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Molecules (Basel, Switzerland) Mar 2022ARV-110, a novel proteolysis-targeting chimera (PROTAC), has been reported to show satisfactory safety and tolerability for prostate cancer therapy in phase I clinical...
ARV-110, a novel proteolysis-targeting chimera (PROTAC), has been reported to show satisfactory safety and tolerability for prostate cancer therapy in phase I clinical trials. However, there is a lack of bioanalytical assays for ARV-110 determination in biological samples. In this study, we developed and validated an LC-MS/MS method for the quantitation of ARV-110 in rat and mouse plasma and applied it to pharmacokinetic studies. ARV-110 and pomalidomide (internal standard) were extracted from the plasma samples using the protein precipitation method. Sample separation was performed using a C18 column and a mobile phase of 0.1% formic acid in distilled water-0.1% formic acid in acetonitrile (30:70, /). Multiple reaction monitoring was used to quantify ARV-110 and pomalidomide with ion transitions at m/z 813.4 → 452.2 and 273.8 → 201.0, respectively. The developed method showed good linearity in the concentration range of 2-3000 ng/mL with acceptable accuracy, precision, matrix effect, process efficiency, and recovery. ARV-110 was stable in rat and mouse plasma under long-term storage, three freeze-thaw cycles, and in an autosampler, but unstable at room temperature and 37 °C. Furthermore, the elimination of ARV-110 via phase 1 metabolism in rat, mouse, and human hepatic microsomes was shown to be unlikely. Application of the developed method to pharmacokinetic studies revealed that the oral bioavailability of ARV-110 in rats and mice was moderate (23.83% and 37.89%, respectively). These pharmacokinetic findings are beneficial for future preclinical and clinical studies of ARV-110 and/or other PROTACs.
Topics: Animals; Male; Mice; Rats; Chromatography, Liquid; Microsomes, Liver; Proteolysis; Reproducibility of Results; Tandem Mass Spectrometry
PubMed: 35335338
DOI: 10.3390/molecules27061977 -
The Oncologist May 2023Because patients with newly diagnosed multiple myeloma (NDMM) do not always receive any treatment beyond first-line (1L) therapy, it is imperative that patients receive... (Comparative Study)
Comparative Study
BACKGROUND
Because patients with newly diagnosed multiple myeloma (NDMM) do not always receive any treatment beyond first-line (1L) therapy, it is imperative that patients receive the best treatment in the 1L setting. However, the optimal initial treatment remains to be identified. We performed a clinical simulation to assess potential outcomes with different treatment sequences.
PATIENTS AND METHODS
We used a partitioned survival model to compare overall survival (OS) with (1) daratumumab, lenalidomide, and dexamethasone (D-Rd) in 1L followed by a pomalidomide- or carfilzomib-based regimen in second line (2L) versus (2) bortezomib, lenalidomide, and dexamethasone (VRd) in 1L followed by a daratumumab-based regimen in 2L versus (3) lenalidomide and dexamethasone (Rd) in 1L followed by a daratumumab-based regimen in 2L. Probabilities of transition between health states (1L, 2L+, and death) were based on published clinical data and real-world data from the Flatiron Health database. The proportion of patients discontinuing treatment after 1L (attrition rates) in the base case was estimated with a binomial logistic model using data from the MAIA trial.
RESULTS
Using D-Rd in 1L conferred a longer median OS compared with delaying daratumumab-based regimens until 2L after VRd or Rd, respectively (8.9 [95% CrI 7.58-10.42] vs. 6.92 [5.92-8.33] or 5.75 [4.50-7.25] years). Results of scenario analyses were consistent with the base case.
CONCLUSION
Our simulation, which incorporates clinically representative treatments and attrition rates, supports the use of D-Rd as initial therapy, rather than delaying the use of daratumumab until later lines of therapy, in patients with transplant-ineligible NDMM.
Topics: Humans; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone; Lenalidomide; Multiple Myeloma
PubMed: 37002943
DOI: 10.1093/oncolo/oyad053 -
Biomarker Research 2020Thalidomide, lenalidomide and pomalidomide are immunomodulatory drugs (IMiDs) effective in the treatment of multiple myeloma, myelodysplastic syndrome (MDS) with... (Review)
Review
Thalidomide, lenalidomide and pomalidomide are immunomodulatory drugs (IMiDs) effective in the treatment of multiple myeloma, myelodysplastic syndrome (MDS) with deletion of chromosome 5q and other hematological malignancies. Recent studies showed that IMiDs bind to CRBN, a substrate receptor of CRL4 E3 ligase, to induce the ubiquitination and degradation of IKZF1 and IKZF3 in multiple myeloma cells, contributing to their anti-myeloma activity. Similarly, lenalidomide exerts therapeutic efficacy via inducing ubiquitination and degradation of CK1α in MDS with deletion of chromosome 5q. Recently, novel thalidomide analogs have been designed for better clinical efficacy, including CC-122, CC-220 and CC-885. Moreover, a number of neo-substrates of IMiDs have been discovered. Proteolysis-targeting chimeras (PROTACs) as a class of bi-functional molecules are increasingly used as a strategy to target otherwise intractable cellular protein. PROTACs appear to have broad implications for novel therapeutics. In this review, we summarized new generation of immunomodulatory compounds, their potential neo-substrates, and new strategies for the design of novel PROTAC drugs.
