c‐MYC expression and maturity phenotypes are associated with outcome benefit from addition of ixazomib to lenalidomide‐dexamethasone in myeloma

Objectives In the TOURMALINE‐MM1 phase 3 trial in relapsed/refractory multiple myeloma, ixazomib‐lenalidomide‐dexamethasone (IRd) showed different magnitudes of progression‐free survival (PFS) benefit vs placebo‐Rd according to number and type of prior therapies, with greater benefit seen in patient...

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Vydané v:European journal of haematology Ročník 105; číslo 1; s. 35 - 46
Hlavní autori: Di Bacco, Alessandra, Bahlis, Nizar J., Munshi, Nikhil C., Avet‐Loiseau, Hervé, Masszi, Tamás, Viterbo, Luísa, Pour, Ludek, Ganly, Peter, Cavo, Michele, Langer, Christian, Kumar, Shaji K., Rajkumar, S. Vincent, Keats, Jonathan J., Berg, Deborah, Lin, Jianchang, Li, Bin, Badola, Sunita, Shen, Lei, Zhang, Jacob, Esseltine, Dixie‐Lee, Luptakova, Katarina, Velde, Helgi, Richardson, Paul G., Moreau, Philippe
Médium: Journal Article
Jazyk:English
Vydavateľské údaje: England Wiley Subscription Services, Inc 01.07.2020
John Wiley and Sons Inc
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ISSN:0902-4441, 1600-0609, 1600-0609
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Abstract Objectives In the TOURMALINE‐MM1 phase 3 trial in relapsed/refractory multiple myeloma, ixazomib‐lenalidomide‐dexamethasone (IRd) showed different magnitudes of progression‐free survival (PFS) benefit vs placebo‐Rd according to number and type of prior therapies, with greater benefit seen in patients with >1 prior line of therapy or 1 prior line of therapy without stem cell transplantation (SCT). Methods RNA sequencing data were used to investigate the basis of these differences. Results The PFS benefit of IRd vs placebo‐Rd was greater in patients with tumors expressing high c‐MYC levels (median not reached vs 11.3 months; hazard ratio [HR] 0.42; 95% CI, 0.26, 0.66; P < .001) compared with in those expressing low c‐MYC levels (median 20.6 vs 16.6 months; HR 0.75; 95% CI, 0.42, 1.2). Expression of c‐MYC in tumors varied based on the number and type of prior therapy received, with the lowest levels observed in tumors of patients who had received 1 prior line of therapy including SCT. These tumors also had higher expression levels of CD19 and CD81. Conclusions PFS analyses suggest that lenalidomide and ixazomib target tumors with different levels of c‐MYC, CD19, and CD81 expression, thus providing a potential rationale for the differential benefits observed in the TOURMALINE‐MM1 study. This trial was registered at www.clinicaltrials.gov as: NCT01564537
AbstractList ObjectivesIn the TOURMALINE‐MM1 phase 3 trial in relapsed/refractory multiple myeloma, ixazomib‐lenalidomide‐dexamethasone (IRd) showed different magnitudes of progression‐free survival (PFS) benefit vs placebo‐Rd according to number and type of prior therapies, with greater benefit seen in patients with >1 prior line of therapy or 1 prior line of therapy without stem cell transplantation (SCT).MethodsRNA sequencing data were used to investigate the basis of these differences.ResultsThe PFS benefit of IRd vs placebo‐Rd was greater in patients with tumors expressing high c‐MYC levels (median not reached vs 11.3 months; hazard ratio [HR] 0.42; 95% CI, 0.26, 0.66; P < .001) compared with in those expressing low c‐MYC levels (median 20.6 vs 16.6 months; HR 0.75; 95% CI, 0.42, 1.2). Expression of c‐MYC in tumors varied based on the number and type of prior therapy received, with the lowest levels observed in tumors of patients who had received 1 prior line of therapy including SCT. These tumors also had higher expression levels of CD19 and CD81.ConclusionsPFS analyses suggest that lenalidomide and ixazomib target tumors with different levels of c‐MYC, CD19, and CD81 expression, thus providing a potential rationale for the differential benefits observed in the TOURMALINE‐MM1 study. This trial was registered at www.clinicaltrials.gov as: NCT01564537
