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Clinical Lymphoma, Myeloma & Leukemia Oct 2014Bortezomib is administered for a finite course; thus, patients might remain sensitive to bortezomib-based therapy at relapse. We report a meta-analysis of... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Bortezomib is administered for a finite course; thus, patients might remain sensitive to bortezomib-based therapy at relapse. We report a meta-analysis of bortezomib-based retreatment in relapsed/refractory myeloma.
PATIENTS AND METHODS
A systematic literature review identified studies of bortezomib-based retreatment in relapsed/refractory myeloma. Proportions of bortezomib-refractory patients and additional prognostic factors were extracted and used in weighted stratified analyses of TTP and OS. Random-effect pooled estimates were calculated for overall response rate (ORR) and rates of common AEs.
RESULTS
Twenty-three studies (n = 1051 patients) were identified. Bortezomib was administered intravenously in all studies. Across studies in which data were available, pooled, weighted average ORR was 39.1% (95% confidence interval, 30.8%-47.4%), and pooled, weighted average median TTP and OS were 7.5 and 16.6 months, respectively. Patients with fewer previous therapies (≤ 4) and relapsed (not refractory) patients achieved higher ORRs, of 43.4% and 57.2%, respectively. Random-effects meta-regression analysis confirmed that relapsed patients were associated with a higher ORR by 28 to 41 percentage points versus refractory patients. In relapsed patients, median TTP and OS were 8.5 and 19.7 months, respectively. Common Grade 3/4 AEs included thrombocytopenia (35%), neutropenia (15%), anemia (14%), pneumonia (10%), and peripheral neuropathy (3%).
CONCLUSION
Based on these findings, bortezomib retreatment is well tolerated and appears efficacious in relapsed patients. In an era of new and emerging treatment options for relapsed and/or refractory myeloma, these data indicate that bortezomib retreatment might be a highly effective option in previously treated patients.
Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Clinical Trials as Topic; Disease-Free Survival; Hematologic Diseases; Humans; Molecular Targeted Therapy; Multiple Myeloma; Neoplasm Proteins; Peripheral Nervous System Diseases; Pneumonia; Proteasome Inhibitors; Pyrazines; Recurrence; Retrospective Studies; Salvage Therapy; Survival Analysis; Treatment Outcome
PubMed: 25023616
DOI: 10.1016/j.clml.2014.03.005 -
Critical Reviews in Oncology/hematology Nov 2019Choice of treatment for newly diagnosed transplant-ineligible multiple myeloma poses a difficult task due to an ever-increasing plethora of different regimens.... (Meta-Analysis)
Meta-Analysis
Upfront treatment for newly diagnosed transplant-ineligible multiple myeloma patients: A systematic review and network meta-analysis of 14,533 patients over 29 randomized clinical trials.
Choice of treatment for newly diagnosed transplant-ineligible multiple myeloma poses a difficult task due to an ever-increasing plethora of different regimens. Attempting to clarify this subject, we performed a systematic review and Bayesian network meta-analysis of 29 randomized clinical trials, enrolling 14,533 patients, and comparing 25 different treatment regimens regarding overall survival(OS), progression-free survival(PFS), complete response(CR), overall response rate(ORR) and toxicity. Head-to-head comparisons for all regimens and ranking of best treatments are reported. OS analysis showed superiority of lenalidomide(R) and bortezomib(V) containing regimens over thalidomide(T) protocols (e.g. Rd/CTD-HR:0.7;95%CrI:0.53-0.93, VMP/TD-HR:95%0.45;CrI:0.29-0.69). Concerning PFS, daratumumab(D) plus V (Dara-VMP) showed superior results over R (e.g. Dara-VMP/MPR-HR:0.52;95%CrI:0.34-0.77), V plus T (Dara-VMP/VTd-HR:0.56;95%CrI:0.37-0.65) and T (Dara-VMP/CTD-HR:0.34;95%CrI:0.23-0.49) containing regimens. Also, VRd and VMPT-VT performed well over other regimens. Dara-VMP showed superior response rates over R (ORR Dara-VMP/MPR-RR:6.27;95%CrI:2.18-18.95, CR Dara-VMP/MPR-RR:1.53;95%CrI:1.21-1.96) and T (ORR Dara-VMP/MPT-T-RR:4.05;95%CrI:1.19-13.26, CR Dara-VMP/MPT-T-RR:1.42;95%CrI:1.09-1.85; ORR