-
Nature Chemistry Feb 2024Proteolysis-targeting chimeras (PROTACs) are molecules that induce proximity between target proteins and E3 ligases triggering target protein degradation. Pomalidomide,...
Proteolysis-targeting chimeras (PROTACs) are molecules that induce proximity between target proteins and E3 ligases triggering target protein degradation. Pomalidomide, a widely used E3 ligase recruiter in PROTACs, can independently degrade other proteins, including zinc-finger (ZF) proteins, with vital roles in health and disease. This off-target degradation hampers the therapeutic applicability of pomalidomide-based PROTACs, requiring development of PROTAC design rules that minimize off-target degradation. Here we developed a high-throughput platform that interrogates off-target degradation and found that reported pomalidomide-based PROTACs induce degradation of several ZF proteins. We generated a library of pomalidomide analogues to understand how functionalizing different positions of the phthalimide ring, hydrogen bonding, and steric and hydrophobic effects impact ZF protein degradation. Modifications of appropriate size on the C5 position reduced off-target ZF degradation, which we validated through target engagement and proteomics studies. By applying these design principles, we developed anaplastic lymphoma kinase oncoprotein-targeting PROTACs with enhanced potency and minimal off-target degradation.
Topics: Proteolysis; Ubiquitin-Protein Ligases; Proteins; Thalidomide
PubMed: 38110475
DOI: 10.1038/s41557-023-01379-8 -
The Lancet. Haematology Oct 2023The primary analysis of the APOLLO trial, done after a median follow-up of 16·9 months, showed that daratumumab plus pomalidomide and dexamethasone significantly... (Randomized Controlled Trial)
Randomized Controlled Trial
Subcutaneous daratumumab plus pomalidomide and dexamethasone versus pomalidomide and dexamethasone in patients with relapsed or refractory multiple myeloma (APOLLO): extended follow up of an open-label, randomised, multicentre, phase 3 trial.
BACKGROUND
The primary analysis of the APOLLO trial, done after a median follow-up of 16·9 months, showed that daratumumab plus pomalidomide and dexamethasone significantly improved progression-free survival versus pomalidomide and dexamethasone. Here, we report the final overall survival and updated safety results from APOLLO.
METHODS
APOLLO was an open-label, randomised, phase 3 trial conducted at 48 academic centres and hospitals across 12 countries in Europe, that included adults aged 18 years or older with relapsed or refractory multiple myeloma who had an ECOG performance status score of 0-2, had received at least one previous line of therapy, including lenalidomide and a proteasome inhibitor, had a partial response or better to one or more previous lines of antimyeloma therapy, and were refractory to lenalidomide if they had received only one previous line of therapy. An interactive web-response system was used to randomly assign patients (1:1) to receive daratumumab plus pomalidomide and dexamethasone or pomalidomide and dexamethasone; patients were stratified by the number of previous lines of therapy and International Staging System disease stage. Oral pomalidomide (4 mg once daily; days 1-21) and dexamethasone (40 mg once daily; days 1, 8, 15, and 22) were given in 28-day cycles until disease progression or unacceptable toxicity. Daratumumab (1800 mg subcutaneously or 16 mg/kg intravenously) was administered weekly (cycles 1-2), every 2 weeks (cycles 3-6), and every 4 weeks thereafter. The primary endpoint of progression-free survival, which has previously been reported, and the pre-planned secondary endpoint of overall survival were assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT03180736) and is no longer enrolling patients.
FINDINGS
Between June 22, 2017, and June 13, 2019, 304 patients were randomly assigned: 151 to the daratumumab plus pomalidomide and dexamethasone group and 153 to the pomalidomide and dexamethasone group. The median age was 67 years (IQR 60-72); 143 (47%) patients were female and 161 (53%) were male, and 272 (89%) were White. At a median follow-up of 39·6 months (IQR 37·1-43·7), median overall survival was 34·4 months (95% CI 23·7-40·3) in the daratumumab plus pomalidomide and dexamethasone group versus 23·7 months (19·6-29·4) in the pomalidomide and dexamethasone group (hazard ratio [HR] 0·82 [95% CI 0·61-1·11]; p=0·20). The most common grade 3-4 treatment-emergent adverse events were neutropenia (103 [69%] of 149 with daratumumab plus pomalidomide and dexamethasone vs 76 [51%] of 150 with pomalidomide and dexamethasone), anaemia (27 [18%] vs 32 [21%]), and thrombocytopenia (27 [18%] vs 28 [19%]). Serious treatment-emergent adverse events occurred in 80 (54%) of 149 patients in the daratumumab plus pomalidomide and dexamethasone group and in 60 (40%) of 150 patients in the pomalidomide and dexamethasone group, the most common of which was pneumonia (23 [15%] of 149 vs 13 [9%] of 150). Treatment-emergent adverse events resulting in death occurred in 13 (9%) of 149 patients in the daratumumab plus pomalidomide and dexamethasone group and in 13 (9%) of 150 patients in the pomalidomide and dexamethasone group, with 4 (3%) of 151 adverse events leading to death within 30 days of the last treatment dose thought to be related to study treatment in the daratumumab plus pomalidomide and dexamethasone group (septic shock [n=1]; sepsis [n=1]; bone marrow failure, campylobacter infection, and liver disorder [n=1]; and pneumonia [n=1]) and none in the pomalidomide and dexamethasone group.
