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4714 Single Cell Multi-Omic Correlation of Single Nucleotide Variants, Copy Number Variation and Surface Epitopes for Clonal Profiling of Myeloma

Program: Oral and Poster Abstracts
Session: 652. Multiple Myeloma: Clinical and Epidemiological: Poster III
Hematology Disease Topics & Pathways:
Technology and Procedures, Minimal Residual Disease , omics technologies
Monday, December 11, 2023, 6:00 PM-8:00 PM

Adam Sciambi, PhD1*, Cedric Dos Santos, PhD2, Yang Li3*, Joanne Bio Nguyen3*, Priyam Priyam3*, Vivek Chopra, PhD2*, Habib Hamidi, MPH, PhD2*, Michael Nixon4*, Yann Nouet, PhD MSc5, Todd E. Druley, MD, PhD3* and Herve Avet-Loiseau, MD, PhD6*

1Mission Bio Inc, South San Francisco
2Genentech, Inc., South San Francisco, CA
3Mission Bio, Inc, South San Francisco, CA
4Roche, Indianapolis, IN
5F. Hoffmann-La Roche Ltd, Basel, Switzerland
6Institut universitaire du cancer de Toulouse Oncopole, Toulouse, France


Multiple myeloma (MM) is a cancer of plasma cells with approximately 200,000 new diagnoses each year and a 54% 5-year overall survival rate. As myeloma cells expand, clonal genetic differences lead to relapse due to acquired resistance in 100% of patients, mandating regular, long-term surveillance. Improvements in precision medicine for MM have come from monoclonal antibodies and antibody-drug conjugates that specifically target the offending cells. However, while existing diagnostic modalities offer exquisite sensitivity, they are unable to correlate subclonal genetic changes and putative antibody targets on refractory myeloma cells, leaving the clinician to use their best judgment on salvage therapy which can lead to unnecessary expense and toxicity to patients due to ineffective treatment. Specifically knowing actual targets on refractory MM cells would better facilitate precision medicine and potentially improve outcomes.


Cryopreserved, human MM patient samples were processed on the Mission Bio Tapestri platform, enabling simultaneous single cell quantification of subclones by single nucleotide variants (SNV), copy number variants (CNV), and surface protein analysis. These single time point samples were thawed from frozen bone marrow mononuclear cells previously enriched for CD38, stained with a 45-plex antibody-oligo cocktail to label common heme-specific surface markers for sequencing analysis, and processed with a 733-plex DNA primer panel that combined whole-genome CNV coverage with MM gene hotspots. Sequencing was performed on an Illumina system with the raw data being analyzed using Mission Bio proprietary algorithms.


We show complex clonal evolution of MM in individual samples as copy gains and losses that were sequentially acquired and correlated with expression changes of MM markers. Across the cases analyzed, complex branching phylogenetic trees were reconstructed with as many as five subclones and clear associated shifts in MM-marker expression. When averaged across subclones, each sample had CNV profiles that matched patient bulk genome-wide array records, ranging from a single gene-level copy gain to arm-level gains and losses across the majority. The progression of protein expression within different samples could be mapped together on a single plot and correlated with generally higher MM-markers as subclonal genetic variants were acquired, though occasional branches saw reversal. The fraction of other cell phenotypes, such as T-cells and those with low viability, decreased within subclones as mutational burden grew.


This high-resolution, single cell assay offers a potential new modality for the diagnosis and surveillance of patients with suspected MGUS, SGUS or high-risk MM. We have demonstrated: 1) exceptional results from cryopreserved human specimens, 2) the ability to use genetic lesion profiling to positively identify subclonal MM and, most importantly, 3) correlate cell surface protein expression of potential therapeutic targets with each clonal and subclonal population

Disclosures: Sciambi: Mission Bio Inc: Current Employment. Dos Santos: Genentech: Current Employment, Current equity holder in publicly-traded company. Li: Mission Bio, Inc: Current Employment. Nguyen: Mission Bio, Inc: Current Employment. Priyam: Mission Bio, Inc: Ended employment in the past 24 months. Chopra: Genentech Inc.: Current Employment; F. Hoffmann-La Roche Ltd, BMS, Amgen: Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. Hamidi: Genentech: Current Employment, Current equity holder in publicly-traded company. Nixon: Roche: Current Employment. Nouet: F. Hoffmann La Roche Ltd: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Druley: Mission Bio, Inc: Current Employment, Current holder of stock options in a privately-held company.

*signifies non-member of ASH