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Cited by 137Protein Degradation and InhibitorsMultiple Myeloma Research and TreatmentsUbiquitin and proteasome pathways

Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide

Open access
Jan, Max, Sperling, Adam S., Ebert, Benjamin L.·2021·Nature Reviews Clinical Oncology
DOI 10.1038/s41571-021-00479-zPMC PMC8903027
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Abstract

For decades, anticancer targeted therapies have been designed to inhibit kinases or other enzyme classes and have profoundly benefited many patients. However, novel approaches are required to target transcription factors, scaffolding proteins and other proteins central to cancer biology that typically lack catalytic activity and have remained mostly recalcitrant to drug development. The selective degradation of target proteins is an attractive approach to expand the druggable proteome, and the selective oestrogen receptor degrader fulvestrant served as an early example of this concept. Following a long and tragic history in the clinic, the immunomodulatory imide drug (IMiD) thalidomide was discovered to exert its therapeutic activity via a novel and unexpected mechanism of action: targeting proteins to an E3 ubiquitin ligase for subsequent proteasomal degradation. This discovery has paralleled and directly catalysed myriad breakthroughs in drug development, leading to the rapid maturation of generalizable chemical platforms for the targeted degradation of previously undruggable proteins. Decades of clinical experience have established front-line roles for thalidomide analogues, including lenalidomide and pomalidomide, in the treatment of haematological malignancies. With a new generation of ‘degrader’ drugs currently in development, this experience provides crucial insights into class-wide features of degraders, including a unique pharmacology, mechanisms of resistance and emerging therapeutic opportunities. Herein, we review these past experiences and discuss their application in the clinical development of novel degrader therapies. The discovery that the anticancer activity of thalidomide and its analogues, such as lenalidomide, reflects drug-induced degradation of specific target proteins has heightened interest in novel ‘degrader’ drugs. Herein, the authors review the wide and expanding use of thalidomide analogues in the treatment of multiple cancers and outline how lessons learned from this experience, particularly with lenalidomide, can guide the clinical development of new targeted protein degradation platforms. Thalidomide analogues including lenalidomide and pomalidomide are anticancer agents used in the treatment of multiple haematological malignancies; induction of targeted protein degradation of disease-relevant proteins is the dominant mechanism of action of these agents. ‘Degrader’ therapeutics have a catalytic, event-driven pharmacology, and their biological effects are a summation of the polypharmacology of multiple degraded neosubstrate proteins. Cancers acquire resistance to thalidomide analogues by circumventing target protein degradation or by rewiring pathways downstream of target protein degradation. Quantitative clinical proteomic assays can be used for pharmacodynamic monitoring of degrader therapeutics. Molecular switches gated by degrader therapeutics can be used to control genetically engineered adoptive cell products that are being developed for anticancer immunotherapy. Multiple classes of degrader therapeutics are expanding the druggable proteome to include previously undruggable, noncatalytic, cancer-relevant proteins, such as transcription factors, mRNA-splicing factors and cyclins. Thalidomide analogues including lenalidomide and pomalidomide are anticancer agents used in the treatment of multiple haematological malignancies; induction of targeted protein degradation of disease-relevant proteins is the dominant mechanism of action of these agents. ‘Degrader’ therapeutics have a catalytic, event-driven pharmacology, and their biological effects are a summation of the polypharmacology of multiple degraded neosubstrate proteins. Cancers acquire resistance to thalidomide analogues by circumventing target protein degradation or by rewiring pathways downstream of target protein degradation. Quantitative clinical proteomic assays can be used for pharmacodynamic monitoring of degrader therapeutics. Molecular switches gated by degrader therapeutics can be used to control genetically engineered adoptive cell products that are being developed for anticancer immunotherapy. Multiple classes of degrader therapeutics are expanding the druggable proteome to include previously undruggable, noncatalytic, cancer-relevant proteins, such as transcription factors, mRNA-splicing factors and cyclins.

AI snapshot

Written from the paper’s full text.

TL;DR

This review uses lenalidomide and other thalidomide analogues as a clinical template for targeted protein degradation, covering molecular glue mechanisms, approved oncology uses, resistance, toxicities, and next-generation degraders. It argues that decades of IMiD experience provide key lessons for developing new degraders against previously undruggable proteins.

Key findings

  • Thalidomide analogues act as molecular glues that recruit neosubstrates to CRL4^CRBN for ubiquitination and proteasomal degradation; lenalidomide degrades IKZF1/IKZF3 in multiple myeloma and CK1α in del(5q) MDS.
  • Clinical activity is broad: lenalidomide plus dexamethasone produced ORRs up to 90% in newly diagnosed MM and superior 4-year OS versus melphalan–thalidomide–prednisone (59% versus 51%; HR 0.78, p=0.02); in relapsed/refractory MCL, lenalidomide improved median PFS versus investigator’s choice (8.7 versus 5.2 months; HR 0.61; p=0.004); in del(5q) MDS, ORRs were 76–83% with cytogenetic CR in 45–50%.
  • Resistance can arise through CRBN pathway alterations, including CRBN mutations in up to a third of pomalidomide-refractory disease, substrate competition, and downstream escape such as TP53 mutations in del(5q) MDS.
  • Toxicities include grade 3/4 neutropenia (28%) and thrombocytopenia (8%), second primary malignancies with lenalidomide maintenance (5.3% versus 0.8% with placebo/observation), and venous thromboembolism (OR 3.51; p<0.001); next-generation agents include avadomide, iberdomide, CC-92480, and CC-90009.

Methods

  • Narrative review of thalidomide analogues and targeted protein degradation, synthesizing mechanistic, preclinical, and clinical literature rather than reporting a new primary study.
  • Data sources are published clinical trials and mechanistic studies across MM, NHL, MDS, AML, KS, and related malignancies; no new patient cohort or systematic search strategy is described.
  • Main analysis is a conceptual and clinical synthesis of degrader pharmacology, resistance mechanisms, toxicities, and emerging therapeutic platforms, including PROTACs and molecular glue degraders.

Limitations

  • The paper does not explicitly state limitations of the review itself.
  • Evident from the text: it is a narrative review without a described systematic search strategy or formal evidence-quality appraisal, so selection and interpretation of cited literature may be subject to bias.
  • The authors also note field limitations: clinical pharmacodynamic monitoring has been limited by semi-quantitative protein detection and limited deployment of such assays, and quantitative proteomic datasets from clinical specimens are currently lacking.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/s41571-021-00479-z

Cites

240 of 240 references verified0 citation errors · 0 not checkable

Statistics

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Claims the paper makes

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  • Premisecitation

    Maintenance lenalidomide following induction therapy with or without autologous haematopoietic stem cell transplantation is a standard of care for patients with MM.

    “Maintenance lenalidomide following induction therapy with or without autologous haematopoietic stem cell transplantation (auto-HSCT) is also a standard of care for patients with MM30,31.”
    Quote in the paperSubstantial claim0 of 2 sources checked
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    • cites [31] Richardson, P. G. et al. Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma. Blood 100, 3063–3067 (2002). source

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  • Premisecitation

    In del(5q) MDS cells, lenalidomide mediates CRBN-dependent ubiquitination and degradation of casein kinase I isoform alpha (CK1α).

    “in del(5q) MDS cells, lenalidomide mediates the CRBN-dependent ubiquitination and degradation of casein kinase I isoform α (CK1α)15.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [15] Krönke, J. et al. Lenalidomide induces ubiquitination and degradation of CK1α in del(5q) MDS. Nature 523, 183–188 (2015). source

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  • Premisecitation

    All pharmacologically active derivatives of thalidomide contain a glutarimide ring that directly binds within a conserved pocket on the surface of CRBN.

    “All pharmacologically active derivatives of thalidomide contain a glutarimide ring that directly binds within a conserved pocket on the surface of CRBN17”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [17] Fischer, E. S. et al. Structure of the DDB1–CRBN E3 ubiquitin ligase in complex with thalidomide. Nature 512, 49–53 (2014). source

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  • Premisecitation

    In 2002, a phase I trial of lenalidomide monotherapy revealed promising signs of efficacy in patients with relapsed and/or refractory MM, about 50% of whom had previously received thalidomide.

