The DOI matches its Crossref record; 240 of the 240 references it cites were found in a registry or an index; 12 of the 277 sources its claims cite were checked for support.
Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide
Open accessAbstract
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.
Overview
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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.
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Claims the paper makes
153 Not checked yet · 19 Own interpretation · 7 No basis given · 2 Partly supported · 1 Not supported · accuracy not yet measured
At least one cited source doesn’t support this claim or points to a different paper, and none confirmed it — see the verdicts below.
In the paper
“Remarkably, these structurally divergent small molecules all directly engage a substrate receptor-less CUL4 E3 ligase complex by binding to its substrate adaptor component, DDB1, whilst simultaneously interacting with and thereby recruiting CDK12 in complex with cyclin K.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Emerging opportunities with degraders > Novel classes of degrader therapeutics
What the sources say
- Disputedcites [182] Ting, T. C. et al. Aryl sulfonamides degrade RBM39 and RBM23 by recruitment to CRL4-DCAF15. Cell Rep. 29, 1499–1510.e6 (2019). sourceExperimental — accuracy not yet measured
The Results section, “In Vitro Reconstitution of RBM39 Ubiquitination” (page unavailable), explicitly identifies DCAF15 as the substrate receptor and DDB1 as the adaptor, contrary to the claimed receptor-less complex. The Discussion (page unavailable) reports sulfonamide-dependent recruitment of RBM39 to CRL4-DCAF15, not recruitment of CDK12–cyclin K through binding to DDB1. (LLM, conf=0.88)
Checked by a reasoning model — may be wrong.
- Disputedcites [183] Faust, T. B. et al. Structural complementarity facilitates E7820-mediated degradation of RBM39 by DCAF15. Nat. Chem. Biol. 16, 7–14 (2020). sourceExperimental — accuracy not yet measured
The Abstract and Discussion describe aryl-sulfonamides recruiting RBM39 through the substrate receptor DCAF15, not recruiting CDK12–cyclin K to a receptor-less CUL4 complex. The Results section on the DCAF15 structure says DCAF15 binds DDB1; it does not say the small molecules bind DDB1. Searches for CDK12 and cyclin K found no passage addressing either protein. (LLM, conf=0.89)
Checked by a reasoning model — may be wrong.
- Not checked yetcites [184] Du, X. et al. Structural basis and kinetic pathway of RBM39 recruitment to DCAF15 by a sulfonamide molecular glue E7820. Structure 27, 1625–1633.e3 (2019). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Disputed
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“CRBN expression levels in patient samples has been positively associated with sensitivity to thalidomide analogues in some studies149–154, but not in others155,156.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > The distinct pharmacology of degraders > Resistance mechanisms
What the sources say
- Could not verifycites [149] Kortüm, K. M. et al. Targeted sequencing of refractory myeloma reveals a high incidence of mutations in CRBN and Ras pathway genes. Blood 128, 1226–1233 (2016). sourceExperimental — accuracy not yet measured
The citation is attached to the claim that some studies did not find a positive association between CRBN expression in patient samples and sensitivity to thalidomide analogues. The CRBN-associated mutations section reports expression-dependent sensitivity in a cell line, while the Discussion addresses mutations in patient samples; neither reports a study finding no association between patient-sample CRBN expression and drug sensitivity. Pages were not provided in our copy. (LLM, conf=0.75)
- Partly supportedcites [150] Thakurta, A. et al. Absence of mutations in cereblon (CRBN) and DNA damage-binding protein 1 (DDB1) genes and significance for IMiD therapy. Leukemia 28, 1129–1131 (2013). sourceExperimental — accuracy not yet measured
The paper’s main text reports lower cereblon levels when patients become resistant to lenalidomide or pomalidomide, and its References section lists studies associating high CRBN expression with better outcomes in treated patients. Our copy does not establish the other half of the claim: that some patient studies found no positive association. The paper primarily investigates gene mutations rather than comparing those expression studies. (LLM, conf=0.82)
- Supportedcites [151] Gooding, S. et al. Multiple cereblon genetic changes associate with acquired resistance to lenalidomide or pomalidomide in multiple myeloma. Blood https://doi.org/10.1182/blood.2020007081 (2020). source
The section on exon 10-spliced CRBN transcripts states that pretherapy CRBN expression did not correlate with subsequent pomalidomide response and that the authors confirmed this result using RNASeq. This supports citing the paper for the ‘but not in others’ portion of the sentence; it does not establish the positive associations reported by other studies. (LLM, conf=0.91)
