene and Janssen, during the conduct of the study; and personal fees and advisory board participation from Celgene, Takeda, Janssen, and Amgen, outside of the submitted work. CD reports personal fees from Janssen, outside the submitted work. TF reports personal fees from Janssen, Bristol Myers Squibb, Takeda, Amgen, Roche, Karyopharm, Sanofi, and Oncopeptides, outside the submitted work. CS reports personal fees from Celgene, outside the submitted work. MMo reports grants from Stemline, BMS, Amgen, Jazz Pharmaceuticals, Novartis, Takeda, Janssen, GSK, Sanofi, and Celgene; non-financial support from Stemline, BMS, Amgen, Jazz Pharmaceuticals, Novartis, Takeda, Janssen, GSK, Sanofi, and Celgene; and personal fees from Stemline, BMS, Amgen, Jazz Pharmaceuticals, Novartis, Takeda, Janssen, GSK, Sanofi, and Celgene, outside the submitted work. LK reports personal fees from Amgen, Janssen, Celgene, Takeda, and AbbVie, outside the submitted work. XL reports personal fees from Janssen, outside the submitted work. MMa reports personal fees from and advisory board participation for Amgen, Celgene, Janssen, and Takeda, outside the submitted work. A-MS reports personal fees from Celgene outside the submitted work. NWCJvdD reports grants from Amgen, Bristol Myers Squibb, Celgene, Janssen, and Novartis, during the conduct of the study; and personal fees from Amgen, Bristol Myers Squibb, Celgene, Janssen, Novartis, Bayer, Roche, Servier, and Takeda, outside the submitted work. AB reports personal fees from Amgen, Celgene, Janssen, and Bristol Myers Squibb, outside the submitted work. CT reports personal fees from Janssen, outside the submitter work. MR reports grants from Janssen, during the conduct of the study; personal fees and travel support from Celgene, Amgen, Sanofi, Takeda, and Janssen, outside the submitted work. M-DL reports grants from AbbVie, Amgen, Janssen, Roche, and Takeda, during the conduct of the study; and personal fees and advisory board participation from AbbVie, Janssen, Roche, and Takeda, outside the submitted work. TA reports employment and equity ownership from Genmab. MK reports employment with Janssen. KZ reports employment with Janssen. CdB reports employment and equity ownership from Janssen. SV reports employment with Janssen. TK reports employment with Janssen. VV reports employment with Janssen. JV reports employment with Janssen. HA-L reports grants from Celgene and Janssen, during the conduct of the study; and personal fees from Celgene, Amgen, Bristol-Myers Squibb, Sanofi, and Janssen, outside the submitted work. PS reports personal fees from Celgene and Janssen, outside the submitted work. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

There is no established standard treatment for relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) in patients who are not eligible to receive an intensive treatment. The combination of rituximab gemcitabine and oxaliplatin (R-GemOx) is widely used in this population but data are scarce. We retrospectively collected the data of 196 patients with R/R DLBCL treated with R-GemOx in two French centers over a period of 15 years. The median age of the population was 72 years (range, 24-89), 63% of the patients had an international prognostic index of 3 or higher and 57% were refractory to the last treatment. At the end of R-GemOx treatment, 33% of the patients obtained a complete response. The median progression-free survival (PFS) of the population was 5 months and the median overall survival (OS) was 10 months. Several factors were predictors of unfavorable survival: age over 75 years, international prognostic index of 2 or higher, refractory disease and de novo DLBCL. The median PFS and OS of the patients who obtained a complete response were 22 months and 40 months, respectively. The most significant toxicities were grade 3-4 hematological toxicities (31% of patients). Given its efficacy and tolerability, R-GemOx can be used in patients ineligible for intensive treatment and serve as a basis for new regimen combinations.

Bortezomib, lenalidomide, and dexamethasone plus transplant is a standard of care for eligible patients with multiple myeloma. Because responses can deepen with time, regimens with longer and more potent induction/consolidation phases are needed. In this phase 2 study, patients received eight 28-day cycles of carfilzomib (K) 20/36 mg/m2 (days 1-2, 8-9, 15-16), lenalidomide (R) 25 mg (days 1-21), and dexamethasone (d) 20 mg (days 1-2, 8-9, 15-16, 22-23). All patients proceeded to transplant after 4 cycles and received 1 year of lenalidomide maintenance (10 mg, days 1-21). The primary objective was stringent complete response at the completion of consolidation. Overall, 48 patients were screened and 46 enrolled; 21% had adverse cytogenetics. Among 42 evaluable patients after consolidation, 26 were in stringent complete response (CR; 61.9%), 27 were at least in CR (64.3%): 92.6% had undetectable minimal residual disease according to flow cytometry (≥2.5 × 10-5) and 63.0% according to next-generation sequencing (10-6). Median time to CR was 10.6 months. According to multiparametric flow cytometry and next-generation sequencing, 69.0% and 66.7% of patients, respectively, had undetectable minimal residual disease at some point. With a median follow-up of 60.5 months, 21 patients progressed, and 10 died (7 of multiple myeloma). Median progression-free survival was 56.4 months. There were no KRd-related deaths. Four patients discontinued the program due to toxicities; 56 serious adverse events were reported in 31 patients, including 8 cardiovascular events (2 heart failures, 5 pulmonary embolisms or deep vein thrombosis). Common grade 3/4 adverse events were hematologic (74%) and infectious (22%). In summary, 8 cycles of KRd produce fast and deep responses in transplant-eligible patients with newly diagnosed multiple myeloma. The safety profile is acceptable, but cardiovascular adverse events should be closely monitored. This clinical trial is registered at www.clinicaltrials.gov as #NCT02405364., (© 2021 by The American Society of Hematology.)

Despite tremendous improvements in the outcome of patients with multiple myeloma in the past decade, high-risk patients have not benefited from the approval of novel drugs. The most important prognostic factor is the loss of parts of the short arm of chromosome 17, known as deletion 17p (del(17p)). A recent publication (on a small number of patients) suggested that these patients are at very high-risk only if del(17p) is associated with TP53 mutations, the so-called "double-hit" population. To validate this finding, we designed a much larger study on 121 patients presenting del(17p) in > 55% of their plasma cells, and homogeneously treated by an intensive approach. For these 121 patients, we performed deep next generation sequencing targeted on TP53. The outcome was then compared with a large control population (2505 patients lacking del(17p)). Our results confirmed that the "double hit" situation is the worst (median survival = 36 months), but that del(17p) alone also confers a poor outcome compared with the control cohort (median survival = 52.8 months vs 152.2 months, respectively). In conclusion, our study clearly confirms the extremely poor outcome of patients displaying "double hit," but also that del(17p) alone is still a very high-risk feature, confirming its value as a prognostic indicator for poor outcome., (© 2021 by The American Society of Hematology.)

