Measurable residual disease (MRD) is a major prognostic factor in Core Binding Factor (CBF) AML. KIT or FLT3 mutations also have prognostic relevance, but little is known about their prognostic value when accounting for MRD. We analyzed the prognostic value of genetic alterations adjusting for early MRD response in adult CBF-AML patients. We grouped data from the retrospective multicenter study RetroCBF (NCT05070208, training set) and the prospective CBF-2006 trial (NCT00428558, validation set). Centralized high-throughput sequencing was performed with 36 genes. 656 CBF-AML patients in first CR were included between 2007 and 2020 (RetroCBF n = 461; CBF-2006 n = 195). In a LASSO-penalized model including MRD and genetic alterations performed in the RetroCBF training cohort, KIT-TKD in RUNX1::RUNX1T1 and FLT3-ITD in CBFB::MYH11 were associated with a higher risk of relapse. Including these genetic alterations with MRD in the training cohort, 3-year cumulative incidence of relapse was 22% (95%CI:13-33%) in low-risk patients (MRD low AND no KIT-TKD [RUNX1::RUNX1T1] or FLT3-ITD [CBFB::MYH11]) versus 53% (95%CI 46%-60%) in high-risk patients (csHR=3.21 [95%CI:1.83-5.62], p < 0.0001). These results were confirmed in the CBF-2006 validation cohort. KIT-TKD mutations in RUNX1::RUNX1T1 and FLT3-ITD in CBFB::MYH11 worsen prognosis independently of MRD and must be included in risk stratification of CBF AMLs.

BACKGROUND:Measurable residual disease (MRD) is a major prognostic factor in newly diagnosed multiple myeloma. An assessment of an MRD-guided consolidation strategy in patients who are eligible for autologous stem-cell transplantation (ASCT) may be useful. METHODS:In this phase 3 trial, we randomly assigned transplantation-eligible patients with newly diagnosed myeloma who had completed induction therapy with isatuximab, carfilzomib, lenalidomide, and dexamethasone (Isa-KRd) to receive consolidation therapy according to their MRD status. Patients who were MRD-negative at 10-5 sensitivity (i.e., <1 cancer cell per 100,000 normal cells, as assessed by next-generation sequencing) were assigned to undergo ASCT and receive Isa-KRd for two cycles (ASCT group) or to receive Isa-KRd for six cycles (Isa-KRd group). Patients who were MRD-positive at 10-5 sensitivity were assigned to undergo tandem ASCT (two ASCTs within a short period; tandem ASCT group) or to undergo ASCT and receive Isa-KRd for two cycles (single ASCT group). The primary end point was an MRD-negative status at 10-6 sensitivity before maintenance therapy. RESULTS:Among 485 patients who were MRD-negative at 10-5 sensitivity after induction, a premaintenance MRD-negative status at 10-6 sensitivity occurred in 86% in the ASCT group and in 84% in the Isa-KRd group (adjusted relative risk, 1.02; 95% confidence interval [CI], 0.95 to 1.10; P = 0.64). Among 233 patients who were MRD-positive at 10-5 sensitivity after induction, a premaintenance MRD-negative status at 10-6 sensitivity occurred in 32% in the tandem ASCT group and in 40% in the single ASCT group (adjusted relative risk, 0.82; 95% CI, 0.58 to 1.15; P = 0.31); 15% of the patients in the tandem ASCT group did not undergo a second ASCT. During consolidation, disease progression occurred in 5 patients and death unrelated to disease progression occurred in 2 patients - all were in the Isa-KRd or tandem ASCT groups. No new safety signals were observed. The median follow-up was 16.8 months in the ASCT and Isa-KRd groups and 16.3 months in the tandem ASCT and single ASCT groups. CONCLUSIONS:Among patients who were MRD-negative at 10-5 sensitivity after induction, the percentage with a premaintenance MRD-negative status at 10-6 sensitivity was not significantly higher with ASCT than with Isa-KRd. Among patients who were MRD-positive status at 10-5 sensitivity after induction, the percentage with a premaintenance MRD-negative status at 10-6 sensitivity was not significantly higher with tandem ASCT than with single ASCT. (Funded by Intergroupe Francophone du Myélome and others; MIDAS ClinicalTrials.gov number, NCT04934475.).

