In the POLLUX study, daratumumab plus lenalidomide/dexamethasone significantly reduced risk of progression/death versus lenalidomide/dexamethasone alone in relapsed/refractory multiple myeloma. We ...provide one additional year of follow-up and include the effect on minimal residual disease and in clinically relevant subgroups. After 25.4 months of follow-up, daratumumab plus lenalidomide/dexamethasone prolonged progression-free survival versus lenalidomide/dexamethasone alone (median not reached vs 17.5 months; hazard ratio, 0.41; 95% confidence interval, 0.31-0.53; P <0.0001). The overall response rate was 92.9% versus 76.4%, and 51.2% versus 21.0% achieved a complete response or better, respectively (both P <0.0001). At the 10e5 sensitivity threshold, 26.2% versus 6.4% were minimal residual disease-negative, respectively (P <0.0001). Post hoc analyses of clinical relevant patient subgroups demonstrated that progression-free survival was significantly prolonged for daratumumab plus lenalidomide/dexamethasone versus lenalidomide/dexamethasone regardless of number of prior lines of therapy. Patients previously treated with lenalidomide or thalidomide and those refractory to bortezomib received similar benefits (all P <0.01). Treatment benefit with daratumumab plus lenalidomide/dexamethasone was maintained in high-risk patients (median progression-free survival 22.6 vs 10.2 months; hazard ratio, 0.53; 95% confidence interval, 0.25-1.13; P = 0.0921) and patients with treatment-free intervals of >12 and ≤12 months, >6 and ≤6 months. No new safety signals were observed. In relapsed/refractory multiple myeloma patients, daratumumab plus lenalidomide/dexamethasone continued to improve progression-free survival and deepen responses versus lenalidomide/dexamethasone.
clinicaltrials.gov identifier: NCT02076009.
Intravenous daratumumab for treatment of patients with multiple myeloma involves a lengthy infusion that affects quality of life, and infusion-related reactions are common. Subcutaneous daratumumab ...is thought to be easier to administer and to cause fewer administration-related reactions. In this study (COLUMBA), we tested the non-inferiority of subcutaneous daratumumab to intravenous daratumumab.
In this ongoing, multicentre (147 sites in 18 countries), open-label, non-inferiority, randomised, phase 3 trial, we recruited adult patients (age ≥18 years) if they had confirmed relapsed or refractory multiple myeloma according to International Myeloma Working Group criteria; received at least three previous lines of therapy, including a proteasome inhibitor and immunomodulatory drug, or were double refractory to both a proteasome inhibitor and immunomodulatory drug; and had an Eastern Cooperative Oncology Group performance status score of 2 or lower. Patients were randomly assigned (1:1) by a computer-generated randomisation schedule and balanced using randomly permuted blocks to receive daratumumab subcutaneously (subcutaneous group) or intravenously (intravenous group). Randomisation was stratified on the basis of baseline bodyweight (≤65 kg, 66-85 kg, >85 kg), previous therapy lines (≤four vs >four), and myeloma type (IgG vs non-IgG). Patients received 1800 mg of subcutaneous daratumumab co-formulated with 2000 U/mL recombinant human hyaluronidase PH20 or 16 mg/kg of intravenous daratumumab once weekly (cycles 1-2), every 2 weeks (cycles 3-6), and every 4 weeks thereafter (28-day cycles) until progressive disease or toxicity. The co-primary endpoints were overall response and maximum trough concentration (C
; cycle 3, day 1 pre-dose). The non-inferiority margin for overall response was defined using a 60% retention of the lower bound (20·8%) of the 95% CI of the SIRIUS trial. Efficacy analyses were done by intention-to-treat population. The pharmacokinetic-evaluable population included all patients who received all eight weekly daratumumab doses in cycles 1 and 2 and provided a pre-dose pharmacokinetics blood sample on day 1 of cycle 3. The safety population included all patients who received at least one daratumumab dose. This trial is registered with ClinicalTrials.gov, NCT03277105.
Between Oct 31, 2017, and Dec 27, 2018, 655 patients were screened, of whom 522 were recruited and randomly assigned (subcutaneous group n=263; intravenous group n=259). Three patients in the subcutaneous group and one in the intravenous group did not receive treatment and were not evaluable for safety. At a median follow-up of 7·5 months (IQR 6·5-9·3), overall response and C
met the predefined non-inferiority criteria. An overall response was seen in 108 (41%) of 263 patients in the subcutaneous group and 96 (37%) of 259 in the intravenous group (relative risk 1·11, 95% CI 0·89-1·37). The geometric means ratio for C
was 107·93% (90% CI 95·74-121·67), and the maximum C
was 593 μg/mL (SD 306) in the subcutaneous group and 522 μg/mL (226) in the intravenous group. The most common grade 3 and 4 adverse events were anaemia (34 13% of 260 patients evaluable for safety in the subcutaneous group and 36 14% of 258 patients in the intravenous group), neutropenia (34 13% and 20 8%), and thrombocytopenia (36 14% and 35 14%). Pneumonia was the only serious adverse event in more than 2% of patients (seven 3% in the subcutaneous group and 11 4% in the intravenous group). There was one death resulting from a treatment-related adverse event in the subcutaneous daratumumab group (febrile neutropenia) and four in the intravenous group (sepsis n=2, hepatitis B reactivation n=1, and Pneumocystis jirovecii pneumonia n=1).
