-
Hematology/oncology Clinics of North... Apr 2024Cereblon-targeting degraders, including immunomodulatory imide drugs lenalidomide and pomalidomide alongside cereblon E3 ligase modulators like iberdomide and... (Review)
Review
Cereblon-targeting degraders, including immunomodulatory imide drugs lenalidomide and pomalidomide alongside cereblon E3 ligase modulators like iberdomide and mezigdomide, have demonstrated significant anti-myeloma effects. These drugs play a crucial role in diverse therapeutic approaches for multiple myeloma (MM), emphasizing their therapeutic importance across various disease stages. Despite their evident efficacy, approximately 5% to 10% of MM patients exhibit primary resistance to lenalidomide, and resistance commonly develops over time. Understanding the intricate mechanisms of action and resistance to this drug class becomes imperative for refining and advancing novel therapeutic combinations.
Topics: Humans; Multiple Myeloma; Lenalidomide; Adaptor Proteins, Signal Transducing; Ubiquitin-Protein Ligases
PubMed: 38302306
DOI: 10.1016/j.hoc.2024.01.001 -
Haematologica Jul 2024The primary and prespecified updated analyses of ICARIA-MM (clinicaltrial gov. Identifier: NCT02990338) demonstrated improved progression-free survival (PFS) and a... (Randomized Controlled Trial)
Randomized Controlled Trial
The primary and prespecified updated analyses of ICARIA-MM (clinicaltrial gov. Identifier: NCT02990338) demonstrated improved progression-free survival (PFS) and a benefit in overall survival (OS) was reported with the addition of isatuximab, an anti-CD38 monoclonal antibody, to pomalidomide-dexamethasone (Pd) in patients with relapsed/refractory multiple myeloma. Here, we report the final OS analysis. This multicenter, randomized, open-label, phase III study included patients who had received and failed ≥2 previous therapies, including lenalidomide and a proteasome inhibitor. Between January 10, 2017, and February 2, 2018, 307 patients were randomized (1:1) to isatuximab-pomalidomide-dexamethasone (Isa-Pd; N=154) or Pd (N=153), stratified based on age (<75 vs. ≥75 years) and number of previous lines of therapy (2-3 vs. >3). At data cutoff for the final OS analysis after 220 OS events (January 27, 2022), median follow-up duration was 52.4 months. Median OS was 24.6 months (95% confidence interval [CI]: 20.3-31.3) with Isa-Pd and 17.7 months (95% CI: 14.4- 26.2) with Pd (hazard ratio=0.78; 95% CI: 0.59-1.02; 1-sided P=0.0319). Despite subsequent daratumumab use in the Pd group and its potential benefit on PFS in the first subsequent therapy line, median PFS2 was significantly longer with Isa-Pd versus Pd (17.5 vs. 12.9 months; log-rank 1-sided P=0.0091). In this analysis, Isa-Pd continued to be efficacious and well tolerated after follow-up of approximately 52 months, contributing to a clinically meaningful, 6.9-month improvement in median OS in patients with relapsed/refractory multiple myeloma.
Topics: Humans; Multiple Myeloma; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Thalidomide; Male; Aged; Female; Middle Aged; Antibodies, Monoclonal, Humanized; Aged, 80 and over; Adult; Drug Resistance, Neoplasm; Treatment Outcome; Recurrence; Survival Analysis
PubMed: 38299578
DOI: 10.3324/haematol.2023.284325 -
Hematology/oncology Clinics of North... Apr 2024Despite improved treatments, most patients with multiple myeloma (MM) will experience relapse. Several novel agents have demonstrated activity and tolerability in early... (Review)
Review
Despite improved treatments, most patients with multiple myeloma (MM) will experience relapse. Several novel agents have demonstrated activity and tolerability in early phase clinical trials. Venetoclax is a B-cell lymphoma 2 (Bcl-2) inhibitor with activity in patients with t(11;14) and/or Bcl-2 expression. Iberdomide and mezigdomide are cereblon E3 ligase modulators with higher potency, immunomodulatory, and antiproliferative activity compared with lenalidomide and pomalidomide. They have shown promising activity in heavily pretreated patients. Modakafusp alfa is an immunocytokine that targets interferons to CD38+ cells. It has demonstrated single agent activity in relapsed/refractory MM in the phase 1 setting.