Introduction. A recent international genomic consensus staging has standardized the high-risk (HR) definition on the basis of an NGS-based definition plus serum beta-2-microglobulin level. Isa-VRd has become a standard-of-care for NDMM Transplant-Ineligible (TI). We studied the 12-24 months sustained MRD (sMRD) in high-risk patients using the genomic consensus staging in BENEFIT study. Methods. BENEFIT is a multicenter, phase 3 study, that randomized NDMM TI to receive Isa-VRd or IsaRd (ClinicalTrials.gov identifier: NCT04751877). Data are presented in intention-to-treat. IMS/IMWG new HR definition was assessed centrally by NGS on sorted plasma cells. Results. With a median follow-up of 33.4 months [95%CI, 33 - 34], 78 (29%) patients discontinued from the study, mostly for progressive disease. The HRMM (n=72, 27%) characterized 42/135 (31%) and 30/135 (22%) patients across Isa-VRd and IsaRd arms. The 18-month MRD negativity rate at 10-5, the primary end point, was similar across HRMM and non-HRMM within the same arm, and Isa-VRd remained superior for HRMM, OR 2.75 (95%CI, 1 to 7.5). Similar differences were observed at 10-6 at 18 months. The sustained MRD 12-24 months negativity rate at 10−5was higher for Isa-VRd than for IsaRd in HRMM, 31% and 13% respectively, OR 2.91 (95%CI, 0.8 to 10). There is no new safety signal observed across arms, including for HRMM. Conclusion. The results from the BENEFIT study continue to demonstrate meaningful benefit of the quadruplet-based Isa-VRd regimen in NDMM TI patients, including sMRD negativity rates. The benefits of the Isa-VRd regimen are observed in HRMM. This data supports Isa-VRd as a new SOC for NDMM TI aged of 65 to 79 patients, including for HRMM.

Background. Teclistamab is a subcutaneous bispecific IgG4 antibody targeting BCMA on myeloma cells and CD3 on T cells, enabling T-cell–mediated cytotoxicity. Daratumumab is an anti-CD38 monoclonal antibody used in combination with standard agents. The current standard-of-care regimens in elderly patients with newly diagnosed multiple myeloma (NDMM) include the triplet DRd (MAIA) or quadruplet combinations of anti-CD38 antibodies with RVd. These regimens show remarkable efficacy with 32% to 61% MRD negativity at 10-5 and prolonged PFS. However, further optimization of treatment strategies remains a key focus of research efforts for patients with MM. Recently, the combination of teclistamab and daratumumab (Tec-Dara) has demonstrated strong efficacy in the relapsed setting with deep responses. Most trials currently evaluate triplet combinations of BCMA-directed bispecific antibodies with daratumumab and lenalidomide (MajesTEC-7 and MagnetisMM-6). The IFM2021-01 trial is a phase 2 study evaluating the doublets teclistamab-daratumumab (Cohort A) and teclistamab-lenalidomide (Cohort B) in frontline transplant-ineligible patients. Here, we report Cohort A (Tec-Dara), an “all-antibody-based” frontline treatment for patients with NDMM. Methods. IFM2021-01 is an open-label, multicenter, single-arm phase 2 study enrolling patients aged ≥65 years with NDMM, ineligible for high-dose chemotherapy with autologous stem cell transplantation. Teclistamab was administered subcutaneously with step-up doses (0.06 mg/kg and 0.3 mg/kg) followed by 1.5 mg/kg treatment doses on Days 8 and 15 of Cycle 1. Maintenance dosing continued at 3 mg/kg every 4 weeks thereafter. Daratumumab SC (1800 mg) was given weekly in Cycles 1–2, every 2 weeks in Cycles 3–6, and every 4 weeks thereafter. The primary endpoint was the rate of very good partial response (VGPR) or better after 4 cycles per IMWG criteria. Secondary endpoints include overall response rate (ORR), complete response (CR) rate, MRD-negativity by NGS at 10-5 and 10-6, progression-free survival (PFS), and overall survival (OS). Safety was assessed per CTCAE v5.0. The protocol was approved by the French Agency (ANSM) and an external Ethics Committee. The study is conducted by Lille University Hospital and the IFM French Myeloma group in collaboration and with financial support from Janssen Pharmaceutica NV, a member of the Johnson & Johnson group of companies (EU CT 2024-514101-65; ClinicalTrial.gov NCT05572229). Results. A total of 37 patients were enrolled in Cohort A. The median age was 73 years, with 11 (30%) patients above the age of 75 years, and 20 (54%) were female. Overall, 33 (89%) patients had ECOG 0 or 1 and 4 (11%) had ECOG 2; 16 (44%) patients were fit, 12 (33%) were intermediate, and 8 (22%) were frail based on the IMWG frailty score. A total of 25 (68%) patients had standard-risk cytogenetics and 12 (32%) had high-risk features (according to the new IMS/IMWG consensus). The primary endpoint - rate of VGPR or better after 4 cycles was 78%. At data cut-off (08/07/2025), the median follow-up time was 7.6 months (13.1 months for 18 patients; 6 months for 19 patients). The ORR at best response was 100%, with 36 (97%) achieving VGPR or better. The MRD negativity rate at 6 months by NGS at 10-6 was 51% in the intention-to-treat population and 100% in the 21 evaluable patients (16 were not evaluable for MRD at 6 months due to missing or invalid samples). Median DOR, PFS, and OS were not reached. No progression or death occurred during the follow up. The rates of PFS, and OS were 100% each. Regarding safety, 28 (76%) of patients had grade ≥3 adverse events (AEs) and 8 (22%) had serious AEs (SAE) – with no grade 5 AEs. The rate of grade ≥3 hematologic AEs was 46%, with 27% neutropenia. Overall, 5 (14%) patients had grade ≥3 infections. All patients received immunoglobulin replacement therapy at inception of treatment. Treatment discontinuation due to AEs occurred in 1 (3%) patient. Conclusions. IFM2021-01 Cohort A demonstrates that an “all-antibody–based” doublet regimen of teclistamab and daratumumab is highly effective and well-tolerated in elderly patients with NDMM, with deep responses, high MRD negativity, and a favorable safety profile.