INTERPRETATION
Although the difference in overall survival observed between treatment groups was not significant, the safety profile results with long-term follow-up reported here continue to support the use of daratumumab plus pomalidomide and dexamethasone in patients with relapsed or refractory multiple myeloma.
FUNDING
European Myeloma Network and Janssen Research & Development.
Topics: Adult; Aged; Female; Humans; Male; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Follow-Up Studies; Lenalidomide; Multiple Myeloma; Pneumonia; Middle Aged
PubMed: 37793772
DOI: 10.1016/S2352-3026(23)00218-1 -
Proceedings of the Japan Academy.... 2020Thalidomide, originally developed as a sedative drug, causes multiple defects due to severe teratogenicity, but it has been re-purposed for treating multiple myeloma,...
Thalidomide, originally developed as a sedative drug, causes multiple defects due to severe teratogenicity, but it has been re-purposed for treating multiple myeloma, and derivatives such as lenalidomide and pomalidomide have been developed for treating blood cancers. Although the molecular mechanisms of thalidomide and its derivatives remained poorly understood until recently, we identified cereblon (CRBN), a primary direct target of thalidomide, using ferrite glycidyl methacrylate (FG) beads. CRBN is a ligand-dependent substrate receptor of the E3 ubiquitin ligase complex cullin-RING ligase 4 (CRL4). When a ligand such as thalidomide binds to CRBN, it recognizes various 'neosubstrates' depending on the shape of the ligand. CRL4 binds many neosubstrates in the presence of various ligands. CRBN has been utilized in a novel protein knockdown technology named proteolysis targeting chimeras (PROTACs). Heterobifunctional molecules such as dBET1 are being developed to specifically degrade proteins of interest. Herein, we review recent advances in CRBN research.
Topics: Animals; Drug Repositioning; Humans; Molecular Targeted Therapy; Thalidomide
PubMed: 32522938
DOI: 10.2183/pjab.96.016 -
Leukemia & Lymphoma Jun 2022Patients with relapsed/refractory multiple myeloma (RRMM) need proven subsequent therapies after early-line lenalidomide treatment failure. The phase 2 MM-014 trial...
Pomalidomide, dexamethasone, and daratumumab immediately after lenalidomide-based treatment in patients with multiple myeloma: updated efficacy, safety, and health-related quality of life results from the phase 2 MM-014 trial.
Patients with relapsed/refractory multiple myeloma (RRMM) need proven subsequent therapies after early-line lenalidomide treatment failure. The phase 2 MM-014 trial (NCT01946477) investigated pomalidomide, dexamethasone, and daratumumab after 1 to 2 prior treatment lines (62.5%, 1 prior line) in patients with RRMM and prior lenalidomide (75.0%, lenalidomide refractory). With a median follow-up of 28.4 months, overall response rate was 77.7% (52.7% achieved very good partial response or better) and median progression-free survival was 30.8 months. For patients with lenalidomide-refractory disease, these outcomes were 76.2%, 47.6%, and 23.7 months, respectively. No new safety signals were observed; 64.3% experienced grade 3/4 neutropenia. Health-related quality of life was preserved or trended toward improvement through 12 treatment cycles. Pomalidomide, dexamethasone, and daratumumab given immediately after early-line lenalidomide-based treatment continues to demonstrate safety and efficacy, supporting pomalidomide-dexamethasone as a foundation of combination therapy in RRMM and providing evidence that the immunomodulatory agent class delivers benefit after lenalidomide treatment failure.
Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Humans; Lenalidomide; Multiple Myeloma; Neoplasm Recurrence, Local; Neoplasms, Plasma Cell; Quality of Life; Thalidomide
PubMed: 35133221
DOI: 10.1080/10428194.2022.2030477 -
Clinical Lymphoma, Myeloma & Leukemia Jul 2022Despite the increasing number of treatment options available for multiple myeloma, relapse is still inevitable and there remains a critical unmet need for treatments for... (Review)
Review
Despite the increasing number of treatment options available for multiple myeloma, relapse is still inevitable and there remains a critical unmet need for treatments for patients with late-stage, highly refractory disease. In this review, we discuss currently approved treatment options for heavily pretreated patients with relapsed and refractory multiple myeloma, with a focus on the optimal management of patients with MM refractory to lenalidomide, bortezomib, and in some cases, daratumumab or an anti-CD38 monoclonal antibody. Data from recent clinical trials of immunomodulatory agents (pomalidomide), proteasome inhibitors (PIs; carfilzomib and ixazomib), monoclonal antibodies (elotuzumab, daratumumab, and isatuximab), and other novel therapies (including panobinostat-based therapy) are summarized. We also provide potential therapeutic strategies for patients according to different treatment histories, and include case studies to illustrate the practical use of various treatment options in a clinical setting. Regimens containing pomalidomide, elotuzumab, next-generation PIs, panobinostat, or selinexor may provide effective treatment options in patients with triple-refractory disease. The choice of agents used, and combinations thereof should be individualized as well as strategically planned from early- to late-stage relapse.
Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Lenalidomide; Multiple Myeloma; Neoplasm Recurrence, Local; Panobinostat; Proteasome Inhibitors
PubMed: 35148975
DOI: 10.1016/j.clml.2022.01.011 -
Journal of Clinical Oncology : Official... Jan 2023In the phase II ELOQUENT-3 trial (ClinicalTrials.gov identifier: NCT02654132), elotuzumab combined with pomalidomide/dexamethasone (EPd) significantly improved... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
In the phase II ELOQUENT-3 trial (ClinicalTrials.gov identifier: NCT02654132), elotuzumab combined with pomalidomide/dexamethasone (EPd) significantly improved progression-free survival (PFS) versus pomalidomide/dexamethasone (Pd) in patients with relapsed/refractory multiple myeloma (RRMM) previously treated with lenalidomide and a proteasome inhibitor (PI). Here, we present the final overall survival (OS) results.
METHODS
Patients with RRMM who had received ≥ 2 prior lines of therapy, with disease refractory to last therapy and either refractory or relapsed and refractory to lenalidomide and a PI were randomly assigned (1:1) to receive EPd or Pd. The primary end point was PFS per investigator assessment. ORR and OS were secondary end points planned to be tested hierarchically.
RESULTS
A total of 117 patients were randomly assigned to EPd (n = 60) and Pd (n = 57). Among treated patients (EPd 60, Pd 55), there were 37 (61.7%) deaths in the EPd group and 41 (74.5%) in the Pd group, most commonly because of disease progression (EPd 41.7%, Pd 49.1%). Median (95% CI) OS was significantly improved with EPd (29.8 [22.9 to 45.7] months) versus Pd (17.4 [13.8 to 27.7] months), with a hazard ratio of 0.59 (95% CI, 0.37 to 0.93; = .0217). OS benefit with EPd was observed in most patient subgroups. The safety profile of EPd was consistent with prior reports with no new safety signals detected.
CONCLUSION
EPd demonstrated a statistically significant improvement in OS versus Pd in patients with RRMM previously treated with lenalidomide and a PI who had disease refractory to last therapy. In this setting, ELOQUENT-3 is the first randomized study of a triplet regimen incorporating a monoclonal antibody and Pd to improve both PFS and OS significantly.
Topics: Humans; Multiple Myeloma; Lenalidomide; Antineoplastic Combined Chemotherapy Protocols; Survival Analysis; Dexamethasone
PubMed: 35960908
DOI: 10.1200/JCO.21.02815 -
Drugs Jun 2020Isatuximab (isatuximab-irfc; Sarclisa) is an IgG1 monoclonal antibody that binds to the glycoprotein CD38 expressed on the surface of haematopoietic and tumour cells. It... (Review)
Review
Isatuximab (isatuximab-irfc; Sarclisa) is an IgG1 monoclonal antibody that binds to the glycoprotein CD38 expressed on the surface of haematopoietic and tumour cells. It is being developed by Sanofi, under a license from Immunogen, for the treatment of haematological malignancies. In March 2020, intravenous isatuximab (in combination with pomalidomide and dexamethasone) was approved in the USA for the treatment of adult patients with multiple myeloma who have received ≥ 2 prior therapies, including lenalidomide and a proteasome inhibitor. Isatuximab has also received a positive opinion in the EU for the treatment of relapsed and refractory multiple myeloma. This article summarizes the milestones in the development of isatuximab leading to the first approval in the USA.
Topics: Adult; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Drug Approval; Humans; Injections, Intravenous; Multiple Myeloma; Thalidomide; United States
PubMed: 32347476
DOI: 10.1007/s40265-020-01311-1