Introduction: Rituximab is a standard treatment for gastric mucosa-associated lymphoid tissue (MALT) lymphoma (GML). We sought to compare the effectiveness and safety of subcutaneous and intravenous rituximab in a retrospective case-control study., Patients and Methods: All consecutive patients with GML treated with subcutaneous rituximab between January 2017 and December 2018 were included and compared to 3 matched control patients (based on Ann Arbor classification, presence of t(11;18) translocation, history of treatment, and type of current treatment) treated with intravenous rituximab between January 2000 and December 2018. Patients with t(11;18) translocation were treated with rituximab in combination with chlorambucil; the other patients were treated with rituximab alone. Effectiveness was assessed at week 52, and safety was assessed through weeks 0 to 52 and compared by the chi-square test., Results: Twenty-five patients were included in the subcutaneous rituximab group and 75 in the intravenous group. There was no difference between the groups in complete remission (78% vs. 76%, P = .99) or overall response rates (91% vs. 89%, P = .99) at week 52. Safety profiles were similar in both groups, with a significant decrease in postinduction grade 2 injection-related reactions and outpatient hospital length of stay in the subcutaneous rituximab group., Conclusion: In a small case-control study, we did not find any difference in the effectiveness or safety profiles between subcutaneously and intravenously delivered rituximab for the treatment of patients with GML. We found a decrease in postinduction grade 2 injection-related reactions and outpatient hospital length of stay in the subcutaneous rituximab group., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: We report a multicenter controlled trial comparing renal recovery and tolerance profile of doublet versus triplet bortezomib-based regimens in patients with initial myeloma cast nephropathy (CN) and acute kidney injury (AKI) without need for dialysis., Methods: After symptomatic measures and high-dose dexamethasone, patients were randomly assigned to receive bortezomib plus dexamethasone (BD), or BD plus cyclophosphamide (C-BD). In patients with < 50% reduction of serum free light chains (sFLCs) after 3 cycles, chemotherapy was reinforced with either cyclophosphamide (BD group) or thalidomide (C-BD group)., Results: Ninety-two patients were enrolled in each group. At random assignment, characteristics of the 2 groups were similar, including median age (68 years) and serum creatinine level (305.5 and 273.5 µmol/L in BD and C-BD group, respectively). At 3 months, renal response rate (primary end point) was not different (41 v 47 responders in the BD and C-BD groups, respectively; relative risk [RR], 0.87; P = .46). Very good partial response (free light chain reduction ≥ 90%) or more was achieved in 36 and 47 patients, respectively (RR, 0.76; P = .10). After 1 cycle of chemotherapy, 69 in the BD group and 67 patients in the C-BD group had achieved sFLC level ≤ 500 mg/L. Serious adverse events were recorded in 30 and 40 patients, respectively. At 12 months, 19 patients had died (9 in the BD group v 10 in the C-BD group), including 10 (6 in the BD group and 4 in the C-BD group) from myeloma progression and 3 (0 in the BD group and 3 in the C-BD group) from infection. Within median follow-up of 27 months, 43 and 42 patients switched to new therapy, respectively. Overall, 50 patients (24 in the BD group and 26 in the C-BD group) had died., Conclusion: This randomized study did not show any benefit of C-BD compared with BD on renal recovery of patients with initial CN not requiring dialysis. Adding cyclophosphamide did not sufficiently improve the efficacy-toxicity balance. Patients with myeloma with AKI are fragile, and indication for doublet or triplet regimen should be adapted to frailty.

The Intergroupe Francophone du Myelome 2009 trial (NCT01191060) assessed health-related quality of life (HRQoL) in patients with newly diagnosed multiple myeloma (NDMM) receiving lenalidomide/bortezomib/dexamethasone (RVd) induction therapy followed by consolidation therapy with either autologous stem cell transplantation (ASCT) plus RVd (RVd-ASCT) or RVd-alone; both groups then received lenalidomide maintenance therapy for 1 year. Global HRQoL, physical functioning, and role functioning scores significantly improved for both cohorts from baseline to the end of consolidation and were sustained during maintenance and follow-up, with clinically meaningful changes (RVd-alone: p  = .0002; RVd-ASCT: p  < .001). Similarly, both groups showed clinically meaningful improvements from baseline in fatigue, pain, and disease symptom scores. Side effects of treatment scores remained stable. In the RVd-ASCT group, there was transient worsening in HRQoL immediately after ASCT. These findings suggest that the clinical improvements observed with RVd-based treatment are accompanied by overall improvements in HRQoL for patients with NDMM.

Primary colonic mucosa-associated lymphoid tissue (MALT) lymphoma accounts for less than 0.5% of all colon cancers. We report 9 cases of colonic MALT lymphomas (median follow up: 9 [IQR 1-26] years). The disease was multi-focal in 4 patients: the most frequent sites were the cecum in 4 and the rectum in 3 patients. The main endoscopic finding was a polypoid lesion. The treatment modalities were rituximab +/- an alkylating agent ( n  = 5), an alkylating agent alone ( n  = 2), surgical resection ( n  = 1), and endoscopic resection ( n  = 1). Remission was achieved in 8 cases. Three patients relapsed, and 2 were re-treated. At the end of the study period, 67% of the patients were in remission. All patients were symptom-free. This current series of colonic MALT lymphomas shows the indolent nature of the disease, which may be treated with various modalities.