Idecabtagene vicleucel (Ide-cel) is the first chimeric antigen receptor (CAR) T-cell therapy targeting the B-cell maturation antigen (BCMA) approved by both the European Medicines Agency and the US FDA. Ide-cel has been first available in France since April 2021 through the Early Access Program for treatment of patients (pts) with relapsed/refractory multiple myeloma (RRMM) having received at least 3 therapies including a proteasome inhibitor, an immunomodulatory drug and an anti-CD38 monoclonal antibody and then via commercial access from November 2024. Here we present an update of characteristics and outcomes of pts enrolled in this program. It is a multicenter, retrospective, observational study that included all consecutive pts with RRMM registered in the DESCAR-T database treated with commercial Ide-cel from April 2021 to February 2025. The main objective was to analyze efficacy in terms of response rates, progression-free survival (PFS) and overall survival (OS). Patients' characteristics and outcomes were analyzed according to two periods: cohort A (April-2021 to April-2023, n=175) and cohort B (May-2023 to February-2025, n=596) corresponding to the first two years with limited open center (n=11) and slot availability and the second one, with unlimited access and increased center number (Nb) (n=29). Secondary objectives were evaluation of safety including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity (ICAN), cytopenia, infection, and second primary malignancies (SPM). 915 pts were included of whom 115 (13%) were not infused and 29 were infused after February 2025. Median age of the 771 infused pts (58% male) was 66 years (range: 29-85) and was superior in cohort B (66.9 y) as compared to cohort A (61.7 y). Median Nb of prior lines of therapies was 3 (range: 0-13). More pts had received <2 lines in cohort B (122/596 [20%] vs 5/175 [3%], p<0.0001). Revised International Staging System (R-ISS) stage 3 was noted in 21% of pts, 37% had high risk cytogenetic abnormalities defined by del(17p) or t(4;14), and high tumor burden (>30% bone marrow plasma cells) was present in 53%, similarly in both cohorts. Triple- (n=559, 73%) and penta-refractory pts (n=168, 22%) were lower in cohort B (69% vs. 83%, p<0.0001 and 19% vs. 31%, p=0.01, respectively). Extramedullary disease (EMD) was observed in 73/764 (10%) of pts and was lower in cohort B (45/589, 8% vs. 28/175, 16%). Overall, 162 pts (21%) did not meet at least one of the KarMMa inclusion criteria. 630 pts (82%) had bridging therapy of which 188(34%) responded (106 partial response [PR]; 50 very good partial response [VGPR]; 32 complete response [CR]). Median vein-to-vein time was 56 days (range: 39-357) and was superior in cohort A (61 vs 55 d, p<0.0001). Best overall response rate at M3 post Ide-cel was 89% (n=638), including CR, VGPR and PR in 299(42%), 192(27%) and 147(20%), respectively and was similar in both cohorts. In univariate analysis for best response >VGPR, only prior BCMA bispecific therapy had a negative impact (odds ratio: 0.35; 95% CI, 0.16 - 0.79). 264 pts (34%) progressed after Ide-cel of which 50% during the first 6 months (m) and 139 pts (18%) died, mostly of disease progression (73%). With a median follow-up after infusion of 11.8 m, median PFS was 14.8 m (95% CI, 12.6 - 16.8) and was similar in both cohorts (hazard ratio: 0.85, p=0.19). Pts achieving >VGPR at M3 post Ide-cel had a significantly better PFS (hazard ratio: 1.78; 95% CI, 1.33 to 2.39, p=0.0001). The median OS was 38.9 m (95% CI, 34.2 – NR). In univariate analysis, EMD, ISS, prior bispecific and penta-refractoriness were negative factors for PFS and OS. CRS occurred in 677 (88%) pts (3% grade ≥3). ICAN occurred in 81 (11%) pts (2% with grade ≥3). 453 (59%) pts received tocilizumab in both cohorts. Persistent grade ≥3 thrombocytopenia, anemia and neutropenia at M1 were noted in 218 (28%), 112 (15%) and 378 (49%) pts, respectively. Infections in the first 6 m after Ide-cel occurred in 187 (24%) pts (grade ≥3: 33 [18%]). 24 pts developed SPM (4 AML and 6 MDS). This large study confirms safety and efficacy of Ide-cel in pts with RRMM in real- world settings across the 4-year period. Response rates, PFS and safety compares favorably to those reported in the registration trial and the real-world studies in the US. Overall, during both periods, selection of less advanced pts leads to a prolonged PFS and OS, never reported to date outside of clinical trial.