    “In 2002, a phase I trial of lenalidomide monotherapy revealed promising signs of efficacy in patients with relapsed and/or refractory (R/R) MM, about 50% of whom had previously received thalidomide23.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [23] Choueiri, T. K. et al. Phase II study of lenalidomide in patients with metastatic renal cell carcinoma. Cancer 107, 2609–2616 (2006). source

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  • Premisecitation

    CRBN serves as a substrate receptor component of the cullin-RING E3 ubiquitin ligase complex 4 (CRL4) comprising cullin-4, DNA damage-binding protein 1 and E3 ubiquitin-protein ligase RBX1.

    “which serves as a substrate receptor component of the cullin-RING E3 ubiquitin ligase complex 4 (CRL4) comprising cullin-4 (CUL4), DNA damage-binding protein 1 (DDB1) and E3 ubiquitin-protein ligase RBX1”
    Quote in the paperSubstantial claim
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  • The quote only partly states this claim. 1

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    Premisecitation

    Thalidomide was introduced to the clinic in the late 1950s as a sedative and antiemetic and was marketed as a treatment for morning sickness in pregnant women.

    “Thalidomide was introduced to the clinic in the late 1950s as a sedative and antiemetic and was marketed as a treatment for morning sickness in pregnant women1.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] Stephens, T. & Brynner, R. Dark Remedy: The Impact of Thalidomide and its Revival as a Vital Medicine (Perseus Publishing, 2009).

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Thalidomide remained on the market for decades as a treatment for erythema nodosum leprosum, an immune-mediated complication of leprosy.

    “thalidomide remained on the market for decades as a treatment for erythema nodosum leprosum (an immune-mediated complication of leprosy)5,6.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [5] Kaur, I., Dogra, S., Narang, T. & De, D. Comparative efficacy of thalidomide and prednisolone in the treatment of moderate to severe erythema nodosum leprosum: a randomized study. Australas. J. Dermatol. 50, 181–185 (2009). source

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    • cites [6] Pearson, J. M. H. & Vedagiri, M. Treatment of moderately severe erythema nodosum leprosum with thalidomide - a double-blind controlled trial. Lepr. Rev. 40, 111–116 (1969).

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In utero exposure to thalidomide caused an embryopathy characterized by foreshortened limb anomalies, known as phocomelia, in thousands of children worldwide.

    “in utero exposure to thalidomide caused an embryopathy characterized by foreshortened limb anomalies, known as phocomelia, in thousands of children worldwide2,3.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [2] Lenz, W., Pfeiffer, R. A., Kosenow, W. & Hayman, D. J. Thalidomide and congenital abnormalities. Lancet 279, 45–46 (1962). source

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    • cites [3] Mcbride, W. G. Thalidomide and congenital abnormalities. Lancet 278, 1358 (1961). source

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    Premisecitation

    Thalidomide and its analogues do not inhibit the enzymatic activity of CRL4CRBN, but instead confer neomorphic activity on CRBN to mediate selective ubiquitination and proteasomal degradation of IKZF1 and IKZF3 in MM cells and T cells.

    “thalidomide and its analogues do not inhibit the enzymatic activity of CRL4CRBN, but instead confer neomorphic activity on CRBN to mediate the selective ubiquitination and resultant proteasomal degradation of the transcription factors Ikaros family zinc finger protein 1 (IKZF1) and IKZF3 (Aiolos) in MM cells and T cells11–13.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [11] Krönke, J. et al. Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science 343, 301–305 (2013). source

      Not checked in the free run.

    • cites [12] Lu, G. et al. The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins. Science 343, 305–309 (2013). source

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    • cites [13] Gandhi, A. K. et al. Immunomodulatory agents lenalidomide and pomalidomide co-stimulate T cells by inducing degradation of T cell repressors Ikaros and Aiolos via modulation of the E3 ubiquitin ligase complex CRL4 CRBN. Br. J. Haematol. 164, 811–821 (2013). source

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    Premisecitation

    For older patients and/or those unfit for autologous transplantation, the preferred induction approach remains lenalidomide in combination with dexamethasone with or without daratumumab, regimens that are effective and well tolerated in this patient population.

    “For older patients and/or those unfit for autologous transplantation, the preferred induction approach remains lenalidomide in combination with dexamethasone with or without daratumumab, regimens that are effective and well tolerated in this patient population27,29.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [27] Dimopoulos, M. et al. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N. Engl. J. Med. 357, 2123–2132 (2007). source

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    • cites [29] List, A. et al. Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N. Engl. J. Med. 355, 1456–1465 (2006). source

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    Premisecitation

    Thalidomide maintenance increased complete remission rates (62% versus 43%; P<0.001) and event-free survival (56% versus 44% at 5 years; P=0.01), but produced no overall survival benefit (5-year OS about 65% in both groups; P=0.90).

    “Such maintenance therapy was first attempted with thalidomide, resulting in an increase in complete remission (CR) rates (62% versus 43% without maintenance; P <0.001) and an event-free survival (EFS) benefit (56% versus 44% at 5 years; P = 0.01), but no overall survival (OS) benefit (5-year OS ~65% in both groups; P = 0.90)32.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [32] Rajkumar, S. V. et al. Combination therapy with lenalidomide plus dexamethasone (Rev/Dex) for newly diagnosed myeloma. Blood 106, 4050–4053 (2005). source

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    Premisecitation

    Lenalidomide doses of up to 50 mg daily were tested and no dose-limiting toxicities were observed, although all patients treated at this dose developed severe myelosuppression after 1-2 cycles and thus 25 mg daily was suggested as the maximum tolerated dose.

    “Lenalidomide doses of up to 50 mg daily were tested and no dose-limiting toxicities were observed, although all patients treated at this dose developed severe myelosuppression after 1–2 cycles and thus 25 mg daily was suggested as the maximum tolerated dose23”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [23] Choueiri, T. K. et al. Phase II study of lenalidomide in patients with metastatic renal cell carcinoma. Cancer 107, 2609–2616 (2006). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Responses to lenalidomide were seen even in patients who had disease progression on prior thalidomide therapy, and the combination of lenalidomide and dexamethasone in patients with one or more prior lines of therapy was FDA approved in 2006.

    “Again, responses were seen even in patients who had disease progression on prior thalidomide therapy and the combination of lenalidomide and dexamethasone in patients with one or more prior lines of therapy was FDA approved in 200624,25.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [24] Eisen, T. et al. Results of a multicenter, randomized, double-blind phase 2/3 study of lenalidomide in the treatment of pretreated relapsed or refractory metastatic malignant melanoma. Cancer 116, 146–154 (2009). source

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      Not checked in the free run.

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    Premisecitation

    A phase II study established 30 mg daily as a safe and active dose of lenalidomide in patients with R/R MM, with a single-agent objective response rate of 25%; a further 29% of patients responded following the addition of dexamethasone.

    “Data from a subsequent phase II study established 30 mg daily as a safe and active dose of lenalidomide in patients with R/R MM, with a single-agent objective response rate (ORR) of 25%; a further 29% of patients responded following the addition of dexamethasone19”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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    Premisecitation

    Patients with high-risk cytogenetic features might be the only exception to the OS benefit of lenalidomide maintenance, although they do derive a progression-free survival benefit.

    “Patients with high-risk cytogenetic features might be the only exception, although they do derive a progression-free survival (PFS) benefit34,35.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [34] Benboubker, L. et al. Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma. N. Engl. J. Med. 371, 906–917 (2014). source

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    • cites [35] Richardson, P. G. et al. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood 116, 679–686 (2010). source

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    Premisecitation

    Lenalidomide and pomalidomide are more potent degraders of IKZF1 and IKZF3 than thalidomide, and all of these agents have distinct patterns of neosubstrate degradation.

