Isatuximab plus pomalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma according to prior lines of treatment and refractory status: ICARIA-MM subgroup analysis.

SB reports honoraria from Amgen, Bristol-Myers Squibb, Celgene, and Janssen; and reports a consultancy/advisory role for Celgene, Janssen, Karyopharm, and Takeda. VV reports a consultancy/advisory role for Astellas, Biocad, Bristol-Myers Squibb, Janssen, Roche, Sanofi, and Takeda. VM reports a consultancy/advisory role for Amgen, Bristol-Myers Squibb, Celgene, Janssen, and Takeda. LK reports honoraria from Amgen, Celgene, Janssen, and Takeda; a consultancy/advisory role for Amgen, Celgene, Janssen, and Takeda; and travel support from Amgen and Janssen. MP reports honoraria from Celgene, Pfizer, and Takeda; consultancy/advisory role for Amgen, Celgene, Janssen, Roche, and Takeda; and research funding from Amgen, Celgene, Janssen, Pfizer, Roche, and Takeda. PGR reports a consultancy/advisory role for Amgen, Janssen, Karyopharm, Oncopeptides, Sanofi, and Takeda; and research funding from Bristol-Myers Squibb, Celgene, Oncopeptides, and Takeda. LP, FV, KW, LB, and YK have no disclosures. FC, SLG, FM, and HvdV are employees of Sanofi

Moxetumomab pasudotox in heavily pre-treated patients with relapsed/refractory hairy cell leukemia (HCL): long-term follow-up from the pivotal trial

Background Moxetumomab pasudotox is a recombinant CD22-targeting immunotoxin. Here, we present the long-term follow-up analysis of the pivotal, multicenter, open-label trial (NCT01829711) of moxetumomab pasudotox in patients with relapsed/refractory (R/R) hairy cell leukemia (HCL). Methods Eligible patients had received ≥ 2 prior systemic therapies, including ≥ 2 purine nucleoside analogs (PNAs), or ≥ 1 PNA followed by rituximab or a BRAF inhibitor. Patients received 40 µg/kg moxetumomab pasudotox intravenously on Days 1, 3, and 5 of each 28-day cycle for up to six cycles. Disease response and minimal residual disease (MRD) status were determined by blinded independent central review. The primary endpoint was durable complete response (CR), defined as achieving CR with hematologic remission (HR, blood counts for CR) lasting > 180 days. Results Eighty adult patients were treated with moxetumomab pasudotox and 63% completed six cycles. Patients had received a median of three lines of prior systemic therapy; 49% were PNA-refractory, and 38% were unfit for PNA retreatment. At a median follow-up of 24.6 months, the durable CR rate (CR with HR > 180 days) was 36% (29 patients; 95% confidence interval: 26–48%); CR with HR ≥ 360 days was 33%, and overall CR was 41%. Twenty-seven complete responders (82%) were MRD-negative (34% of all patients). CR lasting ≥ 60 months was 61%, and the median progression-free survival without the loss of HR was 71.7 months. Hemolytic uremic and capillary leak syndromes were each reported in ≤ 10% of patients, and ≤ 5% had grade 3–4 events; these events were generally reversible. No treatment-related deaths were reported. Conclusions Moxetumomab pasudotox resulted in a high rate of durable responses and MRD negativity in heavily pre-treated patients with HCL, with a manageable safety profile. Thus, it represents a new and viable treatment option for patients with R/R HCL, who currently lack adequate therapy.publishedVersio

Isatuximab plus carfilzomib and dexamethasone in patients with early <i>versus</i> late relapsed multiple myeloma: IKEMA subgroup analysis