- Supportedcites [152] Huang, S.-Y. et al. Expression of cereblon protein assessed by immunohistochemicalstaining in myeloma cells is associated with superior response of thalidomide- and lenalidomide-based treatment, but not bortezomib-based treatment, in patients with multiple myeloma. Ann. Hematol. 93, 1371–1380 (2014). source
The Results and Conclusion report that CRBN-positive myeloma samples were associated with better responses to lenalidomide- and thalidomide-based regimens. This supports the positive-association part of the citing sentence; the contrasting studies are assigned separate citations. (LLM, conf=0.94)
- Supportedcites [153] Franssen, L. E. et al. Cereblon loss and up-regulation of c-Myc are associated with lenalidomide resistance in multiple myeloma patients. Haematologica 103, e368–e371 (2018). source
The Results report no association between Cereblon expression and response, progression-free survival, or overall survival with the lenalidomide-containing REP regimen. This supports the ‘but not in others’ part of the citing sentence, while the paper separately reports reduced Cereblon protein levels with acquired lenalidomide resistance. The supplied copy does not provide page numbers. (LLM, conf=0.90)
- Supportedcites [154] Heintel, D. et al. High expression of cereblon (CRBN) is associated with improved clinical response in patients with multiple myeloma treated with lenalidomide and dexamethasone. Br. J. Haematol. 161, 695–700 (2013). source
The Summary (p. 3) reports a significant positive association between baseline CRBN expression and response to lenalidomide in 49 patients with multiple myeloma. This source supports the positive-association part of the citing sentence; the sentence assigns the contrasting negative findings to other citations. (LLM, conf=0.93)
- Not checked yetcites [155] Jonasova, A. et al. High level of full-length cereblon mRNA in lower risk myelodysplastic syndrome with isolated 5q deletion is implicated in the efficacy of lenalidomide. Eur. J. Haematol. 95, 27–34 (2014). source
- Supportedcites [156] Schuster, S. R. et al. The clinical significance of cereblon expression in multiple myeloma. Leukemia Res. 38, 23–28 (2013). source
Results §3.2 reports that none of the patients with the lowest CRBN expression responded to IMiD therapy, while response rates were higher at greater expression levels. The Discussion likewise describes a correlation between CRBN expression and response. This paper supports the positive-association side of the citing sentence; the contrasting finding is attributed to other citations. (LLM, conf=0.92)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Could not verify
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Thalidomide analogues > Thalidomide analogues in cancer therapy
What the sources say
- Not checked yetcites [30] FDA. FDA grants accelerated approval to pomalidomide for Kaposi sarcoma. US Food & Drug Administration https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pomalidomide-kaposi-sarcoma (2020).
- Not checked yetcites [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
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“in del(5q) MDS cells, lenalidomide mediates the CRBN-dependent ubiquitination and degradation of casein kinase I isoform α (CK1α)15.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Thalidomide analogues > Mechanism of action and chemistry
What the sources say
- Not checked yetcites [15] Krönke, J. et al. Lenalidomide induces ubiquitination and degradation of CK1α in del(5q) MDS. Nature 523, 183–188 (2015). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“All pharmacologically active derivatives of thalidomide contain a glutarimide ring that directly binds within a conserved pocket on the surface of CRBN17”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Thalidomide analogues > Mechanism of action and chemistry
What the sources say
- Not checked yetcites [17] Fischer, E. S. et al. Structure of the DDB1–CRBN E3 ubiquitin ligase in complex with thalidomide. Nature 512, 49–53 (2014). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“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.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Thalidomide analogues > Thalidomide analogues in cancer therapy
What the sources say
- Not checked yetcites [23] Choueiri, T. K. et al. Phase II study of lenalidomide in patients with metastatic renal cell carcinoma. Cancer 107, 2609–2616 (2006). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“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”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Thalidomide analogues > Mechanism of action and chemistry
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“By contrast, lenalidomide has demonstrated a clear OS advantage (~88% versus 80% at 3 years) with a hazard ratio for death of approximately 0.6030,31,33,34.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Thalidomide analogues > Thalidomide analogues in cancer therapy
What the sources say
- Not checked yetcites [30] FDA. FDA grants accelerated approval to pomalidomide for Kaposi sarcoma. US Food & Drug Administration https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pomalidomide-kaposi-sarcoma (2020).