Background. Recent improvements in frontline treatments have led to remarkable outcomes in elderly patients with newly diagnosed multiple myeloma (NDMM), raising the question of a “functional cure”, defined by prolonged disease control, preserved quality of life, and near-normal life expectancy. The IFM2017-03 phase 3 trial, dedicated to frail patients with NDMM, randomized participants to receive either daratumumab-lenalidomide (DR) or lenalidomide-dexamethasone (Rd). This trial provides unique survival data for a largely underrepresented population. The median progression-free survival (PFS) was 53.4 months in the DR group, and the 4-years overall survival (OS) rate was 68%. Considering these improved outcomes, we sought to determine whether frail elderly patients now achieve survival trajectories approaching those of their age- and sex-matched peers in the general population.Methods. Patients included in this analysis were drawn from the IFM2017-03 trial and compared to the general French population using aggregated mortality data stratified by age, sex, and calendar year. OS was estimated using the Kaplan-Meier method within each treatment arm (DR and Rd). Treatment effect was expressed as a hazard ratio (HR) with corresponding two-sided 95% confidence intervals (CI), estimated using a stratified Cox proportional hazards model. Relative survival and its 95% CI were estimated for each treatment arm by comparing observed survival with expected survival from the general French population, adjusted for age, sex, and study entry year. Standardized mortality ratios (SMRs) and their 95% CIs were calculated for each group, defined as the ratio of observed to expected deaths in a population with matching demographics.Results. A total of 295 frail, transplant-ineligible patients with NDMM were randomized in the IFM2017-03 trial to receive either DR (n=200) or Rd (n=95), with enrollment occurring across 61 centers in France between October 2019 and July 2021. Median age was 81 years, and 61% of patients were aged ≥80 years. At 48 months, OS was 67.9% [95% CI: 61.2–75.4] in the DR arm and 47.8% [95% CI: 37.7–60.6] in the Rd arm with a HR of 0.52 [95% CI: 0.35–0.77], p=0.001; relative survival was 0.87 vs 0.63, and SMR was 1.61 [95% CI: 1.22–2.07, p=0.0003] vs 3.07 [95% CI: 2.24–4.11, p<0.0001], respectively.In patients aged ≥80 years (n=180), 48-month OS was 63.9% [95% CI: 55–74.1] in DR vs 37.1% [95% CI: 25.1–54.8] in Rd. Relative survival was 0.88 in DR vs 0.55 in Rd. The SMR for DR in this age group was 1.39 [95% CI: 1.00–1.90, p=0.043], compared to 2.93 [95% CI: 2.03–4.09, p<0.0001] in Rd.Among patients <80 years, (n=115), 48-month OS was 73.9% [95% CI: 64.2-85] in DR vs 66% [95% CI: 51.4-84.7] in Rd. Relative survival was 0.85 in DR vs 0.76 in Rd. The SMR for DR in this age group was 2.35 [95% CI: 1.42–3.68, p=0.002], compared to 3.64 [95% CI: 1.81–6.51, p=0.0007] in Rd. These results in patients <80 years should be interpreted with caution, as all patients included in the trial were classified as frail by inclusion criteria and may therefore not be directly comparable to the general population matched only on age and sex.Conclusion. In this ad-hoc analysis of the IFM2017-03 trial compared to population-based data, the SMR was significantly lower in the DR group across all age subgroups. While excess mortality persists in frail patients with NDMM overall, outcomes among patients aged ≥80 years treated with DR showed a markedly reduced SMR approaching that of the general population. These findings suggest that frail patients aged ≥80 years or older may now achieve survival trajectories consistent with a “functional cure”.