Patients with multiple myeloma (MM) who experience early relapse within 12 months of therapy initiation are considered functional high-risk and represent an unmet need, needing better therapies to improve outcomes. The final IKEMA (clinicaltrials gov. identifier: NCT03275285) progression-free survival (PFS) analysis confirmed the significant PFS improvement reported at interim analysis with isatuximab (Isa) plus carfilzomib and dexamethasone (Kd; Isa-Kd) versus Kd in patients with relapsed MM (updated median PFS: 35.7 vs. 19.2 months; hazard ratio [HR] =0.58, 95% confidence interval [CI]: 0.42- 0.79). This IKEMA subgroup analysis examined efficacy and safety of Isa-Kd versus Kd in patients who experienced early (n=61 [Isa-Kd], n=46 [Kd]) vs. late relapse (n=104 [Isa-Kd], n=72 [Kd]). As expected, more aggressive features in baseline characteristics were observed in early relapse patients. Consistent with IKEMA overall population results, median PFS (early relapse: 24.7 vs. 17.2 months, HR=0.662, 95% CI: 0.407-1.077; late relapse: 42.7 vs. 21.9 months, HR=0.542, 95% CI: 0.355- 0.826), minimal residual disease negativity (MRD−) (early relapse: 24.6% vs. 15.2%; late relapse: 37.5% vs. 16.7%), and MRD− complete response (≥CR) rates (early relapse: 18.0% vs. 10.9%; late relapse: 30.8% vs. 13.9%) were higher with Isa-Kd versus Kd, respectively, in both early and late relapse patients. Grade ≥3, serious treatment-emergent adverse events, and death rates were higher in the late relapse Isa-Kd arm. However, the numbers of deaths were low and treatment exposure was significantly longer in Isa-Kd versus Kd late relapse patients. These results support the addition of Isa to Kd as standardof- care therapy for relapsed and/or refractory MM regardless of relapse timing

Health-Related Quality of Life in Transplant-Ineligible Patients With Newly Diagnosed Multiple Myeloma: Findings From the Phase III MAIA Trial.

PURPOSE: To evaluate the effects of daratumumab, lenalidomide, and dexamethasone (D-Rd) versus lenalidomide and dexamethasone (Rd) on patient-reported outcomes (PROs) in the phase III MAIA study. PATIENTS AND METHODS: PROs were assessed on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item and the EuroQol 5-dimensional descriptive system at baseline and every 3 months during treatment. By mixed-effects model, changes from baseline are presented as least squares means with 95% CIs. RESULTS: A total of 737 transplant-ineligible (TIE) patients with newly diagnosed multiple myeloma were randomly assigned to D-Rd (n = 368) or Rd (n = 369). Compliance with PRO assessments was high at baseline (&gt; 90%) through month 12 (&gt; 78%) for both groups. European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item global health status scores improved from baseline in both groups and were consistently greater with D-Rd at all time points. A global health status benefit was achieved with D-Rd, regardless of age (&lt; 75 and ≥ 75 years), baseline Eastern Cooperative Oncology Group (ECOG) performance status score, or depth of response. D-Rd treatment resulted in significantly greater reduction in pain scores as early as cycle 3 (P = .0007 v Rd); the magnitude of change was sustained through cycle 12. Reductions in pain with D-Rd were clinically meaningful in patients regardless of age, ECOG status, or depth of response. Similarly, PRO improvements were observed with D-Rd and Rd on the EuroQol 5-dimensional descriptive system visual analog scale score. CONCLUSION: D-Rd compared with Rd was associated with faster and sustained clinically meaningful improvements in PROs, including pain, in transplant-ineligible patients with newly diagnosed multiple myeloma regardless of age, baseline ECOG status, or depth of treatment response

A comparison of random sequence reads versus 16S rDNA sequences for estimating the biodiversity of a metagenomic library

The construction of metagenomic libraries has permitted the study of microorganisms resistant to isolation and the analysis of 16S rDNA sequences has been used for over two decades to examine bacterial biodiversity. Here, we show that the analysis of random sequence reads (RSRs) instead of 16S is a suitable shortcut to estimate the biodiversity of a bacterial community from metagenomic libraries. We generated 10 010 RSRs from a metagenomic library of microorganisms found in human faecal samples. Then searched them using the program BLASTN against a prokaryotic sequence database to assign a taxon to each RSR. The results were compared with those obtained by screening and analysing the clones containing 16S rDNA sequences in the whole library. We found that the biodiversity observed by RSR analysis is consistent with that obtained by 16S rDNA. We also show that RSRs are suitable to compare the biodiversity between different metagenomic libraries. RSRs can thus provide a good estimate of the biodiversity of a metagenomic library and, as an alternative to 16S, this approach is both faster and cheaper