- Not checked yetcites [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
- Not checked yetcites [33] Richardson, P. G. et al. A randomized phase 2 study of lenalidomide therapy for patients with relapsed or relapsed and refractory multiple myeloma. Blood 108, 3458–3464 (2006). source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“IKZF1, IKZF3 and CK1α are required for MM or MDS cell survival (BOX 2)”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Thalidomide analogues > Mechanism of action and chemistry
What the sources say
- Not checked yetcites [16] Fink, E. C. & Ebert, B. L. The novel mechanism of lenalidomide activity. Blood 126, 2366–2369 (2015). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“In this subset of patients, maintenance therapy with proteasome inhibitors alone or in combination with lenalidomide seems to be more effective than single-agent lenalidomide34,35.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Thalidomide analogues > Thalidomide analogues in cancer therapy
What the sources say
- Not checked yetcites [34] Benboubker, L. et al. Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma. N. Engl. J. Med. 371, 906–917 (2014). source
- Not checked yetcites [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
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- It may state two separate claims as one. 71
- Probably not a substantial claim. 15
- The quote only partly states this claim. 1
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Thalidomide analogues > Mechanism of action and chemistry
What the sources say
- Partly supportedcites [11] Krönke, J. et al. Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science 343, 301–305 (2013). sourceExperimental — accuracy not yet measured
The paper reports that lenalidomide promotes CRBN-dependent ubiquitination and degradation of IKZF1 and IKZF3 in multiple myeloma cells, and that both proteins decrease in lenalidomide-treated primary T cells (Abstract; page unavailable). It also reports reduced IKZF1 and IKZF3 abundance after thalidomide and pomalidomide treatment. It does not establish that these drugs do not inhibit CRL4–CRBN enzymatic activity, or demonstrate the full ubiquitination mechanism for every analogue in both cell types. (LLM, conf=0.84)
- Partly supportedcites [12] Lu, G. et al. The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins. Science 343, 305–309 (2013). sourceExperimental — accuracy not yet measured
The passages labeled Abstract (page unavailable) show that lenalidomide promotes cereblon-dependent ubiquitination and proteasomal degradation of IKZF1 and IKZF3 in myeloma cells. But the paper explicitly says it is unclear whether lenalidomide’s effect is neomorphic, reports earlier evidence that thalidomide inhibits cereblon autoubiquitination, and does not demonstrate this degradation in T cells. (LLM, conf=0.90)
- Partly supportedcites [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). sourceExperimental — accuracy not yet measured
The Results and Discussion (page unavailable) show that lenalidomide and pomalidomide promote CRBN-dependent ubiquitination and proteasomal degradation of Ikaros (IKZF1) and Aiolos (IKZF3) in T cells. The paper does not establish this mechanism for thalidomide or demonstrate it in MM cells. It also proposes neomorphic activity as one possibility, rather than establishing it or categorically ruling out inhibition of CRL4CRBN activity. (LLM, conf=0.89)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
In the paper
“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.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Introduction
What the sources say
- Not checked yetcites [1] Stephens, T. & Brynner, R. Dark Remedy: The Impact of Thalidomide and its Revival as a Vital Medicine (Perseus Publishing, 2009).
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“thalidomide remained on the market for decades as a treatment for erythema nodosum leprosum (an immune-mediated complication of leprosy)5,6.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Introduction
What the sources say
- Not checked yetcites [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
- Not checked yetcites [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).
