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Clinical Lymphoma, Myeloma & Leukemia Sep 2021Daratumumab plus bortezomib/dexamethasone (D-Vd) significantly improved outcomes versus Vd in patients with relapsed or refractory multiple myeloma (RRMM) in the phase 3... (Randomized Controlled Trial)
Randomized Controlled Trial
Daratumumab, Bortezomib, and Dexamethasone Versus Bortezomib and Dexamethasone in Chinese Patients with Relapsed or Refractory Multiple Myeloma: Phase 3 LEPUS (MMY3009) Study.
BACKGROUND
Daratumumab plus bortezomib/dexamethasone (D-Vd) significantly improved outcomes versus Vd in patients with relapsed or refractory multiple myeloma (RRMM) in the phase 3 CASTOR study. We report the results of a prespecified interim analysis of the phase 3 LEPUS study of D-Vd versus Vd in Chinese patients with RRMM.
PATIENTS AND METHODS
Chinese patients with ≥ 1 prior line of therapy were randomized 2:1 to receive 8 cycles (21 days/cycle) of bortezomib (1.3 mg/m subcutaneously) and dexamethasone (20 mg orally/intravenously) ± daratumumab (16 mg/kg intravenously). The primary endpoint was progression-free survival (PFS).
RESULTS
A total of 211 patients were randomized (D-Vd, 141; Vd, 70). After an 8.2-month median follow-up, D-Vd significantly prolonged PFS versus Vd (median, not reached vs. 6.3 months; hazard ratio, 0.28; 95% confidence interval, 0.17-0.47; P < .00001) and significantly improved the rates of overall response (83% vs. 65%; P = .00527), ≥ very good partial response (65% vs. 33%; P = .00002), ≥ complete response (33% vs. 11%; P = .00079), and minimal residual disease negativity (10 sensitivity; 22% vs. 3%; P = .0002). The PFS benefit of D-Vd versus Vd was maintained across prespecified subgroups, including patients with prior bortezomib treatment and with high-risk cytogenetics. Thrombocytopenia (D-Vd, 51%; Vd, 37%), lymphopenia (44%; 29%), and lung infection (30%; 22%) were the 3 most common grade 3/4 treatment-emergent adverse events. Although patients in both treatment groups experienced higher rates of grade 3/4 lymphopenia and infections versus patients in CASTOR, the safety profile was generally consistent with that of CASTOR.
CONCLUSION
These data support the use of D-Vd in Chinese patients with RRMM.
Topics: Adult; Aged; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; China; Dexamethasone; Female; Humans; Male; Middle Aged; Multiple Myeloma; Neoplasm Recurrence, Local
PubMed: 34108127
DOI: 10.1016/j.clml.2021.04.012 -
Blood Nov 2017The antiapoptotic proteins BCL-2 and myeloid cell leukemia sequence 1 (MCL-1) promote multiple myeloma (MM) cell survival. Venetoclax is a selective, orally bioavailable...
The antiapoptotic proteins BCL-2 and myeloid cell leukemia sequence 1 (MCL-1) promote multiple myeloma (MM) cell survival. Venetoclax is a selective, orally bioavailable small-molecule BCL-2 inhibitor; bortezomib can indirectly inhibit MCL-1. In preclinical studies, venetoclax enhanced bortezomib activity, suggesting that cotargeting of BCL-2 and MCL-1 could be an effective treatment strategy in myeloma. This phase 1b trial studied patients with relapsed/refractory MM receiving daily venetoclax (50-1200 mg per designated dose cohort; 800 mg in safety expansion) in combination with bortezomib and dexamethasone. A total of 66 patients were enrolled (54 in the dose-escalation cohorts and 12 in the safety expansion). Patients had received a median of 3 prior therapies (range, 1-13); 26 (39%) were refractory to prior bortezomib and 35 (53%) to lenalidomide; 39 (59%) had prior stem cell transplant. The combination was generally well tolerated, and common adverse events included mild gastrointestinal toxicities (diarrhea [46%], constipation [41%], and nausea [38%]) and grade 3/4 cytopenias (thrombocytopenia [29%] and anemia [15%]). The overall response rate (ORR) was 67% (44/66); 42% achieved very good partial response or better (≥VGPR). Median time to progression and duration of response were 9.5 and 9.7 months, respectively. ORR of 97% and ≥VGPR 73% were seen in patients not refractory to bortezomib who had 1 to 3 prior therapies. Patients with high expression had a higher ORR (94% [17/18]) than patients with low expression (59% [16/27]). This novel combination of venetoclax with bortezomib and dexamethasone has an acceptable safety profile and promising efficacy in patients with relapsed/refractory MM. This trial was registered at www.clinicaltrials.gov as #NCT01794507.
Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Bridged Bicyclo Compounds, Heterocyclic; Dexamethasone; Female; Humans; Male; Middle Aged; Multiple Myeloma; Neoplasm Recurrence, Local; Sulfonamides; Treatment Outcome
PubMed: 28847998
DOI: 10.1182/blood-2017-06-788323 -
Aging Jul 2017
Topics: Antineoplastic Agents; Bortezomib; Endoplasmic Reticulum Stress; Humans; Multiple Myeloma; Proteasome Endopeptidase Complex; Proteasome Inhibitors
PubMed: 28758893
DOI: 10.18632/aging.101273 -
Nature Nanotechnology Feb 2023Cancer therapies often have narrow therapeutic indexes and involve potentially suboptimal combinations due to the dissimilar physical properties of drug molecules....
Cancer therapies often have narrow therapeutic indexes and involve potentially suboptimal combinations due to the dissimilar physical properties of drug molecules. Nanomedicine platforms could address these challenges, but it remains unclear whether synergistic free-drug ratios translate to nanocarriers and whether nanocarriers with multiple drugs outperform mixtures of single-drug nanocarriers at the same dose. Here we report a bottlebrush prodrug (BPD) platform designed to answer these questions in the context of multiple myeloma therapy. We show that proteasome inhibitor (bortezomib)-based BPD monotherapy slows tumour progression in vivo and that mixtures of bortezomib, pomalidomide and dexamethasone BPDs exhibit in vitro synergistic, additive or antagonistic patterns distinct from their corresponding free-drug counterparts. BPDs carrying a statistical mixture of three drugs in a synergistic ratio outperform the free-drug combination at the same ratio as well as a mixture of single-drug BPDs in the same ratio. Our results address unanswered questions in the field of nanomedicine, offering design principles for combination nanomedicines and strategies for improving current front-line monotherapies and combination therapies for multiple myeloma.
Topics: Humans; Multiple Myeloma; Bortezomib; Prodrugs; Dexamethasone; Antineoplastic Combined Chemotherapy Protocols
PubMed: 36702954
DOI: 10.1038/s41565-022-01310-1 -
Clinical and Experimental Pharmacology... Jun 2022Multiple myeloma (MM) is an incurable plasma cell malignancy with a poor survival rate. Conventional chemotherapeutic agent-induced adverse events, including toxicity,...
Multiple myeloma (MM) is an incurable plasma cell malignancy with a poor survival rate. Conventional chemotherapeutic agent-induced adverse events, including toxicity, neuropathy or drug resistance, significantly decrease the patients' quality of life and can even lead to interruption of treatment. Therefore, novel therapeutic drugs and strategies are urgently needed to improve MM therapy and patient outcomes. Here, we show that solamargine (SM), a steroidal alkaloid glycoside isolated from a Chinese herb Solanum nigrum L., exhibits promising anti-MM activity. In particular, SM suppressed the viability of MM cell lines (ARP-1 and NCI-H929) in a concentration- and time-dependent manner, inducing apoptosis in these cells. RNA-seq analysis showed that treatment with SM led to the upregulation of genes associated with cell death and autophagy in H929 cells. Further, we found that treatment with SM activated autophagy in the MM cells, as incubation with 3-Methyladenine, an inhibitor of autophagy, significantly alleviated SM-triggered apoptosis and inhibition of viability in MM cells. Interestingly, we also observed a synergistic effect between SM and bortezomib (BTZ), a common chemotherapeutic agent for MM, in both MM cells and human bone marrow CD138+ primary myeloma cells. We also confirmed the single-agent efficacy of SM and the synergistic effects between SM and BTZ in an MM xenograft mouse model. Collectively, these findings indicate that SM exerts an anti-MM effect, at least in part, by activating cell autophagy and reveal that SM alone or in combination with BTZ is a potential therapeutic strategy for treating MM.
Topics: Animals; Antineoplastic Agents; Apoptosis; Autophagy; Bortezomib; Cell Line, Tumor; Humans; Mice; Multiple Myeloma; Quality of Life; Solanaceous Alkaloids
PubMed: 35294057
DOI: 10.1111/1440-1681.13643 -
Journal of Healthcare Engineering 2022Multiple myeloma (MM) is one of the hitherto incurable malignant blood tumors. Bortezomib plays an important role in the treatment of MM.
BACKGROUND
Multiple myeloma (MM) is one of the hitherto incurable malignant blood tumors. Bortezomib plays an important role in the treatment of MM.
