-
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 -
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 -
Acta Haematologica 2020The vast majority of patients with light-chain (AL) amyloidosis are not eligible for stem cell transplant and are treated with conventional chemotherapy. Conventional... (Review)
Review
The vast majority of patients with light-chain (AL) amyloidosis are not eligible for stem cell transplant and are treated with conventional chemotherapy. Conventional regimens are based on various combinations of dexamethasone, alkylating agents, proteasome inhibitors, and immunomodulatory drugs. The choice of these regimens requires a careful risk stratification, based on the extent of amyloid organ involvement, comorbidities, and the characteristics of the amyloidogenic plasma cell clone. Most patients are treated upfront with bortezomib and dexamethasone combined with cyclophosphamide or melphalan. Cyclophosphamide does not compromise stem cell mobilization and harvest and is more manageable in renal failure. Melphalan can overcome the effect of t(11;14), which is associated with lower response rates and shorter survival in subjects treated with bortezomib and dexamethasone, or in combination with cyclophosphamide. Lenalidomide and pomalidomide are the mainstay of rescue treatment. They are effective in patients exposed to bortezomib, dexamethasone, and alkylators, but deep hematologic responses are rare. Ixazomib, alone or in combination with lenalidomide, increases the rate of complete responses in relapsed/refractory patients. Conventional chemotherapy regimens will represent the backbone for future combinations, particularly with anti-plasma-cell immunotherapy, that will further improve response rates and outcomes.
Topics: Biomarkers; Combined Modality Therapy; Disease Management; Disease Susceptibility; Humans; Immunoglobulin Light-chain Amyloidosis; Recurrence; Risk Factors; Treatment Outcome
PubMed: 32353854
DOI: 10.1159/000507072 -
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 -
American Journal of Hematology Feb 2024Immunoglobulin light chain amyloidosis is a clonal, nonproliferative plasma cell disorder in which fragments of immunoglobulin light or heavy chain are deposited in...
DISEASE OVERVIEW
Immunoglobulin light chain amyloidosis is a clonal, nonproliferative plasma cell disorder in which fragments of immunoglobulin light or heavy chain are deposited in tissues. Clinical features depend on organs involved but can include heart failure with preserved ejection fraction, nephrotic syndrome, hepatic dysfunction, peripheral/autonomic neuropathy, and "atypical smoldering multiple myeloma or MGUS."
DIAGNOSIS
Tissue biopsy stained with Congo red demonstrating amyloid deposits with apple-green birefringence is required for the diagnosis of AL amyloidosis. Organ biopsy is not required in 85% of patients. Verification that amyloid is composed of immunoglobulin light chains is mandatory. The gold standard is laser capture mass spectroscopy.
PROGNOSIS
N-terminal pro-brain natriuretic peptide (NT-proBNP or BNP), serum troponin T(or I), and difference between involved and uninvolved immunoglobulin free light chain values are used to classify patients into four stages; 5-year survivals are 82%, 62%, 34%, and 20%, respectively.
THERAPY
All patients with a systemic amyloid syndrome require therapy to prevent deposition of amyloid in other organs and prevent progressive organ failure. Current first-line therapy with the best outcome is daratumumab, bortezomib, cyclophosphamide, and dexamethasone. The goal of therapy is a ≥VGPR. In patients failing to achieve this depth of response options for consolidation include pomalidomide, stem cell transplantation, venetoclax, and bendamustine.
FUTURE CHALLENGES
Delayed diagnosis remains a major obstacle to initiating effective therapy prior to the development of end-stage organ failure. Trials of antibodies to deplete deposited fibrils are underway.
