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Background: IMAGE is a retrospective cohort study of patients enrolled in early access programs (EAPs) in France with relapsed/refractory multiple myeloma (RRMM) receiving isatuximab with pomalidomide and dexamethasone (Isa-Pd)., Methods: Patients aged ≥18 years with RRMM who received ≥1 dose of Isa under the EAPs between July 29, 2019 and August 30, 2020 were included. Effectiveness endpoints included progression-free survival (PFS) and response rates. Verbatim terms for adverse events (AEs) were coded using the Medical Dictionary for Regulatory Activities and not graded for severity., Results: A total of 294 and 299 patients were included in the effectiveness and safety populations, respectively. IMAGE included patients who received one prior line of treatment (10.2%) and were daratumumab-refractory (19.1%). At median follow-up of 14.2 months, median PFS in the effectiveness population was 12.4 months (95% CI 9.0-15.0). Overall response and very good partial response rates were 46.3% and 27.9%, respectively. Subgroup analyses reflected similar results. In the safety population, 26.4% of patients reported at least one AE; the most common any-grade AE was neutropenia (9.4%)., Conclusion: IMAGE demonstrated Isa-Pd had meaningful effectiveness in median PFS and depth of response and no new safety signals in a real-world context, consistent with clinical trial results., (© 2024 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

