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Nature Communications Aug 2023Lenalidomide, an immunomodulatory drug (IMiD), is commonly used as a first-line therapy in many haematological cancers, such as multiple myeloma (MM) and 5q...
Lenalidomide, an immunomodulatory drug (IMiD), is commonly used as a first-line therapy in many haematological cancers, such as multiple myeloma (MM) and 5q myelodysplastic syndromes (5q MDS), and it functions as a molecular glue for the protein degradation of neosubstrates by CRL4. Proteolysis-targeting chimeras (PROTACs) using IMiDs with a target protein binder also induce the degradation of target proteins. The targeted protein degradation (TPD) of neosubstrates is crucial for IMiD therapy. However, current IMiDs and IMiD-based PROTACs also break down neosubstrates involved in embryonic development and disease progression. Here, we show that 6-position modifications of lenalidomide are essential for controlling neosubstrate selectivity; 6-fluoro lenalidomide induced the selective degradation of IKZF1, IKZF3, and CK1α, which are involved in anti-haematological cancer activity, and showed stronger anti-proliferative effects on MM and 5q MDS cell lines than lenalidomide. PROTACs using these lenalidomide derivatives for BET proteins induce the selective degradation of BET proteins with the same neosubstrate selectivity. PROTACs also exert anti-proliferative effects in all examined cell lines. Thus, 6-position-modified lenalidomide is a key molecule for selective TPD using thalidomide derivatives and PROTACs.
Topics: Female; Pregnancy; Humans; Lenalidomide; Proteolysis; Immunomodulating Agents; Multiple Myeloma; Myelodysplastic Syndromes; Chromosome Aberrations; Hematologic Neoplasms; Proteolysis Targeting Chimera
PubMed: 37596276
DOI: 10.1038/s41467-023-40385-9 -
Annals of Hematology Jul 2023RE-MIND2 (NCT04697160) compared patient outcomes from the L-MIND (NCT02399085) trial of tafasitamab+lenalidomide with those of patients treated with other therapies for...
RE-MIND2: comparative effectiveness of tafasitamab plus lenalidomide versus polatuzumab vedotin/bendamustine/rituximab (pola-BR), CAR-T therapies, and lenalidomide/rituximab (R2) based on real-world data in patients with relapsed/refractory diffuse large B-cell lymphoma.
RE-MIND2 (NCT04697160) compared patient outcomes from the L-MIND (NCT02399085) trial of tafasitamab+lenalidomide with those of patients treated with other therapies for relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) who are autologous stem cell transplant ineligible. We present outcomes data for three pre-specified treatments not assessed in the primary analysis. Data were retrospectively collected from sites in North America, Europe, and the Asia Pacific region. Patients were aged ≥18 years with histologically confirmed DLBCL and received ≥2 systemic therapies for DLBCL (including ≥1 anti-CD20 therapy). Patients enrolled in the observational and L-MIND cohorts were matched using propensity score-based 1:1 nearest-neighbor matching, balanced for six covariates. Tafasitamab+lenalidomide was compared with polatuzumab vedotin+bendamustine+rituximab (pola-BR), rituximab+lenalidomide (R2), and CD19-chimeric antigen receptor T-cell (CAR-T) therapies. The primary endpoint was overall survival (OS). Secondary endpoints included treatment response and progression-free survival. From 200 sites, 3,454 patients were enrolled in the observational cohort. Strictly matched patient pairs consisted of tafasitamab+lenalidomide versus pola-BR (n = 24 pairs), versus R2 (n = 33 pairs), and versus CAR-T therapies (n = 37 pairs). A significant OS benefit was observed with tafasitamab+lenalidomide versus pola-BR (HR: 0.441; p = 0.034) and R2 (HR: 0.435; p = 0.012). Comparable OS was observed in tafasitamab+lenalidomide and CAR-T cohorts (HR: 0.953, p = 0.892). Tafasitamab+lenalidomide appeared to improve survival outcomes versus pola-BR and R2, and comparable outcomes were observed versus CAR-T. Although based on limited patient numbers, these data may help to contextualize emerging therapies for R/R DLBCL. CLINICAL TRIAL REGISTRATION: NCT04697160 (January 6, 2021).