Subcutaneous daratumumab was non-inferior to intravenous daratumumab in terms of efficacy and pharmacokinetics and had an improved safety profile in patients with relapsed or refractory multiple myeloma. These data could contribute to the approval of the subcutaneous daratumumab formulation by regulatory bodies.
Janssen Research & Development.
•In a cohort of 79 patients relapsing after BCMA-directed CAR T, multiple lines of salvage therapy led to a median overall survival of 17.9 months.•In 35 patients who received a subsequent ...T-cell-engaging therapy (CAR T or bispecific antibody), the response rate was 91.4% and median overall survival was not reached.
Display omitted
B-cell maturation antigen (BCMA)–directed chimeric antigen receptor T-cell (CAR T) therapy has demonstrated remarkable efficacy in patients with relapsed/refractory multiple myeloma, and now there are two US Food and Drug Administration–approved BCMA-directed CAR T products. However, despite high initial response rates, most patients eventually relapse. The outcomes of patients with disease recurrence after BCMA-directed CAR T have not been comprehensively studied, and such an analysis would help define optimal treatment strategies. We analyzed the salvage treatments and outcomes of 79 patients with multiple myeloma from two academic institutions, who had progression of disease after treatment with BCMA-directed CAR T. A total of 237 post–CAR T salvage treatment lines were used, and patients received a median of 2 (range, 1-10) treatment lines. The median overall survival from the date of relapse post-CAR T therapy was 17.9 months (95% confidence interval CI, 14.0 non-estimable). The overall response rate to the first salvage regimen was 43.4%, with a median progression-free survival of 3.5 months (CI, 2.5-4.6). Thirty-five patients (44.3%) received a T-cell–engaging therapy (bispecific antibody or subsequent CAR T) as salvage treatment. The overall survival in patients who received subsequent T-cell–engaging therapy was not reached after a median follow up of 21.3 months. Patients with multiple myeloma who relapse after BCMA-directed CAR T have a limited prognosis but can be potentially treated with multiple lines of salvage therapy. T-cell–engaging therapies appear to maintain pronounced clinical activity in this setting.
Treatment options in multiple myeloma (MM) are increasing with the introduction of complex multi-novel-agent-based regimens investigated in randomized clinical trials. However, application in the ...real-world setting, including feasibility of and adherence to these regimens, may be limited due to varying patient-, treatment-, and disease-related factors. Furthermore, approximately 40% of real-world MM patients do not meet the criteria for phase 3 studies on which approvals are based, resulting in a lack of representative phase 3 data for these patients. Therefore, treatment decisions must be tailored based on additional considerations beyond clinical trial efficacy and safety, such as treatment feasibility (including frequency of clinic/hospital attendance), tolerability, effects on quality of life (QoL), and impact of comorbidities. There are multiple factors of importance to real-world MM patients, including disease symptoms, treatment burden and toxicities, ability to participate in daily activities, financial burden, access to treatment and treatment centers, and convenience of treatment. All of these factors are drivers of QoL and treatment satisfaction/compliance. Importantly, given the heterogeneity of MM, individual patients may have different perspectives regarding the most relevant considerations and goals of their treatment. Patient perspectives/goals may also change as they move through their treatment course. Thus, the 'efficacy' of treatment means different things to different patients, and treatment decision-making in the context of personalized medicine must be guided by an individual's composite definition of what constitutes the best treatment choice. This review summarizes the various factors of importance and practical issues that must be considered when determining real-world treatment choices. It assesses the current instruments, methodologies, and recent initiatives for analyzing the MM patient experience. Finally, it suggests options for enhancing data collection on patients and treatments to provide a more holistic definition of the effectiveness of a regimen in the real-world setting.