Introduction. Sustained minimal residual disease (sMRD) negativity has shown a stronger correlation with survival outcomes than MRD negativity at a single time point or at best response. We evaluated MRD negativity between 12 and 24 months in newly diagnosed multiple myeloma (NDMM) transplant-ineligible (TI) patients enrolled in the BENEFIT study. Methods. BENEFIT is a multicenter, phase 3 randomized trial comparing isatuximab-lenalidomide-dexamethasone with or without bortezomib (Isa-Rd ± V) in NDMM TI patients. In the Isa-VRd arm, bortezomib (V) was administered weekly for up to 18 months, dexamethasone was permanently discontinued after 12 months, and isatuximab-lenalidomide (Isa-R) was continued until progression. Data are presented in the intention-to-treat (ITT) population. Results.With a median follow-up of 33.4 months (95% CI, 33.0–34.0), 78 patients (29%) discontinued treatment, primarily due to progressive disease. At 24 months, the MRD negativity rate at 10⁻⁵ was significantly higher in the Isa-VRd arm (odds ratio [OR] 2.26; 95% CI, 1.35–3.79; p=0.002). Sustained MRD negativity at 10⁻⁵ was also more frequent in the Isa-VRd arm (OR 2.73; 95% CI, 1.50–4.80; p=0.0007). Similar results were observed for sMRD at the 10⁻⁶ threshold. Importantly, MRD negativity at both 10⁻⁵ and 10⁻⁶ was evaluated in the t(11;14) NDMM TI subgroup. In this subgroup, MRD negativity rates were consistently lower at all time points up to 24 months, consistent with recent observations from the MIDAS study. Due to the small number of patients per group, no subgroup-specific analysis was feasible. Larger cohorts are required to determine whether t(11;14) MM in TI patients achieves delayed or less frequent MRD negativity, potentially reflecting a MGUS-like phenotype. No new safety signals were observed in either treatment arm, including in high-risk multiple myeloma (HRMM) patients. Conclusion. The BENEFIT study continues to support the efficacy of the quadruplet Isa-VRd regimen in NDMM TI patients, notably through improved sustained MRD negativity rates. These data support Isa-VRd as a new standard of care (SOC) for NDMM TI patients aged 65–79 years, including those with HRMM. ClinicalTrials.gov Identifier: NCT04751877