Topics: Humans; Adolescent; Adult; Rituximab; Lenalidomide; Bendamustine Hydrochloride; Receptors, Chimeric Antigen; Retrospective Studies; Lymphoma, Non-Hodgkin; Lymphoma, Large B-Cell, Diffuse
PubMed: 37171597
DOI: 10.1007/s00277-023-05196-4 -
Blood Advances Jul 2023CANDOR (NCT03158688) is a phase 3, randomized, open-label trial comparing carfilzomib, daratumumab, and dexamethasone (KdD) vs carfilzomib and dexamethasone (Kd) in...
CANDOR (NCT03158688) is a phase 3, randomized, open-label trial comparing carfilzomib, daratumumab, and dexamethasone (KdD) vs carfilzomib and dexamethasone (Kd) in adults with relapsed/refectory multiple myeloma (RRMM) with 1 to 3 prior therapies. The CANDOR study met its primary end point of progression-free survival (PFS) in the primary analysis. Here, we report the final analysis of the study, including secondary end points and subgroup analyses thereof. The median follow-up was 50 months. Patients treated with KdD had higher minimal residual disease-negative (MRD-) achievement rates (28% vs 9%; odds ratio [OR], 4.22; 95% confidence interval [95% CI], 2.28-7.83) and MRD- complete response rates (22% vs 8%; OR, 3.55; 95% CI, 1.83-6.88) than those treated with Kd. Median PFS was 28.4 months for KdD vs 15.2 months for Kd (hazard ratio [HR], 0.64; 95% CI, 0.49-0.83). Median overall survival (OS) for KdD was 50.8 months vs 43.6 months for Kd (HR, 0.78 [0.60-1.03]; P = .042). Trends toward improved OS occurred in predefined subgroups, including patients refractory to lenalidomide (KdD, not reached vs Kd, 38.2 months; HR, 0.69 [0.43-1.11]) and refractory to proteasome inhibitor (KdD, 43.2 months vs Kd, 30.0 months; HR, 0.70 [0.45-1.09]), and there was significant improvement in patients with high-risk cytogenetics (KdD, 34.3 months vs Kd: 17.1 months; HR, 0.52 [0.29-0.94]). No new safety signals were identified. In summary, the final analysis of CANDOR confirmed the PFS benefit and showed a trend in OS benefit with KdD vs Kd. These findings reinforce KdD as a standard of care for RRMM, especially in clinically relevant patient subgroups. This trial was registered at www.clinicaltrials.gov as #NCT03158688.
Topics: Adult; Humans; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Multiple Myeloma
PubMed: 37163358
DOI: 10.1182/bloodadvances.2023010026 -
Cancers Jul 2023Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are hematological disorders characterized by both proliferative and dysplastic features. According to the 2022... (Review)
Review
Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are hematological disorders characterized by both proliferative and dysplastic features. According to the 2022 International Consensus Classification (ICC), MDS/MPN consists of clonal monocytosis of undetermined significance (CMUS), chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia (aCML), MDS/MPN with SF3B1 mutation (MDS/MPN-T-SF3B1), MDS/MPN with ring sideroblasts and thrombocytosis not otherwise specified (MDS/MPN-RS-T-NOS), and MDS/MPN-NOS. These disorders exhibit a diverse range of genetic alterations involving various transcription factors (e.g., ), signaling molecules (e.g., , ), splicing factors (e.g., , ), and epigenetic regulators (e.g., , , ), as well as specific cytogenetic abnormalities (e.g., 8 trisomies, 7 deletions/monosomies). Clinical studies exploring therapeutic options for higher-risk MDS/MPN overlap syndromes mostly involve hypomethylating agents, but other treatments such as lenalidomide and targeted agents such as JAK inhibitors and inhibitors targeting PARP, histone deacetylases, and the Ras pathway are under investigation. While these treatment modalities can provide partial disease control, allogeneic bone marrow transplantation (allo-BMT) is the only potentially curative option for patients. Important prognostic factors correlating with outcomes after allo-BMT include comorbidities, splenomegaly, karyotype alterations, and the bone marrow blasts percentage at the time of transplantation. Future research is imperative to optimizing therapeutic strategies and enhancing patient outcomes in MDS/MPN neoplasms. In this review, we summarize MDS/MPN diagnostic criteria, biology, and current and future treatment options, including bone marrow transplantation.