Carfilzomib, the next generation of proteasome inhibitor, may increase osteoblast-related markers in patients with multiple myeloma, but the molecular mechanism of its effect on mesenchymal stem cell ...differentiation to osteoblasts remains unknown. Herein, we demonstrated that carfilzomib significantly promoted mesenchymal stem cell differentiation into osteoblasts. In osteoprogenitor cells and primary mesenchymal stem cells from patients with myeloma, carfilzomib induced increases in alkaline phosphatase activity, matrix mineralization, and calcium deposition via Wnt-independent activation of β-catenin/TCF signaling. Using affinity pull-down assays with immunoblotting analysis and immunofluorescence, we found that carfilzomib induced stabilization of both free and active forms of β-catenin in a time- and dose-dependent manner that was not associated with β-catenin transcriptional regulation. Nuclear translocation of β-catenin protein was associated with TCF transcriptional activity that was independent of the effects of GSK3β-activation and of signaling induced by 19 Wnt ligands, 10 Frizzled receptors, and LRP5/6 co-receptors. Blocking activation of β-catenin/TCF signaling by dominant negative TCF1 or TCF4 attenuated carfilzomib-induced matrix mineralization. Thus, carfilzomib induced osteoblast differentiation via Wnt-independent activation of the β-catenin/TCF pathway. These results provide a novel molecular mechanism critical to understanding the anabolic role of carfilzomib on myeloma-induced bone disease.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We explored minimal residual disease (MRD) in relapsed/refractory multiple myeloma (RRMM) and transplant-ineligible (TIE) newly diagnosed multiple myeloma (NDMM) using data from 4 phase 3 studies ...(POLLUX, CASTOR, ALCYONE, and MAIA). Each study previously demonstrated that daratumumab-based therapies improved MRD negativity rates and reduced the risk of disease progression or death by approximately half vs standards of care. We conducted a large-scale pooled analysis for associations between patients achieving complete response or better (≥CR) with MRD-negative status and progression-free survival (PFS). MRD was assessed via next-generation sequencing (10−5 sensitivity threshold). Patient-level data were pooled from all 4 studies and for patients with TIE NDMM and patients with RRMM who received ≤2 prior lines of therapy (≤2 PL). PFS was evaluated by response and MRD status. Median follow-up (months) was 54.8 for POLLUX, 50.2 for CASTOR, 40.1 for ALCYONE, and 36.4 for MAIA. Patients who achieved ≥CR and MRD negativity had improved PFS vs those who failed to reach CR or were MRD positive (TIE NDMM and RRMM hazard ratio HR 0.20, P < .0001; TIE NDMM and RRMM ≤2 PL HR 0.20, P < .0001). This benefit occurred irrespective of therapy or disease setting. A time-varying Cox proportional hazard model confirmed that ≥CR with MRD negativity was associated with improved PFS. Daratumumab-based treatment was associated with more patients reaching ≥CR and MRD negativity. These findings represent the first large-scale analysis with robust methodology to support ≥CR with MRD negativity as a prognostic factor for PFS in RRMM and TIE NDMM. These trials were registered at www.clinicaltrials.gov as #NCT02076009, #NCT02136134, #NCT02195479, and #NCT02252172.
•Patients who are MRD negative with ≥CR have improved PFS, regardless of therapy, vs those who do not reach CR or are MRD positive.•Daratumumab-based therapies lead to higher rates of ≥CR with MRD negativity compared with the standard of care.
Display omitted
multiple myeloma is considered an incurable hematologic cancer but a subset of patients can achieve long-term remissions and survival. The present study examines the clinical features of long-term ...survival as it correlates to depth of disease response.
this was a multi-institutional, international, retrospective analysis of high-dose melphalan-autologous stem cell transplant (HDM-ASCT) eligible MM patients included in clinical trials. Clinical variable and survival data were collected from 7291 MM patients from Czech Republic, France, Germany, Italy, Korea, Spain, the Nordic Myeloma Study Group and the United States. Kaplan-Meier curves were used to assess progression-free survival (PFS) and overall survival (OS). Relative survival (RS) and statistical cure fractions (CF) were computed for all patients with available data.
achieving CR at 1 year was associated with superior PFS (median PFS 3.3 years vs. 2.6 years, p < 0.0001) as well as OS (median OS 8.5 years vs. 6.3 years, p < 0.0001). Clinical variables at diagnosis associated with 5-year survival and 10-year survival were compared with those associated with 2-year death. In multivariate analysis, age over 65 years (OR 1.87, p = 0.002), IgA Isotype (OR 1.53, p = 0.004), low albumin < 3.5 g/dL (OR = 1.36, p = 0.023), elevated beta 2 microglobulin ≥ 3.5 mg/dL (OR 1.86, p < 0.001), serum creatinine levels ≥ 2 mg/dL (OR 1.77, p = 0.005), hemoglobin levels < 10 g/dL (OR 1.55, p = 0.003), and platelet count < 150k/μL (OR 2.26, p < 0.001) appeared to be negatively associated with 10-year survival. The relative survival for the cohort was ~0.9, and the statistical cure fraction was 14.3%.
these data identify CR as an important predictor of long-term survival for HDM-ASCT eligible MM patients. They also identify clinical variables reflective of higher disease burden as poor prognostic markers for long-term survival.
PDF