Background: Bortezomib, thalidomide, and dexamethasone (VTd) plus autologous stem-cell transplantation is standard treatment in Europe for transplant-eligible patients with newly diagnosed multiple myeloma. We evaluated whether the addition of daratumumab to VTd before and after autologous stem-cell transplantation would improve stringent complete response rate in patients with newly diagnosed multiple myeloma., Methods: In this two-part, randomised, open-label, phase 3 CASSIOPEIA trial, we recruited transplant-eligible patients with newly diagnosed multiple myeloma at 111 European sites. Patients were randomly assigned (1:1) to receive four pre-transplant induction and two post-transplant consolidation cycles of VTd alone (VTd group) or in combination with daratumumab (D-VTd group). The primary endpoint of part 1 was stringent complete response assessed 100 days after transplantation. Part 2 (maintenance) is ongoing. The trial is registered with ClinicalTrials.gov, number NCT02541383., Findings: Between Sept 22, 2015, and Aug 1, 2017, 1085 patients were enrolled at 111 European sites and were randomly assigned to the D-VTd group (n=543) or the VTd group (n=542). At day 100 after transplantation, 157 (29%) of 543 patients in the D-VTd group and 110 (20%) of 542 patients in the VTd group in the intention-to-treat population had achieved a stringent complete response (odds ratio 1·60, 95% CI 1·21-2·12, p=0·0010). 211 (39%) patients in the D-VTd group versus 141 (26%) in the VTd group achieved a complete response or better, and 346 (64%) of 543 versus 236 (44%) of 542 achieved minimal residual disease-negativity (10 -5 sensitivity threshold, assessed by multiparametric flow cytometry; both p<0·0001). Median progression-free survival from first randomisation was not reached in either group (hazard ratio 0·47, 95% CI 0·33-0·67, p<0·0001). 46 deaths on study were observed (14 vs 32, 0·43, 95% CI 0·23-0·80). The most common grade 3 or 4 adverse events were neutropenia (28% vs 15%), lymphopenia (17% vs 10%), and stomatitis (13% vs 16%)., Interpretation: D-VTd before and after autologous stem-cell transplantation improved depth of response and progression-free survival with acceptable safety. CASSIOPEIA is the first study showing the clinical benefit of daratumumab plus standard of care in transplant-eligible patients with newly diagnosed multiple myeloma., Funding: The Intergroupe Francophone du Myélome and Dutch-Belgian Cooperative Trial Group for Hematology Oncology., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Purpose: The wide heterogeneity in multiple myeloma (MM) outcome is driven mainly by cytogenetic abnormalities. The current definition of high-risk profile is restrictive and oversimplified. To adapt MM treatment to risk, we need to better define a cytogenetic risk classification. To address this issue, we simultaneously examined the prognostic impact of del(17p); t(4;14); del(1p32); 1q21 gain; and trisomies 3, 5, and 21 in a cohort of newly diagnosed patients with MM., Methods: Data were obtained from 1,635 patients enrolled in four trials implemented by the Intergroupe Francophone du Myélome. The oldest collection of data were used for model development and internal validation. For external validation, one of the two independent data sets was used to assess the performance of the model in patients treated with more current regimens. Six cytogenetic abnormalities were identified as clinically relevant, and a prognostic index (PI) that was based on the parameter estimates of the multivariable Cox model was computed for all patients., Results: In all data sets, a higher PI was consistently associated with a poor survival outcome. Dependent on the validation cohorts used, hazard ratios for patients in the high-risk category for death were between six and 15 times higher than those of patients in the low-risk category. Among patients with t(4;14) or del(17p), we observed a worse survival in those classified in the high-risk category than in those in the intermediate-risk category. The PI showed good performance for discriminating between patients who died and those who survived (Harrell's concordance index greater than 70%)., Conclusion: The cytogenetic PI improves the classification of newly diagnosed patients with MM in the high-risk group compared with current classifications. These findings may facilitate the development of risk-adapted treatment strategies.

Background: Donor-specific antibodies are associated with increased risk of antibody-mediated rejection and decreased allograft survival. Therefore, reducing the risk of these antibodies remains a clinical need in transplantation. Plasma cells are a logical target of therapy given their critical role in antibody production., Methods: To target plasma cells, we treated sensitized rhesus macaques with daratumumab (anti-CD38 mAb). Before transplant, we sensitized eight macaques with two sequential skin grafts from MHC-mismatched donors; four of them were also desensitized with daratumumab and plerixafor (anti-CXCR4). We also treated two patients with daratumumab in the context of transplant., Results: The animals treated with daratumumab had significantly reduced donor-specific antibody levels compared with untreated controls (57.9% versus 13% reduction; P <0.05) and prolonged renal graft survival (28.0 days versus 5.2 days; P <0.01). However, the reduction in donor-specific antibodies was not maintained because all recipients demonstrated rapid rebound of antibodies, with profound T cell-mediated rejection. In the two clinical patients, a combined heart and kidney transplant recipient with refractory antibody-mediated rejection and a highly sensitized heart transplant candidate, we also observed a significant decrease in class 1 and 2 donor-specific antibodies that led to clinical improvement of antibody-mediated rejection and to heart graft access., Conclusions: Targeting CD38 with daratumumab significantly reduced anti-HLA antibodies and anti-HLA donor-specific antibodies in a nonhuman primate model and in two transplant clinical cases before and after transplant. This supports investigation of daratumumab as a potential therapeutic strategy; however, further research is needed regarding its use for both antibody-mediated rejection and desensitization., (Copyright © 2019 by the American Society of Nephrology.)

Objective: To describe the prevalence of and risk factors for renal infarction (RI) in patients with cardiac amyloidosis., Patients and Methods: We evaluated 87 patients with cardiac amyloidosis who underwent renal technetium-99m-labeled dimercaptosuccinic acid scintigraphy in the Amyloidosis Referral Center of Henri-Mondor Hospital from October 1, 2015, through February 28, 2018., Results: Three groups of patients were identified according to the underlying amyloidosis disorder: AL amyloidosis in 24 patients, mutated-transthyretin amyloidosis in 24 patients, and wild-type transthyretin amyloidosis in 39 patients. Patients with wild-type transthyretin amyloidosis were older (P<.001), more likely to be men (P=.02), to have arrhythmic heart diseases (P<.001), and to be receiving anticoagulation treatment (P<.001). Patients with AL amyloidosis had significantly higher N-terminal pro-B-type natriuretic peptide levels (P=.02) and were more likely to have nephrotic syndrome (P<.001). Renal infarction was detected in 18 patients (20.7%), at similar frequencies in the various groups. Baseline urinary protein to creatinine ratio was the only parameter for which a significant difference (P=.03) was found between patients with and without RI diagnoses. The likelihood of RI diagnosis was 47.1% (8 of 17) in the presence of AKI and 14.5% (10 of 69) in its absence (P=.003). Overall, heart transplant-censored patient survival did not differ significantly between patients with and without RI (P=.64), but death- and heart transplant-censored renal survival was significantly lower in patients with RI (P<.001)., Conclusion: Our study suggests that prevalence of RI in patients with cardiac amyloidosis is higher than previously thought, regardless of the underlying amyloidosis disorder. Acute kidney injury in a patient with cardiac amyloidosis should alert clinicians to the possibility of RI., (Copyright © 2019 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