Background: CASSIOPEIA part 1 demonstrated superior depth of response and prolonged progression-free survival with daratumumab in combination with bortezomib, thalidomide, and dexamethasone (D-VTd) versus bortezomib, thalidomide, and dexamethasone (VTd) alone as an induction and consolidation regimen in transplant-eligible patients newly diagnosed with myeloma. In CASSIOPEIA part 2, daratumumab maintenance significantly improved progression-free survival and increased minimal residual disease (MRD)-negativity rates versus observation. Here, we report long-term study outcomes of CASSIOPEIA., Methods: CASSIOPEIA was a two-part, open-label, phase 3 trial of patients done at 111 European academic and community-based centres. Eligible patients were aged 18-65 years with transplant-eligible newly diagnosed myeloma and an Eastern Cooperative Oncology Group performance status of 0-2. In part 1, patients were randomly assigned (1:1) to pre-transplant induction and post-transplant consolidation with D-VTd or VTd. Patients who completed consolidation and had a partial response or better were re-randomised (1:1) to intravenous daratumumab maintenance (16 mg/kg every 8 weeks) or observation for 2 years or less. An interactive web-based system was used for both randomisations, and randomisation was balanced using permuted blocks of four. Stratification factors for the first randomisation (induction and consolidation phase) were site affiliation, International Staging System disease stage, and cytogenetic risk status. Stratification factors for the second randomisation (maintenance phase) were induction treatment and depth of response in the induction and consolidation phase. The primary endpoint for the induction and consolidation phase was the proportion of patients who achieved a stringent complete response after consolidation; results for this endpoint remain unchanged from those reported previously. The primary endpoint for the maintenance phase was progression-free survival from second randomisation. Efficacy evaluations in the induction and consolidation phase were done on the intention-to-treat population, which included all patients who underwent first randomisation, and efficacy analyses in the maintenance phase were done in the maintenance-specific intention-to-treat population, which included all patients who were randomly assigned at the second randomisation. This analysis represents the final data cutoff at the end of the study. The trial is registered with ClinicalTrials.gov, NCT02541383., Findings: Between Sept 22, 2015 and Aug 1, 2017, 1085 patients were randomly assigned to D-VTd (n=543) or VTd (n=542); between May 30, 2016 and June 18, 2018, 886 were re-randomised to daratumumab maintenance (n=442) or observation (n=444). At the clinical cutoff date, Sept 1, 2023, median follow-up was 80·1 months (IQR 75·7-85·6) from first randomisation and 70·6 months (66·4-76·1) from second randomisation. Progression-free survival from second randomisation was significantly longer in the daratumumab maintenance group than the observation-alone group (median not reached [95% CI 79·9-not estimable (NE)] vs 45·8 months [41·8-49·6]; HR 0·49 [95% CI 0·40-0·59]; p<0·0001); benefit was observed with D-VTd with daratumumab maintenance versus D-VTd with observation (median not reached [74·6-NE] vs 72·1 months [52·8-NE]; 0·76 [0·58-1·00]; p=0·048) and VTd with daratumumab maintenance versus VTd with observation (median not reached [66·9-NE] vs 32·7 months [27·2-38·7]; 0·34 [0·26-0·44]; p<0·0001)., Interpretation: The long-term follow-up results of CASSIOPEIA show that including daratumumab in both the induction and consolidation phase and the maintenance phase led to superior progression-free survival outcomes. Our results confirm D-VTd induction and consolidation as a standard of care, and support the option of subsequent daratumumab monotherapy maintenance, for transplant-eligible patients with newly diagnosed multiple myeloma., Funding: Intergroupe Francophone du Myélome, Dutch-Belgian Cooperative Trial Group for Hematology Oncology, and Janssen Research & Development., Competing Interests: Declaration of interests PM served on advisory boards for and received honoraria from Janssen, Bristol Myers Squibb, Amgen, Takeda, AbbVie, Sanofi, and Pfizer. CH received honoraria from Janssen, Bristol Myers Squibb, Amgen, AbbVie, and Pfizer. AP served in a consulting or advisory role for Bristol Myers Squibb, Janssen, and Pfizer; and received research funding from Bristol Myers Squibb, Sanofi, and Takeda. BA received research funding (paid to institution) from Bristol Myers Squibb; received honoraria from Janssen, Bristol Myers Squibb, Sanofi, and GSK; received travel funding from Janssen, Bristol Myers Squibb, and Sanofi; and served on an advisory board for Janssen, Bristol Myers Squibb, and Takeda. KB has a direct financial relationship with Janssen, Bristol Myers Squibb, Amgen, Sanofi, and Pfizer. SZ received research support from Janssen and Takeda; and served on advisory boards for Janssen, Bristol Myers Squibb, Sanofi, Oncopeptides, Amgen, and Takeda. MD received honoraria from and served in a consulting or advisory role for Amgen, Bristol Myers Squibb, Janssen, Sanofi, and Stemline; and received research funding from Janssen. CS received consulting fees or honoraria from Takeda, Bristol Myers Squibb, Janssen, Amgen, Sanofi, and Pfizer. MMo received honoraria from Adaptive Biotechnologies, Amgen, Bristol Myers Squibb, Celgene, Janssen, Takeda, Novartis, and Sanofi; and received research funding from Celgene, Janssen, and Sanofi. LK received honoraria from, served on advisory boards for, or received travel funding from AbbVie, Amgen, Janssen, Celgene/Bristol Myers Squibb, Pfizer, Sanofi, and Takeda. MMa received honoraria from and served in a consulting or advisory role for Janssen, Bristol Myers Squibb/Celgene, Sanofi, and Takeda; received research funding from Janssen and Takeda; and received travel, accommodations, or expenses from Janssen and Sanofi. FO-P served on boards for Janssen, Sanofi, and Pfizer. MR served on an advisory board for Janssen and Pfizer; received research funding from Bristol Myers Squibb, Janssen, and Sanofi; gave lectures for Amgen, Bristol Myers Squibb, Janssen, and Takeda; and had travel, accommodations, or other expenses paid or reimbursed by Amgen, Bristol Myers Squibb, GSK, Janssen, Pfizer, Sanofi, and Takeda. JMSdC served on an advisory board and received honoraria from Janssen, Sanofi, GSK, and AbbVie; and received accommodations from Pfizer and Amgen. NWCJvdD received research support from Janssen, Amgen, Celgene, Novartis, Cellectis, and Bristol Myers Squibb; and serves on advisory boards for Janssen, Amgen, Celgene, Bristol Myers Squibb, Sanofi, Takeda, Roche, Novartis, Bayer, Adaptive, Merck, Pfizer, AbbVie, and Servier (all paid to institution). AB served on advisory boards for Janssen, Sanofi, Amgen, and Bristol Myers Squibb. CT served on an advisory board for and received honoraria from Janssen. NM served on an advisory board for Janssen. M-CV received travel support from Janssen and Sanofi. M-DL received travel expenses from Janssen. WH is an employee of Cytel and is a contractor for Johnson & Johnson. JW, CdB, MR, VV, RC, and JV are employees of Janssen and hold stock in Johnson & Johnson. AT is an employee of Janssen. JC served on advisory boards for Sanofi and Bristol Myers Squibb; served as a consultant for Janssen, Sanofi, Bristol Myers Squibb, Pfizer, and Adaptive; received research support from Sanofi and Bristol Myers Squibb; and received travel support from Janssen, Sanofi, Bristol Myers Squibb, and Pfizer. PS served on an advisory board for Amgen, Bristol Myers Squibb, Celgene, Janssen, Karyopharm, and Pfizer; and received research funding from Amgen, Bristol Myers Squibb, Celgene, Janssen, and Karyopharm. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

