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

Li, Xiaotong ; Saal, Lao LU orcid ; Brueffer, Christian LU orcid ; Chen, Yilun LU ; Asklin, Johanna LU ; Alvi, Saman ; Venkatram, Srinivas and Ross, Jeremy (2023) AACR Annual Meeting 2023 In Cancer Research 83(7_Supplement).
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® 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)... (More)
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 (Less)
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author
; ; ; ; ; ; and
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Myeloma, Multiple myeloma, Digital PCR, Whole Genome Sequencing, Minimal residual disease, Plasma, PBMCs, ctDNA
in
Cancer Research
volume
83
issue
7_Supplement
article number
5710
publisher
American Association for Cancer Research Inc.
conference name
AACR Annual Meeting 2023
conference location
Orlando, United States
conference dates
2023-04-14 - 2023-04-19
ISSN
1538-7445
DOI
10.1158/1538-7445.AM2023-5710
language
English
LU publication?
no
id
7f851d02-8ca1-416c-8a97-9463910b66a2
date added to LUP
2023-05-28 15:04:12
date last changed
2025-04-04 13:52:20
@misc{7f851d02-8ca1-416c-8a97-9463910b66a2,
  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® 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}},
  author       = {{Li, Xiaotong and Saal, Lao and Brueffer, Christian and Chen, Yilun and Asklin, Johanna and Alvi, Saman and Venkatram, Srinivas and Ross, Jeremy}},
  issn         = {{1538-7445}},
  keywords     = {{Myeloma; Multiple myeloma; Digital PCR; Whole Genome Sequencing; Minimal residual disease; Plasma; PBMCs; ctDNA}},
  language     = {{eng}},
  month        = {{04}},
  note         = {{Conference Abstract}},
  number       = {{7_Supplement}},
  publisher    = {{American Association for Cancer Research Inc.}},
  series       = {{Cancer Research}},
  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}},
  url          = {{http://dx.doi.org/10.1158/1538-7445.AM2023-5710}},
  doi          = {{10.1158/1538-7445.AM2023-5710}},
  volume       = {{83}},
  year         = {{2023}},
}