DELETION OF CDKN2C DRIVES THE PROGNOSTIC IMPACT OF DELETION 1P IN MULTIPLE MYELOMA
(Abstract release date: 05/19/16)
EHA Library. Kaiser M. 06/12/16; 135310; S816
Dr. Martin Kaiser
Contributions
Contributions
Abstract
Abstract: S816
Type: Oral Presentation
Presentation during EHA21: On Sunday, June 12, 2016 from 08:45 - 09:00
Location: Hall C14
Background
Survival in multiple myeloma is highly variable and predicting high risk behaviour is key for implementation of risk-adapted therapies. Ultimately, drivers of high risk myeloma need to be identified and directly targeted to turn risk markers into predictive markers for precision medicine.
Aims
To identify the prognostic impact of different genetic lesions affecting chromosome 1p.
Methods
CD138 immunomagnetically selected bone marrow tumour material of 1,036 newly diagnosed myeloma patients enrolled in the NCRI Myeloma XI trial were studied. The trial investigated CTD vs. CRD induction therapy as well as lenalidomide maintenance vs. no maintenance and enrolled both young and fit patients who received intensive chemotherapy (n=598 in this analysis), as well as elderly and less fit patients (n=438) who were treated on the non-intensive arm. Cases were molecularly profiled using a combination of MLPA and qRT-PCR (Boyle EM, et al. Gen Chrom Canc 2015; Kaiser MF, et al. Leukemia 2014). These high-throughput methods run on standard molecular biology equipment and allow for robust parallel assessment of multiple genetic lesions in one molecular reaction, including different lesions at chromosome 1p.
Results
Of the 1,036 patients, 10% carried deletion of CDKN2C at 1p32, 18% deletion DPYP (1p21.3), 15% deletion COL11A1 (1p21.1) and 25% deletion FAM46C (1p12), consistent with previous reports. In 7% CDKN2C and COL11A1 co-occurred and also in 7% CDKN2C and FAM46C co-segregated. In 8% of COL11A1 and 18% of FAM46C deleted cases CDKN2C copy number was normal. Only CDKN2C was affected by recurrent homozygous deletions, which was seen in 2% of cases.Deletion of CDKN2C (1p32) was associated with inferior outcome in the 598 intensively treated, younger patients with median progression free survival (PFS) of 21.8 vs. 33.8 months (P=0.028) and 24-months median overall survival (OS) of 80% vs. 88% (P=0.003). Deletion of CDKN2C was not associated with shorter survival in the elderly group of patients.Deletions of DPYP, COL11A1 and FAM46C were not associated with shorter PFS in the intensively treated group. Deletion of COL11A1 was associated with inferior OS (P=0.02). However, this was dependent on co-occurrence of deletion CDKN2C and was not significant when looking at cases with isolated COL11A1 deletion (P=0.6). No significant impact of deletion FAM46C on outcome was observed.
Conclusion
Deletion of chromosome 1p is an established risk factor in intensively treated patients. Our analysis suggests that CDKN2C at 1p32, rather than DPYP (1p21.3), COL11A1 (1p21.1) or FAM46C (1q12) is the relevant gene conferring poor prognosis. This has important implications for the potential development of therapeutic strategies for del(1p) myeloma.
Session topic: Experimental approaches for plasma cell disorders
Keyword(s): Genetic, High risk
Type: Oral Presentation
Presentation during EHA21: On Sunday, June 12, 2016 from 08:45 - 09:00
Location: Hall C14
Background
Survival in multiple myeloma is highly variable and predicting high risk behaviour is key for implementation of risk-adapted therapies. Ultimately, drivers of high risk myeloma need to be identified and directly targeted to turn risk markers into predictive markers for precision medicine.
Aims
To identify the prognostic impact of different genetic lesions affecting chromosome 1p.