It is important to have an effective therapy for patients with multiple myeloma (MM) at first relapse, particularly if an autologous stem cell transplant (ASCT) is considered at this stage. This multicenter, phase 2 trial evaluated the efficacy and safety of weekly oral pomalidomide-cyclophosphamide-dexamethasone (PCD) in patients with MM in first relapse after treatment with lenalidomide-bortezomib-dexamethasone (RVD). All patients had received RVD as induction and consolidation therapy, plus lenalidomide maintenance for 1 year (arm A). Half had also received an ASCT after induction (arm B). At MM relapse, all patients received 4 oral cycles of pomalidomide 4 mg (days 1-21), cyclophosphamide 300 mg (days 1, 8, 15, and 22), and dexamethasone 40 mg (days 1-4 and days 15-18 of a 28-day cycle; PCD). Responding patients in arm A underwent ASCT and received 2 additional cycles of PCD, whereas those in arm B received 5 cycles of PCD. All patients received pomalidomide-dexamethasone maintenance until disease progression. Primary end point was partial remission or better after the initial 4 cycles of PCD. Responses were obtained in 82/97 (85%) patients evaluated: complete remission (n = 1; 1%), very good partial remission (n = 32; 33%), and partial remission (n = 49; 51%). Three patients (3%) had stable disease, and 6 (6%) had disease progression (6 response failures). Forty-five (94%) of the 48 patients in arm A underwent planned ASCT. PCD was effective therapy after first relapse with RVD. After 4 cycles, the rate of partial remission or better was 85%, and 94% of planned ASCTs were performed. Toxicity was mostly hematologic and manageable. This trial was registered at www.clinicaltrials.gov as #NCT02244125., (© 2018 by The American Society of Hematology.)

The introduction of novel agents has led to major improvements in clinical outcomes for patients with multiple myeloma. To shorten evaluation times for new treatments, health agencies are currently examining minimal residual disease (MRD) as a surrogate end point in clinical trials. We assessed the prognostic value of MRD, measured during maintenance therapy by next-generation sequencing (NGS). MRD negativity was defined as the absence of tumor plasma cell within 1 000 000 bone marrow cells (<10 -6 ). Data were analyzed from a recent clinical trial that evaluated the role of transplantation in newly diagnosed myeloma patients treated with lenalidomide, bortezomib, and dexamethasone (RVD). MRD negativity was achieved at least once during maintenance in 127 patients (25%). At the start of maintenance therapy, MRD was a strong prognostic factor for both progression-free survival (adjusted hazard ratio, 0.22; 95% confidence interval, 0.15-0.34; P < .001) and overall survival (adjusted hazard ratio, 0.24; 95% confidence interval, 0.11-0.54; P = .001). Patients who were MRD negative had a higher probability of prolonged progression-free survival than patients with detectable residual disease, regardless of treatment group (RVD vs transplant), cytogenetic risk profile, or International Staging System disease stage at diagnosis. These results were similar after completion of maintenance therapy. Our findings confirm the value of MRD status, as determined by NGS, as a prognostic biomarker in multiple myeloma, and suggest that this approach could be used to adapt treatment strategies in future clinical trials., (© 2018 by The American Society of Hematology.)

Purpose To analyze the frequency and distribution of low-signal-intensity regions (LSIRs) in lymphoma lesions and to compare these to fluorodeoxyglucose (FDG) uptake and biologic markers of inflammation. Materials and Methods The authors analyzed 61 untreated patients with a bulky lymphoma (at least one tumor mass ≥7 cm in diameter). When a LSIR within tumor lesions was detected on diffusion-weighted images obtained with a b value of 50 sec/mm 2 , a T2-weighted gradient-echo (GRE) sequence was performed and calcifications were searched for with computed tomography (CT). In two patients, Perls staining was performed on tissue samples from the LSIR. LSIRs were compared with biologic inflammatory parameters and baseline FDG positon emission tomography (PET)/CT parameters (maximum standardized uptake value [SUV max ], total metabolic tumor volume [TMTV]). Results LSIRs were detected in 22 patients and corresponded to signal void on GRE images; one LSIR was due to calcifications, and three LSIRS were due to a recent biopsy. In 18 patients, LSIRs appeared to be related to focal iron deposits; this was proven with Perls staining in two patients. The LSIRs presumed to be due to iron deposits were found mostly in patients with aggressive lymphoma (nine of 26 patients with Hodgkin lymphoma and eight of 20 patients with diffuse large B-cell lymphoma vs one of 15 patients with follicular lymphoma; P = .047) and with advanced stage disease (15 of 18 patients). LSIRS were observed in spleen (n = 14), liver (n = 3), and nodal (n = 8) lesions and corresponded to foci FDG uptake, with mean SUV max of 9.8, 6.7, and 16.2, respectively. These patients had significantly higher serum levels of C-reactive protein, α 1 -globulin, and α 2 -globulin and more frequently had microcytic anemia than those without such deposits (P = .0072, P = .003, P = .0068, and P < .0001, respectively). They also had a significantly higher TMTV (P = .0055) and higher levels of spleen involvement (P < .0001). Conclusion LSIRs due to focal iron deposits are detected in lymphoma lesions and are associated with a more pronounced biologic inflammatory syndrome. © RSNA, 2017 Online supplemental material is available for this article.