PubMed: 37568631
DOI: 10.3390/cancers15153815 -
Science China. Life Sciences Aug 2023Protein-biomolecule interactions play pivotal roles in almost all biological processes. For a biomolecule of interest, the identification of the interacting protein(s)...
Protein-biomolecule interactions play pivotal roles in almost all biological processes. For a biomolecule of interest, the identification of the interacting protein(s) is essential. For this need, although many assays are available, highly robust and reliable methods are always desired. By combining a substrate-based proximity labeling activity from the pupylation pathway of Mycobacterium tuberculosis and the streptavidin (SA)-biotin system, we developed the Specific Pupylation as IDEntity Reporter (SPIDER) method for identifying protein-biomolecule interactions. Using SPIDER, we validated the interactions between the known binding proteins of protein, DNA, RNA, and small molecule. We successfully applied SPIDER to construct the global protein interactome for mA and mRNA, identified a variety of uncharacterized mA binding proteins, and validated SRSF7 as a potential mA reader. We globally identified the binding proteins for lenalidomide and CobB. Moreover, we identified SARS-CoV-2-specific receptors on the cell membrane. Overall, SPIDER is powerful and highly accessible for the study of protein-biomolecule interactions.
Topics: Humans; COVID-19; SARS-CoV-2; Proteins; Protein Binding
PubMed: 37059927
DOI: 10.1007/s11427-023-2316-2 -
Haematologica Feb 2024Tafasitamab, an anti-CD19 immunotherapy, is used with lenalidomide for patients with autologous stem cell transplant-ineligible relapsed/refractory diffuse large B-cell...
Tafasitamab, an anti-CD19 immunotherapy, is used with lenalidomide for patients with autologous stem cell transplant-ineligible relapsed/refractory diffuse large B-cell lymphoma based on the results of the phase II L-MIND study (NCT02399085). We report the final 5-year analysis of this study. Eighty patients ≥18 years who had received one to three prior systemic therapies, and had Eastern Cooperative Oncology Group performance status 0-2 received up to 12 cycles of co-administered tafasitamab and lenalidomide, followed by tafasitamab monotherapy until disease progression or unacceptable toxicity. The primary endpoint was the best objective response rate. Secondary endpoints included duration of response, progression-free survival, overall survival, and safety. Exploratory analyses evaluated efficacy endpoints by prior lines of therapy. At data cutoff on November 14, 2022, the objective response rate was 57.5%, with a complete response rate of 41.3% (n=33), which was consistent with prior analyses. With a median follow-up of 44.0 months, the median duration of response was not reached. The median progression-free survival was 11.6 months (95% confidence interval [95% CI]: 5.7-45.7) with a median follow-up of 45.6 months. The median overall survival was 33.5 months (95% CI: 18.3-not reached) with a median follow-up of 65.6 months. Patients who had received one prior line of therapy (n=40) showed a higher objective response rate (67.5%; 52.5% complete responses) compared to patients who had received two or more prior lines of therapy (n=40; 47.5%; 30% complete responses), but the median duration of response was not reached in either subgroup. Other exploratory analyses revealed consistent long-term efficacy results across subgroups. Adverse events were consistent with those described in previous reports, were manageable, and their frequency decreased during tafasitamab monotherapy, with no new safety concerns. This final 5-year analysis of L-MIND demonstrates that the immunotherapy combination of tafasitamab and lenalidomide is well tolerated and has long-term clinical benefit with durable responses.
Topics: Humans; Lenalidomide; Lymphoma, Non-Hodgkin; Lymphoma, Large B-Cell, Diffuse; Antibodies, Monoclonal, Humanized
PubMed: 37646664
DOI: 10.3324/haematol.2023.283480 -
Blood Oct 2023Anti-CD19 immunotherapy tafasitamab is used in combination with lenalidomide in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) who are... (Randomized Controlled Trial)
Randomized Controlled Trial
Anti-CD19 immunotherapy tafasitamab is used in combination with lenalidomide in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) who are ineligible for autologous stem cell transplant. Open-label, phase 1b, First-MIND study assessed safety and preliminary efficacy of tafasitamab + R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) ± lenalidomide as first-line therapy in patients with DLBCL. From December 2019 to August 2020, 83 adults with untreated DLBCL (International Prognostic Index 2-5) were screened and 66 were randomly assigned (33 per arm) to R-CHOP-tafasitamab (arm T) or R-CHOP-tafasitamab-lenalidomide (arm T/L) for 6 cycles. Primary end point was safety; secondary end points included end-of-treatment (EoT) overall response rate (ORR) and complete response (CR) rate. All patients had ≥1 treatment-emergent adverse event, mostly grade 1 or 2. Grade ≥3 neutropenia and thrombocytopenia occurred, respectively, in 57.6% and 12.1% (arm T) and 84.8% and 36.4% (arm T/L) of patients. Nonhematologic toxicities occurred at similar rates among arms. R-CHOP mean relative dose intensity was ≥89% in both arms. EoT ORR was 75.8% (CR 72.7%) in arm T and 81.8% (CR 66.7%) in arm T/L; best ORR across visits was 90.0% and 93.9%. Eighteen-month duration of response and of CR rates were 72.7% and 74.5% (arm T) and 78.7% and 86.5% (arm T/L); 24-month progression-free and overall survival rates were 72.7% and 90.3% (arm T) and 76.8% and 93.8% (arm T/L). Manageable safety and promising signals of efficacy were observed in both arms. Potential benefit of adding tafasitamab + lenalidomide to R-CHOP is being investigated in phase 3 frontMIND (NCT04824092). This study is registered at www.clinicaltrials.gov as #NCT04134936.
Topics: Adult; Humans; Lenalidomide; Antibodies, Monoclonal, Murine-Derived; Rituximab; Lymphoma, Large B-Cell, Diffuse; Vincristine; Cyclophosphamide; Prednisone; Doxorubicin; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37369099
DOI: 10.1182/blood.2023020637 -
Leukemia Jul 2023Patients with newly diagnosed multiple myeloma (NDMM) ineligible for autologous stem cell transplantation (ASCT) have lower survival rates and may benefit from frontline...
Efficacy and safety of isatuximab plus bortezomib, lenalidomide, and dexamethasone in patients with newly diagnosed multiple myeloma ineligible/with no immediate intent for autologous stem cell transplantation.
Patients with newly diagnosed multiple myeloma (NDMM) ineligible for autologous stem cell transplantation (ASCT) have lower survival rates and may benefit from frontline regimens that include novel agents. This Phase 1b study (NCT02513186) evaluated preliminary efficacy, safety, and pharmacokinetics (PK) of isatuximab, an anti-CD38 monoclonal antibody, combined with bortezomib-lenalidomide-dexamethasone (Isa-VRd) in patients with NDMM ineligible for/with no intent for immediate ASCT. Overall, 73 patients received four 6-week induction cycles of Isa-VRd, then maintenance with Isa-Rd in 4-week cycles. In the efficacy population (n = 71), the overall response rate was 98.6%, with 56.3% achieving a complete response or better (sCR/CR), and 36/71 (50.7%) patients reaching minimal residual disease negativity (10 sensitivity). Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 79.5% (58/73) of patients but TEAEs leading to permanent study treatment discontinuation were reported in 14 (19.2%) patients. Isatuximab PK parameters were within the previously reported range, suggesting that VRd does not alter the PK of isatuximab. These data support additional studies of isatuximab in NDMM, such as the Phase 3 IMROZ study (Isa-VRd vs VRd).
Topics: Humans; Multiple Myeloma; Lenalidomide; Bortezomib; Hematopoietic Stem Cell Transplantation; Transplantation, Autologous; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone
PubMed: 37316728
DOI: 10.1038/s41375-023-01936-7