Methods
CD138 immunomagnetically selected bone marrow tumour material of 1,036 newly diagnosed myeloma patients enrolled in the NCRI Myeloma XI trial were studied. The trial investigated CTD vs. CRD induction therapy as well as lenalidomide maintenance vs. no maintenance and enrolled both young and fit patients who received intensive chemotherapy (n=598 in this analysis), as well as elderly and less fit patients (n=438) who were treated on the non-intensive arm. Cases were molecularly profiled using a combination of MLPA and qRT-PCR (Boyle EM, et al. Gen Chrom Canc 2015; Kaiser MF, et al. Leukemia 2014). These high-throughput methods run on standard molecular biology equipment and allow for robust parallel assessment of multiple genetic lesions in one molecular reaction, including different lesions at chromosome 1p.
Results
Of the 1,036 patients, 10% carried deletion of CDKN2C at 1p32, 18% deletion DPYP (1p21.3), 15% deletion COL11A1 (1p21.1) and 25% deletion FAM46C (1p12), consistent with previous reports. In 7% CDKN2C and COL11A1 co-occurred and also in 7% CDKN2C and FAM46C co-segregated. In 8% of COL11A1 and 18% of FAM46C deleted cases CDKN2C copy number was normal. Only CDKN2C was affected by recurrent homozygous deletions, which was seen in 2% of cases.Deletion of CDKN2C (1p32) was associated with inferior outcome in the 598 intensively treated, younger patients with median progression free survival (PFS) of 21.8 vs. 33.8 months (P=0.028) and 24-months median overall survival (OS) of 80% vs. 88% (P=0.003). Deletion of CDKN2C was not associated with shorter survival in the elderly group of patients.Deletions of DPYP, COL11A1 and FAM46C were not associated with shorter PFS in the intensively treated group. Deletion of COL11A1 was associated with inferior OS (P=0.02). However, this was dependent on co-occurrence of deletion CDKN2C and was not significant when looking at cases with isolated COL11A1 deletion (P=0.6). No significant impact of deletion FAM46C on outcome was observed.
Conclusion
Deletion of chromosome 1p is an established risk factor in intensively treated patients. Our analysis suggests that CDKN2C at 1p32, rather than DPYP (1p21.3), COL11A1 (1p21.1) or FAM46C (1q12) is the relevant gene conferring poor prognosis. This has important implications for the potential development of therapeutic strategies for del(1p) myeloma.
Session topic: Experimental approaches for plasma cell disorders
Keyword(s): Genetic, High risk
Abstract: S816
Type: Oral Presentation
Presentation during EHA21: On Sunday, June 12, 2016 from 08:45 - 09:00
Location: Hall C14
Background
Survival in multiple myeloma is highly variable and predicting high risk behaviour is key for implementation of risk-adapted therapies. Ultimately, drivers of high risk myeloma need to be identified and directly targeted to turn risk markers into predictive markers for precision medicine.
Aims
To identify the prognostic impact of different genetic lesions affecting chromosome 1p.
Methods
CD138 immunomagnetically selected bone marrow tumour material of 1,036 newly diagnosed myeloma patients enrolled in the NCRI Myeloma XI trial were studied. The trial investigated CTD vs. CRD induction therapy as well as lenalidomide maintenance vs. no maintenance and enrolled both young and fit patients who received intensive chemotherapy (n=598 in this analysis), as well as elderly and less fit patients (n=438) who were treated on the non-intensive arm. Cases were molecularly profiled using a combination of MLPA and qRT-PCR (Boyle EM, et al. Gen Chrom Canc 2015; Kaiser MF, et al. Leukemia 2014). These high-throughput methods run on standard molecular biology equipment and allow for robust parallel assessment of multiple genetic lesions in one molecular reaction, including different lesions at chromosome 1p.
