This article presents a practical overview of the treatment of younger, newly diagnosed multiple myeloma patients, focusing on novel treatment strategies. With the introduction of effective new ...agents, multiple myeloma is one of the most active and changing fields in clinical oncology. In addition, monitoring technology has become reliable and practical. Achieving and sustaining minimal residual disease negativity (MRD– ), such as multiparameter flow cytometry (MFC) < 10
−5
, is one of the goals of therapy. MRD– is significantly associated with prolonged progression-free survival, whereas MRD persistence (MRD +) is an independent factor for poor progression-free survival. Evidence from several recent studies evaluating modern therapy has further supported the positive correlation between depth of response and outcomes. Multiple myeloma can become a chronic illness with sustained MRD– in a significant number of patients. Our ultimate hope is to leverage tumoricidal-immunomodulatory sequential therapies and to cure a subset of our patients.
The immunostimulatory monoclonal antibody elotuzumab plus lenalidomide and dexamethasone has been shown to be effective in patients with relapsed or refractory multiple myeloma. The immunomodulatory ...agent pomalidomide plus dexamethasone has been shown to be effective in patients with multiple myeloma that is refractory to lenalidomide and a proteasome inhibitor.
Patients with multiple myeloma that was refractory or relapsed and refractory to lenalidomide and a proteasome inhibitor were randomly assigned to receive elotuzumab plus pomalidomide and dexamethasone (elotuzumab group) or pomalidomide and dexamethasone alone (control group). The primary end point was investigator-assessed progression-free survival.
A total of 117 patients were randomly assigned to the elotuzumab group (60 patients) or the control group (57 patients). After a minimum follow-up period of 9.1 months, the median progression-free survival was 10.3 months in the elotuzumab group and 4.7 months in the control group. The hazard ratio for disease progression or death in the elotuzumab group as compared with the control group was 0.54 (95% confidence interval CI, 0.34 to 0.86; P=0.008). The overall response rate was 53% in the elotuzumab group as compared with 26% in the control group (odds ratio, 3.25; 95% CI, 1.49 to 7.11). The most common grade 3 or 4 adverse events were neutropenia (13% in the elotuzumab group vs. 27% in the control group), anemia (10% vs. 20%), and hyperglycemia (8% vs. 7%). A total of 65% of the patients in each group had infections. Infusion reactions occurred in 3 patients (5%) in the elotuzumab group.
Among patients with multiple myeloma in whom treatment with lenalidomide and a proteasome inhibitor had failed, the risk of progression or death was significantly lower among those who received elotuzumab plus pomalidomide and dexamethasone than among those who received pomalidomide plus dexamethasone alone. (Funded by Bristol-Myers Squibb and AbbVie Biotherapeutics; ELOQUENT-3 ClinicalTrials.gov number, NCT02654132 .).
This is a review regarding the current therapeutic strategies in the management of multiple myeloma. Due to the introduction of several new effective therapeutic agents, multiple myeloma is one of ...the most active and changing fields in clinical oncology. Multiple myeloma is caused by the expansion of monoclonal plasma cells and secretion of M-protein (immunoglobulins, Bence Jones protein and free light chain). High-dose chemotherapy supported with autologous peripheral blood stem cells is an effective treatment for the disease. However, multiple myelomas are still difficult to cure and require long-term disease control. In recent years, the introduction of novel drugs (bortezomib, lenalidomide and thalidomide) has improved treatment.
Daratumumab showed promising efficacy alone and with lenalidomide and dexamethasone in a phase 1-2 study involving patients with relapsed or refractory multiple myeloma.
In this phase 3 trial, we ...randomly assigned 569 patients with multiple myeloma who had received one or more previous lines of therapy to receive lenalidomide and dexamethasone either alone (control group) or in combination with daratumumab (daratumumab group). The primary end point was progression-free survival.