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“in utero exposure to thalidomide caused an embryopathy characterized by foreshortened limb anomalies, known as phocomelia, in thousands of children worldwide2,3.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Introduction
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Thalidomide analogues > Thalidomide analogues in cancer therapy
What the sources say
- Not checked yetcites [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 yetcites [29] List, A. et al. Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N. Engl. J. Med. 355, 1456–1465 (2006). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Thalidomide analogues > Thalidomide analogues in cancer therapy
What the sources say
- Not checked yetcites [32] Rajkumar, S. V. et al. Combination therapy with lenalidomide plus dexamethasone (Rev/Dex) for newly diagnosed myeloma. Blood 106, 4050–4053 (2005). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Thalidomide analogues > Thalidomide analogues in cancer therapy
What the sources say
- Not checked yetcites [23] Choueiri, T. K. et al. Phase II study of lenalidomide in patients with metastatic renal cell carcinoma. Cancer 107, 2609–2616 (2006). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Thalidomide analogues > Thalidomide analogues in cancer therapy
What the sources say
- Not checked yetcites [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
- Not checked yetcites [25] Polizzotto, M. N. et al. Pomalidomide for symptomatic kaposi’s sarcoma in people with and without HIV infection: a phase I/II study. J. Clin. Oncol. 34, 4125–4131 (2016). source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“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”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Thalidomide analogues > Thalidomide analogues in cancer therapy
What the sources say
- Not checked yetcites [19] Ramsay, A. G. et al. Chronic lymphocytic leukemia T cells show impaired immunological synapse formation that can be reversed with an immunomodulating drug. J. Clin. Invest. 118, 2427–2437 (2008).
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Patients with high-risk cytogenetic features might be the only exception, although they do derive a progression-free survival (PFS) benefit34,35.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Thalidomide analogues > Thalidomide analogues in cancer therapy
What the sources say
- Not checked yetcites [34] Benboubker, L. et al. Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma. N. Engl. J. Med. 371, 906–917 (2014). source
- Not checked yetcites [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
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“lenalidomide and pomalidomide are more potent degraders of IKZF1 and IKZF3, and all of these agents have distinct patterns of neosubstrate degradation18.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Thalidomide analogues > Mechanism of action and chemistry
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Thalidomide analogues > Thalidomide analogues in cancer therapy
What the sources say
- Not checked yetcites [27] Dimopoulos, M. et al. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N. Engl. J. Med. 357, 2123–2132 (2007). source
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Thalidomide analogues > Thalidomide analogues in cancer therapy
What the sources say
- Not checked yetcites [65] Chamberlain, P. P. & Hamann, L. G. Development of targeted protein degradation therapeutics. Nat. Chem. Biol. 15, 937–944 (2019). source
- Not checked yetcites [47] Moreau, P. et al. Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma. N. Engl. J. Med. 374, 1621–1634 (2016). source
- Not checked yetcites [66] Zonder, J. A. et al. A phase 1, multicenter, open-label, dose escalation study of elotuzumab in patients with advanced multiple myeloma. Blood 120, 552–559 (2012). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Lenalidomide also enhances T cell and NK cell functions, probably via degradation of IKZF3, raising the possibility of mechanistic synergy between these two agents.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Thalidomide analogues > Thalidomide analogues in cancer therapy
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In the paper
“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.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Thalidomide analogues > Thalidomide analogues in cancer therapy
What the sources say
- Not checked yetcites [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
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Thalidomide analogues > Thalidomide analogues in cancer therapy
What the sources say
- Not checked yetcites [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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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“however, whether such combinations have additive or synergistic clinical activity remains unclear.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Thalidomide analogues > Thalidomide analogues in cancer therapy
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“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.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Thalidomide analogues > Thalidomide analogues in cancer therapy
What the sources say
- Not checked yetcites [48] Dimopoulos, M. A. et al. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N. Engl. J. Med. 375, 1319–1331 (2016). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Thalidomide analogues > Thalidomide analogues in cancer therapy
What the sources say
- Not checked yetcites [56] Qian, Z. et al. Lenalidomide synergizes with dexamethasone to induce growth arrest and apoptosis of mantle cell lymphoma cells in vitro and in vivo. Leukemia Res. 35, 380–386 (2011). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Thalidomide analogues > Thalidomide analogues in cancer therapy
What the sources say
- Not checked yetcites [59] Chauhan, D. et al. Combination of novel proteasome inhibitor NPI-0052 and lenalidomide trigger in vitro and in vivo synergistic cytotoxicity in multiple myeloma. Blood 115, 834–845 (2010). source
- Not checked yetcites [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
- Not checked yetcites [61] Siegel, D. S. et al. Vorinostat in combination with lenalidomide and dexamethasone in patients with relapsed or refractory multiple myeloma. Blood Cancer J. 4, e202 (2014).