In the TOURMALINE-MM1 phase 3 trial in relapsed/refractory multiple myeloma, ixazomib-lenalidomide-dexamethasone (IRd) showed different magnitudes of progression-free survival (PFS) benefit vs placebo-Rd according to number and type of prior therapies, with greater benefit seen in patients with >1 prior line of therapy or 1 prior line of therapy without stem cell transplantation (SCT).OBJECTIVESIn the TOURMALINE-MM1 phase 3 trial in relapsed/refractory multiple myeloma, ixazomib-lenalidomide-dexamethasone (IRd) showed different magnitudes of progression-free survival (PFS) benefit vs placebo-Rd according to number and type of prior therapies, with greater benefit seen in patients with >1 prior line of therapy or 1 prior line of therapy without stem cell transplantation (SCT).RNA sequencing data were used to investigate the basis of these differences.METHODSRNA sequencing data were used to investigate the basis of these differences.The PFS benefit of IRd vs placebo-Rd was greater in patients with tumors expressing high c-MYC levels (median not reached vs 11.3 months; hazard ratio [HR] 0.42; 95% CI, 0.26, 0.66; P < .001) compared with in those expressing low c-MYC levels (median 20.6 vs 16.6 months; HR 0.75; 95% CI, 0.42, 1.2). Expression of c-MYC in tumors varied based on the number and type of prior therapy received, with the lowest levels observed in tumors of patients who had received 1 prior line of therapy including SCT. These tumors also had higher expression levels of CD19 and CD81.RESULTSThe PFS benefit of IRd vs placebo-Rd was greater in patients with tumors expressing high c-MYC levels (median not reached vs 11.3 months; hazard ratio [HR] 0.42; 95% CI, 0.26, 0.66; P < .001) compared with in those expressing low c-MYC levels (median 20.6 vs 16.6 months; HR 0.75; 95% CI, 0.42, 1.2). Expression of c-MYC in tumors varied based on the number and type of prior therapy received, with the lowest levels observed in tumors of patients who had received 1 prior line of therapy including SCT. These tumors also had higher expression levels of CD19 and CD81.PFS analyses suggest that lenalidomide and ixazomib target tumors with different levels of c-MYC, CD19, and CD81 expression, thus providing a potential rationale for the differential benefits observed in the TOURMALINE-MM1 study. This trial was registered at www.clinicaltrials.gov as: NCT01564537.CONCLUSIONSPFS analyses suggest that lenalidomide and ixazomib target tumors with different levels of c-MYC, CD19, and CD81 expression, thus providing a potential rationale for the differential benefits observed in the TOURMALINE-MM1 study. This trial was registered at www.clinicaltrials.gov as: NCT01564537.
Objectives In the TOURMALINE‐MM1 phase 3 trial in relapsed/refractory multiple myeloma, ixazomib‐lenalidomide‐dexamethasone (IRd) showed different magnitudes of progression‐free survival (PFS) benefit vs placebo‐Rd according to number and type of prior therapies, with greater benefit seen in patients with >1 prior line of therapy or 1 prior line of therapy without stem cell transplantation (SCT). Methods RNA sequencing data were used to investigate the basis of these differences. Results The PFS benefit of IRd vs placebo‐Rd was greater in patients with tumors expressing high c‐MYC levels (median not reached vs 11.3 months; hazard ratio [HR] 0.42; 95% CI, 0.26, 0.66; P < .001) compared with in those expressing low c‐MYC levels (median 20.6 vs 16.6 months; HR 0.75; 95% CI, 0.42, 1.2). Expression of c‐MYC in tumors varied based on the number and type of prior therapy received, with the lowest levels observed in tumors of patients who had received 1 prior line of therapy including SCT. These tumors also had higher expression levels of CD19 and CD81. Conclusions PFS analyses suggest that lenalidomide and ixazomib target tumors with different levels of c‐MYC, CD19, and CD81 expression, thus providing a potential rationale for the differential benefits observed in the TOURMALINE‐MM1 study. This trial was registered at www.clinicaltrials.gov as: NCT01564537
In the TOURMALINE-MM1 phase 3 trial in relapsed/refractory multiple myeloma, ixazomib-lenalidomide-dexamethasone (IRd) showed different magnitudes of progression-free survival (PFS) benefit vs placebo-Rd according to number and type of prior therapies, with greater benefit seen in patients with >1 prior line of therapy or 1 prior line of therapy without stem cell transplantation (SCT). RNA sequencing data were used to investigate the basis of these differences. The PFS benefit of IRd vs placebo-Rd was greater in patients with tumors expressing high c-MYC levels (median not reached vs 11.3 months; hazard ratio [HR] 0.42; 95% CI, 0.26, 0.66; P < .001) compared with in those expressing low c-MYC levels (median 20.6 vs 16.6 months; HR 0.75; 95% CI, 0.42, 1.2). Expression of c-MYC in tumors varied based on the number and type of prior therapy received, with the lowest levels observed in tumors of patients who had received 1 prior line of therapy including SCT. These tumors also had higher expression levels of CD19 and CD81. PFS analyses suggest that lenalidomide and ixazomib target tumors with different levels of c-MYC, CD19, and CD81 expression, thus providing a potential rationale for the differential benefits observed in the TOURMALINE-MM1 study. This trial was registered at www.clinicaltrials.gov as: NCT01564537.