PubMed: 31938543
DOI: 10.1186/s40364-020-0182-y -
Nature Medicine Feb 2024Due to evolving treatment standards for newly diagnosed multiple myeloma, many patients will be triple-class exposed after initial relapses and have poor survival. Novel...
Due to evolving treatment standards for newly diagnosed multiple myeloma, many patients will be triple-class exposed after initial relapses and have poor survival. Novel therapies and combinations are therefore required to improve outcomes. B cell maturation antigen (BCMA)-targeted biologics have emerged as an important new area of therapeutics for relapsed multiple myeloma. The two-part ALGONQUIN trial evaluated various doses and schedules of the anti-BCMA antibody-drug conjugate belantamab mafodotin plus pomalidomide and dexamethasone for patients who are lenalidomide refractory and proteosome inhibitor exposed. The primary endpoints, including evaluating dose-limiting toxicities, establishing the recommended Part 2 dose (RP2D) and overall response rate for patients treated at the RP2D, were met. Secondary efficacy endpoints included progression-free survival and overall survival. Patients treated on study (N = 87) had a median of three previous regimens and 55.2% were triple-class refractory. At the RP2D the most common adverse events were decrease in best-corrected visual acuity (71.1%), keratopathy (65.8%), fatigue (57.9%), infection (47.4%; 7.9% grade ≥3), neutropenia (39.5%) and thrombocytopenia (39.5%). For RP2D patients (n = 38), the overall response rate was 85.3%, ≥very good partial response 75.7% and estimated two-year progression-free survival 52.8% (95% confidence interval, 33.9% to 82.4%), at a median follow-up of 13.9 months. The RP2D schedule was associated with manageable antibody-drug conjugate-associated corneal adverse events and improved tolerability without compromising efficacy. Belantamab mafodotin plus pomalidomide and dexamethasone induced durable responses with promising overall survival in relapsed multiple myeloma, the results of which are yet to be confirmed in the phase 3 DREAMM-8 study. ClinicalTrials.gov Identifier: NCT03715478 .
Topics: Humans; Multiple Myeloma; Treatment Outcome; Dexamethasone; Antineoplastic Combined Chemotherapy Protocols; Immunoconjugates; Thalidomide; Antibodies, Monoclonal, Humanized
PubMed: 38177852
DOI: 10.1038/s41591-023-02703-y -
Biomedicines Jul 2023Multiple myeloma (MM) is a cancerous condition characterized by the proliferation of plasma cells within the hematopoietic marrow, resulting in multiple osteolytic... (Review)
Review
Multiple myeloma (MM) is a cancerous condition characterized by the proliferation of plasma cells within the hematopoietic marrow, resulting in multiple osteolytic lesions. MM patients typically experience bone pain, kidney damage, fatigue due to anemia, and infections. Historically, MM was an incurable disease with a life expectancy of around three years after diagnosis. However, over the past two decades, the development of novel therapeutics has significantly improved patient outcomes, including response to treatment, remission duration, quality of life, and overall survival. These advancements include thalidomide and its derivatives, lenalidomide and pomalidomide, which exhibit diverse mechanisms of action against the plasma cell clone. Additionally, proteasome inhibitors such as bortezomib, ixazomib, and carfilzomib disrupt protein degradation, proving specifically toxic to cancerous plasma cells. Recent advancements also involve monoclonal antibodies targeting surface antigens, such as elotuzumab (anti-CS1) and daratumumab (anti-CD38), bispecific t-cell engagers such as teclistamab (anti-BCMA/CD3) and Chimeric antigen receptor T (CAR-T)-based strategies, with a growing focus on drugs that exhibit increasingly targeted action against neoplastic plasma cells and relevant effects on the tumor microenvironment.