OBJECTIVE
We aimed to compare effectiveness, safety, and pharmacoeconomic evaluations of the original research drug and the generic drug Bortezomib in the treatment of MM, so as to provide a reasonable basis for the selection of drugs in clinical diagnosis and treatment.
METHODS
A collection of 374 patients with MM were diagnosed and treated with combined Bortezomib in our hospital from July 2019 to January 2020.Two hundred and sixty nine cases met the criteria for inclusion and discharge. According to the different drug manufacturers, divided into the original research drug group ( = 149) and the generic drug group ( = 120). The effectiveness and safety were separately counted, and use the cost-minimization analysis to make the pharmacoeconomic evaluations.
RESULTS
Compared with the results of the two groups, there was no statistical difference between the two groups of treatment efficacy or adverse reaction rates ( > 0.05). The average daily cost of the original research drug group was 2954.38 Chinese yuan (CNY), the average treatment cost per cycle was 32967.69 CNY, the average daily cost of the generic drug group was 2697.29 CNY, and the average treatment cost per cycle was 29129.57 CNY. The price of the generic drug group is lower than the original drug group, and there was a statistical difference between the two groups ( < 0.05).
CONCLUSION
There was no difference between the two groups of effectiveness or safety, and the generic drug is more economical in the treatment.
Topics: Bortezomib; Drugs, Generic; Humans; Multiple Myeloma; Treatment Outcome
PubMed: 35392155
DOI: 10.1155/2022/5201354 -
International Journal of Molecular... Jul 2022, a parasitic intracellular bacterium, is a major human pathogen that causes millions of trachoma, sexually transmitted infections, and pneumonia cases worldwide....
, a parasitic intracellular bacterium, is a major human pathogen that causes millions of trachoma, sexually transmitted infections, and pneumonia cases worldwide. Previously, peptidomimetic inhibitors consisting of a hydrophobic dipeptide derivative exhibited significant inhibitory effects against chlamydial growth. Based on this finding, this study showed that both bortezomib (BTZ) and ixazomib (IXA), anticancer drugs characterized by proteasome inhibitors, have intensive inhibitory activity against . Both BTZ and IXA consisted of hydrophobic dipeptide derivatives and strongly restricted the growth of (BTZ, IC = 24 nM). In contrast, no growth inhibitory effect was observed for other nonintracellular parasitic bacteria, such as . BTZ and IXA appeared to inhibit chlamydial growth bacteriostatically via electron microscopy. Surprisingly, -infected cells that induced a persistent infection state were selectively eliminated by BTZ treatment, whereas uninfected cells survived. These results strongly suggested the potential of boron compounds based on hydrophobic dipeptides for treating chlamydial infections, including persistent infections, which may be useful for future therapeutic use in chlamydial infectious diseases.
Topics: Apoptosis; Bortezomib; Chlamydia Infections; Chlamydia trachomatis; Dipeptides; Humans
PubMed: 35806436
DOI: 10.3390/ijms23137434 -
BioMed Research International 2016This study aimed at comparing bortezomib, thalidomide, and lenalidomide in patients with multiple myeloma (MM) for safety and efficacy using meta-analysis. This... (Meta-Analysis)
Meta-Analysis Review
This study aimed at comparing bortezomib, thalidomide, and lenalidomide in patients with multiple myeloma (MM) for safety and efficacy using meta-analysis. This meta-analysis identified 17 randomized controlled trials (RCTs) including 6742 patients. These RCTs were separated according to the different agent-based regimens and to autologous stem-cell transplantation (ASCT). Complete response (CR), progression-free survival (PFS), overall survival (OS), and adverse events (AE) were combined. The total weighted risk ratio (RR) of CR was 3.29 [95% confidence interval (95% CI): 2.22-4.88] (P < 0.0001) for the novel agent-based regimens. These novel agent-based regimens showed greater benefit in terms of PFS of all subgroups irrespective of whether the patient received ASCT or not. The hazard ratio (HR) for PFS was 0.64 [95% CI: 0.60-0.69] (P < 0.00001). Improvements of OS could be found only in the bortezomib- and thalidomide-based regimens without ASCT. The pooled HRs were 0.74 [95% CI: 0.65-0.86] (P < 0.0001) and 0.80 [95% CI: 0.70-0.90] (P = 0.0004), respectively. Several AEs were shown more frequently in the novel agent-based regimens compared with controls such as hematologic events (neutropenia, anemia, and thrombocytopenia), gastrointestinal infection, peripheral neuropathy, thrombosis, and embolism events. In conclusion, in spite of the AEs, novel agent-based regimens are safe and effective for the treatment of MM.