Background and Aims: To evaluate the prevalence and the long-term course of gastric precancerous lesions in patients with GML., Patients and Methods: In this retrospective single-centre study, we included 179 patients with GML, 70 with gastric diffuse large B-cell lymphoma (GDLBCL) and 152 with Helicobacter pylori-associated gastritis (HpG), from January 1995 to January 2014. The presence of atrophic gastritis, intestinal metaplasia and neoplastic lesion has been assessed at baseline and during follow-up., Results: Atrophic gastritis was more frequent in the GML group whereas there was also a trend for intestinal metaplasia and gastric dysplasia. In patients with GML, atrophic gastritis, intestinal metaplasia and gastric dysplasia were more frequent in the GML area than in other part of the stomach. During follow-up, the prevalence of atrophic gastritis remained stable overtime whereas intestinal metaplasia and dysplasia tend to increase overtime. In multivariate analysis, the occurrence of dysplasia or carcinoma was associated with the presence of intestinal metaplasia at baseline and male gender., Conclusion: GML is associated with gastric precancerous lesion to a higher extent than GDLBCL and HpG. Those precancerous lesions do not regress despite achievement of complete remission of GML and tend to increase overtime., (Copyright © 2017 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

To assess the risk of second primary malignancy (SPM) in patients with gastric mucosa-associated lymphoid tissue (MALT) Lymphoma (GML), we included 175 patients with GML in the present study. The incidence of SPM in the general population, used for reference, was determined from the French network of cancer registries. During the 1442.9 patient-years of follow-up, 29 patients were diagnosed with incident SPM, including five patients diagnosed with gastric cancer (20.1/1000 patient-years). An increased incidence of SPM was observed in patients with GML (standardized incidence ratios [SIR]: 1.71 [1.14-2.45]) compared to the general French population especially for gastric cancer (SIR: 16.1 [5.19-37.56]). This elevated risk of SPM was significantly increased only in patients treated with immuno/chemotherapy but not in patients treated with Helicobacter pylori eradication alone. Long-term follow-up of patients with GML is mandatory even in patients who have achieved complete remission.

Chemotherapy combining cyclophosphamide, bortezomib and dexamethasone is widely used in light-chain amyloidosis. The benefit is limited in patients with cardiac amyloidosis mainly because of adverse cardiac events. Retrospective analysis of our cohort showed that 39 patients died with 42% during the first month. A new escalation-sequential regimen was set to improve the outcomes. Nine newly-diagnosed patients were prospectively treated with close monitoring of serum N-terminal pro-brain natriuretic peptide, troponin-T and free light chains. The results show that corticoids may destabilise the heart through fluid retention. Thus, a sequential protocol may be a promising approach to treat these patients., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: High-dose chemotherapy plus autologous stem-cell transplantation has been the standard treatment for newly diagnosed multiple myeloma in adults up to 65 years of age. However, promising data on the use of combination therapy with lenalidomide, bortezomib, and dexamethasone (RVD) in this population have raised questions about the role and timing of transplantation., Methods: We randomly assigned 700 patients with multiple myeloma to receive induction therapy with three cycles of RVD and then consolidation therapy with either five additional cycles of RVD (350 patients) or high-dose melphalan plus stem-cell transplantation followed by two additional cycles of RVD (350 patients). Patients in both groups received maintenance therapy with lenalidomide for 1 year. The primary end point was progression-free survival., Results: Median progression-free survival was significantly longer in the group that underwent transplantation than in the group that received RVD alone (50 months vs. 36 months; adjusted hazard ratio for disease progression or death, 0.65; P<0.001). This benefit was observed across all patient subgroups, including those stratified according to International Staging System stage and cytogenetic risk. The percentage of patients with a complete response was higher in the transplantation group than in the RVD-alone group (59% vs. 48%, P=0.03), as was the percentage of patients in whom minimal residual disease was not detected (79% vs. 65%, P<0.001). Overall survival at 4 years did not differ significantly between the transplantation group and the RVD-alone group (81% and 82%, respectively). The rate of grade 3 or 4 neutropenia was significantly higher in the transplantation group than in the RVD-alone group (92% vs. 47%), as were the rates of grade 3 or 4 gastrointestinal disorders (28% vs. 7%) and infections (20% vs. 9%). No significant between-group differences were observed in the rates of treatment-related deaths, second primary cancers, thromboembolic events, and peripheral neuropathy., Conclusions: Among adults with multiple myeloma, RVD therapy plus transplantation was associated with significantly longer progression-free survival than RVD therapy alone, but overall survival did not differ significantly between the two approaches. (Supported by Celgene and others; IFM 2009 Study ClinicalTrials.gov number, NCT01191060 .).

Hepatosplenic T-cell lymphoma (HSTL) is a rare and lethal lymphoma; the genetic drivers of this disease are unknown. Through whole-exome sequencing of 68 HSTLs, we define recurrently mutated driver genes and copy-number alterations in the disease. Chromatin-modifying genes, including SETD2, INO80 , and ARID1B , were commonly mutated in HSTL, affecting 62% of cases. HSTLs manifest frequent mutations in STAT5B (31%), STAT3 (9%), and PIK3CD (9%), for which there currently exist potential targeted therapies. In addition, we noted less frequent events in EZH2, KRAS , and TP53 SETD2 was the most frequently silenced gene in HSTL. We experimentally demonstrated that SETD2 acts as a tumor suppressor gene. In addition, we found that mutations in STAT5B and PIK3CD activate critical signaling pathways important to cell survival in HSTL. Our work thus defines the genetic landscape of HSTL and implicates gene mutations linked to HSTL pathogenesis and potential treatment targets. Significance: We report the first systematic application of whole-exome sequencing to define the genetic basis of HSTL, a rare but lethal disease. Our work defines SETD2 as a tumor suppressor gene in HSTL and implicates genes including INO80 and PIK3CD in the disease. Cancer Discov; 7(4); 369-79. ©2017 AACR. See related commentary by Yoshida and Weinstock, p. 352 This article is highlighted in the In This Issue feature, p. 339 ., (©2017 American Association for Cancer Research.)

