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Journal of Biochemistry Apr 2024Recently, the development of protein degraders (protein-degrading compounds) has prominently progressed. There are two remarkable classes of protein degraders:... (Review)
Review
Recently, the development of protein degraders (protein-degrading compounds) has prominently progressed. There are two remarkable classes of protein degraders: proteolysis-targeting chimeras (PROTACs) and molecular glue degraders (MGDs). Almost 70 years have passed since thalidomide was initially developed as a sedative-hypnotic drug, which is currently recognized as one of the most well-known MGDs. During the last two decades, a myriad of PROTACs and MGDs have been developed, and the molecular mechanism of action (MOA) of thalidomide was basically elucidated, including identifying its molecular target cereblon (CRBN). CRBN forms a Cullin Ring Ligase 4 with Cul4 and DDB1, whose substrate specificity is controlled by its binding ligands. Thalidomide, lenalidomide and pomalidomide, three CRBN-binding MGDs, were clinically approved to treat several intractable diseases (including multiple myeloma). Several other MGDs and CRBN-based PROTACs (ARV-110 and AVR-471) are undergoing clinical trials. In addition, several new related technologies regarding PROTACs and MGDs have also been developed, and achievements of protein degraders impact not only therapeutic fields but also basic biological science. In this article, I introduce the history of protein degraders, from the development of thalidomide to the latest PROTACs and related technologies.
Topics: Thalidomide; Humans; Proteolysis; Ubiquitin-Protein Ligases; Adaptor Proteins, Signal Transducing; Multiple Myeloma; Proteolysis Targeting Chimera
PubMed: 38140952
DOI: 10.1093/jb/mvad113 -
Biomolecules Apr 2023The immunomodulatory imide drug (IMiD) class, which includes the founding drug member thalidomide and later generation drugs, lenalidomide and pomalidomide, has... (Review)
Review
The immunomodulatory imide drug (IMiD) class, which includes the founding drug member thalidomide and later generation drugs, lenalidomide and pomalidomide, has dramatically improved the clinical treatment of specific cancers, such as multiple myeloma, and it combines potent anticancer and anti-inflammatory actions. These actions, in large part, are mediated by IMiD binding to the human protein cereblon that forms a critical component of the E3 ubiquitin ligase complex. This complex ubiquitinates and thereby regulates the levels of multiple endogenous proteins. However, IMiD-cereblon binding modifies cereblon's normal targeted protein degradation towards a new set of neosubstrates that underlies the favorable pharmacological action of classical IMiDs, but also their adverse actions-in particular, their teratogenicity. The ability of classical IMiDs to reduce the synthesis of key proinflammatory cytokines, especially TNF-α levels, makes them potentially valuable to reposition as drugs to mitigate inflammatory-associated conditions and, particularly, neurological disorders driven by an excessive neuroinflammatory element, as occurs in traumatic brain injury, Alzheimer's and Parkinson's diseases, and ischemic stroke. The teratogenic and anticancer actions of classical IMiDs are substantial liabilities for effective drugs in these disorders and can theoretically be dialed out of the drug class. We review a select series of novel IMiDs designed to avoid binding with human cereblon and/or evade degradation of downstream neosubstrates considered to underpin the adverse actions of thalidomide-like drugs. These novel non-classical IMiDs hold potential as new medications for erythema nodosum leprosum (ENL), a painful inflammatory skin condition associated with Hansen's disease for which thalidomide remains widely used, and, in particular, as a new treatment strategy for neurodegenerative disorders in which neuroinflammation is a key component.
Topics: Humans; Thalidomide; Immunomodulating Agents; Neuroinflammatory Diseases; Multiple Myeloma; Ubiquitin-Protein Ligases; Neurodegenerative Diseases
PubMed: 37238617
DOI: 10.3390/biom13050747 -
The New England Journal of Medicine Jun 2024Triplet or quadruplet therapies incorporating proteasome inhibitors, immunomodulators, and anti-CD38 antibodies have led to prolonged survival among patients with newly...
BACKGROUND
Triplet or quadruplet therapies incorporating proteasome inhibitors, immunomodulators, and anti-CD38 antibodies have led to prolonged survival among patients with newly diagnosed multiple myeloma; however, most patients have a relapse. Frontline lenalidomide therapy has increased the number of patients with lenalidomide-refractory disease at the time of the first relapse.
METHODS
In this phase 3, randomized, open-label trial, we evaluated belantamab mafodotin, pomalidomide, and dexamethasone (BPd), as compared with pomalidomide, bortezomib, and dexamethasone (PVd), in lenalidomide-exposed patients who had relapsed or refractory myeloma after at least one line of therapy. The primary end point was progression-free survival. Disease response and safety were also assessed.