CD38-targeting immunotherapy is approved in combination with lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma (NDMM) that are transplant ineligible (TI) and is considered the best standard of care (SOC). To improve current SOC, we evaluated the added value of weekly bortezomib (V) to isatuximab plus lenalidomide and dexamethasone (IsaRd versus Isa-VRd). This Intergroupe Francophone of Myeloma phase 3 study randomized 270 patients with NDMM that were TI, aged 65-79 years, to IsaRd versus Isa-VRd arms. The primary endpoint was a minimal residual disease (MRD) negativity rate at 10 -5 by next-generation sequencing at 18 months from randomization. Key secondary endpoints included response rates, MRD assessment rates, survival and safety. The 18-month MRD negativity rates at 10 -5 were reported in 35 patients (26%, 95% confidence interval (CI) 19-34) in IsaRd versus 71 (53%, 95% CI 44-61) in Isa-VRd (odds ratio for MRD negativity 3.16, 95% CI 1.89-5.28, P < 0.0001). The MRD benefit was consistent across subgroups at 10 -5 and 10 -6 , and was already observed at month 12. The proportion of patients with complete response or better at 18 months was higher with Isa-VRd (58% versus 33%; P < 0.0001), as was the proportion of MRD negativity and complete response or better (37% versus 17%; P = 0.0003). At a median follow-up of 23.5 months, no difference was observed for survival times (immature data). The addition of weekly bortezomib did not significantly affect the relative dose intensity of IsaRd. Isa-VRd significantly increased MRD endpoints, including the 18-month negativity rate at 10 -5 , the primary endpoint, compared with IsaRd. This study proposes Isa-VRd as a new SOC for patients with NDMM that are TI. ClinicalTrials.gov identifier: NCT04751877 ., (© 2024. The Author(s).)

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.)

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.

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.)

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.)

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 .).

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.)

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.)

Background: There is no consensus on the standard treatment of gastric mucosa-associated lymphoid tissue (MALT) lymphoma for Helicobacter pylori-negative patients and for patients with persistent disease despite H. pylori eradication., Aim: To evaluate the comparative efficacy and safety of alkylating agents and rituximab alone or in combination., Methods: In this monocentric retrospective study, which included 106 patients who had not been previously treated with anti-cancer agents, we evaluated the efficacy and safety of oral alkylating agents monotherapy (n = 48), rituximab monotherapy (n = 28) and the therapy combining both drugs (n = 30). Evaluations were performed at weeks 6 (W6), 25 (W25), and 52 (W52) and after 2 years (W104)., Results: After a median follow-up period of 4.9 years (range 0.4-17.2 years), complete remission and overall response were significantly higher in patients in the combination therapy group at W104 (92% and 100% respectively) compared with patients treated with alkylating agents alone (66% and 68%) and rituximab alone (64% and 73%). The 5-year progression-free survival probabilities were 68%, 70% and 89% in patients treated with alkylating agents alone, rituximab alone and combination therapy respectively. Haematological adverse events were reported in 32 (30%) patients (mostly grade 1) and were more frequent in the two groups receiving alkylating agents (P = 0.05 and P < 0.001). No toxicity-related death was reported., Conclusions: The use of anti-cancer systemic therapy is safe and efficient in gastric MALT lymphoma. In this retrospective study, the combination of rituximab plus chlorambucil seems more efficient than rituximab or alkylating agents alone. Rituximab has a better safety profile than regimens containing alkylating agents., (© 2014 John Wiley & Sons Ltd.)

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.

Background: As rituximab combined with CHOP improves complete remission and overall survival in diffuse large B-cell lymphoma, intensified chemotherapy followed by autologous stem-cell transplantation has also been advocated for high-risk patients. The aim of this study was to establish whether or not combining rituximab with high-dose chemotherapy and auto-transplantation also benefits patient survival., Design and Methods: The LNH2003-3 study was a phase II trial including diffuse large B-cell lymphoma patients with 2 or 3 International Prognostic Index factors. They received four cycles of intensive biweekly chemotherapy with rituximab, doxorubicine, cyclophosphamide, vindesine, bleomycine, prednisolone (R-ACVBP) followed by auto-transplantation in responding patients. Two hundred and nine patients under 60 years of age were included in the study and 155 responding patients underwent auto-transplantation. In addition, a case-control study was performed by matching (1:1) 181 patients treated with R-ACVBP with ACVBP patients not given rituximab but submitted to auto-transplantation from the previous LNH1998-3 trial., Results: With a median follow up of 45 months, 4-year progression-free survival and overall survival were estimated at 76% (CI: 69-81) and 78% (CI: 72-83), respectively. There was no difference between patients with 2 or 3 International Prognostic Index factors. Four year progression-free survival was significantly higher in R-ACVBP than ACVBP patients (74% vs. 58%; P=0.0005). There was also a significant increase in 4-year overall survival (76% vs. 68%; P=0.0494)., Conclusions: In high-risk diffuse large B-cell lymphoma patients, treatment with R-ACVBP followed by auto-transplantation results in a 78% 4-year overall survival which should be compared to other approaches.