PubMed: 37509726
DOI: 10.3390/biomedicines11072087 -
Journal of Cardiovascular Echography Apr 2020Peripheral artery disease (PAD) and stroke can occur as vascular complication of anticancer treatment. Although the mechanisms, monitoring, and management of... (Review)
Review
Peripheral artery disease (PAD) and stroke can occur as vascular complication of anticancer treatment. Although the mechanisms, monitoring, and management of cardiotoxicities have received broad attention, vascular toxicities remain often underrecognized. In addition, the development of new chemotherapeutic drugs bears the risk of vasotoxicities that are yet to be identified and may not be realized with short-term follow-up periods. The propensity to develop PAD and/or stroke reflects the complex interplay between patient's baseline risk and preexisting vascular disease, particularly hypertension and diabetes, while evidence for genetic predisposition is increasing. Chemotherapeutic agents with a prominent vascular side effect profile have been identified. Interruption of vascular endothelial growth factor (VEGF) inhibitors (VEGFIs) signaling (i.e., bevacizumab) is associated with vascular toxicity and clinical sequelae such as hypertension, stroke, and thromboembolism beyond acute coronary syndromes. Cisplatin and 5-fluorouracil are the main drugs involved in the stroke risk. In addition, circulating concentrations of VEGF are reduced by cyclophosphamide administered at continuous low doses, which might underpin some of the observed vascular toxicity, such as stroke, as seen in patients treated with VEGF inhibitors. The risk of stroke is also increased after treatment with anthracyclines that can induce endothelial dysfunction and increase arterial stiffness. Proteasome inhibitors ( bortezomib and carfilzomib) and immunomodulatory agents (thalidomide, lenalidomide, and pomalidomide), approved for use in multiple myeloma, carry a black box warning for an increased risk of stroke. Finally, head-and-neck radiotherapy is associated with a doubled risk of cerebrovascular ischemic event, especially if exposure occurs in childhood. The mechanisms involved in radiation vasculopathy are represented by endothelial dysfunction, medial necrosis, fibrosis, and accelerated atherosclerosis. However, BCR-ABL tyrosine kinase inhibitor (TKI), used for the treatment of chronic myeloid leukemia (CML), is the main antineoplastic drugs involved in the development of PAD. In particular, second- and third-generation TKIs, such as nilotinib and ponatinib, while emerging as a potent arm in contrasting CML, are associated with a higher risk of PAD development rather than traditional imatinib. Factors favoring vascular complication are the presence of traditional cardiovascular risk factors (CVRF) and predisposing genetic factors, high doses of BCR-ABL TKIs, longer time of drug exposure, and sequential use of potent TKIs. Therefore, accurate cardiovascular risk stratification is strongly recommended in patient candidate to anticancer treatment associated with higher risk of vascular complication, in order to reduce the incidence of PAD and stroke through CVRF correction and selection of appropriate tailored patient strategy of treatment. Then, a clinical follow-up, eventually associated with instrumental evaluation through vascular ultrasound, should be performed.
PubMed: 32566462
DOI: 10.4103/jcecho.jcecho_4_19 -
Blood Advances Dec 2023
Topics: Humans; Multiple Myeloma; Bortezomib; Thalidomide; Renal Insufficiency; Dexamethasone
PubMed: 37922425
DOI: 10.1182/bloodadvances.2023011428 -
Cancers Mar 2023The treatment of multiple myeloma (MM) has greatly evolved these past few years. Recent advances in therapeutics have largely benefited elderly patients now renamed... (Review)
Review
The treatment of multiple myeloma (MM) has greatly evolved these past few years. Recent advances in therapeutics have largely benefited elderly patients now renamed "non-transplant-eligible" (NTE) patients. Since the 1960s, and for several decades, chemotherapy was the only treatment for MM. Then, the field was marked by the emergence of targeted therapies in the 2000s, such as immunomodulating agents (thalidomide, lenalidomide, and pomalidomide) and proteasome inhibitors (bortezomib, carfilzomib, and ixazomib), which were the first steps towards an increase in survival. Thereafter, the apparition of monoclonal antibodies (mAbs) was considered a milestone in the treatment of MM for both transplant-eligible and NTE patients. Anti-CD38 mAbs can be safely administered to older patients with an impressive efficacy leading to a never-achieved-before survival rate with the triple association of anti-CD38 mAbs, lenalidomide, and dexamethasone. However, progress is still expected with the introduction in the armamentarium for NTE patients of the most recent innovative immunotherapy-based treatments newly introduced in MM, e.g., CAR-T cells and bispecific antibodies. These "improved versions" of immune-based treatments will probably also benefit NTE patients, although further studies will be needed to better understand their role in this population.
PubMed: 37046589
DOI: 10.3390/cancers15071929