Abstract 5710: Detection and monitoring of t(11;14) in liquid biopsies from patients with relapsed/refractory multiple myeloma treated with venetoclax-based regimens

Xiaotong Li; Lao Saal; Christian Brueffer; Yilun Chen; Johanna Asklin; Saman Alvi; Srinivas Venkatram; Jeremy Ross

doi:10.1158/1538-7445.AM2023-5710

Sammanfattning

Venetoclax (Ven) is a selective B-cell lymphoma 2 inhibitor being studied in t(11;14)+ relapsed/refractory multiple myeloma (MM). Detection of t(11;14) in MM requires bone marrow (BM) aspiration and evaluation of CD138+ plasma cells by fluorescence in situ hybridization (FISH). Innovative techniques may provide less invasive detection of t(11;14) in liquid biopsies Here we present results of the SAGAsign® integrated approach combining low-coverage whole-genome sequencing (WGS) to characterize t(11;14) breakpoints together with personalized digital polymerase chain reaction (dPCR) assays to efficiently detect and monitor the genomic rearrangements in circulating tumor DNA (ctDNA). Baseline BM aspirates were collected from 270 patients (pts) from Ven clinical trials (NCT02755597, NCT01794520, NCT03314181, NCT02899052). Previously generated WGS to an average coverage ~22 × was used. Paired samples of peripheral blood mononuclear cell (PBMC) DNA and plasma circulating cell-free DNA (cfDNA) were analyzed by dPCR at timepoints after Ven-based treatment. Of the 90 t(11;14)+ pts by FISH, 160 t(11;14) breakpoints were identified by WGS in 74 pts (concordance in Table) At the time of data cutoff, dPCR assays were designed and evaluated in 8 t(11;14)+ pts; 7/8 (88%) and 6/8 (75%) pts had detectable t(11;14) in cfDNA or PBMCs, respectively. Higher levels of t(11;14) mutant allele frequency (MAF) were observed in cfDNA compared with PBMCs. After Ven-based treatment, t(11;14) MAF in cfDNA became undetectable in pts with a complete response. In conclusion, this approach has the capability to reconstruct t(11;14) breakpoints from WGS data that is highly concordant with FISH; translocations appear more readily detectable in cfDNA than PBMC samples from pts with MM. SAGAsign assays detected and monitored t(11;14) in liquid biopsies thus highlighting its potential utility for identifying pts with t(11;14) for targeted therapies

Originalspråk	engelska
Artikelnummer	5710
Tidskrift	Cancer Research
Volym	83
Nummer	7_Supplement
DOI	https://doi.org/10.1158/1538-7445.AM2023-5710
Status	Published - 2023 apr. 1
Externt publicerad	Ja
Evenemang	AACR Annual Meeting 2023 - Orange County Convention Center, Orlando, USA Varaktighet: 2023 apr. 14 → 2023 apr. 19 https://www.aacr.org/meeting/aacr-annual-meeting-2023/

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Cancer och onkologi
Bioinformatik och beräkningsbiologi

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title = "Abstract 5710: Detection and monitoring of t(11;14) in liquid biopsies from patients with relapsed/refractory multiple myeloma treated with venetoclax-based regimens",

abstract = "Venetoclax (Ven) is a selective B-cell lymphoma 2 inhibitor being studied in t(11;14)+ relapsed/refractory multiple myeloma (MM). Detection of t(11;14) in MM requires bone marrow (BM) aspiration and evaluation of CD138+ plasma cells by fluorescence in situ hybridization (FISH). Innovative techniques may provide less invasive detection of t(11;14) in liquid biopsies Here we present results of the SAGAsign{\textregistered} integrated approach combining low-coverage whole-genome sequencing (WGS) to characterize t(11;14) breakpoints together with personalized digital polymerase chain reaction (dPCR) assays to efficiently detect and monitor the genomic rearrangements in circulating tumor DNA (ctDNA). Baseline BM aspirates were collected from 270 patients (pts) from Ven clinical trials (NCT02755597, NCT01794520, NCT03314181, NCT02899052). Previously generated WGS to an average coverage ~22 × was used. Paired samples of peripheral blood mononuclear cell (PBMC) DNA and plasma circulating cell-free DNA (cfDNA) were analyzed by dPCR at timepoints after Ven-based treatment. Of the 90 t(11;14)+ pts by FISH, 160 t(11;14) breakpoints were identified by WGS in 74 pts (concordance in Table) At the time of data cutoff, dPCR assays were designed and evaluated in 8 t(11;14)+ pts; 7/8 (88%) and 6/8 (75%) pts had detectable t(11;14) in cfDNA or PBMCs, respectively. Higher levels of t(11;14) mutant allele frequency (MAF) were observed in cfDNA compared with PBMCs. After Ven-based treatment, t(11;14) MAF in cfDNA became undetectable in pts with a complete response. In conclusion, this approach has the capability to reconstruct t(11;14) breakpoints from WGS data that is highly concordant with FISH; translocations appear more readily detectable in cfDNA than PBMC samples from pts with MM. SAGAsign assays detected and monitored t(11;14) in liquid biopsies thus highlighting its potential utility for identifying pts with t(11;14) for targeted therapies",

keywords = "Myeloma, Multiple myeloma, Digital PCR, Whole Genome Sequencing, Minimal residual disease, Plasma, PBMCs, ctDNA",

author = "Xiaotong Li and Lao Saal and Christian Brueffer and Yilun Chen and Johanna Asklin and Saman Alvi and Srinivas Venkatram and Jeremy Ross",

year = "2023",

month = apr,

day = "1",

doi = "10.1158/1538-7445.AM2023-5710",

language = "English",

volume = "83",

journal = "Cancer Research",

issn = "1538-7445",

publisher = "American Association for Cancer Research Inc.",

number = "7_Supplement",

note = "AACR Annual Meeting 2023, AACR 2023 ; Conference date: 14-04-2023 Through 19-04-2023",

url = "https://www.aacr.org/meeting/aacr-annual-meeting-2023/",

}

TY - JOUR

T1 - Abstract 5710: Detection and monitoring of t(11;14) in liquid biopsies from patients with relapsed/refractory multiple myeloma treated with venetoclax-based regimens