Dara-VMP/CTD-RR:2.72;95%CrI:1.2-6.31, CR Dara-VMP/CTD-RR:1.2;95%CrI:1.05-1.36) including a higher rate of complete remission even when compared to VRd (RR:1.29;95%CrI:1.01-1.66). A higher rate of grade 3-4 adverse events was found for RD and CPR (thrombotic); VTd, VTP and VMPT-VT (neurological); RD and VAD (infectious); MPR-R and VAD (hematological); Vd and VTd (gastrointestinal); VAD, VMPCc and RD (cardiovascular). These results confirm obsolescence of classical regimens (such as VAD and MP) while pointing out benefits in efficacy resulting from incorporation of quadruplets and triplets combining new agents (Dara-VMP, VRd and VMPT-VT) and supports current rational of treatment until progression or prohibitive toxicity, especially when including lenalidomide. Based on this data, we would recommended incorporation of strategies combining novel agents (monoclonal antibodies, immunomodulatory imide drugs and proteasome inhibitors) in triplets or quadruplets and/or those comprising long term use of lenalidomide as standard frontline treatments. Moreover, this study settles daratumumab's place as an attractive alternative for upfront treatment.
Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Bayes Theorem; Bortezomib; Disease-Free Survival; Humans; Lenalidomide; Multiple Myeloma; Network Meta-Analysis; Randomized Controlled Trials as Topic; Thalidomide; Treatment Outcome
PubMed: 31563077
DOI: 10.1016/j.critrevonc.2019.07.001 -
Pancreas Jul 2013Pancreatic cancer is the fourth leading cause of cancer-related death. Most patients present with an advanced stage of disease that has a dismal outcome, with a median... (Review)
Review
Pancreatic cancer is the fourth leading cause of cancer-related death. Most patients present with an advanced stage of disease that has a dismal outcome, with a median survival of approximately 6 months. Evidently, there is a clear need for the development of new agents with novel mechanisms of action in this disease. A number of biological agents modulating different signal transduction pathways are currently in clinical development, inhibiting angiogenesis and targeting epidermal growth factor receptor, cell cycle, matrix metalloproteinases, cyclooxygenase-2, mammalian target of rapamycin, or proteasome. This is the first systematic review of the literature to synthesize all available data coming from trials and evaluate the efficacy and safety of molecular targeted drugs in unresectable and metastatic pancreatic cancer. However, it should be stressed that although multiple agents have been tested, only 9 phase 3 trials have been conducted and one agent (erlotinib) has been approved by the Food and Drug Administration for use in clinical practice. As knowledge accumulates on the molecular mechanisms underlying carcinogenesis in the pancreas, the anticipated development and assessment of molecularly targeted agents may offer a promising perspective for a disease which, to date, remains incurable.
Topics: Antineoplastic Agents; Clinical Trials as Topic; ErbB Receptors; Erlotinib Hydrochloride; Humans; Molecular Targeted Therapy; Neoplasm Metastasis; Pancreatic Neoplasms; Protein Kinase Inhibitors; Quinazolines; Treatment Outcome
PubMed: 23774698
DOI: 10.1097/MPA.0b013e31827aedef -
The Cochrane Database of Systematic... May 2024Multiple myeloma (MM) is a haematological malignancy that is characterised by proliferation of malignant plasma cells in the bone marrow. For adults ineligible to... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Multiple myeloma (MM) is a haematological malignancy that is characterised by proliferation of malignant plasma cells in the bone marrow. For adults ineligible to receive high-dose chemotherapy and autologous stem cell transplant, the recommended treatment combinations in first-line therapy generally consist of combinations of alkylating agents, immunomodulatory drugs, and proteasome inhibitors. Daratumumab is a CD38-targeting, human IgG1k monoclonal antibody recently developed and approved for the treatment of people diagnosed with MM. Multiple myeloma cells uniformly over-express CD-38, a 46-kDa type II transmembrane glycoprotein, making myeloma cells a specific target for daratumumab.