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Thalidomide analogues > Thalidomide analogues in cancer therapy
What the sources say
- Not checked yetcites [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 yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Thalidomide analogues > Thalidomide analogues in cancer therapy
What the sources say
- Not checked yetcites [68] Lonial, S. et al. Elotuzumab therapy for relapsed or refractory multiple myeloma. N. Engl. J. Med. 373, 621–631 (2015). source
- Not checked yetcites [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
- Not checked yetcites [70] Tai, Y.-T. et al. Anti-CS1 humanized monoclonal antibody HuLuc63 inhibits myeloma cell adhesion and induces antibody-dependent cellular cytotoxicity in the bone marrow milieu. Blood 112, 1329–1337 (2008). source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Thalidomide analogues > Thalidomide analogues in cancer therapy
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Thalidomide analogues > Thalidomide analogues in cancer therapy
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Thalidomide analogues > Thalidomide analogues in cancer therapy
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [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
hedged- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Thalidomide analogues > Thalidomide analogues in cancer therapy
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [39] Barlogie, B. et al. Thalidomide and hematopoietic-cell transplantation for multiple myeloma. N. Engl. J. Med. 354, 1021–1030 (2006). source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
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In the paper
“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.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Thalidomide analogues > Thalidomide analogues in cancer therapy
What the sources say
- Not checked yetcites [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 yetcites [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
hedged- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“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.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Thalidomide analogues > Thalidomide analogues in cancer therapy
What the sources say
- Not checked yetcites [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
plainconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Thalidomide analogues > Thalidomide analogues in cancer therapy
What the sources say
- Not checked yetcites [73] Palumbo, A. et al. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N. Engl. J. Med. 375, 754–766 (2016). source
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Of note, IKZF1 is expressed throughout haematopoiesis and regulates myeloid cell development and function100.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Thalidomide analogues > Thalidomide analogues in cancer therapy
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Thalidomide analogues > Thalidomide analogues in cancer therapy
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Thalidomide analogues > Thalidomide analogues in cancer therapy
What the sources say
- Not checked yetcites [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
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Thalidomide analogues > Thalidomide analogues in cancer therapy
What the sources say
- Not checked yetcites [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 yetcites [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
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Iberdomide has a distinct chemical structure compared with other thalidomide analogues (FIG. 1c) and might have a broader target specificity117.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Thalidomide analogues > Next-generation thalidomide analogues
What the sources say
- Not checked yetcites [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
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Thalidomide analogues > Thalidomide analogues in cancer therapy
What the sources say
- Not checked yetcites [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 yetcites [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
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Thalidomide analogues > Thalidomide analogues in cancer therapy
What the sources say
- Not checked yetcites [21] Luptakova, K. et al. Lenalidomide enhances anti-myeloma cellular immunity. Cancer Immunol. Immunother. 62, 39–49 (2013). source
- Not checked yetcites [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
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“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.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Thalidomide analogues > Next-generation thalidomide analogues
What the sources say
- Not checked yetcites [114] Zhang, L. et al. Phase 2 study using oral thalidomide-cyclophosphamide-prednisone for idiopathic multicentric Castleman disease. Blood 133, 1720–1728 (2019). source
plainn = 5- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The mechanistic basis underlying the efficacy of pomalidomide in this disease is not well characterized.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Thalidomide analogues > Thalidomide analogues in cancer therapy
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Thalidomide analogues > Next-generation thalidomide analogues
What the sources say
- Not checked yetcites [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 yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“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.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Thalidomide analogues > Thalidomide analogues in cancer therapy
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Thalidomide analogues > Thalidomide analogues in cancer therapy
What the sources say
- Not checked yetcites [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 yetcites [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
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
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In the paper
“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.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Thalidomide analogues > Next-generation thalidomide analogues
What the sources say
- Not checked yetcites [113] Shimada, K., Hayakawa, F. & Kiyoi, H. Biology and management of primary effusion lymphoma. Blood 132, 1879–1888 (2018). source
- Not checked yetcites [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
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Avadomide (previously known as CC-122) is chemically similar to pomalidomide (FIG. 1c), and accordingly, has similar substrate specificity and potency of degradation113.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Thalidomide analogues > Next-generation thalidomide analogues
What the sources say
- Not checked yetcites [113] Shimada, K., Hayakawa, F. & Kiyoi, H. Biology and management of primary effusion lymphoma. Blood 132, 1879–1888 (2018). source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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).”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > The distinct pharmacology of degraders > Event-driven vs occupancy-driven action
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“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.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Thalidomide analogues > Clinical toxicities
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Solid tumours associated with lenalidomide use are most commonly non-melanoma skin cancers, which can usually be managed conservatively127.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Thalidomide analogues > Clinical toxicities
What the sources say
- Not checked yetcites [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
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Thalidomide analogues > Clinical toxicities
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. It may state two separate claims as one.