RESULTS
A total of 302 patients underwent randomization; 155 were assigned to the BPd group, and 147 to the PVd group. At a median follow-up of 21.8 months (range, <0.1 to 39.2), the 12-month estimated progression-free survival with BPd was 71% (95% confidence interval [CI], 63 to 78), as compared with 51% (95% CI, 42 to 60) with PVd (hazard ratio for disease progression or death, 0.52; 95% CI, 0.37 to 0.73; P<0.001). Data on overall survival were immature. The percentage of patients with a response to treatment (partial response or better) was 77% (95% CI, 70 to 84) in the BPd group and 72% (95% CI, 64 to 79) in the PVd group; 40% (95% CI, 32 to 48) and 16% (95% CI, 11 to 23), respectively, had a complete response or better. Grade 3 or higher adverse events occurred in 94% of the patients in the BPd group and 76% of those in the PVd group. Ocular events occurred in 89% of the patients who received BPd (grade 3 or 4 in 43%) and 30% of those who received PVd (grade 3 or 4 in 2%); ocular events in the BPd group were managed with belantamab mafodotin dose modification. Ocular events led to treatment discontinuation in 9% of the patients in the BPd group and in no patients in the PVd group.
CONCLUSIONS
Among lenalidomide-exposed patients with relapsed or refractory myeloma, BPd conferred a significantly greater benefit than PVd with respect to progression-free survival, as well as deeper, more durable responses. Ocular events were common but were controllable by belantamab mafodotin dose modification. (Funded by GSK; DREAMM-8 ClinicalTrials.gov number, NCT04484623; EudraCT number, 2018-00434-21.).
PubMed: 38828951
DOI: 10.1056/NEJMoa2403407 -
Blood Research Jul 2020The therapeutic strategy for relapsed and refractory multiple myeloma (RRMM) integrates a holistic approach regarding patient, disease, and drug-related factors.... (Review)
Review
The therapeutic strategy for relapsed and refractory multiple myeloma (RRMM) integrates a holistic approach regarding patient, disease, and drug-related factors. Patient-related factors include age, frailty status, and underlying comorbidities, especially cardiovascular and renal diseases and peripheral neuropathies that affect tolerability to multiple drug combinations or transplantations. Disease-related factors encompass these multiple patient-related factors, particularly the aggressiveness of the disease and cytogenetics. Regarding drug-related factors, the approval of novel proteasome inhibitors (such as carfilzomib and ixazomib), immunomodulatory agents (such as pomalidomide), monoclonal antibodies (such as daratumumab and elotuzumab), and new classes of drugs increasingly makes the choice treatment more complex and necessitates a comprehensive summary and an update of the efficacy and toxicities of each antimyeloma drug and its combinations. Further, careful monitoring of the side effects and supportive care throughout the course of treatment are important to achieve better outcomes for patients with RRMM.
PubMed: 32719176
DOI: 10.5045/br.2020.S008 -
Blood Reviews Jan 2020The practice of choosing the next best therapy for patients with relapsed and/or refractory multiple myeloma (RRMM) is becoming increasingly complex. There is no clear... (Review)
Review
The practice of choosing the next best therapy for patients with relapsed and/or refractory multiple myeloma (RRMM) is becoming increasingly complex. There is no clear consensus regarding the best treatment sequence for RRMM. With the approval of novel proteasome inhibitors (ixazomib and carfilzomib), immunomodulatory agents (pomalidomide), monoclonal antibodies (daratumumab and elotuzumab), and other targeted therapies, multiple combination regimens utilizing these agents are being studied with the goal of enhancing disease control, prolonging progression-free survival, and improving overall survival. We, herein, describe a review of FDA-approved regimens for RRMM patients and offer a paradigm in selecting subsequent treatment regimens, focusing on patient specific morbidity, treatment toxicity, and disease-specific characteristics.
Topics: Evidence-Based Practice; Humans; Multiple Myeloma; Neoplasm Recurrence, Local
PubMed: 31500848
DOI: 10.1016/j.blre.2019.100616 -
Blood Jul 2019
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Dexamethasone; Humans; Lenalidomide; Multiple Myeloma; Thalidomide
PubMed: 31296539
DOI: 10.1182/blood-2019-04-901157 -
EJHaem Nov 2023Pomalidomide-dexamethasone (Pd) has been a standard care treatment for relapsed and refractory multiple myeloma since 2013. However, the outcomes of Pd after exposure to...