Topics: Humans; Immunoglobulin Light-chain Amyloidosis; Amyloidosis; Prognosis; Immunoglobulin Light Chains; Hematopoietic Stem Cell Transplantation
PubMed: 38095141
DOI: 10.1002/ajh.27177 -
Critical Reviews in Oncology/hematology Aug 2023Treatment of multiple myeloma (MM) has seen great advances in recent years, and a key contributor to this change has been the effective use of combination therapies,... (Review)
Review
Treatment of multiple myeloma (MM) has seen great advances in recent years, and a key contributor to this change has been the effective use of combination therapies, which have improved both the depth and duration of patient responses. Immunomodulatory drug (IMiD) agents (lenalidomide and pomalidomide) have both tumoricidal and immunostimulatory functions, and due to their multiple mechanisms of action have become the backbone of numerous combination treatments in the newly diagnosed and relapsed/refractory settings. Although IMiD agent-based combination regimens provide improved clinical outcomes for patients with MM, the mechanisms underpinning these combinations are not well understood. In this review we describe the potential mechanisms of synergy leading to the enhanced activity observed when IMiD agents and other drug classes are used in combination through interrogation of the current knowledge surrounding their mechanism of actions.
Topics: Humans; Multiple Myeloma; Lenalidomide; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Immunomodulation
PubMed: 37268176
DOI: 10.1016/j.critrevonc.2023.104041 -
Chembiochem : a European Journal of... Dec 2023Small molecules inducing protein degradation are important pharmacological tools to interrogate complex biology and are rapidly translating into clinical agents....
Small molecules inducing protein degradation are important pharmacological tools to interrogate complex biology and are rapidly translating into clinical agents. However, to fully realise the potential of these molecules, selectivity remains a limiting challenge. Herein, we addressed the issue of selectivity in the design of CRL4 recruiting PROteolysis TArgeting Chimeras (PROTACs). Thalidomide derivatives used to generate CRL4 recruiting PROTACs have well described intrinsic monovalent degradation profiles by inducing the recruitment of neo-substrates, such as GSPT1, Ikaros and Aiolos. We leveraged structural insights from known CRL4 neo-substrates to attenuate and indeed remove this monovalent degradation function in well-known CRL4 molecular glues degraders, namely CC-885 and Pomalidomide. We then applied these design principles on a previously published BRD9 PROTAC (dBRD9-A) and generated an analogue with improved selectivity profile. Finally, we implemented a computational modelling pipeline to show that our degron blocking design does not impact PROTAC-induced ternary complex formation. We believe that the tools and principles presented in this work will be valuable to support the development of targeted protein degradation.
Topics: Ubiquitin-Protein Ligases; Proteolysis
PubMed: 37418539
DOI: 10.1002/cbic.202300351 -
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 -
European Journal of Medicinal Chemistry Sep 2023Multiple myeloma (MM) is a hematologic neoplasm of plasma cells that is currently deemed incurable. Despite the introduction of novel immunomodulators and proteasome... (Review)
Review
Multiple myeloma (MM) is a hematologic neoplasm of plasma cells that is currently deemed incurable. Despite the introduction of novel immunomodulators and proteasome inhibitors, MM remains a challenging disease with high rates of relapse and refractoriness. The management of refractory and relapsed MM patients remains a formidable task, primarily due to the emergence of multiple drug resistance. Consequently, there is an urgent need for novel therapeutic agents to address this clinical challenge. In recent years, a significant amount of research has been dedicated to the discovery of novel therapeutic agents for the treatment of MM. The clinical utilization of proteasome inhibitor carfilzomib and immunomodulator pomalidomide has been successively introduced. As basic research continues to advance, novel therapeutic agents, including panobinostat, a histone deacetylase inhibitor, and selinexor, a nuclear export inhibitor, have progressed to the clinical trial and application phase. This review aims to furnish a comprehensive survey of the clinical applications and synthetic pathways of select drugs, with the intention of imparting valuable insights for future drug research and development geared towards MM.
Topics: Humans; Multiple Myeloma; Neoplasm Recurrence, Local; Panobinostat; Histone Deacetylase Inhibitors; Proteasome Inhibitors; Immunologic Factors; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37210838
DOI: 10.1016/j.ejmech.2023.115492