ANCHOR: melflufen plus dexamethasone and daratumumab or bortezomib in relapsed/refractory multiple myeloma: final results of a phase I/IIa study

Melphalan flufenamide (melflufen), a first-in-class, alkylating peptide-drug conjugate, demonstrated clinical benefit in combination with dexamethasone in triple-class refractory multiple myeloma (MM). The phase I/IIa ANCHOR study evaluated melflufen (30 or 40 mg) and dexamethasone (40 mg with daratumumab; 20 mg followed by 40 mg with bortezomib; dose reduced if aged ≥75 years) in triplet combination with daratumumab (16 mg/kg; daratumumab arm) or bortezomib (1.3 mg/m2; bortezomib arm) in patients with relapsed/refractory MM refractory to an immunomodulatory agent and/or a proteasome inhibitor and who had received one to four prior lines of therapy. Primary objectives were to determine the optimal dose of melflufen in triplet combination (phase I) and overall response rate (phase IIa). In total, 33 patients were treated in the daratumumab arm and 23 patients received therapy in the bortezomib arm. No dose-limiting toxicities were reported at either melflufen dose level with either combination. With both triplet regimens, the most common grade ≥3 treatment-emergent adverse events were thrombocytopenia and neutropenia; thrombocytopenia was the most common treatment-emergent adverse event leading to treatment discontinuation. In the daratumumab arm, patients receiving melflufen 30 mg remained on treatment longer than those receiving the 40-mg dose. In the daratumumab arm, the overall response rate was 73% and median progression-free survival was 12.9 months. Notably, in the bortezomib arm, the overall response rate was 78% and median progression-free survival was 14.7 months. Considering the totality of the data, melflufen 30 mg was established as the recommended dose for use with dexamethasone and daratumumab or bortezomib for future studies in relapsed/refractory MM

Genetically determined telomere length and multiple myeloma risk and outcome

This work was partially supported by intramural funds of Univerity of Pisa and DKFZ; by Fondo de Investigaciones Sanitarias (Madrid, Spain) [PI12/02688 to J. S., PI17/02276 to J.S.]; by Instituto de Salud Carlos III, co-funded by FEDER funds —a way to build Europe—[PI14-00613 to V.M.] and by Agency for Management of University and Research Grants (AGAUR) of the Catalan Government (Barcelona, Spain) [2017SGR723 to V.M.]. Open Access funding enabled and organized by Projekt DEAL.Telomeres are involved in processes like cellular growth, chromosomal stability, and proper segregation to daughter cells. Telomere length measured in leukocytes (LTL) has been investigated in different cancer types, including multiple myeloma (MM). However, LTL measurement is prone to heterogeneity due to sample handling and study design (retrospective vs. prospective). LTL is genetically determined; genome-wide association studies identified 11 SNPs that, combined in a score, can be used as a genetic instrument to measure LTL and evaluate its association with MM risk. This approach has been already successfully attempted in various cancer types but never in MM. We tested the "teloscore" in 2407 MM patients and 1741 controls from the International Multiple Myeloma rESEarch (IMMeNSE) consortium. We observed an increased risk for longer genetically determined telomere length (gdTL) (OR = 1.69; 95% CI 1.36-2.11; P = 2.97 x 10(-6) for highest vs. lowest quintile of the score). Furthermore, in a subset of 1376 MM patients we tested the relationship between the teloscore and MM patients survival, observing a better prognosis for longer gdTL compared with shorter gdTL (HR = 0.93; 95% CI 0.86-0.99; P = 0.049). In conclusion, we report convincing evidence that longer gdTL is a risk marker for MM risk, and that it is potentially involved in increasing MM survival.Univerity of PisaHelmholtz AssociationInstituto de Salud Carlos III PI12/02688 PI17/02276Instituto de Salud Carlos IIIEuropean CommissionFEDER funds-a way to build Europe PI14-00613Agency for Management of University and Research Grants (AGAUR) of the Catalan Government (Barcelona, Spain) 2017SGR723Projekt DEA