Guidelines for monitoring multiple myeloma (MM) patients expressing light chains only (light-chain MM [LCMM]) rely on measurements of monoclonal protein in urine. Alternatively, serum free light chain (sFLC) measurements have better sensitivity over urine methods, however, demonstration that improved sensitivity provides any clinical benefit is lacking. Here, we compared performance of serum and urine measurements in 113 (72κ, 41λ) newly diagnosed LCMM patients enrolled in the Intergroupe Francophone du Myélome (IFM) 2009 trial. All diagnostic samples (100%) had an abnormal κ:λ sFLC ratio, and involved (monoclonal) FLC (iFLC) expressed at levels deemed measurable for monitoring (≥100 mg/L). By contrast, only 64% patients had measurable levels of monoclonal protein (≥200 mg per 24 hours) in urine protein electrophoresis (UPEP). After 1 and 3 treatment cycles, iFLC remained elevated in 71% and 46% of patients, respectively, whereas UPEP reported a positive result in 37% and 18%; all of the patients with positive UPEP at cycle 3 also had elevated iFLC levels. Importantly, elevated iFLC or an abnormal κ:λ sFLC ratio after 3 treatment cycles associated with poorer progression-free survival (P = .006 and P < .0001, respectively), whereas positive UPEP or urine immunofixation electrophoresis (uIFE) did not. In addition, patients with an abnormal κ:λ sFLC ratio had poorer overall survival (P = .022). Finally, early normalization of κ:λ sFLC ratio but not negative uIFE predicted achieving negative minimal residual disease, as determined by flow cytometry, after consolidation therapy (100% positive predictive value). We conclude that improved sensitivity and prognostic value of serum over urine measurements provide a strong basis for recommending the former for monitoring LCMM patients., (© 2016 by The American Society of Hematology.)

Purpose: Primary plasma cell leukemia (pPCL) is a rare and aggressive malignancy with a poor prognosis. With conventional chemotherapy, patients typically die within 1 year. In all but one of the retrospective studies reported to date, bortezomib and lenalidomide seem to improve survival. We conducted a prospective phase II trial in patients with pPCL to assess the efficacy of an alternate regimen that combines standard chemotherapy, a proteasome inhibitor, and high-dose melphalan and autologous stem cell transplantation (HDM/ASCT) followed by either allogeneic transplantation or bortezomib/lenalidomide maintenance., Patients and Methods: Patients 70 years old and younger with newly diagnosed pPCL received four alternating cycles of bortezomib, dexamethasone plus doxorubicin or cyclophosphamide. Peripheral blood stem cells were collected from responding patients with < 1% of circulating plasma cells before HDM/ASCT. As consolidation, young patients received a reduced-intensity conditioning allograft, whereas the remaining patients underwent a second HDM/ASCT followed by 1 year of bortezomib, lenalidomide, dexamethasone. The primary end point was progression-free survival (PFS)., Results: Forty patients (median age, 57 years; range, 27 to 71 years) were enrolled. The median follow-up was 28.7 months. In the intention-to-treat analysis, the median PFS and overall survival were 15.1 (95% CI, 8.4; -) and 36.3 (95% CI, 25.6; -) months, respectively. The overall response rate to induction was 69%. One patient underwent a syngeneic allograft and 25 HDM/ASCT (16 of whom subsequently received a reduced-intensity conditioning allograft and seven a second ASCT followed by maintenance)., Conclusion: In this prospective trial in patients with pPCL, we show that bortezomib, dexamethasone plus doxorubicin or cyclophosphamide induction followed by transplantation induces high response rates and appears to significantly improve PFS., (© 2016 by American Society of Clinical Oncology.)

The Intergroupe Francophone du Myélome conducted a randomized trial to compare bortezomib-thalidomide-dexamethasone (VTD) with bortezomib-cyclophosphamide-dexamethasone (VCD) as induction before high-dose therapy and autologous stem cell transplantation (ASCT) in patients with newly diagnosed multiple myeloma. Overall, a total of 340 patients were centrally randomly assigned to receive VTD or VCD. After 4 cycles, on an intent-to-treat basis, 66.3% of the patients in the VTD arm achieved at least a very good partial response (primary end point) vs 56.2% in the VCD arm (P = .05). In addition, the overall response rate was significantly higher in the VTD arm (92.3% vs 83.4% in the VCD arm; P = .01). Hematologic toxicity was higher in the VCD arm, with significantly increased rates of grade 3 and 4 anemia, thrombocytopenia, and neutropenia. On the other hand, the rate of peripheral neuropathy (PN) was significantly higher in the VTD arm. With the exception of hematologic adverse events and PN, other grade 3 or 4 toxicities were rare, with no significant differences between the VTD and VCD arms. Our data support the preferential use of VTD rather than VCD in preparation for ASCT. This trial was registered at www.clinicaltrials.gov as #NCT01564537 and at EudraCT as #2013-003174-27., (© 2016 by The American Society of Hematology.)

Renal impairment is associated with poor prognosis in myeloma. This analysis of the pivotal phase 3 FIRST trial examined the impact of renally adapted dosing of lenalidomide and dexamethasone on outcomes of patients with different degrees of renal impairment. Transplant-ineligible patients not requiring dialysis were randomized 1:1:1 to receive continuous lenalidomide and dexamethasone until disease progression (n=535) or for 18 cycles (72 weeks; n=541), or melphalan, prednisone, and thalidomide for 12 cycles (72 weeks; n=547). Follow-up is ongoing. Patients were grouped by baseline creatinine clearance into no (≥ 80 mL/min [n=389]), mild (≥ 50 to < 80 mL/min [n=715]), moderate (≥ 30 to < 50 mL/min [n=372]), and severe impairment (< 30 mL/min [n=147]) subgroups. Continuous lenalidomide and dexamethasone therapy reduced the risk of progression or death in no, mild, and moderate renal impairment subgroups vs. melphalan, prednisone, and thalidomide therapy (HR = 0.67, 0.70, and 0.65, respectively). Overall survival benefits were observed with continuous lenalidomide and dexamethasone treatment vs. melphalan, prednisone, and thalidomide treatment in no or mild renal impairment subgroups. Renal function improved from baseline in 52.6% of lenalidomide and dexamethasone-treated patients. The safety profile of continuous lenalidomide and dexamethasone was consistent across renal subgroups, except for grade 3/4 anemia and rash, which increased with increasing severity of renal impairment. Continuous lenalidomide and dexamethasone treatment, with renally adapted lenalidomide dosing, was effective for most transplant-ineligible patients with myeloma and renal impairment. Trial registration: ClinicalTrials.gov (NCT00689936); EudraCT (2007-004823-39). Funding: Intergroupe Francophone du Myélome and the Celgene Corporation., (Copyright© Ferrata Storti Foundation.)