Topics: Humans; Multiple Myeloma; Neoplasm Recurrence, Local; Antineoplastic Agents; Lenalidomide; Proto-Oncogene Proteins c-bcl-2; Dexamethasone; Antineoplastic Combined Chemotherapy Protocols
PubMed: 38216384
DOI: 10.1016/j.hoc.2023.12.013 -
Advanced Materials (Deerfield Beach,... Apr 2024The immunomodulatory effects of many therapeutic agents are significantly challenged by their insufficient delivery efficiency and short retention time in tumors....
The immunomodulatory effects of many therapeutic agents are significantly challenged by their insufficient delivery efficiency and short retention time in tumors. Regarding the distinctively upregulated fibronectin (FN1) and tenascin C (TNC) in tumor stroma, herein a protease-activated FN1 and/or TNC binding peptide (FTF) is designed and an extracellular matrix (ECM)-trapped bioinspired lipoprotein (BL) (FTF-BL-CP) is proposed that can be preferentially captured by the TNC and/or FN1 for tumor retention, and then be responsively dissociated from the matrix to potentiate the antitumor immunity. The FTF-BL-CP treatment produces a 6.96-, 9.24-, 6.72-, 7.32-, and 6.73-fold increase of CD3CD8 T cells and their interferon-γ-, granzyme B-, perforin-, and Ki67-expressing subtypes versus the negative control, thereby profoundly eliciting the antitumor immunity. In orthotopic and lung metastatic breast cancer models, FTF-BL-CP produces notable therapeutic benefits of retarding tumor growth, extending survivals, and inhibiting lung metastasis. Therefore, this ECM-trapping strategy provides an encouraging possibility of prolonging tumor retention to potentiate the antitumor immunity for anticancer immunotherapy.
Topics: Humans; CD8-Positive T-Lymphocytes; Extracellular Matrix; Tenascin; Lung Neoplasms; Lipoproteins
PubMed: 38216153
DOI: 10.1002/adma.202310982 -
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 -
Bioorganic Chemistry Feb 2024Immunomodulatory drugs (e.g. thalidomide, lenalidomide and pomalidomide) have been proven highly successful in clinical treatment of multiple myeloma. However,...
Immunomodulatory drugs (e.g. thalidomide, lenalidomide and pomalidomide) have been proven highly successful in clinical treatment of multiple myeloma. However, systematic degradation of zinc finger transcriptional factors induced by these drugs could lead to severe systematic toxicity in patients. Previous reports of NVOC caged pomalidomide attempted to regulate its activity using UVA irradiation, but their application was limited by high cytotoxicity and low tissue penetration. Here, we reported red-shifted BODIPY caged lenalidomide and pomalidomide that enabled red-light controlled protein degradation with spatiotemporal precision.
Topics: Humans; Thalidomide; Lenalidomide; Proteolysis; Multiple Myeloma
PubMed: 38163423
DOI: 10.1016/j.bioorg.2023.107050 -
Case Reports in Hematology 2023In this case, we describe the potential risk of developing an infectious complication leading to a secondary malignancy after a short course of immunotherapy. We report...
In this case, we describe the potential risk of developing an infectious complication leading to a secondary malignancy after a short course of immunotherapy. We report a patient who presented with Epstein-Barr virus (EBV) driven Hodgkin's lymphoma after treatment with a short course of daratumumab along with pomalidomide and dexamethasone for relapsed multiple myeloma. Although there have been limited documented cases of daratumumab treatment leading to EBV reactivation, in patients presenting with infectious symptoms or neutropenia on a daratumumab-based regimen, testing for EBV should not be overlooked.