BACKGROUND:Patients with frailty and newly diagnosed multiple myeloma have worse outcomes due to higher rates of adverse events (AEs) and treatment discontinuation. This study evaluated a dexamethasone-sparing regimen of daratumumab plus lenalidomide versus lenalidomide plus dexamethasone in frail patients with newly diagnosed multiple myeloma. METHODS:In this prospective, randomised, open-label trial, conducted at 61 active Intergroup Francophone of Myeloma centres, patients aged 65 years or older with newly diagnosed multiple myeloma and an Eastern Cooperative Oncology Group proxy frailty score of 2 or more were randomly assigned 2:1 to receive daratumumab (1800 mg subcutaneously) plus oral lenalidomide (25 mg daily for 21 days of a 28 day cycle) and dexamethasone (20mg weekly) for two cycles (dexamethasone-sparing group) or lenalidomide (25 mg daily) and oral dexamethasone (20 mg weekly; control group), with stratification by International Staging System, age, and centre. The primary endpoint was progression-free survival. Efficacy was assessed in the intention-to-treat population and safety was assessed in all patients exposed to at least one dose of randomised intervention. This trial is registered with ClinicalTrials.gov, NCT03993912, and is complete. FINDINGS:From Oct 18, 2019 to July 20, 2021, 335 patients were screened, of whom 295 patients were randomly assigned (200 to lenalidomide plus daratumumab, 95 to lenalidomide plus dexamethasone). The median age was 81 years (IQR 77-84), with 180 (61%) aged older than 80 years, and 151 (51%) patients were female and 144 (49%) were male. Median follow-up was 46·3 months (IQR 46·0-52·7). Median progression-free survival was 53·4 months (95% CI 35·3-not reached) in the dexamethasone-sparing group versus 22·5 months (16·5-39·0) in the control group (hazard ratio [HR] 0·51, 95% CI 0·37-0·70, p<0·0001). The most common grade 3-5 AEs were neutropenia (110 [55%] of 200 patients in the dexamethasone-sparing group vs 23 [24%] of 95 patients in the control group), and infection (38 [19%] vs 20 [21%]). Serious adverse events occurred in 126 patients (63%) in the dexamethasone-sparing group and 66 patients (69%) in the control group. AEs leading to death occurred in 23 patients (12%) in the dexamethasone-sparing group and 12 patients (13%) in the control group, with 4 (2%) and 2 (2%) grade 5 treatment-emergent adverse events, respectively. INTERPRETATION:In the IFM2017-03 trial, use of lenalidomide plus daratumumab, with dexamethasone limited to the first 2 treatment cycles, reduced the risk of progression or death compared with lenalidomide plus dexamethasone, with no additional safety concerns. Lenalidomide plus daratumumab could therefore be considered as a treatment option for older patients with frailty and newly diagnosed multiple myeloma. FUNDING:The study was funded by Johnson & Johnson.

ABSTRACT:Previous results from CASSIOPEIA demonstrated superior progression-free survival (PFS) and minimal residual disease (MRD) negativity with the addition of daratumumab to bortezomib, thalidomide, and dexamethasone (VTd) induction/consolidation and with daratumumab maintenance vs observation in transplant-eligible, newly diagnosed multiple myeloma. Here, we present long-term MRD status and PFS outcomes after a median follow-up of 80.1 months. Patients were randomly assigned (1:1) to daratumumab plus VTd (D-VTd) or VTd induction/consolidation; patients remaining on study were rerandomized to daratumumab maintenance or observation for ≤2 years. MRD status was assessed at predefined time points during each study phase. D-VTd improved overall MRD-negativity rates (10-5) after induction (34.6% vs 23.1%) and consolidation (63.7% vs 43.7%) and provided PFS benefit, regardless of postinduction MRD status, vs VTd alone. Daratumumab maintenance improved overall MRD-negativity rates over observation, regardless of induction/consolidation treatment (D-VTd/daratumumab vs D-VTd/observation, 10-5 [77.3% vs 70.7%] and 10-6 [60.7% vs 52.0%]; VTd/daratumumab vs VTd/observation, 10-5 [70.9% vs 51.2%] and 10-6 [48.4% vs 30.7%]) and improved MRD-negativity rates, regardless of risk status, as defined by cytogenetic abnormalities or the revised International Staging System score. Furthermore, daratumumab maintenance provided PFS benefit vs observation, regardless of induction/consolidation treatment and postconsolidation MRD status. D-VTd followed by daratumumab maintenance consistently produced the highest landmark, cumulative, and sustained MRD-negativity rates (10-5 and 10-6), translating to superior long-term PFS outcomes. These results demonstrate that daratumumab-based induction/consolidation followed by daratumumab maintenance resulted in the deepest and most durable MRD negativity, leading to superior PFS outcomes. This trial was registered at www.clinicaltrials.gov as #NCT02541383.