The prognosis of multiple myeloma is mainly dependent upon chromosomal changes. The 2 major abnormalities driving poor outcome are del(17p) and t(4;14). However, the outcome of these high-risk patients is not absolutely uniform, with some patients presenting long survival. We hypothesized that these better outcomes might be related to concomitant "good-risk" chromosomal changes exploring hyperdiploidy. We analyzed a large series of 965 myeloma patients, including 168 patients with t(4;14) and 126 patients with del(17p), using high-throughput single-nucleotide polymorphism arrays after plasma cell sorting. As expected, trisomic chromosomes were highly associated. Using the LASSO model, we found that only chromosome 3, when trisomic, was associated with a longer progression-free survival and that 3 trisomies modulated overall survival (OS) in myeloma patients: trisomies 3 and 5 significantly improved OS, whereas trisomy 21 worsened OS. In patients with t(4;14), trisomies 3 and/or 5 seemed to overcome the poor prognosis. For the first time, using a specific modeling approach, we show that not all trisomies display the same prognostic impact. This finding could be important for routine assessment of prognosis in myeloma, and some high-risk patients with a traditional evaluation could in fact be standard-risk patients., (© 2015 by The American Society of Hematology.)

Purpose: To correlate intravoxel incoherent motion (IVIM) diffusion-weighted imaging (DWI) parameters with the enhancement patterns of bone marrow and focal lesion obtained on whole-body (WB) dynamic contrast agent-enhanced (DCE) magnetic resonance (MR) images in patients with stage-III multiple myeloma (MM) before and after systemic therapy., Materials and Methods: Twenty-seven patients with MM were retrospectively included in this institutional review board-approved study. Requirement for written informed consent was waived. All patients underwent WB DCE MR imaging before treatment and 18 patients underwent repeat MR imaging 3 months after treatment. A transverse IVIM DWI sequence with 10 b values (0, 10, 20, 30, 50, 80, 100, 200, 400, and 800 sec/mm(2)) was acquired within bone marrow and focal lesions. The IVIM parameters (perfusion fraction [f], molecular diffusion coefficient [D], and perfusion-related D [D*]) and apparent diffusion coefficient (ADC) were extracted for both focal lesions and bone marrow and correlated with focal lesions and maximal bone marrow enhancement (BMEmax) (Spearman correlation coefficient) at baseline and at follow-up (Wilcoxon signed-rank test)., Results: D and ADC values positively correlated with BMEmax (r = 0.7, P < .001; and r = 0.455, P = .0435, respectively). Patients with increased BMEmax showed significantly increased ADC and D within bone marrow versus patients who did not have increased BMEmax (ADC, 0.67 × 10(-3) mm(2)/sec vs 0.54 × 10(-3) mm(2)/sec, P = .03; D, 0.58 × 10(-3) mm(2)/sec vs 0.42 × 10(-3) mm(2)/sec, P < .001). Within focal lesions, f was the maximum in lesions that showed enhancement followed by washout. After treatment in good responders, the significant decrease in maximal enhancement value of focal lesions (baseline vs after treatment, 213.9% ± 78.7 [standard deviation] vs 131% ± 53.6, respectively; P < .001) was accompanied by a significant decrease in f (baseline vs after treatment, 11% ± 3.8 vs 5.8% ± 4.7, respectively; P < .001)., Conclusion: Diffuse bone marrow involvement is associated with increased D. Hypervascular focal lesions with high maximal enhancement value of focal lesions also show high f value. Likewise, the decreased maximal enhancement value of focal lesions after treatment is accompanied by decreased f.

Diffuse large B-cell lymphoma (DLBCL) with MYC rearrangement (MYC-R) carries an unfavorable outcome. We explored the prognostic value of the MYC translocation partner gene in a series of MYC-R de novo DLBCL patients enrolled in first-line prospective clinical trials (Groupe d'Etudes des Lymphomes de l'Adulte/Lymphoma Study Association) and treated with rituximab-anthracycline-based chemotherapy. A total of 774 DLBCL cases characterized for cell of origin by the Hans classifier were analyzed using fluorescence in situ hybridization with BCL2, BCL6, MYC, immunoglobulin (IG)K, and IGL break-apart and IGH/MYC, IGK/MYC, and IGL/MYC fusion probes. MYC-R was observed in 51/574 (8.9%) evaluable DLBCL cases. MYC-R cases were predominantly of the germinal center B-cell-like subtype 37/51 (74%) with no distinctive morphologic and phenotypic features. Nineteen cases were MYC single-hit and 32 cases were MYC double-hit (MYC plus BCL2 and/or BCL6) DLBCL. MYC translocation partner was an IG gene in 24 cases (MYC-IG) and a non-IG gene (MYC-non-IG) in 26 of 50 evaluable cases. Noteworthy, MYC-IG patients had shorter overall survival (OS) (P = .0002) compared with MYC-negative patients, whereas no survival difference was observed between MYC-non-IG and MYC-negative patients. In multivariate analyses, MYC-IG predicted poor progression-free survival (P = .0051) and OS (P = .0006) independently from the International Prognostic Index and the Hans classifier. In conclusion, we show in this prospective randomized trial that the adverse prognostic impact of MYC-R is correlated to the MYC-IG translocation partner gene in DLBCL patients treated with immunochemotherapy. These results may have an important impact on the clinical management of DLBCL patients with MYC-R who should be routinely characterized according to MYC partner gene. These trials are individually registered at www.clinicaltrials.gov as #NCT00144807, #NCT01087424, #NCT00169143, #NCT00144755, #NCT00140660, #NCT00140595, and #NCT00135499., (© 2015 by The American Society of Hematology.)