AU - Li, Xiaotong

AU - Saal, Lao

AU - Brueffer, Christian

AU - Chen, Yilun

AU - Asklin, Johanna

AU - Alvi, Saman

AU - Venkatram, Srinivas

AU - Ross, Jeremy

PY - 2023/4/1

Y1 - 2023/4/1

N2 - Venetoclax (Ven) is a selective B-cell lymphoma 2 inhibitor being studied in t(11;14)+ relapsed/refractory multiple myeloma (MM). Detection of t(11;14) in MM requires bone marrow (BM) aspiration and evaluation of CD138+ plasma cells by fluorescence in situ hybridization (FISH). Innovative techniques may provide less invasive detection of t(11;14) in liquid biopsies Here we present results of the SAGAsign® integrated approach combining low-coverage whole-genome sequencing (WGS) to characterize t(11;14) breakpoints together with personalized digital polymerase chain reaction (dPCR) assays to efficiently detect and monitor the genomic rearrangements in circulating tumor DNA (ctDNA). Baseline BM aspirates were collected from 270 patients (pts) from Ven clinical trials (NCT02755597, NCT01794520, NCT03314181, NCT02899052). Previously generated WGS to an average coverage ~22 × was used. Paired samples of peripheral blood mononuclear cell (PBMC) DNA and plasma circulating cell-free DNA (cfDNA) were analyzed by dPCR at timepoints after Ven-based treatment. Of the 90 t(11;14)+ pts by FISH, 160 t(11;14) breakpoints were identified by WGS in 74 pts (concordance in Table) At the time of data cutoff, dPCR assays were designed and evaluated in 8 t(11;14)+ pts; 7/8 (88%) and 6/8 (75%) pts had detectable t(11;14) in cfDNA or PBMCs, respectively. Higher levels of t(11;14) mutant allele frequency (MAF) were observed in cfDNA compared with PBMCs. After Ven-based treatment, t(11;14) MAF in cfDNA became undetectable in pts with a complete response. In conclusion, this approach has the capability to reconstruct t(11;14) breakpoints from WGS data that is highly concordant with FISH; translocations appear more readily detectable in cfDNA than PBMC samples from pts with MM. SAGAsign assays detected and monitored t(11;14) in liquid biopsies thus highlighting its potential utility for identifying pts with t(11;14) for targeted therapies

AB - Venetoclax (Ven) is a selective B-cell lymphoma 2 inhibitor being studied in t(11;14)+ relapsed/refractory multiple myeloma (MM). Detection of t(11;14) in MM requires bone marrow (BM) aspiration and evaluation of CD138+ plasma cells by fluorescence in situ hybridization (FISH). Innovative techniques may provide less invasive detection of t(11;14) in liquid biopsies Here we present results of the SAGAsign® integrated approach combining low-coverage whole-genome sequencing (WGS) to characterize t(11;14) breakpoints together with personalized digital polymerase chain reaction (dPCR) assays to efficiently detect and monitor the genomic rearrangements in circulating tumor DNA (ctDNA). Baseline BM aspirates were collected from 270 patients (pts) from Ven clinical trials (NCT02755597, NCT01794520, NCT03314181, NCT02899052). Previously generated WGS to an average coverage ~22 × was used. Paired samples of peripheral blood mononuclear cell (PBMC) DNA and plasma circulating cell-free DNA (cfDNA) were analyzed by dPCR at timepoints after Ven-based treatment. Of the 90 t(11;14)+ pts by FISH, 160 t(11;14) breakpoints were identified by WGS in 74 pts (concordance in Table) At the time of data cutoff, dPCR assays were designed and evaluated in 8 t(11;14)+ pts; 7/8 (88%) and 6/8 (75%) pts had detectable t(11;14) in cfDNA or PBMCs, respectively. Higher levels of t(11;14) mutant allele frequency (MAF) were observed in cfDNA compared with PBMCs. After Ven-based treatment, t(11;14) MAF in cfDNA became undetectable in pts with a complete response. In conclusion, this approach has the capability to reconstruct t(11;14) breakpoints from WGS data that is highly concordant with FISH; translocations appear more readily detectable in cfDNA than PBMC samples from pts with MM. SAGAsign assays detected and monitored t(11;14) in liquid biopsies thus highlighting its potential utility for identifying pts with t(11;14) for targeted therapies

KW - Myeloma

KW - Multiple myeloma

KW - Digital PCR

KW - Whole Genome Sequencing

KW - Minimal residual disease

KW - Plasma

KW - PBMCs

KW - ctDNA

U2 - 10.1158/1538-7445.AM2023-5710

DO - 10.1158/1538-7445.AM2023-5710

M3 - Published meeting abstract

SN - 1538-7445

VL - 83

JO - Cancer Research

JF - Cancer Research

IS - 7_Supplement

M1 - 5710

T2 - AACR Annual Meeting 2023

Y2 - 14 April 2023 through 19 April 2023