At a median follow-up of 13.5 months in a protocol-specified interim analysis, 169 events of disease progression or death were observed (in 53 of 286 patients 18.5% in the daratumumab group vs. 116 of 283 41.0% in the control group; hazard ratio, 0.37; 95% confidence interval CI, 0.27 to 0.52; P<0.001 by stratified log-rank test). The Kaplan-Meier rate of progression-free survival at 12 months was 83.2% (95% CI, 78.3 to 87.2) in the daratumumab group, as compared with 60.1% (95% CI, 54.0 to 65.7) in the control group. A significantly higher rate of overall response was observed in the daratumumab group than in the control group (92.9% vs. 76.4%, P<0.001), as was a higher rate of complete response or better (43.1% vs. 19.2%, P<0.001). In the daratumumab group, 22.4% of the patients had results below the threshold for minimal residual disease (1 tumor cell per 10
white cells), as compared with 4.6% of those in the control group (P<0.001); results below the threshold for minimal residual disease were associated with improved outcomes. The most common adverse events of grade 3 or 4 during treatment were neutropenia (in 51.9% of the patients in the daratumumab group vs. 37.0% of those in the control group), thrombocytopenia (in 12.7% vs. 13.5%), and anemia (in 12.4% vs. 19.6%). Daratumumab-associated infusion-related reactions occurred in 47.7% of the patients and were mostly of grade 1 or 2.
The addition of daratumumab to lenalidomide and dexamethasone significantly lengthened progression-free survival among patients with relapsed or refractory multiple myeloma. Daratumumab was associated with infusion-related reactions and a higher rate of neutropenia than the control therapy. (Funded by Janssen Research and Development; POLLUX ClinicalTrials.gov number, NCT02076009 .).
Abstract Radioprotective agents have been developed to protect patients against the damaging and lethal effects of ionizing radiation. However, in addition to the intrinsic ability to target reactive ...oxygen species (ROS), the ability to retain a significant level of bioavailability is desirable in radioprotective agents because that would increase and prolong their radioprotective efficacy and improve its safety. Here, we report the development of a novel nanoparticle-based radioprotective agent with improved bioavailability, which suppressed the adverse effects typically associated with low-molecular-weight (LMW) antioxidants. We developed biocompatible and colloidally stable nanoparticles in which nitroxide radicals that were covalently conjugated (redox nanoparticles, RNPN ) effectively scavenged radiation-induced ROS with a characteristically prolonged bioavailability and tissue-residence time compared with that of conventional LMW antioxidants. The confinement of the nitroxide radicals in the RNPN core prevented its rapid metabolism and excretion out of the body. The nano-sized formulation prevented internalization of RNPN in healthy cells, thereby preserving the normal function of the redox reactions in the cell. This improved pharmacological performance dramatically reduced the radiation-induced organ dysfunctions and increased the survival time of the lethally irradiated mice when the nanoparticles were administered 3–24 h before whole-body irradiation.
Despite recent advances in the range of therapies available for the treatment of multiple myeloma (MM), there are limited data surrounding survival outcomes and baseline characteristics influencing ...survival in general clinical practice in Japan. The aim of this study was to use electronic medical records (EMRs) to examine overall survival (OS) and prognostic factors in Japanese patients with MM. We extracted EMRs in the Real World Data (RWD) database of patients with a confirmed diagnosis of MM and treatment history with bortezomib, thalidomide, and/or lenalidomide. OS and prognostic factors for OS were analyzed using a univariate analysis and decision tree model. Of the 6509 patients in the database with a diagnosis of MM, 1565 were eligible. Patients had a median (range) age of 72 (23-92) years, a median OS of 53.5 months, and a 5-year OS rate of 45.6%. In alignment with previous studies, International Staging System stage and age were prognostic of OS. In addition, platelet and erythrocyte counts, chloride, total protein, C-reactive protein, and lactate dehydrogenase levels were identified as important prognostic factors for OS and were used to pilot a simple prognostic tool. In conclusion, we found that the survival outcomes extracted from EMRs in the RWD of Japanese patients with MM aligned with a previous retrospective study from Japan. Baseline laboratory parameters prognostic for OS were explored with additional factors to International Staging System and age identified. These might be used to optimize treatment selection, although further investigation using additional data sources is required.