Whole-body imaging, in particular molecular imaging with fluorine 18 ((18)F)-fluorodeoxyglucose (FDG) positron emission tomography (PET), is essential to management of lymphoma. The assessment of disease extent provided by use of whole-body imaging is mandatory for planning appropriate treatment and determining patient prognosis. Assessment of treatment response allows clinicians to tailor the treatment strategy during therapy if necessary and to document complete remission at the end of treatment. Because of rapid technical developments, such as echo-planar sequences, parallel imaging, multichannel phased-array surface coils, respiratory gating, and moving examination tables, whole-body diffusion-weighted (DW) magnetic resonance (MR) imaging that reflects cell density is now feasible in routine clinical practice. Whole-body DW MR imaging allows anatomic assessment as well as functional and quantitative evaluation of tumor sites by calculation of the apparent diffusion coefficient (ADC). Because of their high cellularity and high nucleus-to-cytoplasm ratio, lymphomatous lesions have low ADC values and appear hypointense on ADC maps. As a result, whole-body DW MR imaging with ADC mapping has become a promising tool for lymphoma staging and treatment response assessment. The authors review their 4 years of experience with 1.5-T and 3-T whole-body DW MR imaging used with (18)F-FDG PET/computed tomography at baseline, interim, and end of treatment in patients with Hodgkin lymphoma and diffuse large B-cell lymphoma and discuss the spectrum of imaging findings and potential pitfalls, limitations, and challenges associated with whole-body DW MR imaging in these patients., ((©)RSNA, 2015.)

In multiple myeloma, cytogenetic changes are important predictors of patient outcome. In this setting, the most important changes are deletion 17p, del(17p), and translocation of chromosomes 4 and 14, t(4;14), conferring a poor outcome. However, a certain degree of heterogeneity is observed in the survival of these high-risk patients. We hypothesized that other chromosomal changes may impact the outcome. We retrospectively analyzed a large series of 242 patients displaying either t(4;14) (157 patients) or del(17p) (110 patients), 25 patients presenting both abnormalities, using single nucleotide polymorphism array. In patients with t(4;14), del(1p32), del22q, and >30 chromosomal structural changes negatively impacted progression-free survival (PFS). For overall survival (OS), del(13q14), del(1p32), and the number of chromosomal structural changes worsened the prognosis of patients. For patients with del(17p), del6q worsened the prognosis of patients, whereas trisomy 15 and monosomy 14 were found to have a protective effect on PFS. For OS, del(1p32) worsened the prognosis of patients, whereas having >8 numerical changes was found to have a protective effect on survival. This study, which is the largest series of high-risk patients analyzed with the most modern genomic technique, identified 1 main factor negatively impacting survival: del(1p32).

Anti-CD20-containing chemotherapy regimens have become the standard of care for patients with follicular lymphoma needing cytotoxic therapy. Four randomized trials demonstrated a clinical benefit for patients treated with rituximab. However, no long-term follow up (i.e. > 5 years) of these trials is yet available. Between May 2000 and May 2002, 358 newly diagnosed patients with high tumor burden follicular lymphoma were randomized to receive cyclophosphamide, adriamycin, etoposide and prednisolone plus interferon-α2a or a similar chemotherapy-based regimen plus rituximab, and outcome was up-dated. With a median follow up of 8.3 years, addition of rituximab remained significantly associated with prolonged event-free survival (primary end point) (P=0.0004) with a trend towards a benefit for overall survival (P=0.076). The Follicular Lymphoma International Prognostic Index score was strongly associated with outcome for both event-free and overall survival in univariate analysis and its prognostic value remained highly significant after adjusting for other significant covariates in multivariate models (P<0.0001 and P=0.001, respectively). Considering long-term toxicity, the addition of rituximab in the first-line setting was confirmed as safe with regards to development of secondary malignancies. Long-term follow up of patients with follicular lymphoma treated in the FL2000 study confirms the sustained clinical benefit of rituximab without long-term toxicity.

Forty-nine patients, t(11;18)-positive (n = 31) and t(11;18)-negative (n = 18), were treated without randomization with rituximab-chlorambucil or rituximab alone. Evaluation was performed at week (W) 6, week (W) 25 and every 6 months (Wx). Comparing the rituximab-chlorambucil group to the rituximab-alone group, remission was obtained in 93% vs. 66% at W6 (p = 0.01), in 93% vs. 81% at W25 (p = 0.14) and in 93% vs. 76% at Wx (p = 0.07). Comparing the rituximab-chlorambucil group to the rituximab-alone group in t(11;18)-positive patients, remission was obtained in 100% vs. 45% at W6 (p = 0.0005), in 100% vs. 66% at W25 (p = 0.01) and in 96% vs. 55% at Wx (p = 0.01). Comparing the rituximab-chlorambucil group to the rituximab-alone group in t(11;18)-negative patients, remission was obtained in 66% vs. 83% at W6 (p = 0.32), in 66% vs. 92% at W25 (p = 0.22) and in 83% vs. 92% at Wx (p = 0.47). In conclusion, rituximab-chlorambucil is significantly more rapidly efficient than rituximab alone. In t(11;18)-positive patients, the combination is more efficient than rituximab alone. In t(11;18)-negative patients, rituximab alone is as efficient as rituximab-chlorambucil and may be an alternative treatment.

Epstein-Barr virus (EBV)-infected B cells with Reed-Sternberg-like cell (RS) features may occur in peripheral T-cell lymphomas (PTCLs), especially in angioimmunoblastic T-cell lymphoma. Here, we report 5 patients presenting with lymphadenopathy whose first biopsies demonstrated nodular lymphoid proliferations containing scattered CD30+, CD15+, EBV+ Hodgkin and Reed-Sternberg-like cells, which led to an initial diagnosis of lymphocyte-rich classical Hodgkin lymphoma. However, the uncommon clinical features and/or the occurrence of relapse as PTCL prompted review of the biopsies with expanded immunohistologic and molecular studies and revision of the diagnoses to follicular variant of PTCL (F-PTCL). All cases had atypical small to medium-sized CD3+ T cells that expressed CD10 (4/5) and the follicular helper T-cell (TFH) antigens BCL6, PD1, CXCL13, and ICOS. All demonstrated clonal T cells with a similar pattern in multiple samples from 4 patients. In 2 cases, flow cytometry demonstrated circulating lymphocytes with an abnormal sCD3+, CD4+, ICOS+ immunophenotype. Two patients had a skin rash at presentation, and 1 had B symptoms. Two of the 4 patients treated with polychemotherapy are alive at 3 and 6 years after first diagnosis. These cases highlight how some F-PTCLs may closely mimic lymphocyte-rich classical Hodgkin lymphoma requiring careful assessment of the T cells before rendering the latter diagnosis. The functional properties of TFH cells might lead to the presence of EBV-positive B blasts with RS-like features in TFH-derived PTCL such as angioimmunoblastic T-cell lymphoma and F-PTCL.