OBJECTIVES
To determine the benefits and harms of daratumumab in addition to antineoplastic therapy compared to antineoplastic therapy only for adults with newly diagnosed MM who are ineligible for transplant.
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, EU Clinical Trials Register, ClinicalTrials.gov, WHO ICTRP, and conference proceedings from 2010 to September 2023.
SELECTION CRITERIA
We included randomised controlled trials that compared treatment with daratumumab added to antineoplastic therapy versus the same antineoplastic therapy alone in adult participants with a confirmed diagnosis of MM. We excluded quasi-randomised trials and trials with less than 80% adult participants, unless there were subgroup analyses of adults with MM.
DATA COLLECTION AND ANALYSIS
Two review authors independently screened the results of the search strategies for eligibility. We documented the process of study selection in a flowchart as recommended by the PRISMA statement. We evaluated the risk of bias in included studies with RoB 1 and assessed the certainty of the evidence using GRADE. We followed standard Cochrane methodological procedures.
MAIN RESULTS
We included four open-label, two-armed randomised controlled trials (34 publications) involving a total of 1783 participants. The ALCYONE, MAIA, and OCTANS trials were multicentre trials conducted worldwide in middle- and high-income countries. The AMaRC 03-16 trial was conducted in one high-income country, Australia. The mean age of participants was 69 to 74 years, and the proportion of female participants was between 40% and 54%. All trials evaluated antineoplastic therapies with or without daratumumab. In the ALCYONE and OCTANS trials, daratumumab was combined with bortezomib and melphalan-prednisone. In the AMaRC 03-16 study, it was combined with bortezomib, cyclophosphamide, and dexamethasone, and in the MAIA study, it was combined with lenalidomide and dexamethasone. None of the included studies was blinded (high risk of performance and detection bias). One study was published as abstract only, therefore the risk of bias for most criteria was unclear. The other three studies were published as full texts. Apart from blinding, the risk of bias was low for these studies. Overall survival Treatment with daratumumab probably increases overall survival when compared to the same treatment without daratumumab (hazard ratio (HR) 0.64, 95% confidence interval (CI) 0.53 to 0.76, 2 studies, 1443 participants, moderate-certainty evidence). After a follow-up period of 36 months, 695 per 1000 participants survived in the control group, whereas 792 per 1000 participants survived in the daratumumab group (95% CI 758 to 825). Progression-free survival Treatment with daratumumab probably increases progression-free survival when compared to treatment without daratumumab (HR 0.48, 95% CI 0.39 to 0.58, 3 studies, 1663 participants, moderate-certainty evidence). After a follow-up period of 24 months, progression-free survival was reached in 494 per 1000 participants in the control group versus 713 per 1000 participants in the daratumumab group (95% CI 664 to 760). Quality of life Treatment with daratumumab may result in a very small increase in quality of life after 12 months, evaluated on the EORTC QLQ-C30 global health status scale (GHS), when compared to treatment without daratumumab (mean difference 2.19, 95% CI -0.13 to 4.51, 3 studies, 1096 participants, low-certainty evidence). The scale is from 0 to 100, with a higher value indicating a better quality of life. On-study mortality Treatment with daratumumab probably decreases on-study mortality when compared to treatment without daratumumab (risk ratio (RR) 0.72, 95% CI 0.62 to 0.83, 3 studies, 1644 participants, moderate-certainty evidence). After the longest follow-up available (12 to 72 months), 366 per 1000 participants in the control group and 264 per 1000 participants in the daratumumab group died (95% CI 227 to 304). Serious adverse events Treatment with daratumumab probably increases serious adverse events when compared to treatment without daratumumab (RR 1.18, 95% CI 1.02 to 1.37, 3 studies, 1644 participants, moderate-certainty evidence). After the longest follow-up available (12 to 72 months), 505 per 1000 participants in the control group versus 596 per 1000 participants in the daratumumab group experienced serious adverse events (95% CI 515 to 692). Adverse events (Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 3) Treatment with daratumumab probably results in little to no difference in adverse events (CTCAE grade ≥ 3) when compared to treatment without daratumumab (RR 1.01, 95% CI 0.99 to 1.02, 3 studies, 1644 participants, moderate-certainty evidence). After the longest follow-up available (12 to 72 months), 953 per 1000 participants in the control group versus 963 per 1000 participants in the daratumumab group experienced adverse events (CTCAE grade ≥ 3) (95% CI 943 to 972). Treatment with daratumumab probably increases the risk of infections (CTCAE grade ≥ 3) when compared to treatment without daratumumab (RR 1.52, 95% CI 1.30 to 1.78, 3 studies, 1644 participants, moderate-certainty evidence). After the longest follow-up available (12 to 72 months), 224 per 1000 participants in the control group versus 340 per 1000 participants in the daratumumab group experienced infections (CTCAE grade ≥ 3) (95% CI 291 to 399).