PDF file - 98KB, Biological and clinical features of the 168 CLL patients according to EGR2, NFKBIE and BRAF mutations.

PDF file - 116KB, Association between acquired mutations (P values of Fisher's exact test for independence) among the 168 patients cohort.

XLS file - 336KB, Biological and clinical features of the 24 patients included in the whole-exome study.

PDF file - 211KB, Biological and clinical features of the 24 patients included in the whole-exome study.

PDF file - 136KB, Representative flow chart of the sorting procedure.

PDF file - 170KB, Early mutations affect genes mutated in various human cancers (addition to the main text).

PDF file - 126KB, Analyses of two patients with detectable SF3B1 mutations in CD19+, CD34+ and CD14+ fractions.

XLS file - 75KB, Details of signature and expression analyses.

8042 Background: High-dose therapy (HDT) followed by autologous stem-cell transplantation (ASCT) is the standard of care in TE NDMM. In the phase 3 CASSIOPEIA study, D-VTd significantly improved stringent complete response (sCR), ≥CR, and minimal residual disease (MRD)-negative rates and reduced the risk of progression/death vs VTd in TE NDMM pts. We assessed SC yield and transplantation results among pts receiving D-VTd vs VTd induction prior to HDT/ASCT in Part 1 of CASSIOPEIA. Methods: In Part 1, TE NDMM pts ages 18-65 y were randomized 1:1 to 4 pre-transplant induction and 2 post-transplant consolidation cycles of DARA + VTd or VTd alone. After induction, pts underwent SC mobilization with cyclophosphamide 3 g/m2 (recommended dose) and GCSF. Peripheral blood SCs were harvested based on response to mobilization. Plerixafor was given if SC collection failed at first attempt and in accordance with institutional practice. Melphalan 200 mg/m2 IV was given as HDT prior to ASCT. Results: A total of 1085 pts were randomized (D-VTd, 543; VTd, 542). Among pts who completed mobilization (D-VTd, 506; VTd, 492), more pts receiving D-VTd vs VTd received plerixafor during mobilization (21.7% vs 7.9%). Pts underwent a median (range) of 2 (1-6) vs 1 (1-4) days of apheresis for D-VTd vs VTd. The median number of CD34+ cells collected was lower for D-VTd vs VTd (6.3×106/kg vs 8.9×106/kg). Nevertheless, a similar percentage of ITT pts receiving D-VTd vs VTd underwent ASCT (90.1% vs 89.3%). The median number of CD34+ cells transplanted for D-VTd vs VTd was 3.3×106/kg vs 4.3×106/kg. Hematopoietic reconstitution rates were high and similar for transplanted pts receiving D-VTd vs VTd (99.8% vs 99.6%). For D-VTd vs VTd, a median (range) of 13.0 (6-54) vs 13.0 (4-43) days was required to achieve sustained ANC > 500 cells/mm3, and a median (range) of 14.0 (2-56) vs 12.0 (1-47) days was required to achieve sustained platelets > 20,000 cells/mm3 without transfusion. Conclusions: SC mobilization and collection was feasible with D-VTd induction. Adding DARA to VTd allowed successful transplantation in pts with TE NDMM. Clinical trial information: NCT02541383.