In the paper
“Toxicities included manageable grade 3–4 hypotension (in 13% of patients) and on-target, drug-induced hypocalcaemia (in 22%)122.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Thalidomide analogues > Next-generation thalidomide analogues
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Mechanistically, the rash might be related to immune activation.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Thalidomide analogues > Clinical toxicities
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
In the paper
“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.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Thalidomide analogues > Next-generation thalidomide analogues
What the sources say
- Not checked yetcites [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
boosteddirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > The distinct pharmacology of degraders > Event-driven vs occupancy-driven action
What the sources say
- Not checked yetcites [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 yetcites [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).
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Effective target protein suppression can be prolonged and is reversed only following protein re-synthesis, thereby uncoupling pharmacokinetic and pharmarcodynamic relationships.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > The distinct pharmacology of degraders > Event-driven vs occupancy-driven action
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Thalidomide analogues > Clinical toxicities
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“The rash associated with lenalidomide use occurs in up to 30% of patients, is unpredictable and can occur at any time during treatment134.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Thalidomide analogues > Clinical toxicities
What the sources say
- Not checked yetcites [134] Palumbo, A. et al. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia 22, 414–423 (2008). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“This issue can often be overcome using high-dose cyclophosphamide or the CXCR4 antagonist plerixafor125.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Thalidomide analogues > Clinical toxicities
What the sources say
- Not checked yetcites [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
plainconditional- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The potential for teratogenic effects of analogues other than thalidomide has not been assessed.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Thalidomide analogues > Clinical toxicities
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > The distinct pharmacology of degraders > Resistance mechanisms
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [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).
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Other toxicities commonly associated with thalidomide analogues include rashes, fatigue and diarrhoea.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Thalidomide analogues > Clinical toxicities
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Fatigue is often a dose-limiting toxicity of thalidomide analogues, but its mechanism is unclear.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Thalidomide analogues > Clinical toxicities
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“Thalidomide analogues often lead to peripheral blood cytopenias, most commonly neutropenia (28% grade 3/4) and thrombocytopenia (8% grade 3/4)27.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Thalidomide analogues > Clinical toxicities
What the sources say
- Not checked yetcites [27] Dimopoulos, M. et al. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N. Engl. J. Med. 357, 2123–2132 (2007). source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Whether the thrombotic phenotype occurs through on-target protein degradation remains unclear.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Thalidomide analogues > Clinical toxicities
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Thalidomide analogues > Clinical toxicities
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [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 yetcites [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
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Thalidomide analogues > Clinical toxicities
What the sources say
- Not checked yetcites [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 yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Finally, long-term use of lenalidomide can cause diarrhoea related to fat malabsorption, which can be effectively treated with the bile acid-binder colestipol137.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Thalidomide analogues > Clinical toxicities
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Concomitant use of anti-platelet or anti-thrombotic agents is, therefore, a routine component of clinical care132.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Thalidomide analogues > Clinical toxicities
What the sources say
- Not checked yetcites [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
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“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.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Thalidomide analogues > Clinical toxicities
What the sources say
- Not checked yetcites [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
plain- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Emerging opportunities with degraders > Identification of thalidomide analogue neosubstrates
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“CRBN was first described as a gene that, when mutated, causes a monogenetic intellectual disability169.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Emerging opportunities with degraders > Endogenous substrates of CRBN
What the sources say
- Not checked yetcites [169] An, J. et al. pSILAC mass spectrometry reveals ZFP91 as IMiD-dependent substrate of the CRL4CRBN ubiquitin ligase. Nat. Commun. 8, 15398 (2017).