AUTHORS' CONCLUSIONS
Overall analysis of four studies showed a potential benefit for daratumumab in terms of overall survival and progression-free survival and a slight potential benefit in quality of life. Participants treated with daratumumab probably experience increased serious adverse events. There were likely no differences between groups in adverse events (CTCAE grade ≥ 3); however, there are probably more infections (CTCAE grade ≥ 3) in participants treated with daratumumab. We identified six ongoing studies which might strengthen the certainty of evidence in a future update of this review.
Topics: Adult; Aged; Female; Humans; Middle Aged; Antibodies, Monoclonal; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bias; Bortezomib; Multiple Myeloma; Progression-Free Survival; Quality of Life; Randomized Controlled Trials as Topic
PubMed: 38695605
DOI: 10.1002/14651858.CD013595.pub2 -
Cancer Treatment Reviews Dec 2011Gastric cancer is the second leading cause of cancer related-death. Most patients present with an advanced stage of disease that has a dismal outcome. Evidently, there... (Review)
Review
Gastric cancer is the second leading cause of cancer related-death. Most patients present with an advanced stage of disease that has a dismal outcome. Evidently, there is a clear need for the development of new agents with novel mechanisms of action in the treatment of this disease. A number of biological agents modulating different signal transduction pathways are currently in clinical development, such as angiogenesis inhibitors and agents targeting epidermal growth factor receptor, cell cycle, matrix metalloproteinases, cyclooxygenase-2 (COX-2), mammalian target of rapamycin (mTOR) or proteasome. This is the first systematic review of the literature to synthesize all available data coming from trials and evaluate the efficacy and safety of molecular targeted drugs in unresectable and metastatic gastric cancer. As knowledge accumulates on the molecular mechanisms underlying carcinogenesis in the stomach, the anticipated development and assessment of molecularly targeted agents may offer a promising perspective for a disease which, to date, remains incurable.
Topics: Antineoplastic Agents; Clinical Trials as Topic; Humans; Molecular Targeted Therapy; Neoplasm Proteins; Review Literature as Topic; Stomach Neoplasms
PubMed: 21676549
DOI: 10.1016/j.ctrv.2011.03.007 -
British Journal of Haematology Jul 2020
Meta-Analysis
Topics: Aged; Humans; Middle Aged; Multiple Myeloma; Oligopeptides; Proteasome Inhibitors; Randomized Controlled Trials as Topic
PubMed: 32400886
DOI: 10.1111/bjh.16735 -
Supportive Care in Cancer : Official... Jul 2018We performed a systematic review to quantify the amount of evidence-based data available on patient-reported outcomes (PRO) in Relapsed/Refractory Multiple Myeloma...
PURPOSE
We performed a systematic review to quantify the amount of evidence-based data available on patient-reported outcomes (PRO) in Relapsed/Refractory Multiple Myeloma (RRMM) patients and to examine the added value of such studies in supporting clinical decision-making.