    “lenalidomide and pomalidomide are more potent degraders of IKZF1 and IKZF3, and all of these agents have distinct patterns of neosubstrate degradation18.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18] Bartlett, J. B., Dredge, K. & Dalgleish, A. G. The evolution of thalidomide and its IMiD derivatives as anticancer agents. Nat. Rev. Cancer 4, 314–322 (2004). source

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    Premisecitation

    A randomized study comparing lenalidomide and dexamethasone to melphalan, thalidomide and prednisone in newly diagnosed MM demonstrated superior 4-year OS (59% versus 51%; HR 0.78, p=0.02) and led to FDA approval in 2015.

    “A randomized study comparing lenalidomide and dexamethasone to melphalan, thalidomide and prednisone in newly diagnosed patients demonstrated superior 4-year OS (59% versus 51%; HR 0.78, p=0.02) and led to FDA approval in 201527.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [27] Dimopoulos, M. et al. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N. Engl. J. Med. 357, 2123–2132 (2007). source

      Not checked in the free run.

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    Premisecitation

    Elotuzumab has no anti-myeloma activity as monotherapy, but the addition of elotuzumab to lenalidomide or pomalidomide and dexamethasone improved ORRs, PFS and OS in patients with R/R MM.

    “The anti-SLAMF7 antibody elotuzumab has no anti-myeloma activity as monotherapy65, but the addition of this agent to lenalidomide or pomalidomide and dexamethasone improved ORRs, PFS and OS in patients with R/R MM47,66,67.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
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    • cites [47] Moreau, P. et al. Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma. N. Engl. J. Med. 374, 1621–1634 (2016). source

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    Interpretationreasoning

    Lenalidomide enhances T cell and NK cell functions, probably via degradation of IKZF3, raising the possibility of mechanistic synergy between lenalidomide and elotuzumab.

    “Lenalidomide also enhances T cell and NK cell functions, probably via degradation of IKZF3, raising the possibility of mechanistic synergy between these two agents.”
    Quote in the paperSubstantial claim

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    Premisecitation

    In patients with treatment-naive mantle cell lymphoma, the R2 regimen produced an ORR of 92%, a CR rate of 64%, and 2-year PFS and OS of 85% and 97%, respectively.

    “In patients with treatment-naive MCL, the R2 regimen has produced an ORR of 92%, a CR rate of 64%, and 2-year PFS and OS of 85% and 97%, respectively77.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [77] Andorsky, D. J. et al. MAGNIFY: phase IIIb interim analysis of induction R2 followed by maintenance in relapsed/refractory indolent non-Hodgkin lymphoma [abstract]. J. Clin.Oncol. 37, 7513 (2019). source

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    Interpretationcitation

    Targeted protein degraders have the pharmacological advantage of extended target suppression until protein re-synthesis, which might negate the effects of transient disruption of protein degradation and contribute to the efficacy of the counterintuitive combination of targeted protein degraders and proteasome inhibitors.

    “Notably, targeted protein degraders have the pharmacological advantage of extended target suppression until protein re-synthesis (FIG. 2)58 which might negate the effects of transient disruption of protein degradation and contribute to the efficacy of the counterintuitive combination of targeted protein degraders and proteasome inhibitors.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [58] Das, D. S. et al. Synergistic anti-myeloma activity of the proteasome inhibitor marizomib and the IMiD ® immunomodulatory drug pomalidomide. Br. J. Haematol. 171, 798–812 (2015). source

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    Interpretationreasoning

    Whether combinations of thalidomide analogues with other agents have additive or synergistic clinical activity remains unclear.

    “however, whether such combinations have additive or synergistic clinical activity remains unclear.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Response rates to single-agent lenalidomide have consistently been surpassed by doublet or triplet combinations, which has been taken as evidence for synergistic activity of lenalidomide with other anti-myeloma agents.

    “Response rates to single-agent lenalidomide have consistently been surpassed by those achieved with doublet or triplet combinations, which has been taken as evidence for synergistic activity of this agent with other anti-myeloma agents48.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [48] Dimopoulos, M. A. et al. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N. Engl. J. Med. 375, 1319–1331 (2016). source

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    Premisecitation

    The pharmacokinetic characteristics of lenalidomide plus bortezomib or carfilzomib emphasize independent actions, in keeping with the hypothesis that independent drug effects against differentially sensitive cell populations explain the efficacy of most combination cancer therapies.

    “Indeed, the pharmacokinetic characteristics of these drug combinations emphasize independent actions, in keeping with the hypothesis that independent drug effects against differentially sensitive cell populations explain the efficacy of most combination cancer therapies56.”
    Quote in the paperSubstantial claim0 of 1 sources checked
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    Premisecitation

    These immunomodulatory effects include alterations of immune synapse formation, mimicry of interferon signaling in large B cell lymphoma cells, enhanced T cell co-stimulation, cytokine release and function, and inhibition of TNF secretion by stimulated human monocytes.

    “These effects include alterations of immune synapse formation59, mimicry of interferon signaling in large B cell lymphoma cells60, enhanced T cell co-stimulation61, cytokine release and function, as well as inhibition of TNF secretion by stimulated human monocytes62.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
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    • cites [60] Ocio, E. M. et al. In vitro and in vivo rationale for the triple combination of panobinostat (LBH589) and dexamethasone with either bortezomib or lenalidomide in multiple myeloma. Haematologica 95, 794–803 (2009). source

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    Premisecitation

    The R2 regimen was approved by FDA in 2019 for the treatment of R/R marginal zone lymphoma or follicular lymphoma based on high ORRs (65% in MZL and up to 80% in FL versus 55% and 44%, respectively, with placebo plus rituximab) and a substantial improvement in PFS (39.4 months versus 14.1 months; HR 0.46; 95% CI 0.34-0.62; P<0.0001).

    “which was approved by FDA in 2019 for the treatment of R/R marginal zone lymphoma (MZL) or follicular lymphoma (FL)75,76 based on high ORRs (65% in MZL and up to 80% in FL versus 55% and 44%, respectively with placebo plus rituximab) and a substantial improvement in PFS (39.4 months versus 14.1 months; HR 0.46; 95% CI 0.34–0.62; P <0.0001).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [75] Trněný, M. et al. Lenalidomide versus investigator’s choice in relapsed or refractory mantle cell lymphoma (MCL-002; SPRINT): a phase 2, randomised, multicentre trial. Lancet Oncol. 17, 319–331 (2016). source

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    • cites [76] Leonard, J. P. et al. Randomized trial of lenalidomide alone versus lenalidomide plus rituximab in patients with recurrent follicular lymphoma: CALGB 50401 (Alliance). J. Clin. Oncol. 33, 3635–3640 (2015). source

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    Premisecitation

    Elotuzumab has been proposed to function at least partially through upregulation of IL-2 production by T cells and stimulation of natural killer cell-mediated antibody-dependent cellular cytotoxicity.

    “Elotuzumab has been proposed to function at least partially through upregulation of IL-2 production by T cells and stimulation of natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC)68–70.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [68] Lonial, S. et al. Elotuzumab therapy for relapsed or refractory multiple myeloma. N. Engl. J. Med. 373, 621–631 (2015). source

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    • cites [69] Balasa, B. et al. Elotuzumab enhances natural killer cell activation and myeloma cell killing through interleukin-2 and TNF-α pathways. Cancer Immunol. Immunother. 64, 61–73 (2014). source

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    Premisecitation

    Lenalidomide is dosed daily, whereas bortezomib and carfilzomib are administered once or twice a week and are rapidly metabolized, resulting in a background of prolonged selective lenalidomide-induced protein degradation punctuated by short periods of proteasome inhibition.

    “Specifically, whereas lenalidomide is dosed daily, bortezomib and carfilzomib are administered once or twice a week and are rapidly metabolized57, resulting in a background of prolonged selective, lenalidomide-induced protein degradation punctuated by short periods of proteasome inhibition.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [57] Rychak, E. et al. Pomalidomide in combination with dexamethasone results in synergistic anti-tumour responses in pre-clinical models of lenalidomide-resistant multiple myeloma. Br. J. Haematol. 172, 889–901 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Frontline treatment with the R2 regimen in follicular lymphoma produced CR and 3-year PFS rates similar to those achieved with rituximab plus chemotherapy (48% versus 53% and 77% versus 78%, respectively) but with a lower incidence of grade 3-4 neutropenia (32% versus 50%).