Author Zhang, Jacob
Keats, Jonathan J.
Cavo, Michele
Lin, Jianchang
Moreau, Philippe
Langer, Christian
Richardson, Paul G.
Rajkumar, S. Vincent
Munshi, Nikhil C.
Shen, Lei
Badola, Sunita
Viterbo, Luísa
Li, Bin
Avet‐Loiseau, Hervé
Velde, Helgi
Esseltine, Dixie‐Lee
Kumar, Shaji K.
Berg, Deborah
Ganly, Peter
Di Bacco, Alessandra
Masszi, Tamás
Pour, Ludek
Bahlis, Nizar J.
Luptakova, Katarina
AuthorAffiliation 1 Millennium Pharmaceuticals, Inc. (a wholly owned subsidiary of Takeda Pharmaceutical Company Limited) Cambridge MA USA
8 Hematology and Oncology University Hospital Brno Brno Czech Republic
3 Hematologic Oncology Dana‐Farber Cancer Institute Boston MA USA
7 Instituto Português de Oncologia do Porto Francisco Gentil, Entidade Pública Empresarial (IPOPFG, EPE) Porto Portugal
4 Hematology IUC‐Oncopole Toulouse France
12 Division of Hematology Mayo Clinic Rochester MN USA
6 3rd Department of Internal Medicine Semmelweis University Budapest Hungary
2 Southern Alberta Cancer Research Institute University of Calgary Calgary AB Canada
9 Department of Haematology Christchurch Hospital Christchurch New Zealand
5 Department of Haematology and Stem Cell Transplantation St. István and St. László Hospital of Budapest Budapest Hungary
11 University Hospital of Ulm Ulm Germany
14 Department of Hematology University Hospital Hôtel Dieu University of Nantes Nantes France
13 Translational Genomics Research Institu
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/32145111$$D View this record in MEDLINE/PubMed
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ContentType Journal Article
Copyright 2020 Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited Published by John Wiley & Sons Ltd
2020 Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited European Journal of Haematology Published by John Wiley & Sons Ltd.
2020. This article is published under http://creativecommons.org/licenses/by-nc-nd/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.
Copyright_xml – notice: 2020 Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited Published by John Wiley & Sons Ltd
– notice: 2020 Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited European Journal of Haematology Published by John Wiley & Sons Ltd.
– notice: 2020. This article is published under http://creativecommons.org/licenses/by-nc-nd/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.
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ISSN 0902-4441
1600-0609
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Issue 1
Keywords RNA sequencing
mutation
c-myc Proto-Oncogenes
multiple myeloma
progression-free survival
Language English
License Attribution-NonCommercial-NoDerivs
2020 Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited European Journal of Haematology Published by John Wiley & Sons Ltd.
This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
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Affiliation at the time that the work was conducted: Katarina Luptakova, Tesaro, Waltham, MA, USA; Helgi van de Velde, Sanofi, Cambridge, MA, USA.
ORCID 0000-0003-1780-8746
0000-0003-2072-8712
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Snippet Objectives In the TOURMALINE‐MM1 phase 3 trial in relapsed/refractory multiple myeloma, ixazomib‐lenalidomide‐dexamethasone (IRd) showed different magnitudes...
In the TOURMALINE-MM1 phase 3 trial in relapsed/refractory multiple myeloma, ixazomib-lenalidomide-dexamethasone (IRd) showed different magnitudes of...
ObjectivesIn the TOURMALINE‐MM1 phase 3 trial in relapsed/refractory multiple myeloma, ixazomib‐lenalidomide‐dexamethasone (IRd) showed different magnitudes of...
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StartPage 35
SubjectTerms CD19 antigen
CD81 antigen
c‐myc Proto‐Oncogenes
Dexamethasone
Immunotherapy
Multiple myeloma
mutation
Myc protein
Original
Phenotypes
progression‐free survival
Ribonucleic acid
RNA
RNA sequencing
Stem cell transplantation
Targeted cancer therapy
Tumors
Title c‐MYC expression and maturity phenotypes are associated with outcome benefit from addition of ixazomib to lenalidomide‐dexamethasone in myeloma
URI https://onlinelibrary.wiley.com/doi/abs/10.1111%2Fejh.13405
https://www.ncbi.nlm.nih.gov/pubmed/32145111
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Volume 105
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