METHODS
We conducted a search in PubMed/Medline and the Cochrane Library to identify studies published between January 1990 and May 2017. All studies, regardless of the design, including patients with RRMM and also evaluating PRO were considered. For each study, we collected both PRO and traditional clinical outcomes, such as survival and toxicity information, based on a predefined data extraction form.
RESULTS
After having screened 1680 records, 11 studies were identified and these included six randomized controlled trials (RCT). Overall, there were five studies focusing on proteasome inhibitors (PIs), four on immunomodulatory drugs (IMiDs), one on both PIs and IMiDs, and one on monoclonal antibodies. Considering only RCTs, it was found that primary clinical efficacy endpoints frequently favored experimental arms, while (physician-reported) toxicity data did not. However, inspection of PRO data revealed novel information that often contrasted with standard toxicity, for example, by not indicating worse quality of life outcomes or symptom severity for patients enrolled in the experimental arms.
CONCLUSIONS
There is paucity of evidence-based data regarding the impact of therapies on quality of life and symptom burden of patients with RRMM. Inclusion of PRO in future studies of patients with RRMM is needed to better inform clinical decision-making.
Topics: Antibodies, Monoclonal; Clinical Decision-Making; Humans; Immunomodulation; Multiple Myeloma; Patient Reported Outcome Measures; Proteasome Inhibitors; Quality of Life; Treatment Outcome
PubMed: 29560502
DOI: 10.1007/s00520-018-4137-x -
Cancer Apr 2020Thromboprophylaxis is routinely used with lenalidomide-based regimens in multiple myeloma because of a substantial risk of venous thromboembolism (VTE). However, little... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Thromboprophylaxis is routinely used with lenalidomide-based regimens in multiple myeloma because of a substantial risk of venous thromboembolism (VTE). However, little is known about the incidence of VTE with contemporary lenalidomide-based regimens. The objective of the current study was to estimate the incidence of VTE despite thromboprophylaxis with currently used lenalidomide-based regimens in patients with myeloma.
METHODS
The Ovid MEDLINE, Embase, and Cochrane databases were queried from study inception to January 2019 for keywords to cover the following concepts: "lenalidomide," "venous thromboembolism," and "multiple myeloma." Phase 1, 2, and 3 clinical trials evaluating lenalidomide-based regimens with thromboprophylaxis were included. The pooled incidence rate of VTE was estimated using a random-effects model.
RESULTS
The search generated 1372 citations, with 51 clinical trials and 9069 patients included for analysis. The most common thromboprophylaxis agents were aspirin, low-molecular-weight heparin or warfarin, administered either per risk-stratification or at investigators' discretion. The pooled incidence of VTE in trials of patients who had newly diagnosed and relapsed/refractory myeloma was 6.2% (95% CI, 5.4%-7.1%) over median treatment durations ranging from 2 to 34 cycles, which translated into 1.2 VTE events per 100 patient-cycles (95% CI, 0.9-1.7 VTE events per 100 patient-cycles). Among contemporary regimens, the risk of VTE was low with combined lenalidomide and low-dose dexamethasone (0.2 [95% CI, 0.1-0.6] events/100 patient-cycles) and lenalidomide maintenance (0.0 [95% CI, 0.0-0.7] events per 100 patient-cycles). VTE risk was higher with combined lenalidomide and low-dose dexamethasone plus proteasome inhibitors (1.3 [95% CI, 0.7-2.3] events per 100 patient-cycles).
CONCLUSIONS
Despite adequate thromboprophylaxis, lenalidomide-based regimens have a substantial risk of VTE in controlled clinical trial settings. Further studies are needed on new thromboprophylaxis strategies with regimens that have a high VTE risk.
Topics: Angiogenesis Inhibitors; Anticoagulants; Dexamethasone; Humans; Incidence; Lenalidomide; Multiple Myeloma; Venous Thromboembolism
PubMed: 31913498
DOI: 10.1002/cncr.32682 -
Journal of Hypertension May 2019Cardio-oncology aims to mitigate adverse cardiovascular manifestations in cancer survivors, but treatment-induced hypertension or aggravated hypertension has received...