We report the outcome of patients included in the LNH-98.5 study, which compared cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) to rituximab plus CHOP (R-CHOP) therapy in 399 patients with diffuse large B-cell lymphoma (DLBCL) aged 60 to 80 years, with a median follow-up time of 10 years. Clinical event information was updated in all living patients (with the exception of 3 patients) in 2009. Survival end points were improved in patients treated with R-CHOP: the 10-year progression-free survival was 36.5%, compared with 20% with CHOP alone, and the 10-year overall survival was 43.5% compared with 27.6%. The same risk of death due to other diseases, secondary cancers, and late relapses was observed in both study arms. Relapses occurring after 5 years represented 7% of all disease progressions. The results from the 10-year analysis confirm the benefits and tolerability of the addition of rituximab to CHOP. Our findings underscore the need to treat elderly patients as young patients, with the use of curative chemotherapy.

Background: Revised response criteria for aggressive lymphomas have been proposed (Cheson, J Clin Oncol, 2007) stressing the role of (18)fluorodeoxyglucose-positron emission tomography (PET) in posttreatment evaluation. The value of PET after four cycles compared with the International Workshop Criteria (IWC) remains to be established., Patients and Methods: In all, 103 patients with untreated diffuse large B-cell lymphoma were prospectively enrolled to evaluate the prognostic impact of PET after two and four cycles., Results: Median age was 53 years (19-79), 68% male. The International Prognostic Index was low=22%, low-intermediate=19%, intermediate-high=33% and high risk=26%. Treatment consisted of cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) (30%) or dose-intensified CHOP (70%), with rituximab (49%) or without (51%). Ninety-nine patients were evaluated by PET and IWC at four cycles: 77 (78%) had a negative PET, while 22 (22%) remained positive. The 5-year event-free survival (EFS) was 36% for patients with a positive PET versus 80% with a negative examination, whatever the response [complete response (CR) versus partial response (PR)] according to IWC (P<0.0001). Positive PET patients had a 5-year EFS of 58% if in CR/CR unconfirmed by IWC and 0% if not (P<0.0001). The same observations could be made in patients treated with and without rituximab., Conclusion: The integration of PET in treatment evaluation offers a powerful tool to predict outcome.

Background: High-dose therapy (HDT) with stem-cell support is the reference treatment for relapsed lymphoma, but is not appropriate for all patients. Conventional salvage chemotherapies have been used with limited efficacy and significant toxicity. Rituximab, gemcitabine and oxaliplatin are active as single agents in relapsed or refractory lymphoma, and have demonstrated synergistic effects in vitro and in vivo., Patients and Methods: Forty-six patients with relapsed or refractory B-cell lymphoma received up to eight cycles of R-GemOx (rituximab 375 mg/m(2) on day 1, gemcitabine 1000 mg/m(2) and oxaliplatin 100 mg/m(2) on day 2). The majority (72%) had diffuse large B-cell lymphoma., Results: After four cycles of R-GemOx, the overall response rate was 83% [50% complete response (CR)/unconfirmed CR (CRu)]. High CR/CRu rates were observed in all histological subtypes. In patients who had previously received rituximab, the CR/CRu rate after eight cycles was 65%. The 2-year event-free and overall survival rates (median follow-up of 28 months) were 43% and 66%, respectively. Among responders, the probability of being disease free for 2 years was 62%. Treatment was generally well tolerated., Conclusion: R-GemOx shows promising activity with acceptable toxicity in patients with relapsed/refractory B-cell lymphoma who are not eligible for HDT.

Ongoing studies in B-cell chronic lymphocytic leukemia are evaluating autologous peripheral blood stem cell (PBSC) transplantation in first remission following fludarabine therapy. However, fludarabine could impair PBSC harvest. In 38 patients after frontline oral fludarabine and cyclophosphamide (FDR-CY) therapy, we prospectively evaluated steady state filgrastim- or lenograstim-primed PBSC mobilization to collect 2.0 x 106/kg or more CD34 cells. The first mobilization, performed a median of 178 days (range, 69-377 days) from the last FDR-CY course, was unsuccessful in 32 patients. This result was significantly associated with a low platelet count before mobilization but not with age, interval from last FDR-CY course, initial stage, remission status, or other blood parameters. Finally, after 1, 2, and 3 mobilizations in 27, 10, and 1 patients, 2.0 x 106/kg or more CD34 cells were collected in only 12. Explorations of the mechanism of poor mobilization and adaptation of PBSC harvest policies after fludarabine treatment are therefore warranted.