    “Frontline treatment with this chemotherapy-free regimen has also produced promising results in patients with FL, with CR and 3-year PFS rates similar to those achieved with rituximab plus chemotherapy (48% versus 53% and 77% versus 78%, respectively) but with a lower incidence of grade 3–4 neutropenia (32% versus 50%)75.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [75] Trněný, M. et al. Lenalidomide versus investigator’s choice in relapsed or refractory mantle cell lymphoma (MCL-002; SPRINT): a phase 2, randomised, multicentre trial. Lancet Oncol. 17, 319–331 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Early phase clinical trials and in vitro models indicate that lenalidomide might be active in patients with activated B cell-like DLBCL; however, a phase III study showed no benefit of adding lenalidomide to R-CHOP in newly diagnosed patients with this disease subtype.

    “Data from early phase clinical trials and in vitro models indicate that this agent might be active in patients with activated B cell-like DLBCL81,82; however, a phase III study showed no benefit of adding lenalidomide to chemoimmunotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) in newly diagnosed patients with this disease subtype83.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [81] Chanan-Khan, A. A. et al. Lenalidomide maintenance therapy in previously treated chronic lymphocytic leukaemia (CONTINUUM): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Haematol. 4, e534–e543 (2017). source

      Not checked in the free run.

    • cites [82] Morschhauser, F. et al. Obinutuzumab combined with lenalidomide for relapsed or refractory follicular B-cell lymphoma (GALEN): a multicentre, single-arm, phase 2 study. Lancet Haematol. 6, e429–e437 (2019). source

      Not checked in the free run.

    • cites [83] Yang, Y. et al. Exploiting synthetic lethality for the therapy of ABC diffuse large B cell lymphoma. Cancer Cell 21, 723–737 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Patients who have disease progression while not on treatment with lenalidomide can often be re-treated effectively with this agent, sometimes multiple times, and typically in combination with proteasome inhibitors such as carfilzomib and ixazomib or with daratumumab.

    “Patients who have disease progression while not on treatment with lenalidomide can often be re-treated effectively with this agent37,38, sometimes multiple times, and typically in combination with proteasome inhibitors such as carfilzomib39 and ixazomib40 or with daratumumab41.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [37] McCarthy, P. L. et al. Lenalidomide after stem-cell transplantation for multiple myeloma. New Engl. J. Med. 366, 1770–1781 (2012). source

      Not checked in the free run.

    • cites [38] Attal, M. et al. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N. Engl. J. Med. 366, 1782–1791 (2012). source

      Not checked in the free run.

    • cites [39] Barlogie, B. et al. Thalidomide and hematopoietic-cell transplantation for multiple myeloma. N. Engl. J. Med. 354, 1021–1030 (2006). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The combination of daratumumab with either lenalidomide or bortezomib results in similar ORRs, suggesting that potential mechanistic synergy does not translate into substantial clinical advantages.

    “however, the combination of daratumumab with either lenalidomide or bortezomib results in similar ORRs41,72, suggesting that potential mechanistic synergy does not translate into substantial clinical advantages.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [41] McCarthy, P. L. et al. Lenalidomide maintenance after autologous stem-cell transplantation in newly diagnosed multiple myeloma: a meta-analysis. J. Clin. Oncol. 35, 3279–3289 (2017). source

      Not checked in the free run.

    • cites [72] Veer, M. S. van der et al. Towards effective immunotherapy of myeloma: enhanced elimination of myeloma cells by combination of lenalidomide with the human CD38 monoclonal antibody daratumumab. Haematologica 96, 284–290 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A constellation of immunomodulatory effects resulting from IKZF1 and IKZF3 degradation have been attributed to thalidomide analogues and are proposed to contribute to the activity of these agents.

    “A constellation of immunomodulatory effects resulting from IKZF1 and IKZF3 degradation have been attributed to thalidomide analogues18 and are proposed to contribute to the activity of these agents.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18] Bartlett, J. B., Dredge, K. & Dalgleish, A. G. The evolution of thalidomide and its IMiD derivatives as anticancer agents. Nat. Rev. Cancer 4, 314–322 (2004). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In relapsed mantle cell lymphoma, single-agent lenalidomide produced a significant increase in median PFS (8.7 versus 5.2 months; HR 0.61; p=0.004) compared with provider's choice chemotherapy in patients with relapsed or refractory disease, leading to its FDA approval in 2013.

    “In relapsed mantle cell lymphoma single agent lenalidomide produced a significant increase in median PFS (8.7 versus 5.2 months; HR 0.61; p=0.004) compared to provider’s choice chemotherapy in patients with relapsed or refractory disease, leading to its FDA approval in 201373,74.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [73] Palumbo, A. et al. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N. Engl. J. Med. 375, 754–766 (2016). source

      Not checked in the free run.

    • cites [74] Goy, A. et al. Single-agent lenalidomide in patients with mantle-cell lymphoma who relapsed or progressed after or were refractory to bortezomib: phase II MCL-001 (EMERGE) study. J. Clin. Oncol. 31, 3688–3695 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IKZF1 is expressed throughout haematopoiesis and regulates myeloid cell development and function.

    “Of note, IKZF1 is expressed throughout haematopoiesis and regulates myeloid cell development and function100.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [100] Jädersten, M. et al. TP53 mutations in low-risk myelodysplastic syndromes with del(5q) predict disease progression. J. Clin. Oncol. 29, 1971–1979 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In patients with R/R AML, the combination of high-dose lenalidomide (50 mg daily) with mitoxantrone, etoposide and cytarabine resulted in a CR or CR with incomplete haematological recovery rate of 41%, which is considerably higher than expected with MEC alone (17-28%) based on data from historical cohorts.

    “In patients with R/R AML, the combination of high-dose lenalidomide (50 mg daily) with mitoxantrone, etoposide and cytarabine (MEC) resulted in a CR or CR with incomplete haematological recovery (CR/CRi) rate of 41%104, which is considerably higher than expected with MEC alone (17–28%) based on data from historical cohorts105,106.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [104] Fehniger, T. A. et al. A phase 2 study of high-dose lenalidomide as initial therapy for older patients with acute myeloid leukemia. Blood 117, 1828–1833 (2010). source

      Not checked in the free run.

    • cites [105] Blum, W. et al. Dose escalation of lenalidomide in relapsed or refractory acute leukemias. J. Clin. Oncol. 28, 4919–4925 (2010). source

      Not checked in the free run.

    • cites [106] DeAngelo, D. J. et al. A phase I study of lenalidomide plus chemotherapy with mitoxantrone, etoposide, and cytarabine for the reinduction of patients with acute myeloid leukemia. Am. J. Hematol. 93, 254–261 (2017). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Del(5q) is the most common cytogenetic abnormality in MDS; patients with this genetic aberration often present with a consistent clinical phenotype, termed the 5q− syndrome, which is more common in women than in men and has a relatively indolent course characterized by hypoplastic anaemia.

    “Del(5q) is the most common cytogenetic abnormality in MDS; patients with this genetic aberration often present with a consistent clinical phenotype, termed the ‘5q− syndrome’, which is more common in women than in men and has a relatively indolent course characterized by hypoplastic anaemia95.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [95] Querfeld, C. et al. Results of an open-label multicenter phase 2 trial of lenalidomide monotherapy in refractory mycosis fungoides and Sézary syndrome. Blood 123, 1159–1166 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In 2020, pomalidomide was approved by the FDA for the treatment of Kaposi sarcoma, an endothelial cell-derived solid tumour caused by human herpesvirus 8 infection, based on data from a phase I/II trial that demonstrated an ORR of 73% in patients with newly diagnosed Kaposi sarcoma.