PubMed: 38146540
DOI: 10.1155/2023/6669174 -
European Journal of Haematology May 2024To retrospectively analyze real-world treatment patterns in patients with relapsed/refractory multiple myeloma (RRMM) who initiated third-line treatment in Europe.
Real-world treatment patterns in patients initiating third-line therapy for relapsed or refractory multiple myeloma in Germany, Italy, the United Kingdom, France, and Spain.
OBJECTIVES
To retrospectively analyze real-world treatment patterns in patients with relapsed/refractory multiple myeloma (RRMM) who initiated third-line treatment in Europe.
METHODS
German and Italian administrative claims data were sourced from the German AOK PLUS health insurance fund and Italian local health units (2016-2020). Data for the United Kingdom (UK), France, and Spain were sourced from medical chart reviews (MCRs) from 2016 to 2018 (historical) and 2019 to 2021 (new) using electronic case report forms.
RESULTS
Across all countries, immunomodulatory imide drug (IMiD)-based regimens were prominent in the third-line setting. From 2016 to 2020, lenalidomide-dexamethasone was most common in Italy (18.0%) and Germany (12.7%). From 2019 to 2021, the most common regimen was ixazomib-lenalidomide-dexamethasone (67.5%) in the UK, pomalidomide-dexamethasone (17.1%) in France, and daratumumab-bortezomib-dexamethasone (15.0%) in Spain. In the historical data (2016-2018), third-line lenalidomide- and pomalidomide-dexamethasone doublet use across the UK (>47%), France (>46%), and Spain (>33%) was high. From historical to new, triplet use increased in Spain (>19% to >60%) as did anti-CD38 agent use in France (15.1% to 51.9%) and Spain (19.7% to 42.1%).
CONCLUSIONS
From 2016 to 2021, third-line regimens were mostly IMiD based. The MCR data demonstrated evolving treatment choices from 2016 to 2018 and 2019 to 2021, providing insights into uptake of novel agents and current RRMM European clinical practice.
Topics: Humans; Multiple Myeloma; Lenalidomide; Retrospective Studies; Spain; Dexamethasone; Antineoplastic Combined Chemotherapy Protocols; Thalidomide
PubMed: 38146208
DOI: 10.1111/ejh.14161 -
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 -
Cancers Dec 2023Newer methodologies are needed to assess the real-world comparative effectiveness of a "generation" of pharmaceutical innovation versus the prior standard of care. This...
Does the Simultaneous Introduction of Several Pharmaceuticals in the Post-Lenalidomide Era Translate to Better Outcomes in Relapse Refractory Multiple Myeloma? Findings from the Real-World Innovation in Multiple Myeloma (REAL IMM) Study.
Newer methodologies are needed to assess the real-world comparative effectiveness of a "generation" of pharmaceutical innovation versus the prior standard of care. This chart review study aimed to first evaluate the cumulative clinical benefits of pharmaceutical innovation in everyday relapse/refractory multiple myeloma before analyzing findings in the context of respective real-world outcomes from the bortezomib/lenalidomide era. Study endpoints included the 52-week PFS rate in second and third line of therapy (LOT), mPFS-2 across the first and second LOT, the ORR, reasons for discontinuation, and the treatment duration per therapeutic algorithm. Data from 107 patients were collected. The median follow-up was 2.0 years. Of the subjects who met the selection criteria for the second LOT, 72.2% maintained the PFS at 52 weeks. In the third-line setting, the PFS rate at 52 weeks was 63.5%. The mPFS across the first and second, the second, and the third LOTs were 26, 17, and 15 months, respectively. The ORR was 76.1% in the second and 69.7% in the third LOT. After non-response or progression, the main reason for drug discontinuation was treatment intolerability. The second-line ORR and the 52-week PFS rate were similar to previous real-world findings from the bortezomib/lenalidomide era. The cumulative mPFS across the second and third LOTs was higher than the respective mPFS across the first and second LOTs. Despite its limitations, the methodology and findings from this study may be used in future clinical and economic evaluations across all hematological malignancies.
PubMed: 38136391
DOI: 10.3390/cancers15245846