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Indeed, induced overexpression of one substrate reduced the degradation of other substrates and induced drug resistance in cellular models113.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > The distinct pharmacology of degraders > Resistance mechanisms
What the sources say
- Not checked yetcites [113] Shimada, K., Hayakawa, F. & Kiyoi, H. Biology and management of primary effusion lymphoma. Blood 132, 1879–1888 (2018). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > The distinct pharmacology of degraders > Resistance mechanisms
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > The distinct pharmacology of degraders > Resistance mechanisms
What the sources say
- Not checked yetcites [113] Shimada, K., Hayakawa, F. & Kiyoi, H. Biology and management of primary effusion lymphoma. Blood 132, 1879–1888 (2018). source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Emerging opportunities with degraders > Synthetic biology and cell therapies
What the sources say
- Not checked yetcites [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
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Emerging opportunities with degraders > Novel classes of degrader therapeutics
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Such cellular immunotherapies are emerging as powerful anticancer agents, but these autonomous, ‘living drugs’ are capable of inducing severe toxicities189.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Emerging opportunities with degraders > Synthetic biology and cell therapies
What the sources say
- Not checked yetcites [189] Simonetta, K. R. et al. Prospective discovery of small molecule enhancers of an E3 ligase-substrate interaction. Nat. Commun. 10, 1402 (2019). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Emerging opportunities with degraders > Synthetic biology and cell therapies
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [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 yetcites [197] Verma, R., Mohl, D. & Deshaies, R. J. Harnessing the power of proteolysis for targeted protein inactivation. Mol. Cell 77, 446–460 (2020). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Secondly, comparative chemical screening of hyponeddylated and well-neddylated cell lines revealed three destabilizers of cyclin K183.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Emerging opportunities with degraders > Novel classes of degrader therapeutics
What the sources say
- Not checked yetcites [183] Faust, T. B. et al. Structural complementarity facilitates E7820-mediated degradation of RBM39 by DCAF15. Nat. Chem. Biol. 16, 7–14 (2020). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The quote only partly states this claim.
In the paper
“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.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Emerging opportunities with degraders > Novel classes of degrader therapeutics
What the sources say
- Not checked yetcites [187] Lv, L. et al. Discovery of a molecular glue promoting CDK12-DDB1 interaction to trigger cyclin K degradation. eLife 9, e59994 (2020).
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Emerging opportunities with degraders > Synthetic biology and cell therapies
What the sources say
- Not checked yetcites [190] Kerres, N. et al. Chemically induced degradation of the oncogenic transcription factor BCL6. Cell Rep. 20, 2860–2875 (2017). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“and indeed small-molecule-regulated kill switches for cell therapies192 and transcriptional control systems for gene vectors193 have entered clinical testing for this purpose.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Emerging opportunities with degraders > Synthetic biology and cell therapies
What the sources say
- Not checked yetcites [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 yetcites [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
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“In cells, BI-3802 induced the formation of BCL6 protein foci that were then rapidly degraded by the UPS188.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Emerging opportunities with degraders > Novel classes of degrader therapeutics
What the sources say
- Not checked yetcites [188] Nusse, R. & Clevers, H. Wnt/β-catenin signaling, disease, and emerging therapeutic modalities. Cell 169, 985–999 (2017). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Emerging opportunities with degraders > Novel classes of degrader therapeutics
What the sources say
- Not checked yetcites [186] Mayor-Ruiz, C. et al. Rational discovery of molecular glue degraders via scalable chemical profiling. Nat. Chem. Biol. 16, 1199–1207 (2020). source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Emerging opportunities with degraders > Synthetic biology and cell therapies
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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.”
§ Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide > Emerging opportunities with degraders > Synthetic biology and cell therapies
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
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.”
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?
The cited source says what the claim attributes to it.
In the citing paper
“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]
In the citing paper
“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]
Citations
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Metadata
- Authors
- Jan, M., Sperling, A. S., & Ebert, B. L.
- Affiliations
- Broad Institute (US)
- Corresponding author
- Ebert, Benjamin L.
- Venue
- Nature Reviews Clinical Oncology
- Published
- 2021-03-02
- Volume
- 18
- Issue
- 7
- Pages
- 401-417
- ISSN
- 1759-4774 (ISSN-L)
- 1759-4782
- 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
- green
- www.ncbi.nlm.nih.gov
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-10 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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