    “In 2020, pomalidomide was approved by the FDA for the treatment of KS, an endothelial cell-derived solid tumour caused by human herpesvirus 8 (HHV8) infection110, based on data from a phase I/II trial that demonstrated an ORR of 73% in patients with newly diagnosed KS22.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [110] Craddock, C. et al. combination lenalidomide and azacitidine: a novel salvage therapy in patients who relapse after allogeneic stem-cell transplantation for acute myeloid leukemia. J. Clin. Oncol. 37, 580–588 (2019). source

      Not checked in the free run.

    • cites [22] Muller, G. W. et al. Structural modifications of thalidomide produce analogs with enhanced tumor necrosis factor inhibitory activity. J. Med. Chem. 39, 3238–3240 (1996). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Iberdomide has a distinct chemical structure compared with other thalidomide analogues and might have a broader target specificity.

    “Iberdomide has a distinct chemical structure compared with other thalidomide analogues (FIG. 1c) and might have a broader target specificity117.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [117] Matyskiela, M. E. et al. A cereblon modulator (CC-220) with improved degradation of ikaros and aiolos. J. Med. Chem. 61, 535–542 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Lenalidomide maintenance might have a role in patients with R/R DLBCL who are not fit for potentially curative treatments, and more potent next-generation thalidomide analogues such as avadomide might have greater activity in this disease.

    “Lenalidomide maintenance might have a role in patients with R/R DLBCL who are not fit for potentially curative treatments84, such as auto-HSCT or chimeric antigen receptor (CAR) T cell therapies, and more potent, next-generation thalidomide analogues (such as avadomide) might have greater activity in this disease85.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [84] Nowakowski, G. S. et al. Lenalidomide combined with R-CHOP overcomes negative prognostic impact of non-germinal center B-cell phenotype in newly diagnosed diffuse large B-cell lymphoma: a phase II study. J. Clin. Oncol. 33, 251–257 (2015). source

      Not checked in the free run.

    • cites [85] Vitolo, U. et al. ROBUST: first report of phase III randomized study of lenalidomide/R-CHOP (R 2 -CHOP) vs placebo/R-CHOP in previously untreated ABC-type diffuse large B-cell lymphoma. Hematol. Oncol. 37, 36–37 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Lenalidomide was first approved by the FDA in 2005 for the treatment of transfusion-dependent anaemia resulting from MDS with del(5q), an indication in which it is associated with ORRs of 76-83%, with 45-50% of patients also having a cytogenetic CR.

    “Lenalidomide was first approved by the FDA in 2005 for the treatment of transfusion-dependent anaemia resulting from MDS with del(5q), an indication in which it is associated with ORRs of 76–83%, with 45–50% of patients also having a cytogenetic CR21,94.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [21] Luptakova, K. et al. Lenalidomide enhances anti-myeloma cellular immunity. Cancer Immunol. Immunother. 62, 39–49 (2013). source

      Not checked in the free run.

    • cites [94] Toumishey, E. et al. Final report of a phase 2 clinical trial of lenalidomide monotherapy for patients with T-cell lymphoma: lenalidomide therapy for T-cell lymphoma. Cancer 121, 716–723 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Avadomide has been tested in patients with a variety of solid tumours; although no objective responses were seen in an initial report, five of six patients with brain tumours had stable disease for at least 6 months.

    “This agent has also been tested in patients with a variety of solid tumours; although no objective responses were seen in an initial report114, five of six patients with brain tumours had stable disease for at least 6 months.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [114] Zhang, L. et al. Phase 2 study using oral thalidomide-cyclophosphamide-prednisone for idiopathic multicentric Castleman disease. Blood 133, 1720–1728 (2019). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationnone given

    The mechanistic basis underlying the efficacy of pomalidomide in Kaposi sarcoma is not well characterized.

    “The mechanistic basis underlying the efficacy of pomalidomide in this disease is not well characterized.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Iberdomide has an increased binding affinity for CRBN and greater potency than pomalidomide in multiple myeloma cell lines, with activity observed against some pomalidomide-resistant cell lines.

    “Iberdomide (CC-220) is a thalidomide derivative with an increased binding affinity for CRBN and greater potency than pomalidomide in multiple myeloma cell lines, with activity observed against some pomalidomide-resistant cell lines115,116.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [115] Sperling, A. S. et al. Patterns of substrate affinity, competition, and degradation kinetics underlie biological activity of thalidomide analogs. Blood 134, 160–170 (2019). source

      Not checked in the free run.

    • cites [116] Rasco, D. W. et al. A first-in-human study of novel cereblon modulator avadomide (CC-122) in advanced malignancies. Clin. Cancer Res. 25, 90–98 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Lenalidomide has activity in patients with myelofibrosis, with responses occurring in up to a third of patients when used in combination with prednisone, some of which have lasted as long as 9 years.

    “Lenalidomide also has activity in patients with myelofibrosis, with responses occurring in up to a third of patients when used in combination with prednisone, some of which have lasted as long as 9 years109.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [109] Narayan, R. et al. Sequential azacitidine plus lenalidomide in previously treated elderly patients with acute myeloid leukemia and higher risk myelodysplastic syndrome. Leukemia Lymphoma 57, 609–615 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Lenalidomide provides limited benefit when combined with azacytidine in patients with newly diagnosed AML; however, results are more encouraging when this combination is used following disease relapse after allogeneic HSCT, with almost 50% of patients having a major clinical response, possibly owing to stimulation of graft versus leukaemia immune responses.

    “Lenalidomide provides limited benefit when combined with azacytidine in patients with newly diagnosed AML107; however, the results are more encouraging when this combination is used following disease relapse after allogeneic HSCT, with almost 50% of patients having a major clinical response, possibly owing to stimulation of graft versus leukaemia immune responses108.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [107] Greenberg, P. L. et al. Mitoxantrone, etoposide, and cytarabine with or without valspodar in patients with relapsed or refractory acute myeloid leukemia and high-risk myelodysplastic syndrome: a phase III trial (E2995). J. Clin. Oncol. 22, 1078–1086 (2004). source

      Not checked in the free run.

    • cites [108] Feldman, E. J. et al. Phase III randomized multicenter study of a humanized anti-CD33 monoclonal antibody, lintuzumab, in combination with chemotherapy, versus chemotherapy alone in patients with refractory or first-relapsed acute myeloid leukemia. J. Clin. Oncol. 23, 4110–4116 (2005). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CC-90009 targets GSPT1 and GSPT2, which are essential regulators of translation termination.

    “CC-90009 differs from the other thalidomide analogues in that it targets the substrates G1 to S phase transition protein 1 homologue (GSPT1) and GSPT2, which are also known as eukaryotic peptide chain release factor GTP-binding subunits ERF3A and ERF3B, respectively, reflecting their roles as essential regulators of translation termination113,121.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [113] Shimada, K., Hayakawa, F. & Kiyoi, H. Biology and management of primary effusion lymphoma. Blood 132, 1879–1888 (2018). source

      Not checked in the free run.

    • cites [121] Schafer, P. H. et al. Cereblon modulator iberdomide induces degradation of the transcription factors Ikaros and Aiolos: immunomodulation in healthy volunteers and relevance to systemic lupus erythematosus. Ann. Rheum. Dis. 77, 1516–1523 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Avadomide is chemically similar to pomalidomide and accordingly has similar substrate specificity and potency of degradation.

    “Avadomide (previously known as CC-122) is chemically similar to pomalidomide (FIG. 1c), and accordingly, has similar substrate specificity and potency of degradation113.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [113] Shimada, K., Hayakawa, F. & Kiyoi, H. Biology and management of primary effusion lymphoma. Blood 132, 1879–1888 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Classical inhibitors, covalent or non-covalent, must stoichiometrically occupy the binding site on the target enzyme, and therefore sustained target inhibition requires maintenance of an effective drug concentration.