Real-world study of the efficacy and safety of belantamab mafodotin (GSK2857916) in relapsed or refractory multiple myeloma based on data from the nominative ATU in France: the IFM 2020-04 study

Belantamab mafodotin (BM) is an anti-BCMA antibody-drug conjugate (GSK2857916) that represents an alternative option in multiple myeloma. We sought to assess the efficacy and safety of BM in a real-world setting in patients who benefited from an early access program. We conducted an observational, retrospective, multicenter study. Eligibility criteria were treatment of relapsed or refractory multiple myeloma (RRMM) in monotherapy in adult patients who have received at least three lines of therapy previously, including at least one immunomodulatory agent (IMiD), a proteasome inhibitor (PI) and an anti-CD38 monoclonal antibody, and whose disease progressed during the last treatment period. The primary endpoint of the study is to assess the overall survival (OS). Between November 2019 and December 2020, 106 patients were treated with BM; 97 were eligible for the efficacy evaluation and 104 for safety. The median age was 66 (range, 37–82) years. High-risk cytogenetics were identified in 40.9% of patients. Fifty-five (56.7%) patients were triple-class refractory and 11 (11.3%) were penta-class refractory. The median number of prior lines of treatment was five (range, 3–12). The median number of BM cycles administered was three (range, 1–22). The overall response rate at best response was 38.1% (37/97). The median OS was 9.3 months (95% confidence interval [CI]: 5.9-15.3), and median progression-free survival was 3.5 months (95% CI: 1.9-4.7). The median duration of response was 9 months (range, 4.65-10.4). Treatment was delayed for 55 (52.9%) patients including 36.5% for treatment-related toxicity. Ophthalmic adverse events, mainly grade ≤2, were the most common toxicity (48%). The occurrence of keratopathy was 37.5%. Overall, our data are concordant with the results from DREAMM-2 in terms of efficacy and safety on a non-biased population

Détérioration respiratoire en sortie d'aplasie sous facteur de croissance hématopoïétique (G-CSF) (à propos de 20 cas)

Des cas d aggravation respiratoire en sortie d aplasie ont été décrits chez les patients d onco-hématologie. Le G-CSF aggrave la toxicité pulmonaire de la chimiothérapie et le SDRA en sortie d aplasie (SDRA-SA) chez le rat. Peu de données cliniques sont disponibles. Nous rapportons 20 patients admis en réanimation pour détérioration respiratoire en SA post-chimiothérapie sous G-CSF (12 lymphomes, 5 leucémies, 2 cancers et un myélome ; 8 autogreffes de CSP et 2 allogreffes de moelle). Une pneumopathie avait compliqué la neutropénie chez tous les patients. Malgré un recours à la VNI chez 5 patients et invasive chez 13, seuls 5 patients sont décédés ; les autres ont guéri après arrêt du G-CSF, traitement anti-infectieux et symptomatique. Nous souhaitons alerter les cliniciens ayant en charge des patients sous G-CSF. Devant une suspicion de SDRA-SA, nous recommandons l arrêt du G-CSF, l élimination de toute autre cause de pneumopathie et l utilisation précoce de la VNI en réanimation.Some reports suggest the possibility of respiratory deterioration during neutropenia recovery (NR) in cancer patients. G-CSF aggravates chemotherapy-related pulmonary toxicity, and ARDS during NR in rats. Few clinical data are available. We report 20 cases of critically ill cancer patients admitted for acute respiratory deterioration during G-CSF induced NR: 12 lymphomas, 5 leukemias, 2 solid cancers and 1 myeloma. Eight patients underwent autologous transplantation, 2 allogeneic transplantation. All presented pneumonia increasing during NR. Despite the need of mechanical ventilation (MV) in 16 patients, only 5 died; others were cured after G-CSF interruption, antimicrobiol therapy and supportive care. Clinicians must be aware that during G-CSF induced NR, patients are at high risk of respiratory deterioration, above all if they present with prior lung involvement. In such cases, we recommend interruption of G-CSF, exclusion of other cause of respiratory failure and early NIMV in ICU.PARIS12-CRETEIL BU Médecine (940282101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF