Antigen Discovery in Multiple Myeloma Using Integrated Long-Read Transcriptomics and Immunopeptidomics

Aya Albittar, MD (Advisor: Sachet Shukla, PhD)

Multiple myeloma (MM) remains an incurable plasma cell malignancy, with relapse driven by persistent chemotherapy-resistant cells and residual disease following treatment. Although immunotherapies have transformed MM care, their success depends on identifying tumor-specific antigens that can be safely targeted. While aberrant transcriptional events are increasingly recognized as a source of novel antigens, the HLA-presented antigenic landscape of MM remains incompletely characterized, particularly for non-canonical peptides.

We established an integrated antigen discovery platform combining long-read RNA sequencing (Iso-Seq) with mass spectrometry-based immunopeptidomics to define the antigenic repertoire of high-risk MM. By integrating transcriptomic and HLA ligandome data from MM cell lines and patient samples, this work generated the first long-read transcriptome-informed immunopeptidomic atlas of MM, identifying both canonical and non-canonical antigens. Comparative analyses identified recurrent shared peptides across samples, prioritized tumor-specific candidates based on HLA presentation and predicted immunogenicity and characterized antigen enrichment across common MM-associated HLA alleles. Importantly, a subset of the prioritized shared peptides was experimentally validated, supporting their potential as immunotherapeutic targets.

Together, this work provides a comprehensive resource of candidate MM antigens and establishes a framework for the rational development of next-generation immunotherapies, including T-cell receptor (TCR)-based therapies and mRNA vaccines, aimed at preventing relapse and improving outcomes for patients with multiple myeloma.

Advisory Committee

• Sachet Shukla, PhD, Chair
• Gheath Al-Atrash, MD, PhD
• Isabella Glitza, MD, PhD
• Mathew Gubin, PhD
• Steven Lin, MD
• Muzaffar Qazilbash, MD

Join via Zoom (Please contact Dr. Albittar for her Zoom meeting info.)