    “Classical inhibitors – covalent or non-covalent - must stoichiometrically occupy the binding site on the target enzyme, and therefore, sustained target inhibition requires maintenance of an effective drug concentration (FIG. 2a).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Most patients can be rechallenged with lenalidomide without recurrence of rash; in rare cases in which rashes recur, management with desensitization strategies involving gradual titration from low starting doses has been effective.

    “Most patients can be rechallenged with lenalidomide without recurrence of rash; in rare cases in which rashes recur, management with desensitization strategies involving gradual titration from low starting doses has been effective136.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [136] Nardone, B. et al. Risk of rash associated with lenalidomide in cancer patients: a systematic review of the literature and meta-analysis. Clin. Lymphoma Myeloma Leuk. 13, 424–429 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Solid tumours associated with lenalidomide use are most commonly non-melanoma skin cancers, which can usually be managed conservatively.

    “Solid tumours associated with lenalidomide use are most commonly non-melanoma skin cancers, which can usually be managed conservatively127.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [127] Micallef, I. N. M. et al. Plerixafor (Mozobil) for stem cell mobilization in patients with multiple myeloma previously treated with lenalidomide. Bone Marrow Transpl. 46, 350–355 (2011). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    Both IKZF1 and CK1α have important roles in haematopoietic stem and progenitor cell function and differentiation, although the precise effects of thalidomide analogues on haematopoiesis have not been well studied.

    “Both IKZF1 and CK1α have important roles in haematopoietic stem and progenitor cell (HSPC) function and differentiation, although the precise effects of thalidomide analogues on haematopoiesis have not been well studied.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    CC-90009 toxicities included manageable grade 3-4 hypotension (in 13% of patients) and on-target, drug-induced hypocalcaemia (in 22%).

    “Toxicities included manageable grade 3–4 hypotension (in 13% of patients) and on-target, drug-induced hypocalcaemia (in 22%)122.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [122] Lopez-Girona, A. et al. CC-92480 is a novel cereblon E3 ligase modulator with enhanced tumoricidal and immunomodulatory activity against sensitive and resistant multiple myeloma cells. Blood 134, 1812–1812 (2019). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Mechanistically, the rash might be related to immune activation.

    “Mechanistically, the rash might be related to immune activation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    CC-90009 has been tested in patients with R/R MDS or AML and demonstrated promising single-agent activity: a total of 49 were treated, three of whom had a CRi or better with a morphological leukaemia-free state achieved in one additional patient.

    “CC-90009 has been tested in patients with R/R MDS or AML and demonstrated promising single-agent activity: a total of 49 were treated, three of whom had a CRi or better with a morphological leukaemia-free state achieved in one additional patient122.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [122] Lopez-Girona, A. et al. CC-92480 is a novel cereblon E3 ligase modulator with enhanced tumoricidal and immunomodulatory activity against sensitive and resistant multiple myeloma cells. Blood 134, 1812–1812 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Degrader pharmacology is event-driven; transient target-drug-ligase binding events mediate irreversible target degradation.

    “By contrast to this occupancy-driven action, degrader pharmacology is event-driven; transient target–drug–ligase binding events mediate irreversible target degradation138,139 (FIG. 2b).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [138] Lee, M. J. et al. Lenalidomide desensitization for delayed hypersensitivity reactions in 5 patients with multiple myeloma. Br. J. Haematol. 167, 127–131 (2014). source

      Not checked in the free run.

    • cites [139] FDA. Drugs @ FDA: FDA-approved drugs. US Food & Drug Administration https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&varApplNo=021880 (2019).

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Effective target protein suppression by degraders can be prolonged and is reversed only following protein re-synthesis, thereby uncoupling pharmacokinetic and pharmacodynamic relationships.

    “Effective target protein suppression can be prolonged and is reversed only following protein re-synthesis, thereby uncoupling pharmacokinetic and pharmarcodynamic relationships.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Effects on HSPC function probably contribute to the increased risk of secondary myeloid malignancies, although these effects might also underlie the activity of lenalidomide in these same malignancies.

    “Effects on HSPC function probably contribute to the increased risk of secondary myeloid malignancies, although these effects might also underlie the activity of lenalidomide in these same malignancies.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The rash associated with lenalidomide use occurs in up to 30% of patients, is unpredictable and can occur at any time during treatment.

    “The rash associated with lenalidomide use occurs in up to 30% of patients, is unpredictable and can occur at any time during treatment134.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [134] Palumbo, A. et al. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia 22, 414–423 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    This issue can often be overcome using high-dose cyclophosphamide or the CXCR4 antagonist plerixafor.

    “This issue can often be overcome using high-dose cyclophosphamide or the CXCR4 antagonist plerixafor125.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [125] Kumar, S. et al. Impact of lenalidomide therapy on stem cell mobilization and engraftment post-peripheral blood stem cell transplantation in patients with newly diagnosed myeloma. Leukemia 21, 2035–2042 (2007). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    The potential for teratogenic effects of analogues other than thalidomide has not been assessed.

    “The potential for teratogenic effects of analogues other than thalidomide has not been assessed.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Mutations in CRBN, including missense mutations in the thalidomide analogue binding domain, are associated with progressive thalidomide analogue exposure and occur in up to a third of patients with pomalidomide-refractory disease.

    “Mutations in CRBN, including missense mutations in the thalidomide analogue binding domain, are associated with progressive thalidomide analogue exposure, and ultimately occur in up to a third of patients with pomalidomide-refractory disease146–148 (FIG. 3a).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [146] Sievers, Q. L., Gasser, J. A., Cowley, G. S., Fischer, E. S. & Ebert, B. L. Genome-wide screen identifies cullin-RING ligase machinery required for lenalidomide-dependent CRL4CRBN activity. Blood 132, 1293–1303 (2018). source

      Not checked in the free run.

    • cites [147] Patil, A., Manzano, M. & Gottwein, E. Genome-wide CRISPR screens reveal genetic mediators of cereblon modulator toxicity in primary effusion lymphoma. Blood Adv. 3, 2105–2117 (2019). source

      Not checked in the free run.

    • cites [148] Tateno, S. et al. Genome-wide screening reveals a role for subcellular localization of CRBN in the anti-myeloma activity of pomalidomide. Sci. Rep. 10, 4012 (2020).

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Other toxicities commonly associated with thalidomide analogues include rashes, fatigue and diarrhoea.

    “Other toxicities commonly associated with thalidomide analogues include rashes, fatigue and diarrhoea.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Fatigue is often a dose-limiting toxicity of thalidomide analogues, but its mechanism is unclear.

    “Fatigue is often a dose-limiting toxicity of thalidomide analogues, but its mechanism is unclear.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Thalidomide analogues often lead to peripheral blood cytopenias, most commonly neutropenia (28% grade 3/4) and thrombocytopenia (8% grade 3/4).

    “Thalidomide analogues often lead to peripheral blood cytopenias, most commonly neutropenia (28% grade 3/4) and thrombocytopenia (8% grade 3/4)27.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [27] Dimopoulos, M. et al. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N. Engl. J. Med. 357, 2123–2132 (2007). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Whether the thrombotic phenotype occurs through on-target protein degradation remains unclear.

    “Whether the thrombotic phenotype occurs through on-target protein degradation remains unclear.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Thalidomide analogues are associated with an increased risk of primarily venous thromboembolism (OR 3.51; p<0.001), although arterial events can also rarely occur.

    “Thalidomide analogues are associated with an increased risk of primarily venous thromboembolism128–130 (OR 3.51; p<0.001), although arterial events can also rarely occur131.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [128] Musto, P. et al. Second primary malignancies in multiple myeloma: an overview and IMWG consensus. Ann. Oncol. 28, 228–245 (2017). source

      Not checked in the free run.

    • cites [129] Jones, J. R. et al. Second malignancies in the context of lenalidomide treatment: an analysis of 2732 myeloma patients enrolled to the Myeloma XI trial. Blood Cancer J. 6, e506–e506 (2016). source

      Not checked in the free run.

    • cites [130] Carrier, M., Gal, G. L., Tay, J., Wu, C. & Lee, A. Y. Rates of venous thromboembolism in multiple myeloma patients undergoing immunomodulatory therapy with thalidomide or lenalidomide: a systematic review and meta-analysis: venous thromboembolism in multiple myeloma. J. Thromb. Haemost. 9, 653–663 (2011). source

      Not checked in the free run.

    • cites [131] Chen, C. et al. Expanded safety experience with lenalidomide plus dexamethasone in relapsed or refractory multiple myeloma. Br. J. Haematol. 146, 164–170 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Lenalidomide therapy decreases the efficiency of growth factor-stimulated stem cell mobilization and collection for auto-HSCT, thus limiting its use prior to stem cell harvesting.

    “Lenalidomide therapy decreases the efficiency of growth factor-stimulated stem cell mobilization and collection for auto-HSCT, thus limiting its use prior to stem cell harvesting123,124.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [123] Matyskiela, M. E. et al. A novel cereblon modulator recruits GSPT1 to the CRL4CRBN ubiquitin ligase. Nature 535, 252–257 (2016). source

      Not checked in the free run.

    • cites [124] Uy, G. L. et al. Clinical activity of CC-90009, a cereblon E3 ligase modulator and first-in-class GSPT1 degrader, as a single agent in patients with relapsed or refractory acute myeloid leukemia (R/R AML): first results from a phase I dose-finding study. Blood 134, 232–232 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Long-term use of lenalidomide can cause diarrhoea related to fat malabsorption, which can be effectively treated with the bile acid-binder colestipol.

    “Finally, long-term use of lenalidomide can cause diarrhoea related to fat malabsorption, which can be effectively treated with the bile acid-binder colestipol137.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [137] Tinsley, S. M., Kurtin, S. E. & Ridgeway, J. A. Practical management of lenalidomide-related rash. Clin. Lymphoma Myeloma Leuk. 15, S64–S69 (2015). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Concomitant use of anti-platelet or anti-thrombotic agents is a routine component of clinical care.

    “Concomitant use of anti-platelet or anti-thrombotic agents is, therefore, a routine component of clinical care132.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [132] Knight, R., DeLap, R. J. & Zeldis, J. B. Lenalidomide and venous thrombosis in multiple myeloma. N. Engl. J. Med. 354, 2079–2080 (2006). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The rash can range in severity from mild erythema to toxic epidermal necrolysis, but is often easily managed with corticosteroids and drug cessation.

    “Moreover, this adverse effect can range in severity, from mild erythema to toxic epidermal necrolysis, but is often easily managed with corticosteroids and drug cessation135.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [135] Kaushal, V., Kaushal, G. P., Melkaveri, S. N. & Mehta, P. Thalidomide protects endothelial cells from doxorubicin-induced apoptosis but alters cell morphology. J. Thromb. Haemost. 2, 327–334 (2004). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    These studies identified 11 individual zinc finger domains and six full-length zinc finger-containing proteins subject to drug-mediated degradation, and a larger number of zinc finger domains capable of binding to pomalidomide-engaged CRBN in vitro.

    “These studies resulted in the identification of 11 individual zinc finger domains and six full-length zinc finger-containing that are subject to drug-mediated degradation, as well as a larger number of zinc finger domains that are capable of binding to pomalidomide-engaged CRBN in vitro117.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [117] Matyskiela, M. E. et al. A cereblon modulator (CC-220) with improved degradation of ikaros and aiolos. J. Med. Chem. 61, 535–542 (2017). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    CRBN was first described as a gene that, when mutated, causes a monogenetic intellectual disability.

    “CRBN was first described as a gene that, when mutated, causes a monogenetic intellectual disability169.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [169] An, J. et al. pSILAC mass spectrometry reveals ZFP91 as IMiD-dependent substrate of the CRL4CRBN ubiquitin ligase. Nat. Commun. 8, 15398 (2017).

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Induced overexpression of one substrate reduced the degradation of other substrates and induced drug resistance in cellular models.

    “Indeed, induced overexpression of one substrate reduced the degradation of other substrates and induced drug resistance in cellular models113.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [113] Shimada, K., Hayakawa, F. & Kiyoi, H. Biology and management of primary effusion lymphoma. Blood 132, 1879–1888 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The expression profile of the entire set of substrates, substrate receptors and the CRL4 backbone probably determines the efficiency of drug-induced degradation, which might vary between cell types, states and tumour subclones.

    “Thus, the expression profile of the entire set of substrates, substrate receptors and the CRL4 backbone probably determines the efficiency of drug-induced degradation (FIG. 3a), which might vary not only between different cell types and states but also between tumour subclones.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In a quantitative multiplex mass spectrometry-based assay, a stereotyped order of polysubstrate degradation was identified for various thalidomide analogues, suggesting that substrates with higher affinity and/or greater abundance can outcompete others.

    “In a study using a quantitative multiplex mass spectrometry-based assay to quantitate multiple substrate proteins, a stereotyped order of polysubstrate degradation was identified for various thalidomide analogues113, suggesting that substrates with higher affinity and/or greater abundance can outcompete others.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [113] Shimada, K., Hayakawa, F. & Kiyoi, H. Biology and management of primary effusion lymphoma. Blood 132, 1879–1888 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Koduri and colleagues demonstrated inducible degradation of multiple fusion proteins linked to a 25-amino acid zinc finger degron tag derived from IKZF3 and a >50% reduction in luminescence from tumour cells expressing a degron-tagged luciferase transgene upon treatment with thalidomide analogues.

    “Notably, Koduri and colleagues205 have demonstrated inducible degradation of multiple fusion proteins linked to a 25-amino acid zinc finger degron tag derived from IKZF3 and a >50% reduction in luminescence from tumour cells expressing a degron-tagged luciferase transgene upon treatment with thalidomide analogues.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [205] Clackson, T. et al. Redesigning an FKBP-ligand interface to generate chemical dimerizers with novel specificity. Proc. Natl Acad. Sci. USA 95, 10437–10442 (1998). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CR8, originally developed as a CDK inhibitor, acts as a first-in-class molecular glue degrader of cyclin K.

    “Firstly, by mining correlations between drug sensitivity and the gene-expression profiles of E3 ubiquitin ligase components in hundreds of cell lines, it was discovered that CR8, which was originally developed as a cyclin-dependent kinase (CDK) inhibitor, acts as a first-in-class molecular glue degrader of cyclin K182.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [182] Ting, T. C. et al. Aryl sulfonamides degrade RBM39 and RBM23 by recruitment to CRL4-DCAF15. Cell Rep. 29, 1499–1510.e6 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cellular immunotherapies are emerging as powerful anticancer agents, but autonomous 'living drugs' are capable of inducing severe toxicities.

    “Such cellular immunotherapies are emerging as powerful anticancer agents, but these autonomous, ‘living drugs’ are capable of inducing severe toxicities189.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [189] Simonetta, K. R. et al. Prospective discovery of small molecule enhancers of an E3 ligase-substrate interaction. Nat. Commun. 10, 1402 (2019). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Multiple chemical-genetic systems have been devised to enable tunable regulation of protein stability using small molecules, including FKBP12-based destabilization domains, auxin-inducible degrons and SMASh.

    “Multiple chemical–genetic systems have been devised to enable tunable regulation of protein stability using small molecules194, including FKBP12-based destabilization domains195, auxin-inducible degrons196 and small-molecule-assisted shutoff (SMASh)197.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [194] Roybal, K. T. & Lim, W. A. Synthetic immunology: hacking immune cells to expand their therapeutic capabilities. Annu. Rev. Immunol. 35, 229–253 (2017). source

      Not checked in the free run.

    • cites [195] Stasi, A. D. et al. Inducible apoptosis as a safety switch for adoptive cell therapy. N. Engl. J. Med. 365, 1673–1683 (2011). source

      Not checked in the free run.

    • cites [196] Chiocca, E. A. et al. Regulatable interleukin-12 gene therapy in patients with recurrent high-grade glioma: results of a phase 1 trial. Sci. Transl Med. 11, eaaw5680 (2019). source

      Not checked in the free run.