Topics: Bortezomib; Disease-Free Survival; Humans; Lenalidomide; Multiple Myeloma; Randomized Controlled Trials as Topic; Thalidomide; Treatment Outcome
PubMed: 26949704
DOI: 10.1155/2016/6848902 -
Medicine Jan 2022Autoimmune hemolytic anemia (AIHA) therapy may be associated with severe complications such as diabetes, hypertension, obesity, osteoporosis, peptic ulcers, infection,...
Autoimmune hemolytic anemia (AIHA) therapy may be associated with severe complications such as diabetes, hypertension, obesity, osteoporosis, peptic ulcers, infection, and some other diseases. To reduce those effects, we used low-dose rituximab, bortezomib and dexamethasone (LowR-BD regimen) to treat AIHA. The purpose of this study was to evaluate the efficacy and safety of this regimen.Seven patients with warm AIHA (wAIHA) admitted from March 2020 to October 2020 were treated with LowR-BD regimen: Rituximab 100 mg by intravenous infusion on day 1 combined with bortezomib 1.3 mg/m2 by subcutaneous injection on day 2 plus dexamethasone 20 mg by intravenous infusion on days 2, 3. Clinical efficacy and safety were assessed at the regular reexamination of relevant indicators and follow-up.After 4 cycles of the LowR-BD regimen, the overall response rate (ORR) was 85.71% with a complete response (CR) of 28.57% and a partial response (PR) of 57.14%. After a median follow-up of 12 (range 7-13) months, 5 patients achieved CR and 2 patients had PR status, including 1 patient who did not respond to LowR-BD treatment and reached CR after using methylprednisolone combined with cyclophosphamide. One patient relapsed and achieved PR after retreatment of 2 cycles LowR-BD regimen. The patients tolerated the treatment well and did not complain of apparently adverse reactions except a patient with Sjogren's syndrome and bronchiectasis who developed a severe infection during treatment.Low-dose rituximab combined with bortezomib and dexamethasone is effective and relatively safe in patients with wAIHA.
Topics: Adult; Aged; Anemia, Hemolytic, Autoimmune; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Cyclophosphamide; Dexamethasone; Female; Humans; Male; Methylprednisolone; Middle Aged; Rituximab; Treatment Outcome
PubMed: 35089216
DOI: 10.1097/MD.0000000000028679 -
Journal of Hematology & Oncology Apr 2021Therapeutic regimens for previously treated multiple myeloma (MM) may not provide prolonged disease control and are often complicated by significant adverse events,...
Therapeutic regimens for previously treated multiple myeloma (MM) may not provide prolonged disease control and are often complicated by significant adverse events, including peripheral neuropathy. In patients with previously treated MM in the Phase 3 BOSTON study, once weekly selinexor, once weekly bortezomib, and 40 mg dexamethasone (XVd) demonstrated a significantly longer median progression-free survival (PFS), higher response rates, deeper responses, a trend to improved survival, and reduced incidence and severity of bortezomib-induced peripheral neuropathy when compared with standard twice weekly bortezomib and 80 mg dexamethasone (Vd). The pre-specified analyses described here evaluated the influence of the number of prior lines of therapy, prior treatment with lenalidomide, prior proteasome inhibitor (PI) therapy, prior immunomodulatory drug therapy, and prior autologous stem cell transplant (ASCT) on the efficacy and safety of XVd compared with Vd. In this 1:1 randomized study, enrolled patients were assigned to receive once weekly oral selinexor (100 mg) with once weekly subcutaneous bortezomib (1.3 mg/m) and 40 mg per week dexamethasone (XVd) versus standard twice weekly bortezomib and 80 mg per week dexamethasone (Vd). XVd significantly improved PFS, overall response rate, time-to-next-treatment, and showed reduced all grade and grade ≥ 2 peripheral neuropathy compared with Vd regardless of prior treatments, but the benefits of XVd over Vd were more pronounced in patients treated earlier in their disease course who had either received only one prior therapy, had never been treated with a PI, or had prior ASCT. Treatment with XVd improved outcomes as compared to Vd regardless of prior therapies as well as manageable and generally reversible adverse events. XVd was associated with clinical benefit and reduced peripheral neuropathy compared to standard Vd in previously treated MM. These results suggest that the once weekly XVd regimen may be optimally administered to patients earlier in their course of disease, as their first bortezomib-containing regimen, and in those relapsing after ASCT.Trial registration: ClinicalTrials.gov (NCT03110562). Registered 12 April 2017. https://clinicaltrials.gov/ct2/show/NCT03110562 .
Topics: Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone; Female; Humans; Hydrazines; Male; Multiple Myeloma; Triazoles
PubMed: 33849608
DOI: 10.1186/s13045-021-01071-9