Results
Of the 1,036 patients, 10% carried deletion of CDKN2C at 1p32, 18% deletion DPYP (1p21.3), 15% deletion COL11A1 (1p21.1) and 25% deletion FAM46C (1p12), consistent with previous reports. In 7% CDKN2C and COL11A1 co-occurred and also in 7% CDKN2C and FAM46C co-segregated. In 8% of COL11A1 and 18% of FAM46C deleted cases CDKN2C copy number was normal. Only CDKN2C was affected by recurrent homozygous deletions, which was seen in 2% of cases.Deletion of CDKN2C (1p32) was associated with inferior outcome in the 598 intensively treated, younger patients with median progression free survival (PFS) of 21.8 vs. 33.8 months (P=0.028) and 24-months median overall survival (OS) of 80% vs. 88% (P=0.003). Deletion of CDKN2C was not associated with shorter survival in the elderly group of patients.Deletions of DPYP, COL11A1 and FAM46C were not associated with shorter PFS in the intensively treated group. Deletion of COL11A1 was associated with inferior OS (P=0.02). However, this was dependent on co-occurrence of deletion CDKN2C and was not significant when looking at cases with isolated COL11A1 deletion (P=0.6). No significant impact of deletion FAM46C on outcome was observed.
Conclusion
Deletion of chromosome 1p is an established risk factor in intensively treated patients. Our analysis suggests that CDKN2C at 1p32, rather than DPYP (1p21.3), COL11A1 (1p21.1) or FAM46C (1q12) is the relevant gene conferring poor prognosis. This has important implications for the potential development of therapeutic strategies for del(1p) myeloma.
Session topic: Experimental approaches for plasma cell disorders
Keyword(s): Genetic, High risk
Type: Oral Presentation
Presentation during EHA21: On Sunday, June 12, 2016 from 08:45 - 09:00
Location: Hall C14
Background
Survival in multiple myeloma is highly variable and predicting high risk behaviour is key for implementation of risk-adapted therapies. Ultimately, drivers of high risk myeloma need to be identified and directly targeted to turn risk markers into predictive markers for precision medicine.
Aims
To identify the prognostic impact of different genetic lesions affecting chromosome 1p.
Methods
CD138 immunomagnetically selected bone marrow tumour material of 1,036 newly diagnosed myeloma patients enrolled in the NCRI Myeloma XI trial were studied. The trial investigated CTD vs. CRD induction therapy as well as lenalidomide maintenance vs. no maintenance and enrolled both young and fit patients who received intensive chemotherapy (n=598 in this analysis), as well as elderly and less fit patients (n=438) who were treated on the non-intensive arm. Cases were molecularly profiled using a combination of MLPA and qRT-PCR (Boyle EM, et al. Gen Chrom Canc 2015; Kaiser MF, et al. Leukemia 2014). These high-throughput methods run on standard molecular biology equipment and allow for robust parallel assessment of multiple genetic lesions in one molecular reaction, including different lesions at chromosome 1p.
Results
Of the 1,036 patients, 10% carried deletion of CDKN2C at 1p32, 18% deletion DPYP (1p21.3), 15% deletion COL11A1 (1p21.1) and 25% deletion FAM46C (1p12), consistent with previous reports. In 7% CDKN2C and COL11A1 co-occurred and also in 7% CDKN2C and FAM46C co-segregated. In 8% of COL11A1 and 18% of FAM46C deleted cases CDKN2C copy number was normal. Only CDKN2C was affected by recurrent homozygous deletions, which was seen in 2% of cases.Deletion of CDKN2C (1p32) was associated with inferior outcome in the 598 intensively treated, younger patients with median progression free survival (PFS) of 21.8 vs. 33.8 months (P=0.028) and 24-months median overall survival (OS) of 80% vs. 88% (P=0.003). Deletion of CDKN2C was not associated with shorter survival in the elderly group of patients.Deletions of DPYP, COL11A1 and FAM46C were not associated with shorter PFS in the intensively treated group. Deletion of COL11A1 was associated with inferior OS (P=0.02). However, this was dependent on co-occurrence of deletion CDKN2C and was not significant when looking at cases with isolated COL11A1 deletion (P=0.6). No significant impact of deletion FAM46C on outcome was observed.
Conclusion
Deletion of chromosome 1p is an established risk factor in intensively treated patients. Our analysis suggests that CDKN2C at 1p32, rather than DPYP (1p21.3), COL11A1 (1p21.1) or FAM46C (1q12) is the relevant gene conferring poor prognosis. This has important implications for the potential development of therapeutic strategies for del(1p) myeloma.
Session topic: Experimental approaches for plasma cell disorders
Keyword(s): Genetic, High risk
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