Pomalidomide-dexamethasone (Pd) has been a standard care treatment for relapsed and refractory multiple myeloma since 2013. However, the outcomes of Pd after exposure to CD38 antibodies are not known. Here we describe the real-world use and efficacy of pomalidomide in a Danish, nationwide cohort of daratumumab-exposed patients. We identified 328 patients that were treated with pomalidomide. Of these, 137 received Pd, 65 daratumumab-pomalidomide-dexamethasone (DPd), 43 pomalidomide-cyclophosphamide-dexamethasone (PCd), 19 carfilzomib-pomalidomide-dexamethasone (KPD), 11 pomalidomide-bortezomib-dexamethasone (PVd), and 52 pomalidomide in other combinations. Patients treated with Pd in this cohort had a partial response or better (≥ PR) rate of 35.8% and median time to next treatment (mTNT) of 4.9 months, almost identical to the results of previous prospective clinical trials. Although treatment with the various pomalidomide-containing triplet regimens resulted in higher ≥ PR rates (PCd: 46.5%, PVd: 63.6%, DPd: 55.4%, KPd: 63.2%), the mTNT achieved was not significantly better than with Pd in most cases (PCD: 5.4, PVD: 5.3, DPD: 4.7 months). The exception to this was KPd (mTNT 7.4 months), but this regimen was mainly used earlier in the course of the disease (median time from diagnosis 2.3 years vs. 3.7-4.3 years). The most important predictor of outcomes was not the choice of index regimen ( = 0.72), but prior exposure ( = 0.0116). Compared to CD38 antibody-naïve patients, triple-class-exposed patients achieved reduced ≥ PR rate (38.0% vs. 47.3%), shorter mTNT (4.0 vs. 5.9 months), and shorter median overall survival (12.4 vs. 24.2 months) with pomalidomide treatment.
PubMed: 38024635
DOI: 10.1002/jha2.774 -
ImmunoTargets and Therapy 2021Whereas the treatment of MM was dependent solely on alkylating agents and corticosteroids during the prior three decades, the landscape of therapeutic measures to treat... (Review)
Review
Whereas the treatment of MM was dependent solely on alkylating agents and corticosteroids during the prior three decades, the landscape of therapeutic measures to treat the disease began to expand enormously early in the current century. The introduction of new classes of small-molecule drugs, such as proteasome blockers (bortezomib and carfilzomib), immunomodulators (lenalidomide and pomalidomide), nuclear export inhibitors (selinexor), and histone deacetylase blockers (panobinostat), as well as the application of autologous stem cell transplantation (ASCT), resulted in a seismic shift in how the disease is treated. The picture changed dramatically once again starting with the 2015 FDA approval of two monoclonal antibodies (mAbs) - the anti-CD38 daratumumab and the anti-SLAMF7 elotuzumab. Daratumumab, in particular, has had a great impact on MM therapy and today is often included in various regimens to treat the disease, both in newly diagnosed cases and in the relapse/refractory setting. Recently, other immunotherapies have been added to the arsenal of drugs available to fight this malignancy. These include isatuximab (also anti-CD38) and, in the past year, the antibody-drug conjugate (ADC) belantamab mafodotin and the chimeric antigen receptor (CAR) T-cell product idecabtagene vicleucel (ide-cel). While the accumulated benefits of these newer agents have resulted in a doubling of the disease's five-year survival rate to more than 5 years and improved quality of life, the disease remains incurable. Almost without exception patients experience relapse and/or become refractory to the drugs used, making the search for innovative therapies all the more essential. This review covers the current scope of anti-myeloma immunotherapeutic agents, both those in clinical use and on the horizon, including naked mAbs, ADCs, bi- and multi-targeted mAbs, and CAR T-cells. Emphasis is placed on the benefits of each along with the challenges that need to be overcome if MM is to be considered curable in the future.
PubMed: 34527606
DOI: 10.2147/ITT.S306103 -
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 -
Cancers Sep 2020Immunomodulatory drugs (IMiDs) are analogs of thalidomide. They have immunomodulatory, antiangiogenic and proapoptotic properties and exert a role in regulating the... (Review)
Review
Immunomodulatory drugs (IMiDs) are analogs of thalidomide. They have immunomodulatory, antiangiogenic and proapoptotic properties and exert a role in regulating the tumor microenvironment. Recently IMiDs have been investigated for their pleiotropic properties and their therapeutic applications in both solid tumors (melanoma, prostate carcinoma and differentiated thyroid cancer) and hematological malignancies. Nowadays, they are applied in de novo and relapsed/refractory multiple myeloma, in myelodysplastic syndrome, in del5q syndrome with specific use of lenalidomide and B-cell lymphoma. Several studies have been conducted in the last few years to explore IMiDs possible use in acute myeloid leukemia treatment. Here we report the mechanisms of action of IMiDs in acute myeloid leukemia and their potential future therapeutic application in this disease.
PubMed: 32899586
DOI: 10.3390/cancers12092528