    • cites [197] Verma, R., Mohl, D. & Deshaies, R. J. Harnessing the power of proteolysis for targeted protein inactivation. Mol. Cell 77, 446–460 (2020). source

      Not checked in the free run.

  • The quote only partly states this claim.

    Premisecitation

    Comparative chemical screening of hyponeddylated and well-neddylated cell lines revealed three destabilizers of cyclin K.

    “Secondly, comparative chemical screening of hyponeddylated and well-neddylated cell lines revealed three destabilizers of cyclin K183.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [183] Faust, T. B. et al. Structural complementarity facilitates E7820-mediated degradation of RBM39 by DCAF15. Nat. Chem. Biol. 16, 7–14 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    BI-3802 binds directly to the BTB dimerization domain of BCL6 and acts as a specific BCL6 degrader.

    “small-molecule screening for novel inhibitors of this protein resulted in the identification of BI-3802 as a compound that binds directly to the BTB dimerization domain of BCL6 and acts as a specific BCL6 degrader187.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [187] Lv, L. et al. Discovery of a molecular glue promoting CDK12-DDB1 interaction to trigger cyclin K degradation. eLife 9, e59994 (2020).

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CAR T cells are highly efficacious in patients with B cell malignancies but can cause severe T cell hyperactivation-related toxicities.

    “For example, chimeric antigen receptor (CAR) T cells are highly efficacious in patients with B cell malignancies but can cause severe T cell hyperactivation-related toxicities190.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [190] Kerres, N. et al. Chemically induced degradation of the oncogenic transcription factor BCL6. Cell Rep. 20, 2860–2875 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Small-molecule-regulated kill switches for cell therapies and transcriptional control systems for gene vectors have entered clinical testing.

    “and indeed small-molecule-regulated kill switches for cell therapies192 and transcriptional control systems for gene vectors193 have entered clinical testing for this purpose.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [192] Weber, E. W., Maus, M. V. & Mackall, C. L. The emerging landscape of immune cell therapies. Cell 181, 46–62 (2020). source

      Not checked in the free run.

    • cites [193] Neelapu, S. S. et al. Chimeric antigen receptor T-cell therapy - assessment and management of toxicities. Nat. Rev. Clin. Oncol. 15, 47–62 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In cells, BI-3802 induced formation of BCL6 protein foci that were then rapidly degraded by the UPS.

    “In cells, BI-3802 induced the formation of BCL6 protein foci that were then rapidly degraded by the UPS188.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [188] Nusse, R. & Clevers, H. Wnt/β-catenin signaling, disease, and emerging therapeutic modalities. Cell 169, 985–999 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Simonetta and colleagues prospectively identified and performed rational structure-guided optimization of drug-like small molecules that enhance the interaction between SCFβ-TrCP and mutant forms of β-catenin.

    “Simonetta and colleagues186 prospectively identified and performed subsequent rational structure-guided optimization of drug-like small molecules that profoundly enhance the interaction between SCFβ–TrCP and such mutant forms of β-catenin.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [186] Mayor-Ruiz, C. et al. Rational discovery of molecular glue degraders via scalable chemical profiling. Nat. Chem. Biol. 16, 1199–1207 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A thalidomide analogue-inducible dimerization domain has been generated from a fragment of CRBN and a zinc finger with all lysines substituted to arginines (K0), and split CARs have been built that require drug treatment for dimerization and subsequent activation.

    “Furthermore, a thalidomide analogue-inducible dimerization domain has been generated from a fragment of CRBN and a zinc finger with all lysines substituted to arginines (K0), and with this system split CARs have been built that require drug treatment for dimerization and subsequent activation207.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [207] Weber, E. W. et al. Transient “rest” induces functional reinvigoration and epigenetic remodeling in exhausted CAR-T cells. Preprint at bioRxiv https://doi.org/10.1101/2020.01.26.920496 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Carbonneau and colleagues fused a CAR with a 60-amino acid zinc finger degron derived from IKZF3, enabling reversible thalidomide analogue-mediated CAR depletion, partial inhibition of CAR T cell effector function in vitro, and suppression of anti-tumor function in vivo.

    “Carbonneau and colleagues206 fused a CAR with a 60-amino acid zinc finger degron derived from IKZF3, enabling reversible thalidomide analogue-mediated CAR depletion, partial inhibition of CAR T cell effector function in vitro, and suppression of anti-tumor function in vivo.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [206] Lee, S. M. et al. A chemical switch system to modulate chimeric antigen receptor T cell activity through proteolysis-targeting chimaera technology. ACS Synth. Biol. 9, 987–992 (2020). source

      Not checked in the free run.

83 of 83

  • The authors state this as an assumption.

    The teratogenic effect is common to all thalidomide analogues.

    “Nevertheless, this adverse effect is assumed to be common to all thalidomide analogues, and appropriate precautions are recommended for all drugs of this class.”

  • The paper relies on this without support.

    Transcription factors, scaffolding proteins and other proteins central to cancer biology typically lack catalytic activity and have remained mostly recalcitrant to drug development.

    “Novel approaches are required, however, to target transcription factors, scaffolding proteins and other proteins central to cancer biology that typically lack catalytic activity and have remained mostly recalcitrant to drug development.”

  • The paper relies on this without support.

    Many degraded neosubstrates, such as zinc finger transcription factors, do not contain ligand-binding sites that could be targeted using traditional therapeutic agents.

    “Many of the degraded neosubstrates, such as zinc finger transcription factors, do not contain ligand-binding sites that could be targeted using traditional therapeutic agents.”
3 of 3

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Thalidomide, lenalidomide and pomalidomide are used in clinical settings, providing evidence that MG degraders are an efficacious therapeutic strategy.

    “Currently, thalidomide, lenalidomide and pomalidomide are used in a variety of clinical settings, 59 thus providing evidence that MG degraders are an efficacious therapeutic strategy.”

    From Chasing molecular glue degraders: screening approaches (2022) · cites this paper as [59]

  • Degrader drugs currently on the market (the IMiD class) and the overwhelming majority of newly developed PROTACs and molecular glue compounds currently in clinical trials target various types of cancer.

    “Degrader drugs currently on the market (the IMiD class) and the overwhelming majority of newly developed PROTACs and molecular glue compounds currently in clinical trials (Tables 1,2) target various types of cancer30,163.”

    From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [163]

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Related

Authors
Jan, M., Sperling, A. S., & Ebert, B. L.
Affiliations
Broad Institute (US)
Corresponding author
Ebert, Benjamin L.
ORCID
Venue
Nature Reviews Clinical Oncology
Publisher
Springer Science and Business Media LLC
Published
2021-03-02
Volume
18
Issue
7
Pages
401-417
ISSN
  • 1759-4774 (ISSN-L)
  • 1759-4782
DOI
10.1038/s41571-021-00479-z
PMC
PMC8903027
OpenAlex
W3135294709
Semantic Scholar
91e46f0742426cca4ff9009a7a11f84370a62e28
Cited by
137
References
240
Citations by year
2026: 16 · 2025: 33 · 2024: 21 · 2023: 33 · 2022: 23 · 2021: 11
FWCI
2.31
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Reviews Clinical Oncology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Howard Hughes Medical Institute
  • European Hematology Association (TRTH160)
  • National Heart, Lung, and Blood Institute (R01HL082945)
  • National Cancer Institute (K08CA252174, R35CA253125, P01CA108631, P50CA206963, T32CA009216, P01CA066996)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
  • Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
Keywords
targeted protein degradation, lenalidomide, thalidomide analogues, E3 ubiquitin ligase, proteasomal degradation, undruggable proteins, druggable proteome, fulvestrant, pomalidomide, hematologic malignancies, resistance mechanisms, clinical development
MeSH terms
Drug Development, Lenalidomide, Animals, Antineoplastic Agents, Humans, Neoplasms, Drugs, Investigational, Proteome, Molecular Targeted Therapy, Proteolysis

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Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

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