Cytarabine ocfosfate (YNK01) is a prodrug analogue of cytarabine which is resistant to systemic deamination after oral administration. Following initial studies indicating significant anti-tumour activity of YNK01 a phase II trial was initiated in order to assess the tolerability and efficacy of a combination of this agent with interferon alpha-2b (IFN-alpha2b) in recently diagnosed chronic phase CML patients (n = 98). The treatment was subdivided into cycles consisting of 4 weeks of continuous administration of IFN-alpha-2b (3 MU/m(2)/day 1st week and then 5 MU/m(2)/day) and 14 days of oral YNK01 (600 mg/day 1st cycle). At the end of each cycle the dose of YNK01 was adjusted according to the blood count observed during the previous 4 weeks. The median time from diagnosis to inclusion in the trial was 2 months (range 6 days to 7.5 months). At 12 weeks, 62 patients (63%; 95% CI, 54-73) achieved a complete hematological response. At 24 weeks, of 98 patients, two achieved a complete cytogenetic response, 14 a partial response (16% major cytogenetic response rate; 95% CI, 9-24) and 34 a minor response; 19 patients were not evaluable for cytogenetic response. During the trial, 20 patients progressed to accelerated (6) or blastic phases (14). The median time to progression was 15 months (range 2-38 months). At 3 years the overall survival was 79% (95% CI, 70-88). Although the complete hematological response rate compared favorably with the 40% response rate previously obtained with the subcutaneous formulation of Ara-c, the cytogenetic response rate was less than expected. Most of the patients experienced side-effects and all permanently stopped YNK01. Although the combination seems attractive the initial dose of 600 mg per day is probably too high and should be reconsidered in further trials.

Background: The MINE regimen (mitoguazone, ifosfamide, vinorelbine and etoposide) is a salvage chemotherapy for relapsed and refractory Hodgkin's disease., Case Reports: We report the cases of a 16-year-old girl and a 17-year-old boy who had Hodgkin's disease and developed painful and massive subcutaneous inflammatory edema after MINE chemotherapy. Morphine was unable to control pain leading to major functional disability of joint movement. One patient had an elevated creatine kinase level, hypoalbuminemia, hypodermic and muscular edema at magnetic resonance imaging and diffuse hemorrhagic hypodermic edema at skin biopsy. The other patient was found to have only hypoalbuminemia. The clinical course was favorable in both cases within a few weeks, but with recurrent episodes of pain and localized areas of fat necrosis five months later in one case., Discussion: This side effect of MINE chemotherapy - subcutaneous inflammatory edema, myalgia and skin pain - has not been described previously for the different components of the regimen. Three clinicopathological hypotheses could be put forward: capillary leak syndrome, panniculitis, toxic fasciitis. The causal drug remains undetermined, but the most likely would be vinorelbine because of the chronology of the eruptions during the first and last days of chemotherapy and because of the known vascular toxicity of vinorelbine which could explain a capillary leak syndrome.

Purpose: To identify the prognostic factors that influence overall survival (OS) in patients with stage III-IV follicular lymphomas and evaluate the clinical usefulness and the prognostic value of the International Prognostic Index (IPI)., Patients and Methods: Four hundred eighty-four patients with Ann Arbor stage III-IV follicular lymphomas treated in two phase III trials from 1986 to 1995 were screened for this study. All histologic slides were reviewed by two hematopathologists. The influence of the initial parameters on survival was defined by univariate (log-rank test) and multivariate (Cox model) analyses., Results: The poor prognostic factors for OS (age > 60 years, "B" symptom(s), > or = two extranodal sites, stage IV disease, tumor bulk > 7 cm, at least three nodal sites > 3 cm, liver involvement, serous effusion-compression or orbital/epidural involvement, and erythrocyte sedimentation rate > 30 mm/h) that were significant in univariate analysis were subjected to multivariate analysis. Three factors remained significant: B symptom(s) (risk ratio = 1.80), age greater than 60 years (risk ratio = 1.60), and at least three nodal sites greater than 3 cm (risk ratio = 1.71). When the IPI was applied to these patients, the score was 1, 2, 3, and 4-5 in 49%, 39%, 11%, and 2%, respectively, and it was significant for progression-free survival (P =.002) and OS (P =.0001)., Conclusion: Three prognostic factors for poor OS were identified: B symptoms, age greater than 60 years, and at least three nodal sites greater than 3 cm. The IPI was prognostic for OS, but in this population, a very low number of patients belonged to the high-risk groups.