BACKGROUND
Cardio-oncology aims to mitigate adverse cardiovascular manifestations in cancer survivors, but treatment-induced hypertension or aggravated hypertension has received less attention in these high cardiovascular risk patients.
METHODS
In this systematic review, we searched literature for contemporary data on the prevalence, pathophysiologic mechanisms, treatment implications and preventive strategies of hypertension in patients under antineoplastic therapy.
RESULTS
Several classes of antineoplastic drugs, including mainly vascular endothelial growth factor inhibitors, proteasome inhibitors, cisplatin derivatives, corticosteroids or radiation therapy were consistently associated with increased odds for new-onset hypertension or labile hypertensive status in previous controlled patients. Moreover, hypertension constitutes a major risk factor for chemotherapy-induced cardiotoxicity, which is the most serious cardiovascular adverse effect of antineoplastic therapy. Despite the heterogeneity of pooled studies, the pro-hypertensive profile of examined drug classes could be attributed to common structural and functional disorders. Importantly, certain antihypertensive drugs are considered to be more effective in the management of hypertension in this population and may partially attenuate indirect complications of cancer treatment, such as progressive development of cardiomyopathy and/or cardiovascular death. Nonpharmacological approaches to alleviate hypertension in cancer patients are also described, albeit adjudicated as less effective in general.
CONCLUSION
A growing body of evidence suggests that multiple antineoplastic agents increase the rate of progression of hypertension. Physicians need to balance the life-saving cancer treatment and the inflated risk of adverse cardiovascular events due to suboptimal management of hypertension in order to achieve improved clinical outcomes and sustained survival for their patients.
Topics: Antihypertensive Agents; Antineoplastic Agents; Humans; Hypertension; Incidence; Neoplasms; Risk Factors; Vascular Endothelial Growth Factor A
PubMed: 30624368
DOI: 10.1097/HJH.0000000000002006 -
Expert Review of Hematology Dec 2020A variety of molecular-targeted drugs have been widely used in hematological malignancies and have shown great advances. Nevertheless, as the use of drugs in clinical...
INTRODUCTION
A variety of molecular-targeted drugs have been widely used in hematological malignancies and have shown great advances. Nevertheless, as the use of drugs in clinical practice increases, the problem of relapse or of the disease being refractory to treatment is becoming apparent. This problem is closely related to the C-X-C chemokine receptor 4 (CXCR4).
AREAS COVERED
This review focuses mainly on the effect of CXCR4 on molecular-targeted drug resistance in hematological malignancies as well as the clinical efficacy of CXCR4 antagonists combined with molecular-targeted drugs. Relevant literatures published between 2006 and 2020 were searched using PubMed/Medline for this review.
EXPERT OPINION
Monoclonal antibodies and non-antibody molecular-targeted drugs provide new therapeutic approaches for B-lineage malignancies and leukemia, but the clinical activity of these drugs is affected by CXCR4. In general, high CXCR4 expression or mutation inhibits the effects of molecular-targeted drugs, but there are exceptions, and in studies of proteasome inhibitors bortezomib (Bz) in multiple myeloma (MM), low CXCR4 expression or loss of CXCR4 was associated with Bz resistance (BzR) and poor treatment outcomes. Given that CXCR4 is a critical mediator of molecular-targeted drug resistance, numerous studies have combined molecular-targeted drugs with CXCR4 antagonists, which synergistically enhance the anti-proliferative/pro-apoptotic effect of molecular-targeted drugs.
Topics: Antineoplastic Agents; Antineoplastic Agents, Immunological; Bortezomib; Cell Lineage; Chemokine CXCL12; Drug Resistance, Neoplasm; Hematologic Neoplasms; Humans; Leukemia, Myeloid, Acute; Lymphoma, Non-Hodgkin; Molecular Targeted Therapy; Multiple Myeloma; Neoplasm Proteins; Protease Inhibitors; Receptors, CXCR4; Signal Transduction; Waldenstrom Macroglobulinemia
PubMed: 33170753
DOI: 10.1080/17474086.2020.1839885