In the first phase 3 study in relapsed/refractory AL amyloidosis (TOURMALINE-AL1 NCT01659658), 168 patients with relapsed/refractory AL amyloidosis after 1-2 prior lines were randomized to ixazomib ...(4 mg, days 1, 8, 15) plus dexamethasone (20 mg, days 1, 8, 15, 22; n = 85) or physician's choice (dexamethasone ± melphalan, cyclophosphamide, thalidomide, or lenalidomide; n = 83) in 28-day cycles until progression or toxicity. Primary endpoints were hematologic response rate and 2-year vital organ deterioration or mortality rate. Only the first primary endpoint was formally tested at this interim analysis. Best hematologic response rate was 53% with ixazomib-dexamethasone vs 51% with physician's choice (p = 0.76). Complete response rate was 26 vs 18% (p = 0.22). Median time to vital organ deterioration or mortality was 34.8 vs 26.1 months (hazard ratio 0.53; 95% CI, 0.32-0.87; p = 0.01). Median treatment duration was 11.7 vs 5.0 months. Adverse events of clinical importance included diarrhea (34 vs 30%), rash (33 vs 20%), cardiac arrhythmias (26 vs 15%), nausea (24 vs 14%). Despite not meeting the first primary endpoint, all time-to-event data favored ixazomib-dexamethasone. These results are clinically relevant to this relapsed/refractory patient population with no approved treatment options.
Multiple myeloma (MM) and AL amyloidosis are caused by the expansion of monoclonal plasma cells and secretion of dysproteinemia (Bence Jones protein and free light chain) and some patients require ...the hemodialysis. Myeloma kidney is mainly caused by the cast nephropathy of the distal tubuli, whereas, AL amyloid-protein is mainly deposited in glomeruli with massive fibrillar involvement. Therefore, almost MM patients presents a symptom of renal insufficiency, whereas, almost patients of AL amyloidosis present a nephrotic syndrome with severe hypoalbuminemia. These two diseases have some similar characteristics such as up-regulation of cyclin D1 gene by 11:14 chromosomal translocation. High-dose chemotherapy supported with autologous peripheral blood stem cells is effective for these two diseases. However, they are still difficult to be cured and require long-term disease control. In recent years, introduction of novel agents has changed their treatment strategies from the palliation therapy to the clinical cure.
Lenalidomide and dexamethasone (Rd) treatment is common for patients with newly diagnosed multiple myeloma (NDMM) ineligible for autologous stem-cell transplantation. Daratumumab plus Rd (D-Rd) is ...effective and well tolerated for treating relapsed or refractory multiple myeloma. In this ongoing phase 1b trial, transplant-ineligible Japanese patients with NDMM received daratumumab (16 mg/kg intravenously every week for 8 weeks, every 2 weeks for 16 weeks, then every 4 weeks until disease progression) plus Rd (R 25 mg on Days 1‒21 of 28-day cycle; d 40 mg weekly). The primary objective was to evaluate D-Rd tolerability and safety in Japanese patients with NDMM. Secondary objectives included daratumumab pharmacokinetics and response rate. During the dose-limiting toxicity (DLT) evaluation period, two DLTs occurred in seven (28.6%) patients, indicating D-Rd tolerability. At an 11.0-month median follow-up (interim analysis), grade 3/4 treatment-emergent adverse events occurred in six (85.7%) patients, including lymphopenia (71.4%), leukopenia (57.1%), and neutropenia (42.9%). Three (42.9%) patients experienced infusion-related reactions (IRRs). All IRRs were grade 2, occurred during the first daratumumab infusion, and resolved within 24 h. Pharmacokinetic findings were comparable to those in previous studies. A 100% overall response rate was achieved. These findings suggest D-Rd is tolerable in Japanese patients with transplant-ineligible NDMM.
ClinicalTrials
.
gov identifier
NCT02918331.
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